Novel Compounds

专利摘要:
The present invention relates to compounds of formula (I) as defined in m, n, Z 1 , Z 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 , methods for their preparation , Pharmaceutical compositions containing the same, and their use in treatment. <Formula I>
公开号:KR20030017547A
申请号:KR1020027017280
申请日:2001-06-14
公开日:2003-03-03
发明作者:토마스 에릭손；크리스터 헨릭손
申请人:아스트라제네카 아베；
IPC主号:

专利说明:

Novel Compounds
[1] The present invention relates to novel compounds, methods for their preparation, pharmaceutical compositions containing them and their use in therapy.
[2] Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, and autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These secreted small molecules are an increasingly widening family of 8 to 14 kDa proteins characterized by four conservative cysteine motifs. The chemokine superfamily can be divided into two main groups that exhibit characteristic structural motifs: Cys-X-Cys (C-X-C) and Cys-Cys (C-C). These are distinguished on the basis of insertion and sequence similarity of single amino acids between NH-adjacent pairs of cysteine residues.
[3] C-X-C chemokines include some potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activated peptide 2 (NAP-2).
[4] CC chemokines are potent for monocytes and lymphocytes, but not for neutrophils, such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal) T Expressed and Secreted), eotaxin and macrophage inflammatory proteins 1α and 1β (MIP-1α and MIP-1β).
[5] Studies have demonstrated that chemokine action is mediated by G protein-coupled receptor subfamily, such receptors include CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, There are those named CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. Since agents that modulate these receptors may be useful in the treatment of disorders and diseases as mentioned above, these receptors have been suggested as good targets for drug development.
[6] Thus, according to the present invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
[7]
[8] Where
[9] m is 0, 1, 2 or 3;
[10] Each R ¹ is independently halogen, cyano, nitro, carboxyl, hydroxyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkyl , C ₁ -C ₆ haloalkoxy, -NR ⁹ R ¹⁰ , C ₃ -C ₆ cycloalkylamino, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkylcarbonylamino , Sulfonamido (-SO ₂ NH ₂ ), C ₁ -C ₆ alkylsulfonyl, -C (O) NR ¹¹ R ¹² , -NR ¹³ C (O)-(NH) _p R ¹⁴ , phenyl, or carr carboxyl or C ₁ -C ₆ alkoxycarbonyl, optionally C ₁ -C ₆ alkyl which may be substituted by a;
[11] p is 0 or 1;
[12] X represents an oxygen atom, a CH ₂ group, an OCH ₂ group, a CH ₂₀ group, a CH ₂ NH group, an NH group, a carbonyl group or a sulfonyl group, and Y represents a nitrogen atom, a CH group or a C (OH) group, provided that Y represents a CH group when represents an oxygen atom, a CH ₂ 0 group, a CH ₂ NH group, or an NH group;
[13] Z ¹ represents a bond or a (CH ₂ ) _q group (q is 1 or 2);
[14] Z ² represents a bond or a CH ₂ group, provided that neither Z ¹ nor Z ² can represent a bond at the same time;
[15] Q represents an oxygen atom, a sulfur atom, a CH ₂ group or an NH group;
[16] R ² is Group;
[17] n is 0, 1 or 2;
[18] Each R ³ independently represents C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, —CH ₂ OH or a carboxyl group;
[19] R ⁴ , R ⁵ , R ⁶ and R ⁷ each independently represent a hydrogen atom or a C ₁ -C ₆ alkyl group, or two carbon atoms to which R ⁴ , R ⁵ , R ⁶ and R ⁷ are attached together; C ₁ -C ₄ represented the alkylene chain connecting to form a 4 to 7-membered saturated carboxylic reported Li, or R ^5, R ⁶ and R ⁷ each represent a hydrogen atom R ⁴ and R ⁸ are the they are attached Together with the carbon atoms form a 5-6 membered saturated carbori;
[20] R ⁸ represents a hydrogen atom or a C ₁ -C ₆ alkyl group or is linked to R ⁴ as defined above;
[21] R ⁹ and R ¹⁰ each independently represent a hydrogen atom or a C ₁ -C ₆ alkyl group, or R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form a 4 to 7 membered saturated heterocycle;
[22] R ¹¹ and R ¹² are each independently a hydrogen atom or a C ₁ -C ₆ alkoxy-carbonyl, optionally by a represents a C ₁ -C ₆ alkyl group which may be substituted;
[23] R ¹³ represents a hydrogen atom or a C ₁ -C ₆ alkyl group;
[24] R ¹⁴ represents a hydrogen atom or a C ₁ -C ₆ alkyl group which may be optionally substituted by carboxyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ alkoxycarbonyl;
[25] R ¹⁵ is C ₂ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, C ₅ -C ₆ cycloalkenyl, adamantyl, phenyl, or a group consisting of nitrogen, oxygen and sulfur Saturated or unsaturated 5 to 10 membered heterocyclic systems containing at least one hetero atom selected from, each of which is nitro, hydroxyl, oxo, halogen, carboxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ At least one substituent independently selected from the group consisting of alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, phenyl and -NHC (O) -R ¹⁷ Optionally substituted with the proviso that R ¹⁵ does not represent an unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneiminyl (1-homopiperidinyl) group;
[26] t is 0, 1, 2 or 3;
[27] Each R ¹⁶ is independently halogen, cyano, nitro, carboxyl, hydroxyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkyl , C ₁ -C ₆ haloalkoxy, -NR ¹⁸ R ¹⁹ , C ₃ -C ₆ cycloalkylamino, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkylcarbonylamino , Sulfonamido (-SO ₂ NH ₂ ), C ₁ -C ₆ alkylsulfonyl, -C (O) NR ²⁰ R ²¹ , -NR ²² C (O) (NH) _v R ²³ , phenyl, or carboxyl or C ₁ -C ₆ alkoxy denotes a C ₁ -C ₆ alkyl which may be optionally substituted by a carbonyl;
[28] R ¹⁷ represents a C ₁ -C ₆ alkyl, amino (—NH ₂ ) or phenyl group;
[29] R ¹⁸ and R ¹⁹ each independently represent a hydrogen atom or a C ₁ -C ₆ alkyl group, or R ¹⁸ and R ¹⁹ together with the nitrogen atom to which they are attached form a 4-7 membered saturated heterocycle;
[30] R ²⁰ and R ²¹ each independently represent a hydrogen atom, or C ₁ -C ₆ alkoxy-carbonyl, optionally by a represents a C ₁ -C ₆ alkyl group which may be substituted;
[31] v is 0 or 1;
[32] R ²² represents a hydrogen atom or a C ₁ -C ₆ alkyl group;
[33] R ²³ represents a hydrogen atom or a C ₁ -C ₆ alkyl group which may be optionally substituted by carboxyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ alkoxycarbonyl.
[34] In the present specification, the alkyl or alkenyl substituent, or the alkyl or alkenyl residue on the substituent may be straight or branched chain. In the definition of R ¹⁵ , it should be understood that the unsaturated 5-10 membered heterocyclic system may be aliphatic or aromatic.
[35] It is preferable that the integer m is 1 or 2.
[36] Each R ¹ is independently halogen (eg chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C ₃ -C ₆ cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclo Hexyl), C ₁ -C ₆ alkoxy, preferably C ₁ -C ₄ alkoxy (eg methoxy, ethoxy, n-propoxy or n-butoxy), C ₁ -C ₆ alkoxycarbonyl, Preferably C ₁ -C ₄ alkoxycarbonyl (eg methoxycarbonyl or ethoxycarbonyl), C ₁ -C ₆ haloalkyl, preferably C ₁ -C ₄ haloalkyl (eg Trifluoromethyl), C ₁ -C ₆ haloalkoxy, preferably C ₁ -C ₄ haloalkoxy (eg trifluoromethoxy), —NR ⁹ R ¹⁰ , C ₃ -C ₆ cycloalkylamino ( For example cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino), C ₁ -C ₆ alkylthio, preferably C ₁ -C ₄ alkylthio (Eg methylthio or ethylthio), C ₁ -C ₆ alkylcarbonyl, preferably C ₁ -C ₄ alkylcarbonyl (eg methylcarbonyl, ethylcarbonyl, n-propylcarbonyl Isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C ₁ -C ₆ alkylcarbonylamino, preferably C ₁ -C ₄ alkylcarbonylamino (e.g. For example, methylcarbonylamino or ethylcarbonylamino), sulfonamido, C ₁ -C ₆ alkylsulfonyl, preferably C ₁ -C ₄ alkylsulfonyl (eg methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, n-pentylsulfonyl or n-hexylsulfonyl), -C (O) NR ¹¹ R ¹² , -NR ¹³ C (O)-(NH ) _p R ¹⁴ , phenyl, or carboxyl or optionally substituted by C ₁ -C ₆ alkoxycarbonyl, preferably C ₁ -C ₄ alkoxycarbonyl (eg methoxycarbonyl or ethoxycarbonyl) Could be Is C ₁ -C ₆ alkyl, preferably C ₁ -C ₄ alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n- Hexyl).
[37] Most preferably, each R ¹ is independently halogen (specifically chlorine or fluorine), cyano, nitro, C ₁ -C ₆ alkoxy (particularly methoxy), C ₁ -C ₆ alkylcarbonyl (particularly Methylcarbonyl) or C ₁ -C ₆ alkylcarbonylamino (specifically methylcarbonylamino). Each R ¹ represents in particular halogen or cyano.
[38] X preferably represents an oxygen atom, a CH ₂ group or an NH group.
[39] Preferred combinations of Y, Z ¹ and Z ² include those listed in the table below:
[40] Y Z ^One Z ² CHCH ₂ Combination CHCombinationCH ₂CHCH ₂ CH ₂CH(CH ₂ ) ₂ Combination NCH ₂ CH ₂
[41] Q preferably represents an oxygen atom.
[42] Each R ³ is independently C ₁ -C ₆ alkyl, preferably C ₁ -C ₄ alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n -Pentyl or n-hexyl), C ₁ -C ₆ alkoxycarbonyl, preferably C ₁ -C ₄ alkoxycarbonyl (eg methoxycarbonyl or ethoxycarbonyl), -CH ₂ 0H or carboxyl groups Indicates. It is preferable that R ³ represents methyl, methoxycarbonyl, ethoxycarbonyl, -CH ₂ OH or a carboxyl group.
[43] R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group, preferably a C ₁ -C ₄ alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, tert- butyl, n- pentyl or n- hexyl), or indicate, or R ^4, R ^5, R ⁶ and R ⁷ is C ₁ to connect the two carbon atoms they are attached together Represents a -C ₄ alkylene chain to form a 4 to 7 membered saturated carbori (eg cyclohexyl, or preferably cyclopentyl), or R ⁵ , R ⁶ and R ⁷ each represent a hydrogen atom R ⁴ and R ⁸ together with the carbon atom to which they are attached form a 5 to 6 membered saturated carbori (preferably cyclopentyl).
[44] R ⁸ is a hydrogen atom or a C ₁ -C ₆ alkyl group, preferably a C ₁ -C ₄ alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n -Pentyl or n-hexyl) or linked to R ⁴ as defined above.
[45] R ⁹ and R ¹⁰ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group, preferably a C ₁ -C ₄ alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , tert-butyl, n-pentyl or n-hexyl), or R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form a 4 to 7 membered saturated heterocycle.
[46] R ¹¹ and R ¹² are each independently a hydrogen atom or a C ₁ -C ₆ alkoxycarbonyl, preferably C ₁ -C ₄ alkoxycarbonyl C ₁ -C ₆ alkyl group by a carbonyl substituent may be optionally substituted, preferably Represents a C ₁ -C ₄ alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl).
[47] R ¹³ is a hydrogen atom or a C ₁ -C ₆ alkyl group, preferably a C ₁ -C ₄ alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n Pentyl or n-hexyl).
[48] R ¹⁴ is optionally selected by a hydrogen atom or by carboxyl, C ₁ -C ₆ alkoxy, preferably C ₁ -C ₄ alkoxy or C ₁ -C ₆ alkoxycarbonyl, preferably C ₁ -C ₄ alkoxycarbonyl C ₁ -C ₆ alkyl groups which may be substituted, preferably C ₁ -C ₄ alkyl groups (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl Or n-hexyl).
