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    • 专利摘要:
    Wherein A is a group having the formula IIA, IIB, IIC, X, U, Y, R 3 - R 12 , Z, W, n and m are as defined above. The compound is an effective serotonin reuptake inhibitor and has 5-HT 1A receptor antagonistic activity.
    公开号:KR20010071513A
    申请号:KR1020007014399
    申请日:1999-06-14
    公开日:2001-07-28
    发明作者:몰트젠유네르크누드；미켈센이반；크로그-젠센크리스티안
    申请人:피터슨 존 메이달；하. 룬트벡 아크티에 셀스카브；
    IPC主号:
    专利说明:

    4,5,6 and 7-indole and indoline derivatives, their preparation and use {4,5,6 AND 7-INDOLE AND INDOLINE DERIVATIVES, THEIR PREPARATION AND USE}
    [2] Selective serotonin (or 5-HT) reuptake inhibitors (SSRI's), such as fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram, have been shown to be more effective than the first generation of antidepressants It represents an important step developed in the treatment of depression because it has fewer and less serious side effects. Side effects associated with the first generation of antidepressants were the cause of withdrawal of some patients from treatment.
    [3] Currently available SSRI's and all other antidepressants have serious drawbacks that several weeks of treatment are needed to produce a therapeutic effect. Late onset of action is a serious problem, especially in the treatment of patients with severe depression and suicidal potential. Furthermore, one of the three patients does not respond to SSRI's.
    [4] Electrophysiological studies on rats show that SSRI's proprietary administration reduces the ignition of 5-HT neurons in the islet nucleus in rodent brains, whereas continuous treatment with SSRI's results in normalization of the 5-HT neuron's ignition activity Et al., Br. J. Pharmacol., 1995 , 115 , 1064; Chaput, Y. et al., Arunelius, L., et al., Naunyn-Schmiediberg's Arch. Pharmacol., 1995 , 352 , 157; , et al., Naunyn-Schmiedeberg ' s Arch. Pharmacol., 1986 , 33 , 342). Furthermore, it is shown that restoration of the ignition activity of 5-HT neurons is associated with a desensitization of 5-HT 1A autoreceptors in somatic dendrites (Le Poul, E., et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 1995 , 352 , 141, Invernizzi, R., et al., Eur. J. Pharmacol., 1994 , 260 , 243).
    [5] Thus, it has been suggested that simultaneous administration of agents that cause rapid desensitization or inhibition of the SSRI's and 5-HT 1A receptor mediated feedback mechanisms results in a rapid onset of antidepressant effect (Artigas, F., et al., Trends Neurosci. , 1996 , 19 , 378; De Vry, J., et al., Drug News Perspec., 1996 , 9 , 270).
    [6] The effect of mixed administration of a compound inhibiting serotonin reuptake and a 5-HT 1A receptor antagonist was evaluated in several studies (Innis, RB, et al., Eur. J. Pharmacol., 1987 , 143 , p 195-204 and Gartside , SE, Br. J. Pharmacol., 1995 , 115 , p 1064-1070 , Blier, P., et al., Trends Pharmacol. Sci., 1994 , 15 , 220). In these studies, it has been found that 5-HT 1A receptor antagonists inhibit the reduction of ignition caused by the property administration of a serotonin reuptake inhibitor.
    [7] Moreover, treatment with Pindolol (5-HT 1A receptor and β-adrenoceptor antagonist) and SSRI's was used in clinical trials. Significant improvements in patient mood were reported within one week. In addition, mixed administration of pindolol and SSRI has been shown to have a beneficial effect in patients who do not respond to treatment with currently available antidepressants (Artigas, F., et al., Arch. Gen. Psychiatry, 1994 , 51 , p 248-251 and Blier, P. et al., J. Clin. Psychopharmacol., 1995 , 15 p 217-222 ).
    [8] Several patent applications have been filed (EP-A2-687 472 and EP-A2-714 663), including the mixed use of 5-HT 1A antagonists and serotonin reuptake inhibitors in the treatment of depression.
    [9] German Patent Application No. 4414113 discloses a compound of formula
    [10]
    [11] (Indol-3-yl) -1- (indol-3-yl-alkylene) -piperidine having the formula: Wherein n is 2-6 and the other substituents are as defined in the application. The compounds were claimed to have serotonin antagonistic and agonistic activity and effects on DOPA-accumulation in the striatum and 5-HTP accumulation in N. raphe. Biological data was not given.
    [12] International Patent Publication No. 94/21626 discloses a compound of formula
    [13]
    [14] ≪ / RTI > Wherein R 2 is heteroaryl and the other substituents are as defined in the application. Compounds in which R 2 is closely related in structure to the compounds of the present invention are 5-indolyl are specifically mentioned. No data was given. In a test on the potential of 3 H spiperone from the human dopamine D 4 receptor subtype of the clone line, the compound was known to give a K j value of only 1.5 μM or less. International Patent Publication Nos. 94/21627 and 94/21630 relate to similar compounds having affinity for the human dopamine D 4 receptor.
    [15] International Patent Publication No. < RTI ID = 0.0 > 95/33721 &
    [16]
    [17] (Indanemethyl, dihydrobenzofuranylmethyl, dihydrobenzothiophenylmethyl) piperidine, tetrahydro-pyridine, or piperazine derivatives having the formula Wherein one of X and Y is CH 2 and the remainder is selected from the group consisting of CH 2 , O, or S, and Ar is aryl or heteroaryl, such as 1-, 2-, or 3- And the other substituents are as defined in the application. The compounds interact with central 5-HT receptors, particularly 5-HT 1A and 5-HT 2A . Some compounds are known to have a 5-HT reuptake inhibitory effect.
    [1] The present invention relates to 4,5,6 and 7-indole and indoline derivatives which are potent serotonin reuptake inhibitors, pharmaceutical compositions containing these compounds and their use for the treatment of disorders or disorders responsive to the inhibition of serotonin reuptake Lt; / RTI > The compounds of the present invention also have antagonistic activity at the 5HT 1A receptor, and are thought to be particularly useful in the treatment of depression.
    [18] (Object of the Invention)
    [19] The present invention aims to provide an effective serotonin reuptake inhibitory activity and a compound having an antagonistic property at the 5-HT 1A receptor. Such compounds may be useful as agents for the rapid onset of treatment of emotional disorders, such as depression.
    [20] The present invention further provides a pharmaceutical composition comprising these compounds as active ingredients.
    [21] (Summary of the Invention)
    [22] In particular, the present invention includes, alone or in combination, the following:
    [23] 4-, 5-, 6-, or 7-indole or indoline derivatives substituted with A of formula I, or acid addition salts thereof.
