WO2005019182A1 - Pyrazolylmethylbenzamide derivatives as p2xt-receptor antagonists - Google Patents

Pyrazolylmethylbenzamide derivatives as p2xt-receptor antagonists Download PDF

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WO2005019182A1
WO2005019182A1 PCT/EP2004/009172 EP2004009172W WO2005019182A1 WO 2005019182 A1 WO2005019182 A1 WO 2005019182A1 EP 2004009172 W EP2004009172 W EP 2004009172W WO 2005019182 A1 WO2005019182 A1 WO 2005019182A1
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optionally substituted
halogen
mono
tri
amino
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PCT/EP2004/009172
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French (fr)
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Arnel Concepcion
Tadashi Inoue
Yuki Mochizuki
Aiko Muramatsu
Florian Gantner
Kosuke Nakashima
Klaus Urbahns
Kevin B. Bacon
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Bayer Healthcare Ag
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Purinergic receptors are cell surface ATP receptors which can be divided into two major families, the metabotropic receptor family (the P2Y/P2U receptor family) and the ionotropic receptor family (the P2X receptor family). Whereas metabotropic receptor family members are G-protein coupled receptors, ionotropic receptor family members are ligand-gated channels mediating fast permeability changes to mono- and divalent cations (Na + , K + , Ca 2+ ).
  • P2X7 receptor antagonists can therefore be useful for the treatment of a wide variety of diseases such as rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), hyperresponsiveness of the airway, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, Alzheimer's disease, meningitis, osteoporosis, burn injury, ischaemic heart disease, stroke and varicose veins.
  • diseases such as rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), hyperresponsiveness of the airway, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative
  • the alkenyl per se represent a linear or branched alkenyl radical having generally 2 to 6, preferably 2 to 4 and particularly preferably 3 to 4 carbon atoms, representing illustratively ethenyl, propenyl, and butenyl.
  • the compounds of the present invention surprisingly show excellent P2X7 receptor antagonistic activity. They are, therefore, suitable for the production of medicament or medical composition, which may be useful to treat diseases related to P2X7 receptor activity. More specifically, since the pyrazolylmethylbenzamide derivatives of the present invention inhibit P2X7 receptor activity, they are useful for treatment and prophylaxis of diseases as follows:
  • R 1 represents phenyl optionally substituted at a substitutable position with one or two substituents selected from the group consisting of halogen, amino, nitro, hydroxy, carbamoyl, C ⁇ . 6 alkylamino, di(C ⁇ -6 )alkylamino, N-(C ⁇ . 6 alkanoyl)amino, C ]-6 alkyl optionally substituted by mono-, di-, or tri- halogen, and C 1-6 alkoxy optionally substituted by mono-, di-, or tri- halogen, pyridiyl or quinolinyl optionally having one or two substituents selected from the group consisting of halogen, amino, carbamoyl, C ⁇ .
  • the reaction temperature can be optionally set depending on the compounds to be reacted.
  • the reaction temperature is usually, but not limited to, about 0 ⁇ C to 200°C and preferably about 20°C to 100°C.
  • the reaction may be conducted for, usually, 10 minutes to 48 hours and preferably 30minutes to 24 hours.
  • the compound of formula (X) (wherein R 2 and R 3 are the same as defined above and Y is protecting group such as C ⁇ -6 alkyl, benzyl , 4-methoxybenzyl and 3,4-dimethoxybenzyl) can be prepared by the reaction of the compound of formula (V) (wherein R 2 and R 3 are the same as defined above) with the compound of formula (DC) (wherein L is a leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom, or C 6 . ⁇ o arylsulfonyloxy group such as benzenesulfonyloxy, or p-toluenesulfonyloxy; and C alkylsulfonyloxy group such as trifluoro- methanesulfonyloxy and methanesulfonyloxy and Y is the same as defined above).
  • DC wherein L is a leaving group including, for instance, halogen
  • the reaction temperature is usually, but not limited to, about 0°C to 200°C and preferably about 50°C to 200°C.
  • the reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 hours to 24 hours.
  • the active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol.
  • a suitable organic solvent for example, aqueous propylene glycol.
  • Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.
  • Examplel-1 Melting point: ⁇ 70 °C Molecular weight: 441.53 Mass spectrometry: 442 (M + H) + In vitro activity class: A In a similar method according to the Examplel-1 above, the compounds in Example 1-2 to 1-21 were synthesized.

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Abstract

The present invention relates to novel pyrazolylmethylbenzamide derivatives of formula (I), processes for preparing them and pharmaceutical preparations containing them. The pyrazolylmethylbenzamide derivatives of the present invention exhibit enhanced potency for P2X7 receptor antagonism and can be used for the prophylaxis and treatment of diseases associated with P2X7 receptor activity. More specifically, the pyrazolylmethylbenzamide derivatives of the. present invention are useful for treatment and prophylaxis of diseases as follows: rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), hyperresponsiveness of the airway, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative: colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, Alzheimer's disease, meningitis, osteoporosis, burn injury, ischaemic heart disease, stroke and varicose veins.

Description

PYRAZOLYLMETHYLBENZAMIDE DERIVATIVES AS P2X7-RECEPTOR ANTAGONISTS
DETAILED DESCRIPTION OF INVENTION
TECHNICAL FD2LD
The present invention relates to novel pyrazolylmethylbenzamide derivatives and pharmaceutical preparations containing them. The pyrazolylmethylbenzamide derivatives of the present invention exhibit enhanced potency for P2X7 receptor antagonism and can be used for the prophylaxis and treatment of diseases associated with P2X7 receptor activity.
More specifically, the pyrazolylmethylbenzamide derivatives of the present invention are useful for treatment and prophylaxis of diseases as follows: rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), hyperresponsiveness of the airway, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, Alzheimer's disease, meningitis, osteoporosis, burn injury, ischaemic heart disease, stroke and varicose veins.
BACKGROUND ART
Purinergic receptors (P2) are cell surface ATP receptors which can be divided into two major families, the metabotropic receptor family (the P2Y/P2U receptor family) and the ionotropic receptor family (the P2X receptor family). Whereas metabotropic receptor family members are G-protein coupled receptors, ionotropic receptor family members are ligand-gated channels mediating fast permeability changes to mono- and divalent cations (Na+, K+, Ca2+).
The P2X7 receptor is a member of the P2X receptor family (Surprenant et al. (1996), Science272:735- 738; Rassendren et al. (1997), J. Biol. Chem.272:5482-5486; Michel et al. (1998), Br. J. Pharmacol.125:1194-1201). P2X7 is expressed primarily in cells of hematopoietic origin including monocytes, macrophages, dendritic cells and some lymphocyte populations (Di Virgilio (1995), Immunol. Todayl6:524-528; Collo et al. (1997), Neuropharmacol. 36: 1277-1283). The receptor also has been reported to exist on microglial cells (Sanz et al. (2000), J. Immunol. 164:4893-4898), some cancer cells (Thunberg et al. (2002), Lancet 360:1935-1939), and in rat bone tissue and osteoclasts (Hoebertz et al. (2000) Bone 27: 503-510). The P2X7 receptor has been reported to participate in a diverse list of cellular activities including lymphocyte proliferation (Baricordi et al. (1999), J. Biol. Chem.274:33206- 33208), giant cell formation (Chiozzi et al. (1997), J. Cell Biol.138:697-706), cell death (Ferrari et al. (1999), FEBS Lett. 447:71-75), killing of invading mycobacteria (Lammas et al. (1997), Immunity 7:433-444), and IL-1 post-translational processing (Ferrari et al. (1997), J. Exp. Med., 185: 579-582). Further, ligation of the P2X7 receptor has been associated with activation of some forms of NF- K B (Ferrari et al. (1997), J. Cell Biol. 139:1635-1643).
P2X7 receptor antagonists can therefore be useful for the treatment of a wide variety of diseases such as rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), hyperresponsiveness of the airway, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, Alzheimer's disease, meningitis, osteoporosis, burn injury, ischaemic heart disease, stroke and varicose veins.