[49] R ¹⁵ is a C ₂ -C ₆ alkyl group, preferably a C ₂ -C ₄ alkyl group (eg ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl), C ₂ -C ₆ alkenyl, preferably C ₂ -C ₄ alkenyl, C ₃ -C ₆ cycloalkyl (eg cyclobutyl or cyclopentyl), C ₅ -C ₆ cycloalkenyl, adamantyl, Phenyl or a saturated or unsaturated 5 to 10 membered heterocyclic system comprising at least one hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, each of which is nitro, hydroxyl, oxo, halogen (e.g. Fluorine, chlorine, bromine or iodine), carboxyl, C ₁ -C ₆ alkyl, preferably C ₁ -C ₄ alkyl (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , tert- butyl, n- pentyl or n- hexyl), C ₁ -C ₆ alkoxy, preferably C ₁ -C ₄ alkoxy (e.g., methoxy, ethoxy, n- propoxy or n- Ethoxy), C ₁ -C ₆ alkylthio, preferably C ₁ -C ₄ alkylthio (e.g. methylthio or ethylthio), C ₁ -C ₆ alkyl is C ₁ -C be carbonyl, preferably ₄ Alkylcarbonyl (eg, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C ₁ -C ₆ alkoxycarbonyl, preferably one or more independently selected from C ₁ -C ₄ alkoxycarbonyl (eg methoxycarbonyl or ethoxycarbonyl), phenyl and -NHC (O) -R ¹⁷ (Eg, 1, 2, 3 or 4) may be optionally substituted.
[50] Saturated or unsaturated 5-10 membered heterocyclic systems can be monocyclic or polycyclic (eg, bicyclic) and can contain up to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. . Examples of ring systems that can be used include pyrrolidinyl, piperidinyl, pyrazolyl, thiazolidinyl, thienyl, isoxazolyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, indolyl, quinolinyl, benz Imidazolyl, triazolyl, tetrazolyl and pyridinyl.
[51] Each R ¹⁶ is independently halogen (eg chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C ₃ -C ₆ cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclo Hexyl), C ₁ -C ₆ alkoxy, preferably C ₁ -C ₄ alkoxy (eg methoxy, ethoxy, n-propoxy or n-butoxy), C ₁ -C ₆ alkoxycarbonyl, Preferably C ₁ -C ₄ alkoxycarbonyl (eg methoxycarbonyl or ethoxycarbonyl), C ₁ -C ₆ haloalkyl, preferably C ₁ -C ₄ haloalkyl (eg Trifluoromethyl), C ₁ -C ₆ haloalkoxy, preferably C ₁ -C ₄ haloalkoxy (eg trifluoromethoxy), -NR ¹⁸ R ¹⁹ , C ₃ -C ₆ cycloalkylamino ( For example cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino), C ₁ -C ₆ alkylthio, preferably C ₁ -C ₄ alkylthio (Eg methylthio or ethylthio), C ₁ -C ₆ alkylcarbonyl, preferably C ₁ -C ₄ alkylcarbonyl (eg methylcarbonyl, ethylcarbonyl, n-propylcarbonyl Isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C ₁ -C ₆ alkylcarbonylamino, preferably C ₁ -C ₄ alkylcarbonylamino (e.g. For example, methylcarbonylamino or ethylcarbonylamino), sulfonamido, C ₁ -C ₆ alkylsulfonyl, preferably C ₁ -C ₄ alkylsulfonyl (eg methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, n-pentylsulfonyl or n-hexylsulfonyl), -C (O) NR ²¹ R ²² , -NR ²³ C (O)-(NH ) _v R ²⁴ , phenyl, or carboxyl or optionally substituted by C ₁ -C ₆ alkoxycarbonyl, preferably C ₁ -C ₄ alkoxycarbonyl (eg methoxycarbonyl or ethoxycarbonyl) Could be Is C ₁ -C ₆ alkyl, preferably C ₁ -C ₄ alkyl (e.g., methyl, ethyl, n- propyl, isopropyl, n- butyl, isobutyl, tert- butyl, n- pentyl or n- Hexyl).
[52] Preferably, R ¹⁶ is each independently halogen (specifically chlorine or fluorine), cyano, C ₁ -C ₄ alkoxy (particularly methoxy), C ₁ -C ₄ alkoxycarbonyl (particularly methoxycarb) Carbonyl), C ₁ -C ₄ haloalkyl (particularly trifluoromethyl), C ₁ -C ₄ alkylcarbonyl (specifically methylcarbonyl), phenyl or C ₁ -C ₄ alkyl (eg methyl Or tert-butyl). Each R ¹⁶ is in particular a halogen atom or a methyl group.
[53] R ¹⁷ is a C ₁ -C ₆ alkyl group, preferably a C ₁ -C ₄ alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), amino or phenyl group.
[54] R ¹⁸ and R ¹⁹ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group, preferably a C ₁ -C ₄ alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , tert-butyl, n-pentyl or n-hexyl), or R ¹⁹ and R ²⁰ together with the nitrogen atom to which they are attached form a 4 to 7 membered saturated heterocycle.
[55] R ²⁰ and R ²¹ are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group which may be optionally substituted by a C ₁ -C ₆ alkoxycarbonyl, preferably C ₁ -C ₄ alkoxycarbonyl substituent, Represents a C ₁ -C ₄ alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl).
[56] R ²² is a hydrogen atom or a C ₁ -C ₆ alkyl group, preferably a C ₁ -C ₄ alkyl group (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n Pentyl or n-hexyl).
[57] R ²³ is optionally selected by a hydrogen atom or by carboxyl, C ₁ -C ₆ alkoxy, preferably C ₁ -C ₄ alkoxy or C ₁ -C ₆ alkoxycarbonyl, preferably C ₁ -C ₄ alkoxycarbonyl C ₁ -C ₆ alkyl groups which may be substituted, preferably C ₁ -C ₄ alkyl groups (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl Or n-hexyl).
[58] Preferred compounds of the invention include
[59] N- (5-Chloro-2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -isobutyramide,
[60] Thiophene-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
[61] N-[(2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenylcarbamoyl) -methyl] -benzamide ,
[62] Pyrazine-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
[63] Cyclohexanecarboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
[64] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -phthalamic acid methyl ester,
[65] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-hydroxy-butyramide,
[66] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -2-ureido-acetamide,
[67] 4-acetylamino-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -butyramide,
[68] 1-acetyl-piperidine-4-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl )-amides,
[69] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-methoxy-benzamide,
[70] 2-acetylamino-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-methyl- Butyramide,
[71] 2-acetylamino-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-hydroxy Butyramide,
[72] Adamantane-1-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
[73] 2-acetylamino-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-phenyl- Propionamide,
[74] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -2-methoxy-benzamide,
[75] 5-Methyl-thiophene-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amides,
[76] 1-acetyl-pyrrolidine-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl )-amides,
[77] 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy } -Phenyl) -amide,
[78] 5-Oxo-pyrrolidine-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl )-amides,
[79] 1H-indole-6-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
[80] Cyclobutanecarboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
[81] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -propionamide,
[82] Pentanic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
[83] Pent-4-enoic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
[84] Cyclopentanecarboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
[85] Cyclopropanecarboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
[86] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -isobutyramide,
[87] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -2-methylsulfanyl-acetamide,
[88] 2-acetylamino-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -propionamide,
[89] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -butyramide,
[90] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-methyl-butyramide,
[91] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -2-methoxy-acetamide,
[92] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -2,2-dimethyl-propionamide,
[93] 5-oxo-hexanoic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
[94] Hexanoic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
[95] 2-chloro-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -benzamide,
[96] 3-chloro-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -benzamide,
[97] (4R) -N- (2- {3- [3- (4-chlorophenoxy) -1-pyrrolidinyl] -2-hydroxypropoxy} phenyl) -1,3-thiazolidine-4- Carboxamide ditrifluoroacetate,
[98] Thiophene-2-carboxylic acid (2- {3- [4- (3,4-dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide ,
[99] N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -benzamide,
[100] N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -nicotinamide,
[101] Pyridine-2-carboxylic acid (2- {3- [4- (3,4-dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
[102] N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -isonicotinamide,
[103] Cyclohexanecarboxylic acid (2- {3- [4- (3,4-dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
[104] N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-hydroxy-butyr amides,
[105] 5-Methyl-thiophene-2-carboxylic acid (2- {3- [4- (3,4-dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy}- Phenyl) -amide,
[106] Cyclobutanecarboxylic acid (2- {3- [4- (3,4-dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
[107] N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -propionamide,
[108] Pentanic acid (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
[109] Pent-4-enoic acid (2- {3- [4- (3,4-dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
[110] Cyclopentanecarboxylic acid (2- {3- [4- (3,4-dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
[111] N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-methyl-butyramide ,
[112] N- (2- {3- [3- (4-chlorophenoxy) -1-pyrrolidinyl] -2-hydroxypropoxy} phenyl) -2,2,2-trifluoroacetamide hydrochloride,
[113] 4- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenylcarbamoyl) -3-methyl- Butyric Acid,
[114] N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -succinic acid,
[115] Furan-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl)- amides,
[116] 1H-Pyrrole-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl )-amides,
[117] Thiophene-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl) -amides,
[118] Cyclopentanecarboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl) -amide,
[119] 5-Methyl-thiophene-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4- Methyl-phenyl) -amide,
[120] 3-Chloro-thiophene-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4- Methyl-phenyl) -amide,
[121] 5-Methyl-isoxazole-4-carboxylic acid 2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4- Methyl-phenyl) -amide,
[122] [1,2,3] thiadiazole-4-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy } -4-methyl-phenyl) -amide,
[123] 3-Methyl-furan-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl -Phenyl) -amide,
[124] Cyclopent-1-enecarboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl )-amides,
[125] 2-Methyl-furan-3-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl -Phenyl) -amide,
[126] 3-Methyl-thiophene-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4- Methyl-phenyl) -amide,
[127] 5-Nitro-1H-pyrazole-3-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy}- 4-methyl-phenyl) -amide,
[128] Thiophene-3-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl) -amides,
[129] Cyclobutanecarboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxypropoxy} -4-methyl-phenyl) -amide,
[130] Furan-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl) -amides,
[131] 1H-Pyrrole-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl- Phenyl) -amide,
[132] Thiophene-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl )-amides,
[133] 3-Chloro-thiophene-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4 -Methyl-phenyl) -amide,
[134] 5-Methyl-isoxazole-4-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy}- 4-methyl-phenyl) -amide,
[135] 3-Methyl-furan-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4- Methyl-phenyl) -amide,
[136] Cyclopent-1-enecarboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl- Phenyl) -amide,
[137] 2-Methyl-furan-3-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4- Methyl-phenyl) -amide,