    [24]
    [25] Wherein W is N, C, CH or COH, the dashed line represents a selective bond,
    [26] Wherein A is a group having formula (IIA);
    [27]
    [28] (In the formula, X is CR 1A, 1A CHR, N, NR 1B, O, or S, where R 1A is as defined for R 3 -R 9 below, R 1B R 10 is below Lt; / RTI >
    [29] Y is CR 2A, CHR 2A, N, NR 2B, O, or S, where R 2A is as defined for R 3 -R 9 below, R 2B are as defined for R 10 below The same,
    [30] The dashed line represents a selective bond, and
    [31] X and Y are not both O or S;
    [32] A is a group having the formula IIB;
    [33]
    [34] (In the formula, X is CR 1A, 1A CHR, N, NR 1B, O, or S, where R 1A is as defined for R 3 -R 9 below, R 1B R 10 is below Lt; / RTI >
    [35] U is C, CH, or N, and
    [36] The dotted line represents an optional bond);
    [37] A is a group having the formula IIC;
    [38]
    [39] Wherein U is C, CH, or N,
    [40] Y is CR 2A, CHR 2A, N, NR 2B, O, or S, where R 2A is as defined for R 3 -R 9 below, R 2B are as defined for R 10 below Same, and
    [41] The dotted line represents an optional bond);
    [42] n is 0, 1, 2, 3, 4, or 5, and m is 0, 1, 2, 3, 4, or 5;
    [43] Z is CH 2 , O, S, CO, SO, or SO 2 , and when n is 0, Z is CH 2 ;
    [44] R 3 -R 9 and R 11 -R 12 are selected from the group consisting of hydrogen, halogen, cyano, nitro, C 1-6 -alk (in / phosphorus) yl, C 1-6 -alkoxy, C 1-6 -alkylthio, hydroxy, hydroxy -C 1-6 - alkyl, C 1-6 - alkoxycarbonyl, C 3-8 - cycloalkyl alk (en) yl, C 3-8 - cycloalkyl alk (en) yl -C 1-6 - alk (en / in) yl, C 1-6 - alkyl-carbonyl, phenyl-carbonyl, halogen substituted phenyl carbonyl as methylsulfonyl, methyl, trifluoromethyl trifluoromethyl sulfonyl oxy, C 1-6 - alkylsulfonyloxy, ≪ / RTI > aryl and heteroaryl,
    [45] And / or two adjacent groups taken from R < 3 > -R < 9 > may together form a methylenedioxy group,
    [46] And / or two adjacent groups R 7 -R 9 together may form a cyclopentyl or cyclohexyl ring which may be substituted with one or more methyl groups,
    [47] And / or one of R 3 -R 9 may also be a -NR 13 R 14 group, wherein R 13 is as defined for R 10 below and R 14 is hydrogen, C 1-6 -alk / in) yl, C 3-8 - cycloalkyl alk (en) yl, C 3-8 - cycloalkyl alk (en) yl -C 1-6 - alk (en / in) yl, aryl, heteroaryl, aryl, -C 1-6 -alkyl, or heteroaryl-Ci- 6 -alkyl;
    [48] R 10 is
    [49] Hydrogen, C 1-6 - alk (en / in) yl, C 3-8 - cycloalkyl alk (en) yl, C 3-8 - cycloalkyl alk (en) yl -C 1-6 - alk (en / in) Aryl, heteroaryl, aryl-C 1-6 -alkyl, heteroaryl-C 1-6 -alkyl, acyl, thioacyl, C 1-6 -alkylsulfonyl, trifluoromethylsulfonyl, arylsulfonyl , Or heteroarylsulfonyl; or
    [50] R 15 VCO-, wherein V is O or S and R 15 is C 1-6 -alk (en / in), C 3-8 -cycloalk (en) yl, C 3-8 -cycloalk En-yl-C 1-6 -alk (in / phosphorus) yl, aryl, or heteroaryl; or
    [51] R 16 R 17 NCO- or R 16 R 17 NCS- group wherein R 16 and R 17 are independently selected from the group consisting of hydrogen, C 1-6 -alk (en / in), C 3-8 -cycloalk R 16 and R 17 together with the N atom to which they are attached are independently selected from C 3-8 -cycloalk (en) yl -C 1-6 -alk (en / in), heteroaryl, 17 forms a pyrrolidinyl, piperidinyl, morpholinyl, or perhydroazepin group;
    [52] In certain embodiments, the compounds of the present invention are those compounds of formula (IIA) comprising a compound wherein A is a group having the following formulas:
    [53]
    [54] Wherein R 3 -R 6 and the dotted line are as defined above.
    [55] In another specific embodiment, A is a group having the formula:
    [56]
    [57] Wherein R 3 -R 6 and the dotted line are as defined above.
    [58] In certain embodiments, the invention relates to compounds having formula (II).
    [59]
    [60] Wherein R 7 -R 12 , W, A, Z, n, m, and the dotted line are as defined above.
    [61] In certain embodiments, Z is CH 2 and n + m is 0, 1, 2, 3, 4, 5, or 6.
    [62] In another embodiment, the present invention relates to a compound having formula (II), wherein A is a group having formula (IIA).
    [63] In another specific embodiment, the present invention relates to a compound having the formula (II), wherein A is a group having the following formula:
    [64]
    [65] Wherein R 3 -R 6 and the dotted line are as defined above.
    [66] In further particular embodiments, the present invention relates to compounds having formula (II), wherein A is a group having the formula:
    [67]
    [68] Wherein R 3 -R 6 and the dotted line are as defined above.
    [69] In certain embodiments, the compounds of the present invention are those wherein R 3 -R 9 and R 11 -R 12 are selected from the group consisting of hydrogen, halogen, cyano, nitro, C 1-6 -alkyl, C 1-6 -alkoxy, -C 1-6 -alkyl, C 1-6 -alkoxycarbonyl and trifluoromethyl; And R < 10 > is hydrogen.
    [70] In another specific embodiment of the present invention, W is N.
    [71] Examples of compounds according to the present invention include compounds
    [72] 1- (2- (3-benzofuranyl) ethyl) -4- (1H-indol-4-yl) piperazine,
    [73] 1- (3-benzofuranylmethyl) -4- (1H-indol-4-yl) piperazine,
    [74] 1- (2- (5-fluoro-3-benzofuranyl) ethyl) -4- (lH-indol-4- yl) piperazine,
    [75] 1- (4- (5-fluoro-3-benzofuranyl) -1-butyl) -4- (lH-indol-
    [76] 1- (2- (lH-indol-3-yl) ethyl) -4- (lH-indol-4- yl) piperazine,
    [77] 1- (3- (lH-indol-3-yl) -1-propyl) -4- (lH-indol-
    [78] 1- (4- (1H-indol-3-yl) -1-butyl) -4- (1H-
    [79] 1- (3- (5-fluoro-3-benzofuranyl) -l-propyl) -4- (lH-indol-
    [80] (2- (2-methyl-4,5,6,7-tetrafluoro-3-benzofuranyl) ethyl) -4- (1H-
    [81] 1- (2- (3-indazolyl) ethyl) -4- (lH-indol-4- yl) piperazine,
    [82] 1- (2- (6-Chloro-3-indazolyl) ethyl) -4- (lH-indol-4- yl) piperazine,
    [83] L- (2- (7-Cyano-lH-indol-3-yl) ethyl) -4- (lH-
    [84] L- (2- (6-chloro-lH-indol-3-yl) ethyl) -4- (lH-indol-
    [85] L- (2- (4-chloro-lH-indol-3-yl) ethyl) -4- (lH-indol-
    [86] (2- (5-fluoro-lH-indol-3-yl) ethyl) -4- (lH-
    [87] 4- (1H-indol-4-yl) -1,2,3,6-tetrahydropyridine,
    [88] 4- (1H-indol-4-yl) -1,2,3,6-tetrahydropyridine,
    [89] L- (2- (7-Bromo-lH-indol-3-yl) ethyl) -4- (lH-indol-