WO200190078 discloses pyrrazole derivatives represented by the general formula:
Figure imgf000003_0001
wherein
R1P is Ci to C15 hydrocarbyl,
R2P is selected from H, Me, Et, Pr, and OH,
R3P is selected from H, Me, Et, Pr, etc.
R4P is Ci to Ci5 hydrocarbyl, aralkenyl, aryl, cycloalkyl, etc,
R5Pis C, to C15 hydrocarbyl,
Z and Q is also defined in the specification,
Which can be used as gastrin and cholecystokin in receptor ligands.
WO0007996 discloses pyrrazole derivatives represented by the general formula:
Figure imgf000003_0002
wherein
Re] and Rc3 independently represent optionally substituted alkyl, aryl, heteroaryl, etc,
Ra2 is hydrogen, halogen, cyano, alkyl, aralkyl, etc,
Ra4 is optionally substituted aryl, aralkyl, cycloalkyl, etc,
as an estrogen receptor modulator.
However, none of the references and other reference disclose pyrazolylmethylbenzamide derivatives having P2X7 receptor antagonistic activity.
The development of a compound, having effective actions based on a specific and selective antagonistic activity to P2X7 receptor and can be used for the prophylaxis and treatment of diseases associated with P2X7 receptor activity has been still desired.
SUMMARY OF THE INVENTION
As a result of extensive studies on chemical modification of pyrazolylmethylbenzamide derivatives, the present inventors have found that the compounds of novel chemical structure related to the present invention have unexpectedly excellent antagonistic activity to P2X7 receptor. The present invention has been accomplished based on these findings.
This invention is to provide novel pyrazolylmethylbenzamide derivatives of the formula (I) their tautomeric and stereoisomeric forms, and salts thereof.
Figure imgf000004_0001
wherein
R1 represents aryl optionally substituted at a substitutable position with one or more substituents selected from the group consisting of halogen, arnino, carboxy, carbamoyl, cyano, hydroxy, nitro, Cι-6alkylamino, di(Cι.6)alkylamino, N-(Cι-6alkanoyl)amino, C)-6alkoxycarbonyl, Cι-6 alkylthio, C].6 alkyl optionally substituted by mono-, di-, or tri- halogen, and Cι-6 alkoxy optionally substituted by phenyl, or mono-, di-, or tri- halogen, heteroaryl optionally having one or more substituents selected from the group consisting of halogen, amino, carboxy, carbamoyl, cyano, hydroxy, nitro, Ci-βalkylamino, di(C1-6)alkyl- amino, N-(Cι-6alkanoyl)amino, C1-6alkoxycarbonyl, Cι-6alkylthio, C^alkyl optionally substituted by mono-, di-, or tri- halogen, and Cι.6alkoxy optionally substituted by aryl, or mono-, di-, or tri- halogen, or
CI-6 alkyl optionally substituted by Cι-6alkoxy, C3-8cycloalkyl, heterocyclyl, or heteroaryl or phenyl optionally having one or more substituents selected from the group consisting of halogen, amino, carboxy, carbamoyl, cyano, hydroxy, nitro, C]-6alkylamino, di(Cι-6)alkyl- amino, N-(Cι-6alkanoyl)amino, Cι-6alkoxycarbonyl, Cι.6alkylthio, Cι.6alkyl optionally substituted by mono-, di-, or tri- halogen, and Cι-6alkoxy optionally substituted by aryl, or mono-, di-, or tri- halogen,
R2 represents C].6 alkyl optionally substituted by mono-, di-, or tri- halogen,
R3 represents heteroaryl or phenyl optionally substituted at a substitutable position with one or more radicals selected from the group consisting of halogen, .6 alkyl optionally substituted by mono-, di-, or tri- halogen and Cι-6 alkoxy optionally substituted by mono-, di-, or tri- halogen, C1-6 alkyl optionally substituted by heteroaryl or phenyl optionally substituted at a substitutable position with one or more radicals selected from halogen, Cι.6 alkyl optionally substituted by mono-, di-, or tri- halogen, and Cι.6 alkoxy optionally substituted by mono-, di-, or tri- halogen;
R4 represents alkenyl or alkyl optionally substituted by one or two substituents selected from the group consisting of alkoxy, hydroxy, cycloalkyloxy, heterocyclyloxy, cyano, halogen, nitro, sulfamoyl, alkoxycarbonyl, hydroxyl- carbonyl, amino, alkylamino di(alkyl)amino, hydroxyalkyl(alkyl)amino, hydroxylalkyl- amino, -C(0)NR41R42, and 5-10 membered mono- or bi cyclic ring or heterocyclic ring wherein said 5-10 membered ring is saturated or unsaturated, and optionally contains one to two heteroatoms selected from the group consisting of N, O and S, and optionally substituted by oxo, and R41 and R42 independently represent hydrogen, alkyl, or cycloalkyl, or R41 and R42 together with the adjacent N atom form 5 to 8 membered saturated heterocyclic ring.
The Alkyl per se and "alk" and "alkyl" in alkoxy, alkanoyl, alkylamino, alkylaminocarbonyl, alkylaminosulphonyl, alkylsulphonylamino, alkoxycarbonyl, alkoxycarbonylamino and alkanoyl- amino represent a linear or branched alkyl radical having generally 1 to 6, preferably 1 to 4 and particularly preferably 1 to 3 carbon atoms, representing illustratively and preferably methyl, ethyl, n- propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
The alkenyl per se represent a linear or branched alkenyl radical having generally 2 to 6, preferably 2 to 4 and particularly preferably 3 to 4 carbon atoms, representing illustratively ethenyl, propenyl, and butenyl.
Alkoxy illustratively and preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
Alkanoyl illustratively and preferably represents acetyl and propanoyl.
Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methylamino, ethylamino, n-propylamino, iso- propylamino, tert-butylamino, n-pentylamino, n-hexyl-amino, N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-t-butyl-N- methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.
Alkylaminocarbonyl or alkylcarbamoyl represents an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methyl- aminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylamino-carbonyl, tert- butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl, N- isopropyl-N-n-propylaminocarbonyl, N-t-butyl-N-methylaminocarbonyl, N-ethyl-N-n-pentylamino- carbonyl and N-n-hexyl-N-methylaminocarbonyl.
Alkylaminosulphonyl represents an alkylaminosulphonyl radical having one or two (independently selected) alkyl substituents, illustratively and preferably representing methylaminosulphonyl, ethyl- aminosulphonyl, n-propylaminosulphonyl, isopropylaminosulphonyl, tert-butylaminosulphonyl, n- pentylaminosulphonyl, n-hexyl-aminosulphonyl, N,N-dimethylaminosulphonyl, N,N-diethyl- aminosulphonyl, N-ethyl-N-methylamino-sulphonyl, N-methyl-N-n-propylaminosulphonyl, N-iso- propyl-N-n-propylaminosulphonyl, N-t-butyl-N-methylaminosulphonyl, N-ethyl-N-n-pentylamino- sulphonyl and N-n-hexyl-N-methylaminosulphonyl.
Alkylsulphonylamino illustratively and preferably represents methylsulphonylamino, ethyl- sulphonylamino, n-propylsulphonylamino, isopropylsulphonylamino, tert-butyl-sulphonylamino, n- pentylsulphonylamino and n-hexylsulphonylamino.
Alkoxycarbonyl illustratively and preferably represents methoxycarbonyl, ethoxycarbonyl, n- propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxy- carbonyl. Alkoxycarbonylamino illustratively and preferably represents methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, tert-butoxycarbonyl- amino, n-pentoxycarbonylamino and n-hexoxycarbonylamino.
Alkanoylamino illustratively and preferably represents acetylamino and ethylcarbonylamino.