[138] 3-Methyl-thiophene-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4 -Methyl-phenyl) -amide,
[139] 5-Chloro-thiophene-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4 -Methyl-phenyl) -amide,
[140] Thiophene-3-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl )-amides,
[141] 2,5-dimethyl-furan-3-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy}- 4-methyl-phenyl) -amide,
[142] Cyclobutanecarboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl) -amide ,
[143] Furan-3-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl) -amides,
[144] N- {2-[(3- {3-[(4-fluorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] -4-methylphenyl} -1 H-pyrrole-2- Carboxamide,
[145] N- {2-[(3- {3-[(4-chlorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] -4-methylphenyl} -3-thiophenecarboxamide ,
[146] N- {2-[(3- {3-[(4-chlorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxy-2-methylpropyl) oxy] phenyl} -2-thiophenecarbox Amides, compounds with trifluoroacetic acid,
[147] N- {2-[(3- {3-[(4-fluorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] -4-methylphenyl} -2-thiophenecarbox amides,
[148] N- {2-[(3- {3-[(4-chlorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] phenyl} -2-furancarboxamide,
[149] N- {2-[(3- {3-[(4-chlorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] phenyl} -1-pyrrole-2-carboxamide,
[150] N- {2-[(3- {3-[(4-chlorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] -4-methylphenyl} -1 H-pyrrole-3-carr Voxamide,
[151] N- {2-[(3- {3-[(4-fluorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] -4-methylphenyl} -2-furancarboxamide ,
[152] N- {2-[(3- {3-[(4-chlorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxy-2-methylpropyl) oxy] phenyl} cyclopentanecarboxamide, tri Compound with fluoroacetic acid,
[153] N- (2- {3- [3- (4-Fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-2-methyl-propoxy} phenyl) -benzamide,
[154] N- (2- {3- [3- (4-Cyano-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-2-methyl-propoxy} -phenyl) -benzamide,
[155] N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-2-methyl-propoxy} -phenyl) -benzamide,
[156] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-2-methyl-propoxy} -phenyl) -benzamide, and
[157] N- (2- {3- [4- (3,4-Dichloro-phenylamino) -piperidin-1-yl] -2-hydroxy-2-methyl-propoxy} -phenyl) -benzamide Included.
[158] In addition, the present invention reacts a compound of Formula II or a salt thereof (e.g., acid addition salts such as hydrochloride) with a compound of Formula III or a chemically equivalent derivative thereof (e.g., an acyl halide or anhydride derivative), There is then provided a method of preparing a compound of formula (I) as defined above, which optionally comprises forming a pharmaceutically acceptable salt or solvate of the compound of formula (I).
[159]
[160] Wherein m, n, t, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁶ , Q, Z ¹ and Z ² are as defined in formula (I)
[161] R ¹⁵ -CO ₂ H
[162] Wherein R ¹⁵ is as defined in formula (I)
[163] The process of the present invention may be carried out by organic solvents such as alcohols (eg methanol or ethanol), hydrocarbons (eg toluene), amines (eg triethylamine or diisopropylethylamine) or acetonitrile, and the like. In the solvent, for example, it may be easily performed at a temperature of 15 ° C or higher, such as in the range of 20 to 120 ° C.
[164] Compounds of formulas (II) and (III) are commercially available, are well known in the literature, or can be readily prepared using known techniques.
[165] It will be apparent to those skilled in the art that certain functional groups, such as hydroxyl or amino groups, of the starting material or intermediate compound may need to be protected by protecting groups in the process of the invention. Thus, the process for preparing the compound of formula (I) may comprise removing one or more protecting groups in a suitable step.
[166] Protection and deprotection of functional groups are described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 2nd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1991).
[167] The compound of formula (I) is a pharmaceutically acceptable salt or solvate thereof, preferably hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartarate, citrate, oxalate, methanesulfonate or p- Acid addition salts such as toluenesulfonic acid salts.
[168] The compounds of formula (I) may exist in stereoisomeric forms. It will be appreciated that the present invention encompasses the use of all geometric and optical isomers and mixtures thereof of the compounds of formula I, including racemates. In addition, the use of tautomers and mixtures thereof also forms an aspect of the present invention.
[169] Compounds of formula (I) have activity as modulators of pharmaceutical activity, specifically chemokine receptor (particularly MIP-1α chemokine receptor) activity, and have autoimmune diseases, inflammatory diseases, proliferative diseases, hyperproliferative diseases, and transplanted organs or tissues It can be used for the treatment of immunological mediated diseases, including rejection and acquired immunodeficiency syndrome (AIDS).
[170] Examples of these symptoms include:
[171] (1) airway diseases, including COPD, such as ( respiratory ) irreversible chronic obstructive pulmonary disease (COPD); Bronchial, allergic, endogenous, exogenous and dust asthma, specifically asthma, such as chronic or chronic asthma (eg, delayed asthma and airway hypersensitivity); bronchitis; Acute, allergic, atrophic rhinitis and chronic rhinitis including casein rhinitis, hypertrophic rhinitis, pyogenic rhinitis, dry rhinitis and drug rhinitis; Membranous rhinitis and nematode rhinitis, including croupous, fibrogenic and capsular rhinitis; Seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; Sarcoidosis, farmer's lung and related diseases, pulmonary fibrosis and idiopathic interstitial pneumonia;
[172] (2) ( bone and joint) rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrom and systemic sclerosis;
[173] (3) ( Skin ) Psoriasis, atopic dermatitis, contact dermatitis and other eczema dermatitis, seborrheic dermatitis, squamous gland, pemphigus, blistering bleb, bleb epidermis, urticaria, angioedema, vasculitis, erythema, skin Eosinophilia, uveitis, alopecia areata and spring conjunctivitis;
[174] (4) ( gastrointestinal tract ) celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, food-related allergies unrelated to the intestines, such as migraine, rhinitis and eczema;
[175] (5) ( Other tissue and systemic diseases ) Multiple sclerosis, atherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, renal Syndrome, eosinophilic fasciitis, excessive IgE syndrome, najongna, sezary syndrome and idiopathic thrombocytopenic purpura;
[176] (6) ( allograft rejection ) acute and chronic following, such as transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; And chronic graft versus host disease;
[177] (7) cancer, in particular non-small cell lung cancer (NSCLC) and squamous cell carcinoma;
[178] (8) diseases in which neovascularization is associated with increased amounts of chemokines (eg, NSCLC); And
[179] (9) cystic fibrosis, stroke, reperfusion injury of the heart, brain, peripheral limbs, and sepsis.
[180] Accordingly, the present invention provides a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.
[181] In another aspect, the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in therapy.
[182] As used herein, the term "treatment" also includes "prevention" unless otherwise specified. The terms "therapeutic" and "therapeutic" should be interpreted in this manner.
[183] In addition, the present invention comprises administering to a patient suffering from or at risk of an inflammatory disease, a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined above. Provided are methods for treating an inflammatory disease.
[184] In addition, the present invention comprises administering to a patient suffering from or at risk of airway disease a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined above. A method of treating airway disease is provided.
[185] For the above therapeutic uses, of course, the dosage administered will vary depending on the compound used, the mode of administration, the desired treatment and the disease presented. The daily dosage of the compound of formula (I) may range from 0.001 mg / kg to 30 mg / kg.
[186] The compounds of formula (I), and pharmaceutically acceptable salts and solvates thereof, may also be used on their own, but in general the compounds / salts / solvates (active ingredients) of formula (I) may be combined with pharmaceutically acceptable auxiliaries, diluents or carriers. It is administered in the form of a pharmaceutical composition included together. Depending on the mode of administration, the pharmaceutical composition preferably has an activity of 0.05 to 99% by weight, more preferably 0.05 to 80% by weight, even more preferably 0.10 to 70% by weight and even more preferably 0.10 to 50% by weight. Components, all weight percents being based on the total amount of the composition.
[187] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, together with a pharmaceutically acceptable adjuvant, diluent or carrier.
[188] The invention also provides a process for the preparation of a pharmaceutical composition of the invention comprising mixing a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutically acceptable adjuvant, diluent or carrier. To provide.
[189] Pharmaceutical compositions may be administered topically (eg, in the lung and / or airways, or into the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; Or systemically, for example, orally in the form of tablets, capsules, syrups, powders or granules, or parenteral in the form of solutions or suspensions, or rectally, or transdermally in the form of suppositories.
[190] The invention will be further described with reference to the following exemplary examples, in which the ¹ H NMR spectra were recorded in Varian Unity Inova 400. The central solvent peak of chloroform-d (δ _H 7.27 ppm) was used as internal standard. Low resolution mass spectra and precise mass measurements were recorded on a Hewlett-Packard 1100 LC-MS system equipped with an APCI / ESI ionization chamber. All solvents and commercial reagents were laboratory grade and used as received. The nomenclature used for the compound was generated by ACD / IUPAC Name Pro.
[191] The following abbreviations are used in the examples:
[192] NMP: 1-methyl-2-pyrrolidinone
[193] DIEA: N, N-diisopropylethylamine
[194] HBTU: 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate
[195] HoBT: 1-hydroxybenzotriazole
[196] THF: Tetrahydrofuran
[197] Example 1
[198] N- (5-Chloro-2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -isobutyramide
[199] a) N- (5-chloro-2-hydroxy-phenyl) -isobutyramide
[200] To the flask was added 4-chloro-2-aminophenol (1.2 g, 8.39 mmole) and water (25 ml). This suspension was vigorously stirred and isobutyric anhydride (1.6 ml, 10.5 mmole) was added. The mixture was heated to 60 ° C. for 30 minutes with vigorous stirring. The emulsion was cooled to form a precipitate which was then collected by filtration. The solid was washed twice with water on a filter and finally dried to give 1.4 g (78%) of the subtitle compound as a white solid.
[201]
[202] b) N- (5-chloro-2-oxyranylmethoxy-phenyl) -isobutyramide