    [90] L- (l-allyl-lH-indol-4-yl) -4-
    [91] Yl) -4- (2- (5-fluoro-lH-indol-3-yl) ethyl) piperazine,
    [92] (L- (6-chloro-lH-indol-3-yl) ethyl) piperazine,
    [93] (L-benzyl-lH-indol-4-yl) -4-
    [94] (L-benzyl-lH-indol-4-yl) -4-
    [95] L- (2- (6-chloro-lH-indol-3-yl) ethyl) -4- (l-
    [96] L- (2- (lH-indol-3-yl) ethyl) -4- (1-propargyl-lH-indol-
    [97] L- (2- (5-fluoro-lH-indol-3-yl) ethyl) -4- (l-propargyl-
    [98] 1 - (2- (5-Bromo-1 H-indol-3-yl) ethyl) -4- (1-propargyl-
    [99] 4- (2- (lH-indol-3-yl) ethyl) piperazine, l-
    [100] (2- (5-bromo-1H-indol-3-yl) ethyl) -4- (lH- indol-
    [101] L- (2- (5-chloro-lH-indol-3-yl) ethyl) -4- (lH- indol-
    [102] 4- (6-hydroxymethyl-1 H-indol-4-yl) piperazine,
    [103] 4- (6-hydroxymethyl-1 H-indol-4-yl) piperazine,
    [104] 4- (6-hydroxymethyl-1 H-indol-4-yl) piperazine,
    [105] 1- (3- (6-fluoro-1,2-benzisoxazol-3-yl)
    [106] 1- (2- (lH-indol-3-yl) ethyl) -4- (6-methoxycarbonyl-lH-indol-
    [107] 4- (6-methoxycarbonyl-lH-indol-4-yl) piperazine,
    [108] 1- (2- (5-Fluoro-3-benzofuranyl) ethyl) -4- (6-methoxycarbonyl-lH-indol-
    [109] (5-fluoro-3-benzofuranylmethyl) -4- (lH-indol-4-yl) piperazine,
    [110] (3-cyano-lH-indol-4-yl) -4- (2- (lH-
    [111] 4- (2- (5-fluoro-3-benzofuranyl) ethyl) piperazine,
    [112] 4- (3-cyano-lH-indol-4-yl) piperazine,
    [113] L- (2- (3-benzofuranyl) ethyl) -4- (3-cyano-lH-indol-4- yl) piperazine,
    [114] 4- (2- (5-methyl-3-benzofuranyl) ethyl) piperazine,
    [115] 4- (2- (4-methyl-3-benzofuranyl) ethyl) piperazine,
    [116] Propyl) -4- (1H-indol-4-yl) -1,2,3,6-tetrahydropyridine,
    [117] 1- (2- (5-chloro-3-benzofuranyl) ethyl) -4- (lH-indol-4- yl) piperazine,
    [118] 4- (2- (6-methyl-3-benzofuranyl) ethyl) piperazine,
    [119] 1- (2- (7-chloro-3-benzofuranyl) ethyl) -4- (lH-indol-4- yl) piperazine,
    [120] 4- (3-cyano-lH-indol-4-yl) piperazine,
    [121] (2- (6-chloro-lH-indol-3-yl) -4- (lH- indol- 4- yl) piperidine,
    [122] (2- (5-chloro-lH-indol-3-yl) ethyl) -4- (lH-
    [123] L- (2- (7-Bromo-lH-indol-3-yl) ethyl) -4- (lH-indol-
    [124] L- (2- (4-chloro-lH-indol-3-yl) ethyl) -4- (lH-indol-
    [125] 4- (lH-indol-4-yl) piperazine, l- (2-
    [126] 4- (2- (5-methyl-lH-indol-3-yl) ethyl) piperazine,
    [127] 4- (2- (6-methyl-lH-indol-3-yl) ethyl) piperazine,
    [128] 4- (2- (7-methyl-lH-indol-3-yl) ethyl) piperazine,
    [129] 1- (2- (4,5-Dichloro-3-benzofuranyl) ethyl) -4- (lH-indol-4- yl) piperazine,
    [130] 1- (2- (5-bromo-3-benzofuranyl) ethyl) -4- (lH-indol-4- yl) piperazine,
    [131] L- (2- (4-chloro-lH-indol-3-yl) ethyl) -4- (lH-indol-
    [132] 4-yl) -1- (2- (5-methyl-1H-indol-3-yl) ethyl) piperidine,
    [133] 4- (lH-indol-4-yl) -1- (2- (lH-indol-3- yl) ethyl) piperidine,
    [134] 4- (3- (4-methyl-3-benzofuranyl) -1-propyl) piperazine,
    [135] 4- (1H-indol-4-yl) -1- (3- (4-methyl-3- benzofuranyl)
    [136] 1- (3- (4-Chloro-3-benzofuranyl) -l-propyl) -4- (lH-indol-
    [137] 4- (6-chloro-lH-indol-4-yl) piperazine,
    [138] 4- (6-fluoro-lH-indol-4-yl) piperazine,
    [139] 4- (6-cyano-lH-indol-4-yl) piperazine,
    [140] L- (2- (6-chloro-lH-indol-3-yl) ethyl) -4-
    [141] L- (2- (6-chloro-lH-indol-3-yl) ethyl) -4- (7-
    [142] 4- (2-cyano-lH-indol-4-yl) piperazine,
    [143] L- (2- (6-chloro-lH-indol-3-yl) ethyl) -4- (lH-indolin-
    [144] L- (2- (6-Chloro-lH-indol-3-yl) ethyl) -4- (lH- indol-6-yl)
    [145] L- (2- (6-chloro-lH-indol-3-yl) ethyl) -4- (lH- indol-
    [146] Or an acid addition salt thereof.
    [147] The present invention also relates to a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent.
    [148] Another aspect of the invention relates to the use of a compound of the invention or a pharmaceutically acceptable acid addition salt thereof for the treatment of disorders or disorders responsive to inhibition of serotonin reuptake and antagonism of the 5-HT 1A receptor.
    [149] In its ultimate goal, the present invention provides a method of inhibiting serotonin reuptake and inhibiting the production of 5- Lt; RTI ID = 0.0 > HT 1A < / RTI > receptor.
    [150] Diseases or disorders responsive to the inhibition of serotonin reuptake and to the antagonistic activity of 5-HT 1A receptors include depression, psychoses, generalized anxiety disorders, and anxiety disorders including panic disorders and affective disorders such as obsessive-compulsive disorder.
    [151] Because of the antagonistic effect of mixed 5-HT 1A receptors and the mixed effect on inhibition of serotonin reuptake, the compounds of the present invention are particularly useful as agonists of fast onset for the treatment of depression. The compounds may also be useful in the treatment of depression in patients who are currently resistant to antidepressants.
    [152] In the formulas IIA, IIB and IIC groups, the presence and position of the double bond in the ring containing X, U and Y depends on the meaning of X, U and Y.
    [153] Thus, with respect to the formula IIA group, when X is N or CR 1A , the dotted line from X is a bond and, when X is CHR 1A , NR 1B , O, or S, the dashed line is not a bond; It is quite obvious to those skilled in the art that when Y is N or CR 1B , the dotted line from Y is a bond and when Y is CHR 2 A , NR 2B , O, or S, the dotted line is not a bond.
    [154] Furthermore, with respect to the formula IIB group, when X is N or CR 1A , the dotted line from X is a bond and, when X is CHR 1A , NR 1B , O, or S, the dotted line is not a bond; It is quite obvious to those skilled in the art that when U is C, the dotted line from U is a bond and when U is CH or N, the dotted line is not a bond.
    [155] And finally, with respect to the formula IIC group, when U is C, the dotted line from U is a bond and when U is CH or N, the dotted line is not a bond; When Y is N or CR 2A, the dotted line is a bond, if Y is CHR 2A, 2B NR, O, or S, the dotted line is quite evident that those skilled in the art is not a bond.
    [156] The same applies to W, and when W is N, CH, or COH, the dotted line from W does not show bonding, and in the case of C, the dotted line shows bonding.