Cycloalkyl per se and in cycloalkylamino and in cycloalkylcarbonyl represents a cycloalkyl group having generally 3 to 8 and preferably 5 to 7 carbon atoms, illustratively and preferably representing cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
Cycloalkylamino represents a cycloalkylamino radical having one or two (independently selected) cycloalkyl substituents, illustratively and preferably representing cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino and cycloheptylamino.
Cycloalkylcarbonyl illustratively and preferably represents cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and cycloheptylcarbonyl.
Aryl per se and in arylamino and in arylcarbonyl represents a mono- to tricyclic aromatic carbocyclic radical having generally 6 to 14 carbon atoms, illustratively and preferably representing phenyl, naphthyl and phenanthrenyl.
Arylamino represents an arylamino radical having one or two (independently selected) aryl substituents, illustratively and preferably representing phenylamino, diphenylamino and naphthylamino.
Arylcarbonyl illustratively and preferably represents phenylcarbonyl and naphthylcarbonyl.
Heteroaryl per se and in heteroarylamino and heteroarylcarbonyl represents an aromatic mono- or bicyclic radical having generally 5 to 10 and preferably 5 or 6 ring atoms and up to 5 and preferably up to 4 hetero atoms selected from the group consisting of S, O and N, illustratively and preferably representing thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl. Heteroarylamino represents an heteroarylamino radical having one or two (independently selected) heteroaryl . substituents, illustratively and preferably representing thienylamino, furylamino, pyrrolylamino, thiazolylamino, oxazolylamino, imidazolyl-amino, pyridylamino, pyrimidylamino, pyridazinylamino, indolylamino, indazolylamino, benzofuranylamino, benzothiophenylamino, quinolinyl-amino, isoquinolinylamino.
Heteroarylcarbonyl illustratively and preferably represents thienylcarbonyl, furylcarbonyl, pyrrolylcarbonyl, thiazolylcarbonyl, oxazolylcarbonyl, imidazolyl-carbonyl, pyridylcarbonyl, pyrimidylcarbonyl, pyridazinylcarbonyl, indolylcarbonyl, indazolylcarbonyl, benzofuranylcarbonyl, benzothiophenylcarbonyl, quinolinyl-carbonyl, isoquinolinylcarbonyl.
Heterocyclyl per se or in heterocyclylcarbonyl or in heterocyclyloxy represents a mono- or polycyclic, preferably mono- or bicyclic, nonaromatic heterocyclic radical having generally 4 to 10 and preferably 5 to 8 ring atoms and up to 3 and preferably up to 2 hetero atoms and/or hetero groups selected from the group consisting of N, O, S, SO and S02. The heterocyclyl radicals can be saturated or partially unsaturated. Preference is given to 5- to 8-membered monocyclic saturated heterocyclyl radicals having up to two hetero atoms selected from the group consisting of O, N and S, such as illustratively and preferably tetrahydrofuran-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, piperidinyl, morpholinyl, perhydroazepinyl.
Heterocyclylcarbonyl illustratively and preferably represents tetrahydrofuran-2-carbonyl, pyrrolidine- 2-carbonyl, pyrrolidine-3-carbonyl, pyrrolinecarbonyl, piperidinecarbonyl, morpholinecarbonyl, perhydroazepinecarbonyl.
Halogen represents fluorine, chlorine, bromine and iodine.
This invention is also to provide a method for treating or preventing a disorder or disease associated with P2X7 receptor activity in a human or animal subject, comprising administering to said subject a therapeutically effective amount of the pyrazolylmethylbenzamide derivative shown in the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof.
Further this invention is to provide a use of the pyrazolylmethylbenzamide derivative shown in the formula (I), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof in the preparation of a medicament. Preferably, said medicament is suitable for treating or preventing a disorder or disease associated with P2X7 receptor activity.
The compounds of the present invention surprisingly show excellent P2X7 receptor antagonistic activity. They are, therefore, suitable for the production of medicament or medical composition, which may be useful to treat diseases related to P2X7 receptor activity. More specifically, since the pyrazolylmethylbenzamide derivatives of the present invention inhibit P2X7 receptor activity, they are useful for treatment and prophylaxis of diseases as follows:
rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease (COPD), hyperresponsiveness of the airway, septic shock, glomerulonephritis, irritable bowel disease, Crohn's disease, ulcerative colitis, atherosclerosis, growth and metastases of malignant cells, myoblastic leukaemia, diabetes, Alzheimer's disease, meningitis, osteoporosis, burn injury, ischaemic heart disease, stroke and varicose veins.
Therefore, P2X7 is an important target and inhibition of P2X7 is likely to be effective in the treatment of such inflammatory and immunoregulatory disorders and diseases.
In one embodiment, the compounds of formula (I) are those wherein:
R1 represents aryl optionally substituted at a substitutable position with one or more substituents selected from the group consisting of halogen, amino, carboxy, carbamoyl, cyano, hydroxy, nitro, Ci-βalkylamino, di(Cι.6)alkylamino, N-(C1-6alkanoyl)amino, Cι.6alkoxycarbonyl, C1-6 alkylthio, Cι.6 alkyl optionally substituted by mono-, di-, or tri- halogen, and Cι-6 alkoxy optionally substituted by phenyl, or mono-, di-, or tri- halogen, heteroaryl optionally having one or more substituents selected from the group consisting of halogen, amino, carboxy, carbamoyl, cyano, hydroxy, nitro, Cι.6alkylamino, di(C1.6)alkyl- amino, N-(Cι.6alkanoyl)amino, Cι-6alkoxycarbonyl, .6alkylthio, d.6alkyl optionally substituted by mono-, di-, or tri- halogen, and Cι.6alkoxy optionally substituted by aryl, or mono-, di-, or tri- halogen, or
C)-6 alkyl optionally substituted by Cι_6alkoxy, C3.8cycloalkyl, heterocyclyl, or heteroaryl or phenyl optionally having one or more substituents selected from the group consisting of halogen, amino, carboxy, carbamoyl, cyano, hydroxy, nitro, Cι-6alkylamino, di(Cι.6)alkyl- amino, N-(Cι-6alkanoyl)amino, Cι-6alkoxycarbonyl, Cι.6alkylthio, Cι.6alkyl optionally sub- stituted by mono-, di-, or tri- halogen, and C1-6alkoxy optionally substituted by aryl, or mono-, di-, or tri- halogen,
R2 represents Cι-6 alkyl optionally substituted by mono-, di-, or tri- halogen,
R3 represents heteroaryl or phenyl optionally substituted at a substitutable position with one or more radicals selected from the group consisting of halogen, Cι-6 alkyl optionally substituted by mono-, di-, or tri- halogen and Cι-6 alkoxy optionally substituted by mono-, di-, or tri- halogen, Cι-6 alkyl optionally substituted by heteroaryl or phenyl optionally substituted at a substitutable position with one or more radicals selected from halogen, Cι_6 alkyl optionally substituted by mono-, di-, or tri- halogen, and C1-6 alkoxy optionally substituted by mono-, di- , or tri- halogen,
R4 represents alkenyl or alkyl optionally substituted by one or two substituents selected from the group consisting of alkoxy, hydroxy, cycloalkyloxy, heterocyclyloxy, cyano, halogen, nitro, sulfamoyl, alkoxycarbonyl, hydroxycarbonyl, -C(0)NR41R42, and -NR^R44 wherein R41 and R42 independently represent hydrogen, alkyl, or cycloalkyl, or R41 and R42 together with the adjacent N atom form 5 to 8 membered saturated heterocyclic ring, and R43 and R44 independently represent hydrogen, alkyl, or cycloalkyl, or R43 and R44 together with the adjacent N atom form 5 to 10 membered mono- or bi- heterocyclic ring that is saturated or unsaturated, and optionally contains one to two additional heteroatoms selected from the group consisting of N, O and S and optionally substituted by oxo.