[203] Compound (0.4 g, 1.87 mmole), epibromohydrin (0.28 g, 2.06 mmole), K ₂ CO ₃ (0.5 g, 3.7 mmole) and DMF (2 ml) obtained in a) were added to the vial. This vial was sealed and heated (2 hours, 60 degreeC), stirring. The mixture was then partitioned between EtOAc and water, and the organic phase was washed twice with water and once with brine and finally evaporated to give a brown solid. Crude epoxide was purified on silica to yield 0.22 g (44%) of the subtitle compound as a white solid.
[204] c) Compound (0.026 g, 0.13 mmole), 3- (4-chlorophenoxy) -pyrrolidine (0.035 g, 0.13 mmole) obtained in b) in ethanol (2 ml) was added to the vial. The vial was sealed and heated to 75 ° C. for 3 hours with stirring. The solution is cooled and the solvent is evaporated. The crude product was purified on silica to collect pure fractions. The title compound was lyophilized as hydrochloride to give 0.055 g (84%) as a white solid. This compound was a mixture of four stereoisomers and showed such an effect on the NMR-spectrum.
[205]
[206] APCI-MS: m / z 467.2 [MH &lt; + &gt;]
[207] <Aniline intermediate 1>
[208] 1- (2-aminophenoxy) -3- [4- (3,4-dichlorophenoxy) -1-piperidinyl] -2-propanol dihydrochloride
[209] N- (2- {3- [4- (3,4-dichlorophenoxy) -1-piperidinyl] -2-hydroxypropoxy} phenyl) acetamide (1.418 g, 3.13 mmol, with Example 1 Similarly) was dissolved in 50 ml of HCl (35% aqueous solution, puriss) and refluxed overnight. The product was charged and it was filtered and dried to give 0.835 g (65%) of the title compound.
[210] APCI-MS m / z: 411, 413 [M−H ⁺ ]
[211]
[212] <Aniline intermediate 2>
[213] 1-[(2-aminophenyl) oxy] -3- {3-[(4-chlorophenyl) oxy] -1-pyrrolidinyl} -2-propanol dihydrochloride
[214] Prepared according to the method described in aniline intermediate 1.
[215] APCI-MS m / z: 363, 365 [MH ⁺ ]
[216] The aniline intermediates 1 and 2 described above were used in the examples below.
[217] Example 2
[218] Thiophene-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide
[219] In 80 μl of a solution of 0.2 M 2-thiophenecarboxylic acid in NMP, HBTU (80 μl, 0.2 M / NMP), HoBT (80 μl, 0.2 M / NMP), DIEA (30 μl, 0.5 M / NMP) and pyridine (30 μl, 0.5 M / NMP) was added and stirred for 30 minutes, then 1-[(2-aminophenyl) oxy] -3- {3-[(4-chlorophenyl) oxy] -1-pyrroli Diyl} -2-propanol (75 μl, 0.2 M / NMP) was added. The mixture was stirred at rt overnight, then concentrated to dryness under reduced pressure. The product was diluted with 1000 μl dichloromethane and washed with saturated aqueous NaHCO ₃ solution (800 μl), 1.8% aqueous HCl solution (800 μl) and saturated aqueous NaCl solution. The organic layer was concentrated to dryness under reduced pressure and then used without further purification. Yield 3.6 mg, 51%.
[220] APCI-MS m / z: 473.2 [MH ⁺ ]
[221]
[222] Examples 3 to 53 below were prepared by methods analogous to those described in Example 2.
[223] Example 3
[224] N-[(2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenylcarbamoyl) -methyl] -benzamide
[225] APCI-MS m / z: 524.3 [MH ⁺ ]
[226] Example 4
[227] Pyrazine-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide
[228] APCI-MS m / z: 469.2 [M−H ⁺ ]
[229] Example 5
[230] Cyclohexanecarboxylic acid (2- {3- [3- (4-Chloro-phenoxy) pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide
[231] APCI-MS m / z: 473.3 [MH ⁺ ]
[232] Example 6
[233] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -phthalamic acid methyl ester
[234] APCI-MS m / z: 525.2 [M−H ⁺ ]
[235] Example 7
[236] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-hydroxy-butyramide
[237] APCI-MS m / z: 449.2 [M−H ⁺ ]
[238] Example 8
[239] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -2-ureido-acetamide
[240] APCI-MS m / z: 463.2 [M−H ⁺ ]
[241] Example 9
[242] 4-acetylamino-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -butyramide
[243] APCI-MS m / z: 490.3 [MH ⁺ ]
[244] Example 10
[245] 1-acetyl-piperidine-4-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl )-amides
[246] APCI-MS m / z: 516.3 [MH ⁺ ]
[247] Example 11
[248] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-methoxy-benzamide
[249] APCI-MS m / z: 497.2 [M−H ⁺ ]
[250] Example 12
[251] 2-acetylamino-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-methyl- Butyramide
[252] APCI-MS m / z: 504.3 [MH ⁺ ]
[253] Example 13
[254] 2-acetylamino-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-hydroxy Butyramide
[255] APCI-MS m / z: 506.2 [MH ⁺ ]
[256] Example 14
[257] Adamantane-1-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide
[258] APCI-MS m / z: 525.3 [MH ⁺ ]
[259] Example 15
[260] 2-acetylamino-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-phenyl- Propionamide
[261] APCI-MS m / z: 552.3 [MH ⁺ ]
[262] Example 16
[263] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -2-methoxy-benzamide
[264] APCI-MS m / z: 497.2 [M−H ⁺ ]
[265] Example 17
[266] 5-Methyl-thiophene-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amides
[267] APCI-MS m / z: 487.2 [M−H ⁺ ]
[268] Example 18
[269] 1-acetyl-pyrrolidine-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl )-amides
[270] APCI-MS m / z: 502.3 [MH ⁺ ]
[271] Example 19
[272] 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy } -Phenyl) -amide
[273] APCI-MS m / z: 485.3 [MH ⁺ ]
[274] Example 20
[275] 5-Oxo-pyrrolidine-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl )-amides
[276] APCI-MS m / z: 474.2 [M−H ⁺ ]
[277] Example 21
[278] 1 H-indole-6-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide
[279] APCI-MS m / z: 506.2 [M−H ⁺ ]
[280] Example 22
[281] Cyclobutanecarboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide
[282] APCI-MS m / z: 445.3 [MH ⁺ ]
[283] Example 23
[284] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -propionamide
[285] APCI-MS m / z: 419.2 [MH ⁺ ]
[286] Example 24
[287] Pentanic Acid (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide
[288] APCI-MS m / z: 447.3 [MH ⁺ ]
[289] Example 25
[290] Pent-4-enoic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide
[291] APCI-MS m / z: 445.3 [MH ⁺ ]
[292] Example 26
[293] Cyclopentanecarboxylic acid (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide
[294] APCI-MS m / z: 459.3 [MH ⁺ ]
[295] Example 27
[296] Cyclopropanecarboxylic acid (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide
[297] APCI-MS m / z: 431.2 [M−H ⁺ ]
[298] Example 28
[299] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -isobutyramide
[300] APCI-MS m / z: 433.3 [MH ⁺ ]
[301] Example 29
[302] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -2-methylsulfanyl-acetamide
[303] APCI-MS m / z: 451.2 [MH ⁺ ]
[304] Example 30
[305] 2-acetylamino-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -propionamide
[306] APCI-MS m / z: 476.2 [MH ⁺ ]
[307] Example 31
[308] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -butyramide
[309] APCI-MS m / z: 433.3 [MH ⁺ ]
[310] Example 32
[311] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-methyl-butyramide
[312] APCI-MS m / z: 447.3 [MH ⁺ ]
[313] Example 33
[314] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -2-methoxy-acetamide
[315] APCI-MS m / z: 435.2 [M−H ⁺ ]
[316] Example 34
[317] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -2,2-dimethyl-propionamide
[318] APCI-MS m / z: 447.2 [M−H ⁺ ]
[319] Example 35
[320] 5-Oxo-hexanoic acid (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide
[321] APCI-MS m / z: 475.3 [MH ⁺ ]
[322] Example 36
[323] Hexanoic acid (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide
[324] APCI-MS m / z: 461.3 [MH ⁺ ]
[325] Example 37
[326] 2-Chloro-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -benzamide
[327] APCI-MS m / z: 501.2, 503.2 [MH ⁺ ]
[328] Example 38
[329] 3-Chloro-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -benzamide
[330] APCI-MS m / z: 501.2, 503.2 [MH ⁺ ]
[331] Example 39
[332] (4R) -N- (2- {3- [3- (4-chlorophenoxy) -1-pyrrolidinyl] -2-hydroxypropoxy} phenyl) -1,3-thiazolidine-4- Carboxamide Ditrifluoroacetate
[333] APCI-MS m / z: 478.2 [M−H ⁺ ]
[334] Example 40
[335] Thiophene-2-carboxylic acid (2- {3- [4- (3,4-dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide
[336] APCI-MS m / z: 521.0, 523.0 [M−H ⁺ ]
[337] Example 41
[338] N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -benzamide
[339] APCI-MS m / z: 515.2, 517.2 [MH ⁺ ]
[340] Example 42
[341] N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -nicotinamide
[342] APCI-MS m / z: 516.2, 518.2 [M−H ⁺ ]
[343] Example 43
[344] Pyridine-2-carboxylic acid (2- {3- [4- (3,4-dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide
[345] APCI-MS m / z: 516.2, 518.2 [M−H ⁺ ]
[346] Example 44
[347] N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -isonicotinamide
[348] APCI-MS m / z: 516.2, 518.2 [M−H ⁺ ]
[349] Example 45
[350] Cyclohexanecarboxylic acid (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide
[351] APCI-MS m / z: 521.3, 523.3 [MH ⁺ ]
[352] Example 46
[353] N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-hydroxy-butyr amides
[354] APCI-MS m / z: 497.2, 499.3 [MH ⁺ ]
[355] Example 47
[356] 5-Methyl-thiophene-2-carboxylic acid (2- {3- [4- (3,4-dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy}- Phenyl) -amide
[357] APCI-MS m / z: 535.2, 537.2 [M−H ⁺ ]
[358] Example 48
[359] Cyclobutanecarboxylic acid (2- {3- [4- (3,4-dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide
[360] APCI-MS m / z: 493.3, 495.2 [MH ⁺ ]
[361] Example 49
[362] N- (2- {3- [4- (3,4-Dichloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -propionamide
[363] APCI-MS m / z: 467.2, 469.2 [MH ⁺ ]
[364] Example 50
[365] Pentanic Acid (2- {3- [4- (3,4-Dichloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} phenyl) -amide
[366] APCI-MS m / z: 495.3, 497.3 [M−H ⁺ ]
[367] Example 51
[368] Pent-4-enoic acid (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide
[369] APCI-MS m / z: 493.3, 495.2 [MH ⁺ ]
[370] Example 52
[371] Cyclopentanecarboxylic acid (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide
[372] APCI-MS m / z: 507.3, 509.3 [M−H ⁺ ]
[373] Example 53
[374] N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-methyl-butyramide
[375] APCI-MS m / z: 495.3, 497.3 [M−H ⁺ ]
[376] Example 54
[377] N- (2- {3- [3- (4-chlorophenoxy) -1-pyrrolidinyl] -2-hydroxypropoxy} phenyl) -2,2,2-trifluoroacetamide hydrochloride
[378] 1- (2-aminophenoxy) -3- [3- (4-chlorophenoxy) -1-pyrrolidinyl] -2-propanol (10 mg, 0.022 mmol), dichloromethane (3 ml) and triethyl The mixture of amines was cooled in an ice bath. Then a solution of trifluoro acetic anhydride (3.5 μl, 0.025 mmol) in dichloromethane (2 ml) was added and the mixture was stirred at 0 ° C. until the reaction was complete. The mixture was diluted with dichloromethane, washed with 1 MH ₂ SO ₄ and water, then dried over sodium sulfate and concentrated to give an oil. This oil was treated with 1.OM etheric HCl solution to give the product as a solid (9 mg).
[379] APCI-MS: m / z 459, 460 [M−H ⁺ ]
[380] Example 55
[381] 4- (2- {3- [4- (3,4-Dichloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenylcarbamoyl) -3-methyl- Butyric acid
[382] 1- (2-aminophenoxy) -3- [4- (3,4-dichlorophenoxy) -1-piperidinyl] -2-propanol (75 μl, 0.2 M / NMP) Mixing with acid anhydride (3 equiv, 225 μl, 0.2 M / NMP) gave a product containing both ester and amide. After evaporating the mixture, it was hydrolyzed with 80 M 2 equivalents of 0.5 M LiOH in THF / water (1: 4) for 2 hours to hydrolyze the ester. The reaction mixture was diluted with additional water (2 ml) and the desired product was extracted five times with 500 μl EtOAc and evaporated to dryness.