    [157] Representative C 1-6 -alk (n / in) workings mean C 1-6 -alkyl, C 2-6 -alkenyl, or C 2-6 -alkynyl groups. Representative C 3-8 -cycloalk (en) yl means a C 3-8 -cycloalkyl- or cycloalkenyl group.
    [158] The term C 1-6 -alkyl is considered to be a branched or straight-chain alkyl group having a generic 1-6 carbon atom and includes methyl, ethyl, 1-propyl, 2-propyl, -Propyl and 2-methyl-1-propyl.
    [159] Likewise, C 2-6 -alkenyl and C 2-6 -alkynyl each represent a group having 2-6 carbon atoms each containing one double bond and one triple bond, and ethenyl, propenyl, Decenyl, ethynyl, propynyl, and butynyl.
    [160] The term C 1-6 -alkoxy, C 1-6 -alkylthio, C 1-6 -alkylsulfonyl, C 1-6 -alkylamino, C 1-6 -alkylcarbonyl, hydroxy-C 1-6- Alkyl or the like represents such a group as C 1-6 -alkyl is as defined above.
    [161] The term C 3-8 -cycloalkyl represents a single ring or double ring carbon ring having 3-8 carbon atoms and includes, but is not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like.
    [162] The term C 3-8 -cycloalkenyl refers to a single ring or double ring carbon ring having 3-8 carbon atoms and containing one double bond.
    [163] The term aryl is considered to be an aromatic carbon ring group such as phenyl, naphthyl, especially phenyl. Aryl as used herein may be substituted one or more times by halogen, nitro, cyano, trifluoromethyl, Ci- 6 -alkyl, hydroxy and Ci- 6 -alkoxy.
    [164] The term heteroaryl refers to a heteroaromatic ring of mono- or bicyclic rings such as indolyl, thienyl, pyrimidyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, benzofuranyl, benzothienyl, pyridyl and furanyl Is considered to be a ring group, in particular pyrimidyl, indolyl, and thienyl.
    [165] The heteroaryl as used herein may be substituted one or more times by halogen, nitro, cyano, trifluoromethyl, C 1-6 -alkyl, hydroxy and C 1-6 -alkoxy.
    [166] Aryl-C 1-6 -alkyl and heteroaryl-C 1-6 -alkyl, aryl, heteroaryl and C 1-6 -alkyl are as defined above.
    [167] Halogen means fluorine, chlorine, boron and iodine.
    [168] The term acyl as used herein, is formyl, C 1-6 - alk (en / in) ylcarbonyl, arylcarbonyl, aryl -C 1-6 - alk (en / in) ylcarbonyl, C 3 -8-cycloalkyl alk (en) ylcarbonyl, or a C 3-8 - cycloalkyl alk (en) yl -C 1-6 - are considered alk (en / in) ylcarbonyl group, the term thio-acyl group is a thio group Lt; / RTI >
    [169] The acid addition salts of the present invention are preferably the pharmaceutically acceptable salts of the compounds of the invention formed using non-toxic acids. Examples of such organic salts include, but are not limited to, maleic, benzo, ascorbic, succinic, oxalic, bis-methylenesalicyl, methanesulfone, ethanedisulfone, acet, propion, tartar, salicyl, citr, glucon, lact, , 8-halo theophylline, such as 8-bromo theophylline, as well as citracon, aspartate, stearate, palmitate, itacon, glycol, p-aminobenzo, glutam, benzenesulfone and theophylline acetic acid. Examples of such inorganic salts are those using hydrogen chloride, boron chloride, sulfur, sulfam, phosphorus, and nitric acid.
    [170] Furthermore, the compounds of the present invention may exist in solvated form using pharmaceutically acceptable solvents such as water, ethanol, etc., as well as the unsolvated state. Generally, for purposes of the present invention, the solvated form is considered equivalent to the unsolvated form.
    [171] Some of the compounds of the present invention contain a chiral center, and such compounds exist in the form of isomers (e. G., Enantiomers). The present invention includes any mixtures thereof including all such isomers and racemic mixtures.
    [172] Racemic forms can be separated into optically symmetric forms by known methods, for example by separating their stereoisomeric salts using optically active acids and treating optically active amine compounds by treatment with a base. Another method of separating racemic mixtures into optically symmetric sieves is based on chromatography of optically active matrices. The racemic compounds of the present invention may also be separated into their optically symmetrical forms by, for example, fractional crystallization of d- or l- (tartrate, mandelate, or camphorsulfonate) salts. The compounds of the present invention may also be separated by formation of stereoisomeric derivatives.
    [173] Additional methods may be used to isolate optical isomers, known to those skilled in the art. Such methods include those discussed by J, Jaques, A. Collet, and S. Wilen in " Enantiomers, Racemates, and Resolutions ", John Wiley and Sons, New York (1981).
    [174] Optically active compounds can also be prepared from optically active starting materials.
    [175] Finally, Formula I includes certain tautomeric forms of the compounds of the present invention.
    [176] The compounds of the present invention can be prepared by any of the following methods.
    [177] a) reduction of the carbonyl group of the compound of formula III;
    [178]
    [179] Wherein R 3 -R 12 , W and the dotted line are as defined above;
    [180] b) alkylation of an amine of formula IV;
    [181]
    [182] Wherein R 7 -R 12 , W and the dotted line are as defined above, using a reagent of formula V;
    [183]
    [184] Wherein A, Z, n and m are as defined above and G is a suitable leaving group such as halogen, mesylate, or tosylate;
    [185] c) reductive alkylation of the amine of formula IV;
    [186] (IV)
    [187]
    [188] Wherein R 7 -R 12 , W and the dotted line are as defined above, using reagents of formula VI;
    [189]
    [190] Wherein A, Z, n and m are as defined above and E is either an aldehyde or a carboxylic acid group;
    [191] d) reduction of the double bond of the indole ring bound to the amine component of the ring of formula I to obtain the corresponding 2,3-dihydroindole derivative;
    [192] e) reduction of the double bond of the tetrahydropyridine of formula VII to obtain the corresponding piperidine derivative;
    [193]
    [194] Wherein R 7 -R 12 , A, Z, n, m and the dashed line are as previously defined;
    [195] f) reduction of the amide group of the compound of formula VIII;
    [196]
    [197] Wherein R 7 -R 12 , A, Z, n, m and the dashed line are as previously defined;
    [198] g) at least one of the halogen substituents R 3 -R 9 and R 11 -R 12 of the compound of formula I, wherein at least one of the substituents is selected from chlorine, boron, or iodine;
    [199] h) dialkylation of an amine of formula IX;
    [200]
    [201] Wherein R 7 -R 12 and the dashed line are as defined above and uses a reagent of formula X;
    [202]
    [203] Wherein A, Z, n and m are as defined above and G is a suitable leaving group such as halogen, mesylate, or tosylate;
    [204] i) Dialkylating an amine of formula XI;
    [205]
    [206] Wherein A, Z, n and m are as defined above and the reagent of formula (XII) is used;
    [207]
    [208] Wherein R 7 -R 12 , W and the dotted line are as defined above and G is a suitable leaving group such as halogen, mesylate, or tosylate;
    [209] j) alkylation, arylation or acylation of one or two indole nitrogen atoms of a compound of formula I wherein R < 10 > is hydrogen and / or X and / or Y is NH; or
    [210] k) reduction of a compound of formula I wherein R 7 , R 8 , or R 9 is an alkoxycarbonyl group, to obtain the corresponding hydroxymethyl group;
    [211] As a result, the compounds of formula (I) can be isolated in the form of free bases or their acid addition salts.