In another embodiment, the compounds of formula (I) are those wherein:
R1 represents phenyl optionally substituted at a substitutable position with one or two substituents selected from the group consisting of halogen, amino, nitro, hydroxy, carbamoyl, Cι.6alkylamino, di(Cι-6)alkylamino, N-(Cι.6alkanoyl)amino, C]-6 alkyl optionally substituted by mono-, di-, or tri- halogen, and C1-6 alkoxy optionally substituted by mono-, di-, or tri- halogen, pyridiyl or quinolinyl optionally having one or two substituents selected from the group consisting of halogen, amino, carbamoyl, Cι.6alkylamino, di(Cι-6)alkylamino, N-(Cι.6. alkanoyl)amino, Cι.6 alkyl optionally substituted by mono-, di-, or tri- halogen, and Cι-6 alkoxy optionally substituted by mono-, di-, or tri- halogen, or Ci.6 alkyl optionally substituted by Cι.6 alkoxy, C3.8 cycloalkyl, phenyl, heterocyclyl, or heteroaryl.
In another embodiment, the compounds of formula (I) are those wherein:
R3 represents phenyl optionally substituted at a substitutable position with one or more radicals selected from the group consisting of halogen, Cj.6 alkyl optionally substituted by mono-, di-, or tri- halogen and Cι-6 alkoxy optionally substituted by mono-, di-, or tri- halogen, C3-8 ' cycloalkyl, Cι-6 alkyl optionally substituted by heteroaryl or phenyl optionally substituted at a substitutable position with one or more radicals selected from halogen, Cι-6 alkyl optionally substituted by mono-, di-, or tri- halogen, and Cι_6 alkoxy optionally substituted by mono-, di- , or tri- halogen, C3.8 cycloalkyl, or heteroaryl.
In yet, further embodiment, the compounds of formula (I) are those wherein:
R4 represents C2-C6 alkenyl or Q-Cβ alkyl optionally substituted by one or two substituents selected from the group consisting of C C6 alkoxy, hydroxy, tetrahydropyranyloxy, cyano, halogen, nitro, sulfamoyl, alkoxycarbonyl, hydroxycarbonyl, -C(0)NR4IR42, and -NR43R44, wherein R41 and R42 independently represent hydrogen, alkyl, or cycloalkyl, or R41 and R42 together with the adjacent N atom form piperidino, pyrrolidino, or morpholino, and
R43 and R44 independently represent hydrogen, alkyl, or cycloalkyl, or R43 and R44 together with the adjacent N atom form piperidino, pyrrolidino, or isoindolino optionally substitued at a substitutable position with one or more oxo.
The preferable compounds of the present invention are as follows:
Ethyl[4-(3-{[(3-methoxyphenyl)amino]carbonyl}benzyl)-3-methyl-5-phenyl-lH-pyrazol-l- yl]acetate;
N-(3 -methoxyphenyl)-3 -( { 3 -methyl- 1 -[2-(methylamino)-2-oxoethyl]-5-phenyl- 1 H-pyrazol-4- yl } methyl)benzamide; 3-({l-[2-(cyclohexylamino)-2-oxoethyl]-3-methyl-5-phenyl-lH-pyrazol-4-yl}methyl)-N-(3- methoxyphenyl)benzamide;
3 - { [ 1 -(2-cyanoethyl)-3 -methyl-5 -phenyl- 1 H-pyrazol-4-yl]methyl } -N-(3 - methoxyphenyl)benzamide; and
3 - { [ 1 -(2-hydroxyethyl)-3 -methyl-5 -phenyl- 1 H-pyrazol-4-yl]methyl } -N-(3 - methoxyphenyl)benzamide
and their tautomeric and stereoisomeric form, and salts thereof.
Further, the present invention provides a medicament which include one of the compounds described above and optionally pharmaceutically acceptable excipient. EMBODIMENT OF INVENTION
The compound of the formula (I) of the present invention can be, but not limited to be, prepared by combining various known methods. In some embodiments, one or more of the substituents, such as amino group, carboxyl group, and hydroxyl group of the compounds used as starting materials or intermediates are advantageously protected by a protecting group known to those skilled in the art. Examples of the protecting groups are described in "Protective Groups in Organic Synthesis (3rd Edition)" by Greene and Wuts, John Wiley and Sons, New York 1999.
The compound of the formula (I) of the present invention can be, but not limited to be, prepared by the Method [A] ,[B] or [C] below.
[Method A]
Figure imgf000012_0001
(ID (ill) (I)
The compound of formula (I) (wherein R1, R2, R3 and R4 are the same as defined above) can be prepared, for example, by the reaction of the compound of formula (II) (wherein R2, R3 and R4 are the same as defined above) with the compound of formula (IJJ) (wherein R1 is the same as defined above).
The reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea such as l,3-dimethyl-2- imidazolidinone (DMI); sulfoxides such as dimethylsulfoxide (DMSO); and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.
The reaction temperature can be optionally set depending on the compounds to be reacted. The reaction temperature is usually, but not limited to, about 0βC to 200°C and preferably about 20°C to 100°C. The reaction may be conducted for, usually, 10 minutes to 48 hours and preferably 30minutes to 24 hours. The reaction can be advantageously carried out using coupling agent including, for instance, carbodiimides such as N, N-dicyclohexylcarbodiimide and l-(3-dimethylaminopropyl)-3-ethyl- carbodiimide, 1-hydroxybenzotiazole monohydrate (HOBt), benzotriazole-1-yl-oxy-tris-pyrrolidino- phosphonium hexafluorophosphate (PyBOP), and others.
The compound of formula (IJJ) can be prepared by the use of known techniques or is commercially available.
[Method B]
Figure imgf000013_0001
(II) (IV)
Figure imgf000013_0002
(I)
The compound of formula (I) (wherein R', R2, R3 and R4 are the same as defined above) can also be prepared by the following procedures in two steps;
In the Step B-1, the compound of the formula (IV) (wherein R2, R3 and R4 are the same as defined above and L is a leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom, and azole such as 1,3-imiazole and 1,2,4-triazole.) can be prepared by the reaction of the compound of formula (JJ) (wherein R2, R3 and R4 are the same as defined above) with a agent such as SOCl2, SOBr2, POCl3, l,l '-carbonyldi(l,3-imiazole)(CDJ , l,l'-carbonyldi(l,2,4-triazole)(CDT) and others.
The reaction may be carried out without solvent, or in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used. The reaction temperature is usually, but not limited to, about 40°C to 200°C and preferably about 20°C to 180°C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 hours to 12 hours.
In the Step B-2, the compound of formula (I) (wherein R1, R2, R3 and R4 are the same as defined above) can be prepared by the reaction of the compound of formula (IV) (wherein L, R2, R3 and R4 are the same as defined above) with the compound of formula (DH) (wherein R1 is the same as defined above).
The reaction may be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1 ,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC) and N-methylpyrrolidone (NMP); urea such as 1,3- dimethyl-2-imidazolidinone (DMI); sulfoxides such as dimethylsulfoxide (DMSO); and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.
The reaction temperature is usually, but not limited to, about 0°C to 200°C and preferably about 20°C to 180°C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 hours to 12 hours.
The reaction can be advantageously conducted in the presence of a base, including, for instance, such as pyridine, triethylamine and N,N-diisopropylethylamine, dimethylaniline, diethylaniline, and others.
The reagents used for the preparation of the compound of the formula (IV) are commercially available.
[Method C]
Figure imgf000014_0001
The compound of formula (I) (wherein R1, R2, R3 and R4 are the same as defined above) can also be prepared by the following procedures in two steps;
In the Step C-l, the compound of formula (VIJ) (wherein R1, R2 and R3 are the same as defined above) can be prepared by the reaction of the compound of formula (V) (wherein R2 and R3 are the same as defined above) with the compound of formula (VI) (wherein L' is a leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom, or Cβ-io arylsulfonyloxy group such as benzenesulfonyloxy, or p-toluenesulfonyloxy; and CM alkylsulfonyloxy group such as trifluoro- methanesulfonyloxy and methanesulfonyloxy).