[383] APCI-MS m / z: 539.2, 541.2 [M−H ⁺ ]
[384] Example 56
[385] N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -succinic acid
[386] Prepared according to the method described in Example 55.
[387] APCI-MS m / z: 511.2, 513.2 [MH ⁺ ]
[388] <Aniline intermediate 3>
[389] 1- (2-amino-5-methylphenoxy) -3- [3- (4-chlorophenoxy) -1-pyrrolidinyl] -2-propanol
[390] APCI-MS m / z: 377.2, 379.1 [MH &lt; + &gt;]
[391]
[392] <Aniline intermediate 4>
[393] 1- (2-amino-5-methylphenoxy) -3- [3- (4-fluorophenoxy) -1-pyrrolidinyl] -2-propanol
[394] APCI-MS m / z: 361.1 [MH &lt; + &gt;]
[395]
[396] The compounds of Examples 57-85 were prepared using either aniline intermediates 3 and 4.
[397] Example 57
[398] Furan-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl)- amides
[399] APCI-MS m / z: 471.5, 473.5 [MH +]
[400] Example 58
[401] 1H-Pyrrole-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl )-amides
[402] APCI-MS m / z: 470.5, 472.5 [MH +]
[403] Example 59
[404] Thiophene-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl) -amides
[405] APCI-MS m / z: 487.5, 489.5 [MH +]
[406] Example 60
[407] Cyclopentanecarboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl) -amide
[408] APCI-MS m / z: 473.6, 475.5 [MH +]
[409] Example 61
[410] 5-Methyl-thiophene-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4- Methyl-phenyl) -amide
[411] APCI-MS m / z: 501.5, 503.5 [MH &lt; + &gt;]
[412] Example 62
[413] 3-Chloro-thiophene-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4- Methyl-phenyl) -amide
[414] APCI-MS m / z: 521.5, 532.5 [MH +]
[415] Example 63
[416] 5-Methyl-isoxazole-4-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4 -Methyl-phenyl) -amide
[417] APCI-MS m / z: 486.5, 488.6 [MH &lt; + &gt;]
[418] Example 64
[419] [1,2,3] thiadiazole-4-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy } -4-methyl-phenyl) -amide
[420] APCI-MS m / z: 489.5, 491.5 [MH +]
[421] Example 65
[422] 3-Methyl-furan-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl -Phenyl) -amide
[423] APCI-MS m / z: 485.5, 487.6 [MH +]
[424] Example 66
[425] Cyclopent-1-enecarboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl )-amides
[426] APCI-MS m / z: 471.6, 473.6 [MH +]
[427] Example 67
[428] 2-Methyl-furan-3-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl -Phenyl) -amide
[429] APCI-MS m / z: 485.6, 487.6 [MH +]
[430] Example 68
[431] 3-Methyl-thiophene-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4- Methyl-phenyl) -amide
[432] APCI-MS m / z: 501.6, 503.5 [MH +]
[433] Example 69
[434] 5-Nitro-1H-pyrazole-3-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy}- 4-methyl-phenyl) -amide
[435] APCI-MS m / z: 516.5, 518.5 [MH +]
[436] Example 70
[437] Thiophene-3-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl) -amides
[438] APCI-MS m / z: 487.5, 489.5 [MH +]
[439] Example 71
[440] Cyclobutanecarboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl) -amide
[441] APCI-MS m / z: 459.5, 461.5 [MH +]
[442] Example 72
[443] Furan-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl) -amides
[444] APCI-MS m / z: 455.5 [MH +]
[445] Example 73
[446] 1H-Pyrrole-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl- Phenyl) -amide
[447] APCI-MS m / z: 454.6 [MH +]
[448] Example 74
[449] Thiophene-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl )-amides
[450] APCI-MS m / z: 471.5 [MH +]
[451] Example 75
[452] 3-Chloro-thiophene-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4 -Methyl-phenyl) -amide
[453] APCI-MS m / z: 505.5, 507.5 [MH &lt; + &gt;]
[454] Example 76
[455] 5-Methyl-isoxazole-4-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy}- 4-methyl-phenyl) -amide
[456] APCI-MS m / z: 470.5 [MH +]
[457] Example 77
[458] 3-Methyl-furan-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4- Methyl-phenyl) -amide
[459] APCI-MS m / z: 469.6 [MH +]
[460] Example 78
[461] Cyclopent-1-enecarboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl- Phenyl) -amide
[462] APCI-MS m / z: 455.6 [MH +]
[463] Example 79
[464] 2-Methyl-furan-3-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4- Methyl-phenyl) -amide
[465] APCI-MS m / z: 469.6 [MH +]
[466] Example 80
[467] 3-Methyl-thiophene-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4 -Methyl-phenyl) -amide
[468] APCI-MS m / z: 485.5 [MH +]
[469] Example 81
[470] 5-Chloro-thiophene-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4 -Methyl-phenyl) -amide
[471] APCI-MS m / z: 505.5, 507.5 [MH &lt; + &gt;]
[472] Example 82
[473] Thiophene-3-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl )-amides
[474] APCI-MS m / z: 471.5 [MH +]
[475] Example 83
[476] 2,5-dimethyl-furan-3-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy}- 4-methyl-phenyl) -amide
[477] APCI-MS m / z: 483.6 [MH +]
[478] Example 84
[479] Cyclobutanecarboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl) -amide
[480] APCI-MS m / z: 443.6 [MH +]
[481] Example 85
[482] Furan-3-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl) -amides
[483] APCI-MS m / z: 455.5 [MH +]
[484] Example 86
[485] N- {2-[(3- {3-[(4-fluorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] -4-methylphenyl} -1 H-pyrrole-2- Carboxamide
[486] APCI-MS: m / z 454.1 [M + H ⁺ ]
[487] Example 87
[488] N- {2-[(3- {3-[(4-chlorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] -4-methylphenyl} -3-thiophenecarboxamide
[489] APCI-MS: m / z 471.1 [M + H ⁺ ]
[490] Example 88
[491] N- {2-[(3- {3-[(4-chlorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxy-2-methylpropyl) oxy] phenyl} -2-thiophenecarbox Amides, Compounds with Trifluoroacetic Acid
[492] Aniline intermediate 3 (60 mg, 0.159 mmol), 2-thiophenecarboxylic acid (20.4 mg, 0.159 mmol) and HATU (72 mg, 0.191 mmol) were stirred in dichloromethane (2 ml). Diisopropylethylamine was added to bring it to pH 8. The mixture was stirred overnight and then concentrated. The residue was purified on silica (dichloromethane / methanol 98/2) and then purified on C18 (2 g Isolute, acetonitrile / water 20/80 at 35/65, 0.5% trifluoroacetic acid) to give the title compound (75 mg, 79%) was obtained.
[493]
[494] MS-APCI +: m / z 487 [MH ⁺ ]
[495] Example 89
[496] N- {2-[(3- {3-[(4-fluorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] -4-methylphenyl} -2-thiophenecarbox amides
[497] APCI MS APCI-MS: m / z 471.1 [M + H ⁺ ]
[498] Example 90
[499] N- {2-[(3- {3-[(4-chlorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] phenyl} -2-furancarboxamide
[500] APCI-MS: m / z 456.9 [M + H ⁺ ]
[501] Example 91
[502] N- {2-[(3- {3-[(4-chlorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] phenyl} -1-pyrrole-2-carboxamide
[503] APCI-MS: m / z 456.1 [M + H ⁺ ]
[504] Example 92
[505] N- {2-[(3- {3-[(4-chlorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] -4-methylphenyl} -1 H-pyrrole-3-carr Voxamide
[506] APCI-MS: m / z 470.0 [M + H ⁺ ]
[507] Example 93
[508] N- {2-[(3- {3-[(4-fluorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] -4-methylphenyl} -2-furancarboxamide
[509] APCI-MS: m / z 455.1 [M + H ⁺ ]
[510] Example 94
[511] N- {2-[(3- {3-[(4-chlorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxy-2-methylpropyl) oxy] phenyl} cyclopentanecarboxamide, tri Compound with fluoroacetic acid
[512] The compound (80 mg, 86%) was prepared from aniline intermediate 3 (60 mg, 0.159 mmol) and cyclopentanecarboxylic acid (18 μl, 0.159 mmol) as described in Example 88.
[513]
[514] MS-APCI +: m / z 473 [MH ⁺ ]
[515] Example 95
[516] N- (2- {3- [3- (4-Fluoro-phenoxy) -pyrrolidin-1-yl1-2-hydroxy-2-methyl-propoxy} -phenyl) -benzamide
[517] The compound was prepared using a method similar to that of Example 88.
[518] APCI-MS: m / z 465 [MH ⁺ ]
[519] Example 96
[520] N- (2- {3- [3- (4-Cyano-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-2-methyl-propoxy} -phenyl) -benzamide
[521] The compound was prepared using a method similar to that of Example 88.
[522] APCI-MS: m / z 472 [MH ⁺ ]
[523] Example 97
[524] N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-2-methyl-propoxy} -phenyl) -benzamide
[525] The compound was prepared using a method similar to that of Example 88.
[526] APCI-MS: m / z 529 [MH ⁺ ]
[527] Example 98
[528] N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-2-methyl-propoxy} -phenyl) -benzamide
[529] The compound was prepared using a method similar to that of Example 88.
[530] APCI-MS: m / z 481 [MH ⁺ ]
[531] Example 99
[532] N- (2- {3- [4- (3,4-Dichloro-phenylamino) -piperidin-1-yl] -2-hydroxy-2-methyl-propoxy} phenyl) -benzamide
[533] The compound was prepared using a method similar to that of Example 88.
[534] APCI-MS: m / z 528 [M−H ⁺ ]
[535] THP-1 Chemotaxis Analysis
[536] Introduction
[537] This assay measured the chemotactic response caused by MIP-1α chemokine in human monocyte cell line THP-1. The compounds of the examples were evaluated by their ability to lower chemotactic response to standard concentrations of MIP-1α chemokine.
[538] Way
[539] Culture of THP-1 Cells
[540] Cells from frozen aliquots were thawed rapidly at 37 ° C. and supplemented with 5 ml of RPMI-1640 medium (RPMI + 10% HIFCS) supplemented with Glutamax and 10% heat inactivated fetal bovine serum without antibiotics. Resuspend in a 25 cm flask containing). On day 3, the medium was discarded and replaced with fresh medium.
[541] THP-1 cells were commonly cultured in RPMI-1640 medium supplemented with 10% heat inactivated fetal bovine serum and glutamax without antibiotics. Best cell growth required cells to be passaged every 3 days and a minimum passage density of 4 × 10 ⁺⁵ cells / ml.
[542] Chemotaxis Analysis
[543] Cells were removed from the flasks and washed by centrifugation in RPMI + 10% HIFCS + Glutamax. Cells were then 2 × 10 in fresh medium (RPMI + 10% HIFCS + Glutamax) to which calcein-AM (5 μl of stock solution was made 1 ml and the final concentration was 5 × 10 ⁻⁶ M). ^{Resuspended at +7} cells / ml. After gentle mixing, the cells were incubated for 30 minutes in a CO ₂ incubator at 37 ° C. Cells were then diluted to 50 ml using medium and washed twice by centrifugation at 400 × g. The labeled cells are resuspended at a cell concentration of 1 × 10 ⁺⁷ cells / ml and moistened CO ₂ at 37 ° C. for 30 minutes with an equal volume of MIP-1α antagonist ( ^10-10 M to ^10-6 M final concentration). Incubate in incubator.
[544] Chemotaxis was performed using a Neurooprobe 96-well chemotaxis plate using an 8 μm filter (cat no. 101-8). 30 μl of chemotactic factor supplemented with various concentrations of antagonist or vehicle were added in triplicate to the lower wells of the plate. The filter was then carefully placed on top and 25 μl of cells preincubated with the corresponding concentration of antagonist or vehicle were added to the surface of the filter. The plate was then incubated in a humidified CO ₂ incubator at 37 ° C. for 2 hours. Cells remaining on the surface were removed by adsorption and the whole plate was centrifuged at 2000 rpm for 10 minutes. The filter was then removed and the cells transferred to the lower wells quantified by phosphors of cells bound to calcein-AM. Cell migration was expressed in units of phosphor after subtracting the blank reagent, and the value was normalized to% migration by comparing the phosphor value with that of a known number of labeled cells. The effect of the antagonist was calculated as percent inhibition when compared to the number of migrated cells.