    [212] The reduction according to method a) is preferably carried out in an inert organic solvent such as diethyl ether or tetrahydrofuran in the presence of a reflux temperature and lithium aluminum hydride. The starting compounds of formula (III) are generally prepared in the presence of a base such as triethylamine or potassium carbonate in the presence of a base such as 3-chlorooxalyl indole (Houben-Weyl, Methoden der Organischen Chemie, Vol E6B2, ) With an amine of formula (IV).
    [213] The alkylation according to process b) is easily carried out in an inert organic solvent such as a suitable boiling alcohol or ketone at reflux temperature and preferably in the presence of an organic or inorganic base (potassium carbonate or triethylamine).
    [214] The indolylpiperazine derivatives of formula IV are described by Martin et al. In J. Med. Chem. 32 (1989) 1052, or by Kruse et al., Rec. Trav. Chim. Is readily prepared from the corresponding arylamine according to the method described in Pays-Bas 107 (1988) 303. The starting materials arylamine are either commercially available or are described in the literature.
    [215] Indolyl tetrahydropyridine derivatives of formula IV are known from the literature (see, for example, French Pat. 2458549). Conveniently, the 1-protected 4,5,6 or 7-bromoindole is lithiated by using BuLi, followed by dehydration as outlined in the examples below by addition of 1-protected 4-piperidone do. Bromoindol, the starting material, is either commercially available or is described in the literature. The reagents of formula V are either commercially available or can be prepared by literature methods, for example by reduction of the corresponding carboxylic acid derivative to the corresponding hydroxy derivative and subsequent conversion of the hydroxy group to the G group by conventional methods .
    [216] The reductive alkylation according to process c) is carried out by standard methods in the literature. The reaction is carried out in two steps: coupling the reagent of formula (VI) with a derivative of formula (IV) by standard methods with a chlorinated carboxylic acid or by using coupling reagents such as, for example, dicyclohexylcarbodiimide Followed by reduction of the resulting amide using lithium aluminum hydride or allyl. The reaction can also be performed by standard one-port procedures. Carboxylic acids or aldehydes of formula (VI) are commercially available or are described in the literature.
    [217] Reduction of the indole double bond according to method d) can be accomplished by heating the diborane or diborane precursor, such as trimethylamine or dimethyl sulfide complex, in an inert solvent such as tetrahydrofuran or dioxane, , Followed by acid catalysed hydrolysis of the borane derivative, which is an intermediate. Alternatively, the reduction may be carried out by treatment with sodium cyanoborohydride in trifluoroacetic acid.
    [218] Reduction of the double bond according to process e) is most easily carried out by hydrogenation in alcohols in the presence of a noble metal catalyst such as, for example, platinum or palladium.
    [219] Reduction of the amide group according to method f) is most easily carried out at 0 < 0 > C to reflux temperature, for example using lithium aluminum hydride or allyl in an inert organic solvent such as tetrahydrofuran or diethyl ether.
    [220] Removal of the halogen substituent according to method g) is easily carried out by catalytic hydrogenation in an alcohol in the presence of a palladium catalyst or by treatment with an ammonium formate in an alcohol at elevated temperature and in the presence of a palladium catalyst.
    [221] The dialkylation of the amine according to methods h) and i) is most easily carried out at elevated temperature and in an inert solvent such as chlorobenzene, toluene, N-methylpyrrolidinone, dimethylformamide, or acetonitrile. The reaction can be carried out, for example, in the presence of a base such as potassium carbonate or triethylamine. The starting materials of processes h) and i) are either commercially available or can be prepared using conventional methods.
    [222] The indole N-alkylation or N-acylation is carried out at elevated temperature and, for example, in the presence of potassium carbonate or triethylamine, for example in an inert solvent such as an alcohol or a ketone. Alternatively, phase-transfer reagents can be used. The corresponding N-arylation is best performed under Ullmann-conditions as described in the literature.
    [223] Reduction of the alkoxycarbonyl group according to method k) is most easily carried out using lithium aluminum hydride or allyl in an inert organic solvent such as, for example, tetrahydrofuran.
    [224] The following examples will further illustrate the invention. However, they are not construed as limitations.
    [225] The melting point was measured with a Buchi B-540 instrument and not calibrated. The mass spectra were obtained from VG Biotech, MS-MS system from Fisons Instruments or Sciex API 150EX from Perkin Elmer. The spectra were obtained in two sets of operating conditions using electrospray ionization: one set to obtain molecular weight information (MH +, 20 eV) and the other set to derive a fission pattern (70-100 eV). The background value was subtracted. Obtain the relative intensity of the ions from the fission pattern. If the intensity is not shown for the molecular ion (MH +), then this ion exists only under the first set of operating conditions. 1 H NMR spectra were recorded on a Bruker AC 250 at 250 MHz or a Bruker DRX 500 at 500 MHz. Deuterated chloroform (99.8%) or dimethyl sulfoxide (99.9%) was used as a solvent. TMS was used as internal reference material. Chemical shifts are expressed in ppm. The following abbreviations are used for the multiplicities of the NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qv = Double triplet, dq = double quadruplet, tt = triplet triplet, m = polyline, b = broad. NMR signals corresponding to acidic protons have been omitted to some extent. The moisture content of the crystalline compound was determined by Karl Fischer titration. Appropriate elemental analysis for all target compounds was obtained. The standard work-up procedure is to extract the organic solvent from the appropriate aqueous solution, dry the combined organic extracts (anhydrous MgSO 4 or NaSO 4 ), filter and evaporate the solvent in vacuo. In column chromatography, silica gel type Kiesilgel 60, 40-60 mesh ASTM was used.
    [226] Preparation of intermediate
    [227] A. Preparation of 1- (1H-indol-4-yl) piperazine
    [228] L- (lH-Indol-4-yl) piperazine
    [229] Dinitrotoluene (25 g) was dissolved in DMSO (60 ml). Triton-B (40% in methanol, 6.4 ml) was added to make a dark purple solution. The mixture was heated to 30 < 0 > C and then a solution of paraformaldehyde (4.5 g) in DMSO (40 ml) was slowly added. After addition, the mixture was heated to 65 DEG C for 1.5 hours. Standard work-up with ethyl acetate gave 2- (2,6-dinitrophenyl) ethanol (29 g) as a dark red oil. The oil (27 g) was dissolved in ethanol (250 ml) and 5% palladium on charcoal (3 g) was added. The mixture was treated with hydrogen gas at 3 atmospheres in a Parr apparatus for 16 hours. Filtration and removal of the solvent in vacuo afforded 19.4 g of 2- (2,6-diaminophenyl) ethanol as a brown oil and crystallized. A portion (15.8 g) of this product was dissolved in toluene (250 ml) and tris (triphenylphosphine) ruthenium (II) chloride (2.9 g) was added. The mixture was refluxed using a water separator for 8 hours, then the solvent was removed in vacuo. The remaining reaction mixture was purified by flash chromatography (eluent: heptane / ethyl acetate 3: 1) to give 4-amino-1H-indole (7.6 g) as a crystalline solid. The solid was dissolved in chlorobenzene (150 ml), bis (2-chloroethyl) amine hydrochloride (9 g) was added and then refluxed for 90 hours. Filtration afforded the crystalline product (9.2 g) which was heated in a mixture of concentrated aqueous ammonia (50 ml) and ethyl acetate (200 ml) for 15 min. The organic layer was separated, dried and evaporated to give the title compound (5.6 g) as a crystalline material.