The reaction can be conducted in the presence of a base, including, for instance, such as sodium hydride, magnesium hydroxide, sodium carbonate, potassium carbonate, potassium fluoride,
The reaction can be advantageously conducted in the presence of phase transfer reagent such as 18- Crown-6, 15-Crown-5.
The reaction can be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1 ,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1 ,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; dimethylformamide (DMF), dimethylacetamide (DMAC), l,3-dimethyl-3,4,5,6- tetrahydro-2(lH)-pyrimidinone (DMPU), l,3-dimethyl-2-imidazolidinone (DMI), N-methyl- pyrrolidinone (NMP), sulfoxides such as dimethylsulfoxide (DMSO), alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.
The reaction temperature is usually, but not limited to, about 0°C to 200°C and preferably about 50°C to 200°C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 hours to 24 hours.
In the Step C-2, the compound of formula (T) (wherein R1, R2, R3 and R4 are the same as defined above) can be prepared by the reaction of the compound of formula (VJJ) (wherein R], R2 and R3 are the same as defined above) with the compound of formula (VIJJ) (wherein R4 is the same as defined above).
The reaction can be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol, water and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.
The reaction temperature is usually, but not limited to, about 0°C to 200°C and preferably about 50°C to 200°C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 hours to 24 hours.
The reaction can be advantageously conducted in the presence of HC1 solution.
The compound (VET) is commercially available or can be synthesized by conventional method.
Preparation of the compound of formula (II)
The compound of formula (II) (wherein R2' R3 and R4 are the same as defined above) can be, for instance, prepared by the following procedures.
Figure imgf000016_0001
In the Step-1, the compound of formula (X) (wherein R2 and R3 are the same as defined above and Y is protecting group such as Cι-6 alkyl, benzyl , 4-methoxybenzyl and 3,4-dimethoxybenzyl) can be prepared by the reaction of the compound of formula (V) (wherein R2 and R3 are the same as defined above) with the compound of formula (DC) (wherein L is a leaving group including, for instance, halogen atom such as chlorine, bromine, or iodine atom, or C6.ιo arylsulfonyloxy group such as benzenesulfonyloxy, or p-toluenesulfonyloxy; and C alkylsulfonyloxy group such as trifluoro- methanesulfonyloxy and methanesulfonyloxy and Y is the same as defined above).
The reaction can be conducted in the presence of a base, including, for instance, such as sodium hydride, magnesium hydroxide, sodium carbonate, potassium carbonate, potassium fluoride, The reaction can be advantageously conducted in the presence of phase transfer reagent such as 18- Crown-6, 15-Crown-5.
The reaction can be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; dimethylformamide (DMF), dimethylacetamide (DMAC), l,3-dimethyl-3 ,4,5,6- tetrahydro-2(lH)-pyrimidinone (DMPU), l,3-dimethyl-2 -imidazolidinone (DMI), N-methyl- pyrrolidinone (NMP), sulfoxides such as dimethylsulfoxide (DMSO), alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol, and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.
The reaction temperature is usually, but not limited to, about 0°C to 200°C and preferably about 50°C to 200°C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 hours to 24 hours.
In the Step-2, the compound of formula (XI) (wherein R2, R3, R4 and Y are the same as defined above) can be prepared by the reaction of the compound of formula (X) (wherein R2, R3 and Y are the same as defined above) with the compound of formula (VJJI) (wherein R4 is the same as defined above).
The reaction can be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1 ,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; dimethylformamide (DMF), dimethylacetamide(DMAC), l,3-dimethyl-3,4,5,6- tetrahydro-2(lH)-pyrimidinone (DMPU), l,3-dimethyl-2-imidazolidinone (DMI), N-methyl- pyrrolidinone (NMP), sulfoxides such as dimethylsulfoxide (DMSO), alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol, water and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.
The reaction temperature is usually, but not limited to, about 0°C to 200°C and preferably about 50°C to 200°C. The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 hours to 24 hours.
In the Step-3, the compound of formula (JJ) (wherein R2,R3 and R4 are the same as defined above) can be prepared by deprotection of the compound of formula (XI) (wherein R2, R3, R4 and Y are the same as defined above).
The deprotection of carboxyl group can be conducted by using a base including, for instance, sodium hydroxide, lithium hydroxide and potassium hydroxide, or an acid including, for instance, HC1, HBr, trifluoroacetic acid and BBr3. The deprotection can also be done by hydrogenation using a catalyst including, for instance, palladium on carbon and palladium hydroxide, when Y is benzyl , 4- methoxybenzyl or 3,4-dimethoxybenzyl.
The reaction can be carried out in a solvent including, for instance, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1 ,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; dimethylformamide (DMF), dimethylacetamide(DMAC), l,3-dimethyl-3,4,5,6- tetrahydro-2(lH)-pyrimidinone (DMPU), l,3-dimethyl-2-imidazolidinone (DMI), N-methyl- pyrrolidinone (NMP), sulfoxides such as dimethylsulfoxide (DMSO), alcohols such as methanol, ethanol, 1-propanol, isopropanol and tert-butanol, water and others. Optionally, two or more of the solvents selected from the listed above can be mixed and used.
The reaction temperature is usually, but not limited to, about 0°C to 200°C and preferably about 20°C to lOO . The reaction may be conducted for, usually, 30 minutes to 48 hours and preferably 2 hours to 24 hours.
The compound (V), (DC) and (VUT) are commercially available or can be synthesized by conventional method.
When the compound shown by the formula (I) or a salt thereof has an asymmetric carbon(s) in the structure, their optically active compounds and racemic mixtures are also included in the scope of the present invention.
Typical salts of the compound shown by the formula (I) include salts prepared by the reaction of the compound of the present invention with a mineral or organic acid, or an organic or inorganic base. Such salts are known as acid addition and base addition salts, respectively.
Acids to form acid addition salts include inorganic acids such as, without limitation, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like, and organic acids, such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
Base addition salts include those derived from inorganic bases, such as, without limitation, ammonium hydroxide, alkaline metal hydroxide, alkaline earth metal hydroxides, carbonates, bicarbonates, and the like, and organic bases, such as, without limitation, ethanolamine, triethylamine, tri(hydroxymethyl)aminomethane, and the like. Examples of inorganic bases include, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
The compound of the present invention or a salts thereof, depending on its substituents, may be modified to form lower alkylesters or known other esters; and or hydrates or other solvates. Those esters, hydrates, and solvates are included in the scope of the present invention.
The compound of the present invention may be administered in oral forms, such as, without limitation normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, solution, suspensions, syrups, solid and liquid aerosols and emulsions. They may also be administered in parenteral forms, such as, without limitation, intravenous, intraperitoneal, subcutaneous, intramuscular, and the like forms, well-known to those of ordinary skill in the pharmaceutical arts. The compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal delivery systems well-known to those of ordinary skilled in the art.
The dosage regimen with the use of the compounds of the present invention is selected by one of ordinary skill in the arts, in view of a variety of factors, including, without limitation, age, weight, sex, and medical condition of the recipient, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the recipient, the dosage form employed, the particular compound and salt thereof employed.
The compounds of the present invention are preferably formulated prior to administration together with one or more pharmaceutically-acceptable excipients. Excipients are inert substances such as, without limitation carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
Yet another embodiment of the present invention is pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically-acceptable excipients that are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Pharmaceutical formulations of the invention are prepared by combining a therapeutically effective amount of the compounds of the invention together with one or more pharmaceutically-acceptable excipients. In making the compositions of the present invention, the active ingredient may be mixed with a diluent, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. The carrier may serve as a diluent, which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
For oral administration, the active ingredient may be combined with an oral, and non-toxic, pharmaceutically-acceptable carrier, such as, without limitation, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate, methyl cellulose, and the like; together with, optionally, disintegrating agents, such as, without limitation, maize, starch, methyl cellulose, agar bentonite, xanthan gum, alginic acid, and the like; and optionally, binding agents, for example, without limitation, gelatin, natural sugars, beta-lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like; and, optionally, lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc, and the like.