权利要求:
Claims (20)
[1" claim-type="Currently amended] A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
<Formula I>

Where
m is 0, 1, 2 or 3;
Each R ¹ is independently halogen, cyano, nitro, carboxyl, hydroxyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkyl , C ₁ -C ₆ haloalkoxy, -NR ⁹ R ¹⁰ , C ₃ -C ₆ cycloalkylamino, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkylcarbonylamino , Sulfonamido, C ₁ -C ₆ alkylsulfonyl, -C (O) NR ¹¹ R ¹² , -NR ¹³ C (O)-(NH) _p R ¹⁴ , phenyl, or carboxyl or C ₁ -C ₆ C ₁ -C ₆ alkyl which may be optionally substituted by alkoxycarbonyl;
p is 0 or 1;
X represents an oxygen atom, a CH ₂ group, an OCH ₂ group, a CH ₂₀ group, a CH ₂ NH group, an NH group, a carbonyl group or a sulfonyl group, and Y represents a nitrogen atom, a CH group or a C (OH) group, provided that Y represents a CH group when represents an oxygen atom, a CH ₂ 0 group, a CH ₂ NH group, or an NH group;
Z ¹ represents a bond or a (CH ₂ ) _q group (q is 1 or 2);
Z ² represents a bond or a CH ₂ group, provided that neither Z ¹ nor Z ² can represent a bond at the same time;
Q represents an oxygen atom, a sulfur atom, a CH ₂ group or an NH group;
R ² is Group;
n is 0, 1 or 2;
Each R ³ independently represents C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxycarbonyl, —CH ₂ OH or a carboxyl group;
R ⁴ , R ⁵ , R ⁶ and R ⁷ each independently represent a hydrogen atom or a C ₁ -C ₆ alkyl group, or two carbon atoms to which R ⁴ , R ⁵ , R ⁶ and R ⁷ are attached together; C ₁ -C ₄ represented the alkylene chain connecting to form a 4 to 7-membered saturated carboxylic reported Li, or R ^5, R ⁶ and R ⁷ each represent a hydrogen atom R ⁴ and R ⁸ are the they are attached Together with the carbon atoms form a 5-6 membered saturated carbori;
R ⁸ represents a hydrogen atom or a C ₁ -C ₆ alkyl group or is linked to R ⁴ as defined above;
R ⁹ and R ¹⁰ each independently represent a hydrogen atom or a C ₁ -C ₆ alkyl group, or R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form a 4 to 7 membered saturated heterocycle;
R ¹¹ and R ¹² are each independently a hydrogen atom or a C ₁ -C ₆ alkoxy-carbonyl, optionally by a represents a C ₁ -C ₆ alkyl group which may be substituted;
R ¹³ represents a hydrogen atom or a C ₁ -C ₆ alkyl group;
R ¹⁴ represents a hydrogen atom or a C ₁ -C ₆ alkyl group which may be optionally substituted by carboxyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ alkoxycarbonyl;
R ¹⁵ is C ₂ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, C ₅ -C ₆ cycloalkenyl, adamantyl, phenyl, or a group consisting of nitrogen, oxygen and sulfur Saturated or unsaturated 5 to 10 membered heterocyclic systems containing at least one hetero atom selected from, each of which is nitro, hydroxyl, oxo, halogen, carboxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ At least one substituent independently selected from the group consisting of alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, phenyl and -NHC (O) -R ¹⁷ Optionally substituted with the proviso that R ¹⁵ does not represent an unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneiminyl group;
t is 0, 1, 2 or 3;
Each R ¹⁶ is independently halogen, cyano, nitro, carboxyl, hydroxyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ haloalkyl , C ₁ -C ₆ haloalkoxy, -NR ¹⁸ R ¹⁹ , C ₃ -C ₆ cycloalkylamino, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkylcarbonylamino , Sulfonamido (-SO ₂ NH ₂ ), C ₁ -C ₆ alkylsulfonyl, -C (O) NR ²⁰ R ²¹ , -NR ²² C (O) (NH) _v R ²³ , phenyl, or carboxyl or C ₁ -C ₆ alkoxy denotes a C ₁ -C ₆ alkyl which may be optionally substituted by a carbonyl;
R ¹⁷ represents a C ₁ -C ₆ alkyl, amino or phenyl group;
R ¹⁸ and R ¹⁹ each independently represent a hydrogen atom or a C ₁ -C ₆ alkyl group, or R ¹⁸ and R ¹⁹ together with the nitrogen atom to which they are attached form a 4-7 membered saturated heterocycle;
R ²⁰ and R ²¹ each independently represent a hydrogen atom, or C ₁ -C ₆ alkoxy-carbonyl, optionally by a represents a C ₁ -C ₆ alkyl group which may be substituted;
v is 0 or 1;
R ²² represents a hydrogen atom or a C ₁ -C ₆ alkyl group;
R ²³ represents a hydrogen atom or a C ₁ -C ₆ alkyl group which may be optionally substituted by carboxyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ alkoxycarbonyl.
[2" claim-type="Currently amended] The compound of claim 1, wherein X represents an oxygen atom, a CH ₂ group, or an NH group.
[3" claim-type="Currently amended] The compound of claim 1, wherein Y represents a CH group.
[4" claim-type="Currently amended] The compound of any of claims 1-3, wherein Q represents an oxygen atom.
[5" claim-type="Currently amended] 5. The compound of claim 1, wherein R ¹⁵ is C ₂ -C ₅ alkyl, C ₂ -C ₄ alkenyl, C ₃ -C ₆ cycloalkyl, C ₅ -C ₆ cycloalkenyl, Monovalent, unsaturated, 5-10 membered heterocyclic systems containing one or more heteroatoms selected from the group consisting of dantilyl, phenyl, or nitrogen, oxygen, and sulfur, each of which is hydroxyl, oxo, halogen, carboxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkoxycarbonyl, phenyl and -NHC (O) -R ¹⁷ A compound which may be optionally substituted by one, two or three substituents independently selected from.
[6" claim-type="Currently amended] The saturated or unsaturated 5 to 10 membered heterocyclic system comprising at least one hetero atom selected from nitrogen, oxygen and sulfur is pyrrolidinyl, piperidinyl, pyrazolyl, thiazolidinyl, thienyl, Thiadizolyl, isoxoxazolyl, pyrrolyl, furanyl, thiazolyl, indolyl, quinolinyl, benzimidazolyl, triazolyl, tetrazolyl or pyridinyl.
[7" claim-type="Currently amended] 7. The compound of claim 1, wherein each R ¹⁶ is independently halogen, cyano, C ₁ -C ₄ alkoxy, C ₁ -C ₄ alkoxycarbonyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkylcarbonyl, phenyl or C ₁ -C ₄ alkyl.
[8" claim-type="Currently amended] The method of claim 1,
N- (5-Chloro-2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -isobutyramide,
Thiophene-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
N-[(2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenylcarbamoyl) -methyl] -benzamide ,
Pyrazine-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
Cyclohexanecarboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -phthalamic acid methyl ester,
N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-hydroxy-butyramide,
N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -2-ureido-acetamide,
4-acetylamino-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -butyramide,
1-acetyl-piperidine-4-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl )-amides,
N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-methoxy-benzamide,
2-acetylamino-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-methyl- Butyramide,
2-acetylamino-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-hydroxy Butyramide,
Adamantane-1-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
2-acetylamino-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-phenyl- Propionamide,
N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -2-methoxy-benzamide,
5-Methyl-thiophene-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amides,
1-acetyl-pyrrolidine-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl )-amides,
1,5-dimethyl-1H-pyrazole-3-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy } -Phenyl) -amide,
5-Oxo-pyrrolidine-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl )-amides,
1H-indole-6-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
Cyclobutanecarboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -propionamide,
Pentanic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
Pent-4-enoic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
Cyclopentanecarboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
Cyclopropanecarboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -isobutyramide,
N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -2-methylsulfanyl-acetamide,
2-acetylamino-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -propionamide,
N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -butyramide,
N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-methyl-butyramide,
N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -2-methoxy-acetamide,
N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -2,2-dimethyl-propionamide,
5-oxo-hexanoic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
Hexanoic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
2-chloro-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -benzamide,
3-chloro-N- (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -phenyl) -benzamide,
(4R) -N- (2- {3- [3- (4-chlorophenoxy) -1-pyrrolidinyl] -2-hydroxypropoxy} phenyl) -1,3-thiazolidine-4- Carboxamide ditrifluoroacetate,
Thiophene-2-carboxylic acid (2- {3- [4- (3,4-dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide ,
N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -benzamide,
N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -nicotinamide,
Pyridine-2-carboxylic acid (2- {3- [4- (3,4-dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -isonicotinamide,
Cyclohexanecarboxylic acid (2- {3- [4- (3,4-dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-hydroxy-butyr amides,
5-Methyl-thiophene-2-carboxylic acid (2- {3- [4- (3,4-dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy}- Phenyl) -amide,
Cyclobutanecarboxylic acid (2- {3- [4- (3,4-dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -propionamide,
Pentanic acid (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
Pent-4-enoic acid (2- {3- [4- (3,4-dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
Cyclopentanecarboxylic acid (2- {3- [4- (3,4-dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -amide,
N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -3-methyl-butyramide ,
N- (2- {3- [3- (4-chlorophenoxy) -1-pyrrolidinyl] -2-hydroxypropoxy} phenyl) -2,2,2-trifluoroacetamide hydrochloride,
4- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenylcarbamoyl) -3-methyl- Butyric Acid,
N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-propoxy} -phenyl) -succinic acid,
Furan-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl)- amides,
1H-Pyrrole-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl )-amides,
Thiophene-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl) -amides,
Cyclopentanecarboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl) -amide,
5-Methyl-thiophene-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4- Methyl-phenyl) -amide,
3-Chloro-thiophene-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4- Methyl-phenyl) -amide,
5-Methyl-isoxazole-4-carboxylic acid 2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4- Methyl-phenyl) -amide,
[1,2,3] thiadiazole-4-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy } -4-methyl-phenyl) -amide,
3-Methyl-furan-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl -Phenyl) -amide,
Cyclopent-1-enecarboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl )-amides,
2-Methyl-furan-3-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl -Phenyl) -amide,
3-Methyl-thiophene-2-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4- Methyl-phenyl) -amide,
5-Nitro-1H-pyrazole-3-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy}- 4-methyl-phenyl) -amide,
Thiophene-3-carboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl) -amides,
Cyclobutanecarboxylic acid (2- {3- [3- (4-chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxypropoxy} -4-methyl-phenyl) -amide,
Furan-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl) -amides,
1H-Pyrrole-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl- Phenyl) -amide,
Thiophene-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl )-amides,
3-Chloro-thiophene-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4 -Methyl-phenyl) -amide,
5-Methyl-isoxazole-4-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy}- 4-methyl-phenyl) -amide,
3-Methyl-furan-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4- Methyl-phenyl) -amide,
Cyclopent-1-enecarboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl- Phenyl) -amide,
2-Methyl-furan-3-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4- Methyl-phenyl) -amide,
3-Methyl-thiophene-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4 -Methyl-phenyl) -amide,
5-Chloro-thiophene-2-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4 -Methyl-phenyl) -amide,
Thiophene-3-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl )-amides,
2,5-dimethyl-furan-3-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy}- 4-methyl-phenyl) -amide,
Cyclobutanecarboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl) -amide ,
Furan-3-carboxylic acid (2- {3- [3- (4-fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-propoxy} -4-methyl-phenyl) -amides,
N- {2-[(3- {3-[(4-fluorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] -4-methylphenyl} -1 H-pyrrole-2- Carboxamide,
N- {2-[(3- {3-[(4-chlorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] -4-methylphenyl} -3-thiophenecarboxamide ,
N- {2-[(3- {3-[(4-chlorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxy-2-methylpropyl) oxy] phenyl} -2-thiophenecarbox Amides, compounds with trifluoroacetic acid,
N- {2-[(3- {3-[(4-fluorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] -4-methylphenyl} -2-thiophenecarbox amides,
N- {2-[(3- {3-[(4-chlorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] phenyl} -2-furancarboxamide,
N- {2-[(3- {3-[(4-chlorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] phenyl} -1-pyrrole-2-carboxamide,
N- {2-[(3- {3-[(4-chlorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] -4-methylphenyl} -1 H-pyrrole-3-carr Voxamide,
N- {2-[(3- {3-[(4-fluorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxypropyl) oxy] -4-methylphenyl} -2-furancarboxamide ,
N- {2-[(3- {3-[(4-chlorophenyl) oxy] -1-pyrrolidinyl} -2-hydroxy-2-methylpropyl) oxy] phenyl} cyclopentanecarboxamide, tri Compound with fluoroacetic acid,
N- (2- {3- [3- (4-Fluoro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-2-methyl-propoxy} phenyl) -benzamide,
N- (2- {3- [3- (4-Cyano-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-2-methyl-propoxy} -phenyl) -benzamide,
N- (2- {3- [4- (3,4-Dichloro-phenoxy) -piperidin-1-yl] -2-hydroxy-2-methyl-propoxy} -phenyl) -benzamide,
N- (2- {3- [3- (4-Chloro-phenoxy) -pyrrolidin-1-yl] -2-hydroxy-2-methyl-propoxy} -phenyl) -benzamide, and
N- (2- {3- [4- (3,4-Dichloro-phenylamino) -piperidin-1-yl] -2-hydroxy-2-methyl-propoxy} -phenyl) -benzamide
Or a pharmaceutically acceptable salt or solvate thereof.
[9" claim-type="Currently amended] A method of claim 1 comprising reacting a compound of Formula II or a salt thereof with a compound of Formula III or a chemically equivalent derivative thereof, and then forming a pharmaceutically acceptable salt or solvate of the compound of Formula I, optionally obtained. A process for preparing a compound of formula (I) as defined in.
<Formula II>