    [230] The following piperazine was prepared analogously:
    [231] L- (6-methoxycarbonyl-lH-indol-4-yl) piperazine
    [232] L- (6-t-butyl-5-methoxy-lH-indol-4- yl) piperazine
    [233] L- (6-t-Butyl-7-methoxy-lH-indol-4- yl) piperazine
    [234] 1- (6,7-dihydro-6,6,8,8-tetramethylcyclopent (g) -1H-indol-4-yl) piperazine
    [235] 1- (1H-indol-5-yl) piperazine
    [236] This piperazine was prepared by treatment with 5-aminoindole and bis (2-chloroethyl) amine by a procedure analogous to that described above for the preparation of 1- (1H-indole-4-yl) piperazine.
    [237] L- (3-cyano-lH-indol-4-yl) piperazine
    [238] A mixture of l- (lH-indol-4-yl) piperazine hydrochloride (1 g) and potassium carbonate (2.9 g) in tetrahydrofuran (25 ml) and water (25 ml) was stirred for 15 minutes, A solution of di-t-butyl dicarbonate (2.3 g) in a 1: 1 mixture of furan and water (20 ml) was added. The mixture was stirred at 50 < 0 > C for 16 hours. Standard work-up was performed with ethyl acetate to obtain 1-t-butoxycarbonyl-4- (1H-indol-4-yl) piperazine (1.1 g) as heavy oil.
    [239] The oil was dissolved in acetonitrile (50 ml) and then chlorosulfonyl isocyanate (1 ml) was added dropwise at -20 째 C. Dimethylformamide (5 ml) was added dropwise over 20 minutes while maintaining the mixture at a low temperature. Finally, the mixture was stirred at 0 占 폚 for 30 minutes. An aqueous solution (30 ml) of sodium carbonate was added and the mixture was stirred for 30 minutes. The organic layer was separated, dried and concentrated. The resulting oil was purified by column chromatography (eluent: ethyl acetate / heptane / methanol 16: 3: 1) to give 1-tert-butoxycarbonyl-4- (3- Yl) piperazine (0.5 g).
    [240] The oil was dissolved in methanol (2 ml) and etheral hydrochloride (20 ml) was added. Stirred for 2 hours, and filtered to obtain the title compound (0.34 g) as a crystalline material.
    [241] L- (l-allyl-lH-indol-4-yl) piperazine
    [242] A solution of 1-t-butoxycarbonyl-4- (1H-indol-4-yl) piperazine (prepared as described above) in tetrahydrofuran (50 ml) was added at room temperature to a solution of sodium Hydride (0.7 g of 60% mineral oil suspension). After stirring for 30 minutes or more, a solution of allyl bromide (3.5 ml) in tetrahydrofuran (50 ml) was added dropwise. After stirring for 48 hours, the mixture was subjected to ice work-up followed by standard work-up with ethyl acetate to give an oil which was purified by flash chromatography (eluent: heptane / ethyl acetate 85:15) to give 1-t- Butoxycarbonyl-4- (1-allyl-lH-indol-4-yl) piperazine (3.2 g). The oil was dissolved in methanol (15 ml) and a saturated solution of HCl in diethyl ether (100 ml) was added. After stirring at room temperature for 16 h, drying in vacuo and vacuum gave the resultant colorless crystals (2.5 g) containing the hydrochloride of the title compound.
    [243] The following piperazine was prepared analogously:
    [244] L- (l-Benzyl-lH-indol-4-yl) piperazine
    [245] L- (l-Propyl-lH-indol-4-yl) piperazine
    [246] B. Preparation of 4- (1H-indol-4-yl) -1,2,3,6-tetrahydropyridine
    [247] A solution of 4-bromo-1H-indole (36 g) in dimethylformamide (80 ml) was treated with a NaH suspension (60% in mineral oil, 6.9 g) in dimethylformamide (200 ml) at 20 ° C. After stirring for 30 minutes, the mixture was cooled to -10 C, treated with t-butyldimethylsilyl chloride (38 g), and then stirred at room temperature for 1 hour. Standard work-up with ethyl acetate gave an oil which was purified by flash chromatography to give 4-bromo-1- (tert-butyldimethylsilyl) -1H-indole (38 g) as a crystalline material.
    [248] The product was dissolved in dry tetrahydrofuran (500 ml), cooled to -78 캜, and 1.6 M BuLi in hexane (154 ml) was added dropwise. After stirring at -78 ° C for 30 minutes, a solution of 1-carbethoxy-4-piperidone (18.2 ml) in tetrahydrofuran (200 ml) was added dropwise and the mixture was stirred for 16 hours did. Standard work-up with diethyl ether yielded an oil which was purified by flash chromatography (eluent: heptane / ethyl acetate / triethylamine 6: 3: 1) to give 1- (tert- butyldimethylsilyl) -4- (1-carbethoxy-4-hydroxy-4-piperidinyl) -1H-indole (20.5 g).
    [249] This product was treated with trifluoroacetic acid (15 ml) in methylene chloride (250 ml) at 0 ° C for 20-30 minutes (the reaction was then treated with a thin layer of silica gel eluting with ethyl acetate / heptane / triethylamine 10: 9: Chromatography). 2M sodium hydroxide was added and the organic layer was separated, dried and the solvent removed in vacuo to give an oil which was purified by flash chromatography (eluting as described above for TLC) as a crystalline material (1H-indol-4-yl) -1,2,3,6-tetrahydropyridine (9.1 g) was obtained.
    [250] Was treated with potassium hydroxide (5 g) in ethanol (150 ml) with a small amount of water at reflux for 3 days and after standard workup the title compound (4.5 g) was obtained as a yellow oil.
    [251] C. Preparation of 5-fluorobenzofuran-3-acetic acid
    [252] A solution of 5-fluorobenzofuran-3-carboxylic acid (56 g) in methanol (600 ml) and saturated solution of hydrogen chloride gas (300 ml) was stirred at room temperature for 16 hours. Additional etheric HCl (300 ml) was added, followed by stirring for 24 hours. And concentrated in vacuo to give a dark crystalline material, methyl 5-fluorobenzofuran-3-carboxylate (58 g).
    [253] Lithium aluminum hydride (15 g) was suspended in tetrahydrofuran (400 ml) under nitrogen atmosphere, followed by dropwise addition of a solution of methyl 5-fluorobenzofuran-3-carboxylate (58 g) in tetrahydrofuran He said. The temperature was increased to 55 ° C during the addition. After stirring for 2 h, the reaction was washed sequentially with water (30 ml), 15% aqueous sodium hydroxide (15 ml), and water (75 ml). Tetrahydrofuran (500 ml) was further added, and the mixture was stirred for 1 hour. The mixture was filtered and the precipitate was extracted using a mixture of methylene chloride (1 L) and ethanol (0.5 L). The combined organic layers were concentrated in vacuo to obtain an oil, which was subjected to silica gel property chromatography (eluent: methylene chloride / 25% aqueous NH 3 99: 1). The resulting yellow oil, 5-fluorobenzofuran-3-ylmethanol (14.4 g) was crystallized.
    [254] A solution of 5-fluorobenzofuran-3-ylmethanol (14 g) in methylene chloride (250 ml) was successively treated with 5 drops of dimethylformamide and thienyl chloride (28 ml). After stirring at room temperature for 16 h, the reaction was concentrated in vacuo to give 3-chloromethyl-5-fluorobenzofuran (19.4 g) as an oil.