In powder forms, the carrier may be a finely divided solid which is in admixture with the finely divided active ingredient. The active ingredient may be mixed with a carrier having binding properties in suitable proportions and compacted in the shape and size desired to produce tablets. The powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the novel composition of the present invention. Suitable solid carriers are magnesium carboxymethyl cellulose, low melting waxes, and cocoa butter.
Sterile liquid formulations include suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent, or a mixture of both sterile water and a sterile organic solvent.
The active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol. Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.
The formulation may be in unit dosage form, which is a physically discrete unit containing a unit dose, suitable for administration in human or other mammals. A unit dosage form can be a capsule or tablets, or a number of capsules or tablets. A "unit dose" is a predetermined quantity of the active compound of the present invention, calculated to produce the desired therapeutic effect, in association with one or more excipients. The quantity of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved. Typical oral dosages of the present invention, when used for the indicated effects, will range from about O.Olmg/kg/day to about lOOmg/kg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, and most preferably from about 0.5 mg kg/day to about 10 mg/kg/day. In case of parenteral administration, it has generally proven advantageous to administer quantities of about 0.001 to 100 mg/kg/day, preferably from O.Ol mg/kg/day to lmg kg/day. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three, or more times per day. Where delivery is via transdermal forms, of course, administration is continuous.
EXAMPLES
The present invention will be described in detail below in the form of examples, but they should by no means be construed as defining the metes and bounds of the present invention.
In the examples below, all quantitative data, if not stated otherwise, relate to percentages by weight.
Η NMR spectra were recorded using either Bruker DRX-300 (300 MHz for Η) spectrometer or Brucker 500 UltraShieled™ (500 MHz for IH) . Chemical shifts are reported in parts per million (ppm) with tetramethylsilane (TMS) as an internal standard at zero ppm. Coupling constant (J) are given in hertz and the abbreviations s, d, t, q, m, and br refer to singlet, doublet, triplet, quartet, multiplet, and broad, respectively. The mass determinations were carried out by MAT95 (Finnigan MAT).
Liquid Chromatography - Mass spectroscopy (LC-MS) data were recorded on a Micromass Platform LC with Shimadzu Phenomenex ODS column(4.6 mm φ X 30 mm) flushing a mixture of acetonitrile- water (9:1 to 1:9) at 1 ml/min of the flow rate. Mass spectra were obtained using electrospray (ES) ionization techniques (Micromass Platform LC). TLC was performed on a precoated silica gel plate (Merck silica gel 60 F-254). Silica gel (WAKO-gel C-200 (75-150 μm)) was used for all column chromatography separations. All chemicals were reagent grade and were purchased from Sigma- Aldrich, Wako pure chemical industries, Ltd., Tokyo kasei kogyo Co., Ltd., Nacalai tesque, Inc., Watanabe Chemical Ind. Ltd., Maybridge pic, Lancaster Synthesis Ltd., Merck KgaA, Kanto Chemical Co., Ltd.
The effects of the compounds of the present invention were examined by the following assays and pharmacological tests.
[Measurement of Ca2+ influx in the human P2X7-transfected HEK293 cell line] (Assay 1)
Human embryonic kidney cells (HEK293) stably transfected with human P2X7 (HEK-P2X7, for details see Rassendren al., (1997), J. Biol. Chem, 272:5482-5486) were used for testing compounds' antagonistic potential against P2X7-agonist induced Ca2+ signals. Cells were maintained in D-MEM/F12 medium (Gibco, NY, USA) supplemented with 10 % FCS, P/S/G (penicilline (100 U/ml), streptomycine (100 μg ml), and glutamine (292 μg/ml)), 0.3 mg/ml G418, and 1 % MC210 (Dainippon Seiyaku, Osaka, J) in 75 cm2 flasks. Before the experiments, culture medium was removed and 3 ml of lmM EDTA was added to detach cells. Cells were then washed in HBSS containing 1 mM probenecid, 20 mM Hepes, 1 mg ml BSA (Sigma, cat#A3059, St. Louis, MO, USA), no Mg2+, and 0.3 mM Ca2+(wash buffer), and resuspended in HBSS containing 1 mM probenecid, 20 mM Hepes, 1 mg/ml BSA (Sigma, cat#A3059), 0.9 mM Mg2+, 1.3 mM Ca2+, 2 μM Fluo-3 (Molecular Probe), and 0.2 % pluonic F-127 (Molecular Probe, OR, USA), and incubated for 60 minutes at 30 °C. Fluo-3 loaded cells were washed, resuspended in wash buffer, plated (3000 cells/well), and mixed with 30 μM ADP, 30 μM UTP, and test compound in 384 well black plates with an optical bottom (Nalge Nunc Int, NY, USA). As an agonist, 60 μM 2'- & 3'-0-(4-benzoylbenzoyl) adenosine 5'- triphosphate (bzATP, Sigma) was added and fluorescence intensity was recorded by a flurometer (FDSS3000, Hamamatsu Photonics, Hamamatsu, J).
[BzATP-induced IL-lβ release in LPS-primed human peripheral blood mononuclear cells (PBMC)] (Assay 2) Heparinized blood was collected from healthy volunteers. Red blood cells were removed by sedimentation with dextran. PBMC were isolated using a Percoll density gradient. PBMC were re-suspended in R10 medium, RPMI1640 (Gibco) supplemented with 10 % FCS (JRH Biosciences, KS, USA) and P/S/G (Gibco) and placed into 96-well flat-bottomed plates at a density of lxl05/well. R10 including test compound or DMSO was added. The final cone, of DMSO in each well was 0.1 %. Cells were primed with LPS (B8, Sigma) for 2.5 hours (final LPS concentration: 100 ng/ml). BzATP (300 μM, Sigma) was added, and one hour later, the culture supernatant was collected and stored at -30°C. IL-l β was measured by a commercially availabe anti human JL-lβ antibody pair according to the provider's recommendation (Genzyme Techne, Minneapolis, USA).
[BzATP-induced IL-lβ release in LPS-primed mouse splenocytes] (Assay 3)
Splenocytes from naive BALB/c mice were plated in 96-well flat-bottomed plates at a density of . R10 including a test compound or DMSO was added. The final concentration of DMSO in each well was 0.1 %. Cells were primed with LPS for 2.5 hours (final LPS concentration: 1 μg/ml), before BzATP (1 mM) was added. The total test volume was 200 μl/well. One hour after, the culture supernatant was collected and stored at -30°C. JL-1 β was examined by ELISA (Genzyme Techne).
[LPS/ATP-induced EL-lβ release in mice in vivo] (Assay 4)
Balb/c mice (female, 6 weeks of age, 20-25 g) were challenged by intraperitoneal injection of LPS (10 mg/mouse) and 2 h later by ATP (5.51 mg/mouse, i.p.). Test compounds were given i.p. in 10% cremophor 40 min before ATP. The amount of JL-lβ was determined by ELISA (Genzyme Techne) in the peritoneal lavage fluid 40 min after ATP challenge. Assay results in Assay 1 are shown in Examples and tables of the Examples below. The data corresponds to the compounds as yielded by solid phase synthesis and thus to levels of purity of about 40 to 90%. For practical reasons, the compounds are grouped in four classes of activity as follows:
IC50= A (< or =) 0.2μM < B (< or =) 0.5 μM < C (< or =) 1.0 μM < D
The compounds of the present invention also show excellent selectivity, and potent activity in Assays 2 - 4 described above.