Wherein m, n, t, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ¹⁶ , Q, Z ¹ and Z ² are as defined in formula (I)
<Formula III>
R ¹⁵ -CO ₂ H
Wherein R ¹⁵ is as defined in formula (I).
[10" claim-type="Currently amended] A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof of any one of claims 1 to 8 together with a pharmaceutically acceptable adjuvant, diluent or carrier.
[11" claim-type="Currently amended] A method of preparing the pharmaceutical composition of claim 10 comprising mixing the compound of formula I of any one of claims 1 to 8 or a pharmaceutically acceptable salt or solvate thereof with a pharmaceutically acceptable adjuvant, diluent or carrier. .
[12" claim-type="Currently amended] The compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof according to any one of claims 1 to 8 for use in therapy.
[13" claim-type="Currently amended] Use of the compound of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for use in therapy.
[14" claim-type="Currently amended] Use of the compound of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of a human disease or condition in which modulation of chemokine receptor activity is beneficial.
[15" claim-type="Currently amended] Use of the compound of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of rheumatoid arthritis.
[16" claim-type="Currently amended] Use of the compound of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease.
[17" claim-type="Currently amended] Use of the compound of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of asthma.
[18" claim-type="Currently amended] Use of the compound of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of multiple sclerosis.
[19" claim-type="Currently amended] In said patient comprising administering to a patient suffering from or at risk of an inflammatory disease, a therapeutically effective amount of the compound of formula I of claim 1 or a pharmaceutically acceptable salt or solvate thereof. How to treat an inflammatory disease.
[20" claim-type="Currently amended] In said patient comprising administering to a patient suffering from or at risk of airway disease a therapeutically effective amount of the compound of formula I of any one of claims 1 to 8 or a pharmaceutically acceptable salt or solvate thereof. How to treat airway disease.