    [255] A suspension of sodium cyanide (10 g) in dimethyl sulfoxide (150 ml) was heated to 80 ° C and then a solution of 3-chloromethyl-5-fluorobenzofurane (10 g) in dimethylsulfoxide (50 ml) was added rapidly. The mixture was kept at 80 DEG C for 30 minutes and then followed by ice. Standard work-up with diethyl ether yielded a dark crystalline material, 5-fluorobenzofuran-3-yl acetonitrile (8.8 g).
    [256] A solution of 5-fluorobenzofuran-3-yl acetonitrile (8.8 g) in methanol (350 ml) was treated with saturated solution of hydrogen chloride (350 ml) and stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and standard work-up with diethyl ether / water to give 5-fluorobenzofuran-3-yl acetate as an oil.
    [257] The obtained methyl ether was dissolved in methanol (200 ml), 6M aqueous sodium hydroxide (400 ml) was added, and then the mixture was stirred at room temperature for 16 hours. The organic solvent was removed in vacuo and then acidified with 6M hydrochloric acid. Standard work-up with ethyl acetate gave 5-fluorobenzofuran-3-ylacetic acid (9.2 g) as a crystalline material.
    [258] The following benzofuran-3-acetic acid was prepared analogously:
    [259] 2-Methyl-4,5,6,7-tetrafuran [0157] Benzofuran-3-acetic acid
    [260] Benzofuran-3-acetic acid
    [261] 6-methylbenzofuran-3-acetic acid
    [262] 5-methylbenzofuran-3-acetic acid
    [263] 4-methylbenzofuran-3-acetic acid
    [264] 7-chlorobenzofuran-3-acetic acid
    [265] 5-chlorobenzofuran-3-acetic acid
    [266] 5-Fluorobenzofuran-3-propionic acid and -butanoic acid were prepared by a chain extension procedure analogous to the procedure described above, respectively.
    [267] 6-chloroindazol-3-acetic acid was prepared according to J. Med. Chem. 35 (1922) 2155.
    [268] 3- (6-Fluorobenz [l, 2] isoxazol-3-yl) propionic acid was obtained from Drug Design Discov. 8 (1992) 225.
    [269] Preparation of the compounds of the invention
    [270] (Example 1)
    [271] 1a. 1- (2- (3-benzofuranyl) ethyl) -4- (1H-indol-4-yl) piperazine, oxalate
    [272] 2- (3-benzofuranyl) acetic acid (0.95 g), l- (lH-indol-4-yl) piperazine (1.3 g) in a mixture of dry tetrahydrofuran (50 ml) and dry dimethylformamide (10 ml) And N, N-dicyclohexylcarbodiimide (1.3 g) was stirred at room temperature for 16 hours. Filtration and removal of the solvent in vacuo gave an oil which was purified by flash chromatography (eluent: ethyl acetate / heptane / triethylamine 10: 9: 1) to give 1- (3-benzofuranyl) methyl Carbonyl-4- (1H-indol-4-yl) piperazine (0.5 g).
    [273] The oil was dissolved in tetrahydrofuran (20 ml) and treated with a suspension of lithium aluminum hydride (0.26 g) in tetrahydrofuran (20 ml) at room temperature and under nitrogen atmosphere and then refluxed for 4 hours. The reaction mixture was cooled to 0 C and treated sequentially with water (1 ml), 15% aqueous sodium hydroxide (0.5 ml), and water (2.5 ml). After stirring for 30 minutes, the mixture was filtered and concentrated. The remaining oil was dissolved in acetone, followed by addition of oxalic acid and filtration to give the title compound (0.4 g) as a crystalline material.
    [274]
    [275] The following compounds were prepared analogously:
    [276] 1b. 1- (3-benzofuranylmethyl) -4- (1H-indol-4-yl) piperazine, oxalate.
    [277]
    [278] 1c. 1- (2- (5-Fluoro-3-benzofuranyl) ethyl) -4- (1H-indol-4-yl) piperazine, oxalate.
    [279]
    [280] 1d. 1- (4- (5-Fluoro-3-benzofuranyl-1-butyl) -4- (lH-indol-4-yl) -piperazine, dihydrochloride.
    [281]
    [282] 1e. 1- (2- (1H-indol-3-yl) ethyl-4- (1H-indol-4-yl) piperazine, hemioxalate.
    [283]
    [284] 1f. 1- (3- (lH-indol-3-yl) -1-propyl) -4- (lH-indol-4-yl) piperazine, oxalate.
    [285]
    [286] 1g. 1- (4-1H-indol-3-yl) -1-butyl) -4- (lH-indol-4-yl) piperazine oxalate.
    [287]
    [288] 1H. 1- (3- (5-Fluoro-3-benzofuranyl) -1-propyl) -4- (1H-indol-4-yl) piperazine, dihydrochloride.
    [289]
    [290] 1i. 1- (2- (2-methyl-4,5,6,7-tetrafluoro-3-benzofuranyl) ethyl) -4- (1H-indol-4-yl) piperazine, dihydrochloride.
    [291]
    [292] 1j. 1- (2- (3-indazolyl) ethyl) -4- (1H-indol-4-yl) piperazine, oxalate.
    [293]
    [294] 1k. 1- (2- (6-Chloro-3-indazolyl) ethyl) -4- (1H-indol-4-yl) piperazine, oxalate.
    [295]
    [296] 1 l. 1- (2- (7-Cyano-1H-indol-3-yl) ethyl) -4- (1H-indol-4-yl) piperazine, oxalate.
    [297]
    [298] (Example 2)
    [299] 2a. 1- (2- (6-Chloro-lH-indol-3-yl) ethyl) -4- (lH-indol-4-yl) piperazine oxalate.
    [300] A solution of 6-chloro-lH-indole (15 ml) in diethyl ether (300 ml) was cooled to 0 C and treated with a solution of oxalyl chloride (9.4 ml) in diethyl ether (30 ml). The mixture was stirred at room temperature for 16 hours. Filtration afforded 2- (6-chloro-lH-indol-3-yl) -2-oxoacetyl chloride (15.5 g) as a crystalline material.
    [301] A portion of this product (2.5 g) was dissolved in dry tetrahydrofuran (25 ml) and a solution of l- (lH-indol-4-yl) piperazine (1.4 g) and triethylamine ) Was added dropwise. After stirring for 16 hours, the reaction mixture was concentrated in vacuo. The remaining oil was purified by flash chromatography (eluent: ethyl acetate / methanol / triethylamine 85: 10: 5) to give 1- (2- (6- chloro-lH-indol- (1,2-dioxoethyl) -4- (1H-indol-4-yl) piperazine (1.6 g). This product was suspended in tetrahydrofuran (25 ml), and a suspension of lithium aluminum hydride (1.5 g) in tetrahydrofuran (50 ml) was added dropwise. The mixture was refluxed for 4 hours, cooled to 0 C and then water (3 ml), 15% aqueous sodium hydroxide (1.5 ml) and water (7.5 ml) were added in turn. Filtration and standard work-up afforded a yellow oil which was converted to the title oxalate salt (1.5 g) from an acetone solution by the addition of oxalic acid.
    [302]
    [303] The following compounds were prepared analogously:
    [304] 2b. 1- (2- (4-Chloro-lH-indol-3-yl) ethyl) -4- (lH-indol-4-yl) piperazine, oxalate.
    [305]
    [306] 2c. 1- (2- (5-Fluoro-lH-indol-3-yl) ethyl) -4- (lH-indol-4-yl) piperazine, fumarate.
    [307]
    [308] 2g. 1- (2- (6-Chloro-lH-indol-3-yl) ethyl) -4- (lH-indol-4-yl) 1,2,3,6-tetrahydropyridine, 1.5 fumarate.