Example 1-1
3-(Chloromethyl)-N-(3-methoxyphenyl)benzamide
Figure imgf000024_0001
To a mixture of 3-chloromethylbenzoyl chloride (11.21g; 59.3mmol) and m-anisidine (7.30g; 59.3mmol) in CH2C12 (100ml) was added dropwise, Et3N (9.1ml; 65.23mmol) at 0°C. The resulting mixture was stirred at 0°C for 10 min and at rt for 2 hours. The reaction was quenched by addition of water and partitioned between CH2C12 and water. The organic layer was dried and concentrated in vacuo. The residue was purified by column chromatography (Hex/EtOAc = 2/1) to give 3- (chloromethyl)-N-(3-methoxyphenyl) benzamide (16.25g; 99% yield).
3-(Iodomethyl)-N-(3-methoxyphenyl)benzamide
Figure imgf000024_0002
A mixture of 3-(chloromethyl)-N-(3-methoxyphenyl) benzamide (16.25g, 58.93mmol) and Nal (13.25g, 88.4mmol) in acetone (300ml) was refluxed for 2 hours. After evaporation of the solvent under reduced pressure, the residue was partitioned between water and CH2C12. The organic layer was washed with aq solution of Na2S203, dried and concentrated in vacuo. The residue was purified by column chromatography (Hex/EtOAc = 2/1) to give 3-(iodomethyl)-N-(3-methoxyphenyl) benzamide as brown solid (21.20g; 98% yield). 3-(2-Benzoyl-3-oxobutyl)-N-(3-methoxyphenyl)benzamide
Figure imgf000025_0001
To a mixture of 3-(iodomethyl)-N-(3-methoxyphenyl) benzamide (21.20g; 57.74mmol) and 1-phenyl- 1,3-butanedione (14.05g; 86.6mmol) in dioxane/propanol (296ml/74ml) were added Na2C03 (12.24g; 115.48mmol) and 18-Cr-6 (3.82g; 14.44mmol). The mixture was stirred at 85°C overnight and partitioned between CHC13 and water. The organic layer was dried and evaporated in vacuo. The residue was purified by column chromatography (Hex/EtOAc = 2/1) to give 3-(2-benzoyl-3-oxobutyl)- N-(3-methoxyphenyl)benzamide as brown syrup (17.60g; 75.9% yield).
3-{[l-(2-hydroxyethyl)-3-methyI-5-phenyl-lH-pyrazol-4-yl]methyl}-N-(3- methoxyphenyl)benzamide
Figure imgf000025_0002
To a mixture of 3-(2-benzoyl-3-oxobutyl)-N-(3-methoxyphenyl)benzamide (3.0g; 7.47mmol) and 2- hydrazinoethanol (1.14g; 14.95mmol) in ethanol (72ml) was added 6N HC1 solution (10 drops). The resulting mixture was refluxed overnight. After cooling to rt the mixture was concentrated in vacuo, the residue was dissolved in CHC13 and water and organic phase was separated. The organic phase was dried, concentrated and purified by column chromatography (CHCl3/MeOH = 20/1) to give 3-{[l- (2-hydroxyethyl)-3-methyl-5-phenyl-lH-pyrazol-4-yl]methyl}-N-(3-methoxyphenyl)benzamide as an oil (3.36g; 79% yield).
'H NMR (500 MHz, CDC13) δ: 2.04(3H, s), 3.70(2H, dt, J=5.7Hz, J=5.7Hz), 3.47(2H, s), 3.75(3H, s), 3.92(2H, t, J=6.0Hz), 4.83(1H, t, J=5.4Hz), 6.68(1H, m), 7.15(1H, d, J=7.6Hz), 7.24(1H, t, J=8.2Hz), 7.33-7.58(8H, m), 7.58(1H, s), 7.71(1H, d, J=7.9), 10.12(1H, s)
Melting point: <70 °C Molecular weight: 441.53 Mass spectrometry: 442 (M + H)+ In vitro activity class: A In a similar method according to the Examplel-1 above, the compounds in Example 1-2 to 1-21 were synthesized.
Table 1
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001

Claims

1. An pyrazolylmethylbenzamide derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof:
Figure imgf000032_0001
wherein
R1 represents aryl optionally substituted at a substitutable position with one or more substituents selected from the group consisting of halogen, amino, carboxy, carbamoyl, cyano, hydroxy, nitro, Cι-6alkylamino, di(Cι.6)alkylamino, N-(Cι-6 alkanoyl)amino, Ci-βalkoxycarbonyl, Cj.6 alkylthio, .6 alkyl optionally substituted by mono-, di-, or tri- halogen, and Cι_6 alkoxy optionally substituted by phenyl, or mono-, di-, or tri- halogen, heteroaryl optionally having one or more substituents selected from the group consisting of halogen, amino, carboxy, carbamoyl, cyano, hydroxy, nitro, C e- alkylamino, di(Cι.6)alkylamino, N-(C1-6alkanoyl)amino, Cι-6alkoxycarbonyl, Cι-6- alkylthio, Cι-6alkyl optionally substituted by mono-, di-, or tri- halogen, and Cι.6. alkoxy optionally substituted by aryl, or mono-, di-, or tri- halogen, or
Cj.6 alkyl optionally substituted by Cι.6alkoxy, C3-8cycloalkyl, heterocyclyl, or heteroaryl or phenyl optionally having one or more substituents selected from the group consisting of halogen, amino, carboxy, carbamoyl, cyano, hydroxy, nitro, Cι.6. alkylamino, di(Cι.6)alkylamino, N-(Cι.6alkanoyl)amino, Cι-6alkoxycarbonyl, Cι.6alkylthio, Cι-6alkyl optionally substituted by mono-, di-, or tri- halogen, and Cι-6- alkoxy optionally substituted by aryl, or mono-, di-, or tri- halogen,
R2 represents Cι-6 alkyl optionally substituted by mono-, di-, or tri- halogen,
R3 represents heteroaryl or phenyl optionally substituted at a substitutable position with one or more radicals selected from the group consisting of halogen, .6 alkyl optionally substituted by mono-, di-, or tri- halogen and C]-6 alkoxy optionally substituted by mono-, di-, or tri- halogen, Ci-β alkyl optionally substituted by heteroaryl or phenyl optionally substituted at a substitutable position with one or more radicals selected from halogen, CI-6 alkyl optionally substituted by mono-, di-, or tri- halogen and Cι-6 alkoxy optionally substituted by mono-, di-, or tri- halogen,
R4 represents alkenyl or alkyl optionally substituted by one or two substituents selected from the group consisting of alkoxy, hydroxy, cycloalkyloxy, heterocyclyloxy, cyano, halogen, nitro, sulfamoyl, alkoxycarbonyl, hydroxycarbonyl, amino, alkylamino di(alkyl)amino, hydroxyalkyl(alkyl)amino, hydroxyalkylamino, -C(0)NR41R42, and 5-10 membered mono- or bicyclic ring or heterocyclic ring wherein said 5-10 membered ring is saturated or unsaturated, and optionally contains one to two heteroatoms selected from the group consisting of N, O and S, and optionally substituted by oxo, and
R41 and R42 independently represent hydrogen, alkyl, or cycloalkyl, or R41 and R42 together with the adjacent N atom form 5 to 8 membered saturated heterocyclic ring.