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同族专利:

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公开号 | 公开日

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DE60102020T2|2004-08-19|

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ES2214427T3|2004-09-16|

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JP2004501137A|2004-01-15|

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DE60102020D1|2004-03-18|

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PT1299356E|2004-05-31|

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EP1299356B1|2004-02-11|

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HU0301254A2|2003-12-29|

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AT259354T|2004-02-15|

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AR028947A1|2003-05-28|

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EE200200697A|2004-08-16|

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HU0301254A3|2008-03-28|

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EP1299356A1|2003-04-09|

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TR200401052T4|2004-11-22|

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NO20026081D0|2002-12-18|

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AU7476401A|2002-01-02|

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MXPA02012426A|2003-04-25|

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NZ523110A|2004-05-28|

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WO2001098272A1|2001-12-27|

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HK1051372A1|2004-07-23|

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IS6657A|2002-12-17|

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DK1299356T3|2004-05-17|

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CN1447794A|2003-10-08|

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PL359414A1|2004-08-23|

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CZ20024147A3|2003-05-14|

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CA2411255A1|2001-12-27|

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SK17942002A3|2003-10-07|

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BR0111669A|2003-04-01|

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IL153168D0|2003-06-24|

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NO20026081L|2003-02-04|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2000-06-20|Priority to SE0002330A

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2000-06-20|Priority to SE0002330-9

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2000-10-31|Priority to SE0003980-0

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2000-10-31|Priority to SE0003980A

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2001-06-14|Application filed by 아스트라제네카 아베

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2003-03-03|Publication of KR20030017547A

优先权:

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申请号 | 申请日 | 专利标题

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SE0002330A|SE0002330D0|2000-06-20|2000-06-20|Novel compounds|

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SE0002330-9|2000-06-20|

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SE0003980-0|2000-10-31|

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SE0003980A|SE0003980D0|2000-10-31|2000-10-31|Novel compounds|