2. An pyrazolylmethylbenzamide derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1 : wherein
R1 represents aryl optionally substituted at a substitutable position with one or more substituents selected from the group consisting of halogen, amino, carboxy, carbamoyl, cyano, hydroxy, nitro, Cι_6alkylamino, di(Cι_6)alkylamino, N- (Cι-6alkanoyl)amino, Cι.6alkoxycarbonyl, Cι-6 alkylthio, C β alkyl optionally substituted by mono-, di-, or tri- halogen, and Cι.6 alkoxy optionally substituted by phenyl, or mono-, di-, or tri-halogen, heteroaryl optionally having one or more substituents selected from the group consisting of halogen, amino, carboxy, carbamoyl, cyano, hydroxy, nitro, Ci-β- alkylamino, di(Cι.6)alkylamino, N-(Cι-6alkanoyl)amino, d-βalkoxycarbonyl, Ci-β- alkylthio, Cι.6alkyl optionally substituted by mono-, di-, or tri- halogen, and Cι-6- alkoxy optionally substituted by aryl, or mono-, di-, or tri- halogen, or Ci.6 alkyl optionally substituted by C1-6alkoxy, C3-8cycloalkyl, heterocyclyl, or heteroaryl or phenyl optionally having one or more substituents selected from the group consisting of halogen, amino, carboxy, carbamoyl, cyano, hydroxy, nitro, Cι-6- alkylamino, di(Cι-6)alkylamino, N-(Cι.6alkanoyl)amino, C].6alkoxycarbonyl, Cι-6alkyl- thio, Cι-6alkyl optionally substituted by mono-, di-, or tri- halogen, and C].6alkoxy optionally substituted by aryl, or mono-, di-, or tri-halogen,
R2 represents Cι-6 alkyl optionally substituted by mono-, di-, or tri- halogen,
R3 represents heteroaryl or phenyl optionally substituted at a substitutable position with one or more radicals selected from the group consisting of halogen, Cι_6 alkyl optionally substituted by mono-, di-, or tri- halogen and .6 alkoxy optionally substituted by mono-, di-, or tri- halogen, C].6 alkyl optionally substituted by heteroaryl or phenyl optionally substituted at a substitutable position with one or more radicals selected from halogen, Cι-6 alkyl optionally substituted by mono-, di-, or tri- halogen and Ci_6 alkoxy optionally substituted by mono-, di-, or tri- halogen,
R4 represents alkenyl or alkyl optionally substituted by one or two substituents selected from the group consisting of alkoxy, hydroxy, cycloalkyloxy, heterocyclyloxy, cyano, halogen, nitro, sulfamoyl, alkoxycarbonyl, hydroxycarbonyl, -C(0)NR4IR42, and -NR43R44 wherein R41 and R42 independently represent hydrogen, alkyl, or cycloalkyl, or R41 and R42 together with the adjacent N atom form 5 to 8 membered saturated heterocyclic ring, and R43 and R44 independently represent hydrogen, alkyl, or cycloalkyl, or R43 and R44 together with the adjacent N atom form 5 to 10 membered mono- or bi- heterocyclic ring that is saturated or unsaturated, and optionally contains one to two additional heteroatoms selected from the group consisting of N, O and S and optionally substituted by oxo.
The pyrazolylmethylbenzamide derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1,
wherein
R1 represents phenyl optionally substituted at a substitutable position with one or two substituents selected from the group consisting of halogen, amino, nitro, hydroxy, carbamoyl, Cι-6alkylamino, di(Cι.6)alkylamino, N-(Cι.6alkanoyl)amino, Cι-6 alkyl optionally substituted by mono-, di-, or tri- halogen, and Cι-6 alkoxy optionally substituted by mono-, di-, or tri- halogen, pyridiyl or quinolinyl optionally having one or two substituents selected from the group consisting of halogen, amino, carbamoyl, d-6alkylamino, di(Ci-6)alkylamino, N-(C!.6alkanoyl)amino, Cι-6 alkyl optionally substituted by mono-, di-, or tri- halogen, and Cι-6 alkoxy optionally substituted by mono-, di-, or tri- halogen, or
Cι-6 alkyl optionally substituted by .6 alkoxy, C3.8 cycloalkyl, phenyl, heterocyclyl, or heteroaryl.
4. The pyrazolylmethylbenzamide derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1 , wherein
R3 represents phenyl optionally substituted at a substitutable position with one or more radicals selected from the group consisting of halogen, -6 alkyl optionally substituted by mono-, di-, or tri- halogen and Cι-6 alkoxy optionally substituted by mono-, di-, or tri- halogen, C3-8 cycloalkyl, Cι-6 alkyl optionally substituted by heteroaryl or phenyl optionally substituted at a substitutable position with one or more radicals selected from halogen, Cι-6 alkyl optionally substituted by mono-, di-, or tri- halogen, and C1-6 alkoxy optionally substituted by mono-, di-, or tri- halogen, C3.8 cycloalkyl, or heteroaryl.
5. The pyrazolylmethylbenzamide derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1 , wherein
R4 represents C2-C6 alkenyl or Cι-C6 alkyl optionally substituted by one or two substituents selected from the group consisting of Cι-C6 alkoxy, hydroxy, tetra- hydropyranyloxy, cyano, halogen, nitro, sulfamoyl, alkoxycarbonyl, hydroxycarbonyl, -C(0)NR41R42, and -NR43R44, wherein R41 and R42 independently represent hydrogen, alkyl, or cycloalkyl, or R41 and R42 together with the adjacent N atom form piperidino, pyrrolidinyl, or morpholino, and R43 and R44 independently represent hydrogen, alkyl, or cycloalkyl, or R43 and R44 together with the adjacent N atom form piperidino, pyrrolidino, or isoindolinyl optionally substitued at a substitutable position with one or more oxo.
6. The pyrazolylmethylbenzamide derivative of the formula (I), its tautomeric or stereoisomeric form, or a salt thereof as claimed in claim 1 , wherein said derivative is selected from the group consisting of the following compounds:
Ethyl [4-(3- { [(3 -methoxyphenyl)amino]carbonyl } benzyl)-3 -methyl-5 -phenyl- 1 H-pyrazol- 1 - yl] acetate; N-(3-methoxyphenyl)-3-({3-methyl-l-[2-(methylamino)-2-oxoethyl]-5-phenyl-lH-pyrazol-4- yl} methyl)benzamide;
3 -( { 1 -[2-(cyclohexylamino)-2-oxoethyl] -3 -methyl-5 -phenyl- 1 H-pyrazol-4-yl } methyl)-N-(3 - methoxyphenyl)benzamide;
3- {[ 1 -(2-cyanoethyl)-3-methyl-5-phenyl- 1 H-pyrazol-4-yl]methyl} -N-(3- methoxyphenyl)benzamide; and
3-{[l-(2-hydroxyethyl)-3-methyl-5-phenyl-lH-pyrazol-4-yl]methyl}-N-(3- methoxyphenyl)benzamide .
7. A medicament comprising the pyrazolylmethylbenzamide derivative , its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof as claimed in claim 1 as an active ingredient.
8. The medicament as claimed in claim 7, further comprising one or more pharmaceutically acceptable excipients.
9. The medicament as claimed in claim 7, wherein said pyrazolylmethylbenzamide derivative of the formula (1), its tautomeric or stereoisomeric form, or a physiologically acceptable salt thereof is a P2X7 receptor antagonist.
10. The medicament as claimed in claim 7 for the treatment and/or prevention of an inflammatory disorder or disease.
11. The medicament as claimed in claim 9, wherein said inflammatory disorder or disease is asthma or COPD.
12. The medicament as claimed in claim 7 for the treatment and/or prevention of pain.
13. The medicament as claimed in claim 11, wherein said pain is chronic pain, neuropathic pain, postoperative pain, or rheumatoid arthritic pain.
14. The medicament as claimed in claim 7 for the treatment and/or prevention of an autoimmune disorder or disease.
15. The medicament as claimed in claim 13, wherein said autoimmune disorder or disease is rheumatoid arthritis, Grave's disease, or atherosclerosis.
16. Use of a compound according to claim 1 for manufacturing a medicament for the treatment and/or prevention of an inflammatory disorder or disease.
17. Use of a compound according to claim 1 for manufacturing a medicament for the treatment and/or prevention of pain.
18. Use of a compound according to claim 1 for manufacturing a medicament for the treatment and/or prevention of an autoimmune disorder or disease.
19. Process for controlling an inflammatory disorder or disease in humans and animals by administration of a P2X7 receptor antagonisticly effective amount of a compound according to claim 1.
20. Process for controlling pain in humans and animals by administration of a P2X7 receptor antagonisticly effective amount of a compound according to claim 1.
21. Process for controlling an autoimmune disorder or disease in humans and animals by administration of a P2X7 receptor antagonisticly effective amount of a compound according to claim 1.
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