    [309]
    [310] 2h. 1- (2- (5-fluoro-1H-indol-3-yl) ethyl) -4- (1H-indol-4-yl) -1,2,3,6-tetrahydropyridine, tripurmate.
    [311]
    [312] 2i. 1- (2- (7-bromo-1H-indol-3-yl) ethyl) -4- (1H-indol-4-yl) piperazine, hemioxalate.
    [313]
    [314] 2j. L- (l-allyl-lH-indol-4-yl) -4- (2- (6-chloro-lH-indol-3-yl) ethyl) piperazine, fumarate.
    [315]
    [316] 2k. L- (l-allyl- lH-indol-4-yl) -4- (2- (5-fluoro-lH-indol-3-yl) ethyl) piperazine, 1.25 fumarate.
    [317]
    [318] 2l. 1- (l-Benzyl-lH-indol-4-yl) -4- (2- (6-chloro-lH-indol-3-yl) ethyl) piperazine, hemifumarate.
    [319]
    [320] 2m. L- (l-Benzyl-lH-indol-4-yl) -4- (2-5-fluoro-lH-indol-3-yl) ethyl) piperazine, fumarate.
    [321]
    [322] 2n. 1- (l-Benzyl-lH-indol-4-yl) -4- (2- (5-bromo-lH-indol-3-yl) ethyl) piperazine, fumarate.
    [323]
    [324]
    [325] 2o. 1- (2- (6-Chloro-lH-indol-3-yl) ethyl) -4- (l-propargyl-lH-indol-4-yl) piperazine.
    [326]
    [327] 2p. 1- (2- (lH-indol-3-yl) ethyl) -4- (l-propargyl-lH-indol-4-yl) piperazine, hemifumarate.
    [328]
    [329] 2q. 1- (2- (5-Fluoro-lH-indol-3-yl) ethyl) -4- (l-propargyl-lH-indol-4-yl) piperazine.
    [330]
    [331] 2r. 1- (2- (5-Bromo-1 H-indol-3-yl) ethyl) -4- (l-propargyl-lH-indol-4-yl) piperazine.
    [332]
    [333] 2s. 1- (l-Benzyl-lH-indol-4-yl) -4- (2- (lH-indol-3-yl) ethyl) piperazine, hemifumarate.
    [334]
    [335] 2t. 1- (2- (5-Bromo-1 H-indol-3-yl) ethyl) -4- (1H-indol-5-yl) piperazine, fumarate.
    [336]
    [337] 2u. 1- (2- (5-chloro-lH-indol-3-yl) ethyl) -4- (lH-indol-5-yl) piperazine, hemifumarate.
    [338]
    [339] (Example 3)
    [340] 3a. 1- (2- (5-Fluoro-lH-indol-3-yl) ethyl) -4- (6-hydroxymethyl-lH-indol-4-yl) piperazine.
    [341] (5-fluoro-lH-indol-3-yl) -1,2-dioxoethyl) -4- (6- methoxycarbonyl- (5-fluoro-lH-indol-3-yl) -2-oxoacetyl chloride and 1- (6-methoxycarb Yl) piperazine was added dropwise to a suspension of lithium aluminum hydride (1.7 g) in tetrahydrofuran (125 ml) at room temperature, and the mixture was refluxed for 4 hours.
    [342] The reaction mixture was cooled to 5 C and then water (3.4 ml), 15% aqueous sodium hydroxide (1.7 ml), and water (8.5 ml) were added in turn. Filtration and removal of the solvent in vacuo gave an oil which was purified by flash chromatography (eluent: ethyl acetate / methanol / triethylamine 85: 10: 5) to give the title compound (0.9 g) Crystallization with isopropyl ether.
    [343]
    [344] The following compounds were prepared analogously:
    [345] 3b. 1- (2- (6-Chloro-lH-indol-3-yl) ethyl) -4- (6-hydroxymethyl-lH-indol-4-yl) piperazine.
    [346]
    [347] 3c. 1- (2- (5-Bromo-1 H-indol-3-yl) ethyl) -4- (6-hydroxymethyl-1 H-indol-4-yl) piperazine.
    [348]
    [349] (Example 4)
    [350] 4a. 1- (3- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-propyl) -4- (1H-indol-4-yl) piperazine fumarate.
    [351] To a solution of 3- (3-bromo-1-propyl) -6-fluoro-1,2-benzisoxazole (1.1 g), 1- (1H- -Yl) piperazine (1.0 g), potassium carbonate (1.9 g), and potassium iodide (50 mg) was refluxed for 16 hours. Filtration and removal of the solvent in vacuo yielded an oil which was purified by flash chromatography (eluent: heptane / ethyl acetate / triethylamine 75: 20: 5) to give an oil, which was dissolved in acetone The title fumarate was crystallized.
    [352]
    [353] The following compounds were prepared analogously:
    [354] 4f. 1- (2-1H-Indol-3-yl) ethyl) -4- (6-methoxycarbonyl-lH-indol-4-yl) piperazine oxalate.
    [355]
    [356] 4g. 1- (2- (6-Chloro-lH-indol-3-yl) ethyl) -4- (6-methoxycarbonyl-lH-indol-4-yl) piperazine oxalate.
    [357]
    [358] 4h. 1- (2- (5-Fluoro-3-benzofuranyl) ethyl) -4- (6-methoxycarbonyl-1H-indol-4-yl) piperazine, oxalate.
    [359]
    [360] 4l. 1- (5-Fluoro-3-benzofuranylmethyl) -4- (1H-indol-4-yl) piperazine, dihydrochloride.
    [361]
    [362] 4m. 1- (3-Cyano-lH-indol-4-yl) -4- (2- (lH-indol-3-yl) ethyl) piperazine, fumarate.
    [363]
    [364] 4n. 1- (3-Cyano-1H-indol-4-yl) -4- (2- (5-fluoro-3-benzofuranyl) ethyl) piperazine, hemifumarate.
    [365]
    [366]
    [367] 4o. 1- (2- (6-Chloro-lH-indol-3-yl) ethyl) -4- (3-cyano-lH-indol-4-yl) piperazine, hemifumarate.
    [368]
    [369] 4p. 1- (2- (3-benzofuranyl) ethyl) -4- (3-cyano-lH-indol-4-yl) piperazine, sesquioxalate.
    [370]
    [371] 4q. 1- (1H-Indol-4-yl) -4- (2- (5-methyl-3-benzofuranyl) ethyl) piperazine hydrochloride.
    [372]
    [373] 4r. 1- (1H-Indole-4-yl) -4- (2- (4-methyl-3-benzofuranyl) ethyl) piperazine, oxalate.
    [374]
    [375] 4s. 1- (3- (5-Fluoro-3-benzofuranyl) -1-propyl) -4- (1H-indol-4-yl) -1,2,3,6-tetrahydropyridine, fumarate.
    [376]
    [377]
    [378] 4t. 1- (2- (5-Chloro-3-benzofuranyl) ethyl) -4- (lH-indol-4-yl) piperazine, oxalate.
    [379]
    [380] 4u. 1- (1H-Indole-4-yl) -4- (2- (6-methyl-3-benzofuranyl) ethyl) piperazine oxalate.
    [381]
    [382] 4v. 1- (2- (7-chloro-3-benzofuranyl) ethyl) -4- (1H-indol-4-yl) piperazine, hemioxalate.
    [383]
    [384] 4x. 1- (2- (4-Chloro-lH-indol-3-yl) ethyl) -4- (3-cyano-lH-indol-4-yl) piperazine, hemifumarate.
    [385]
    [386] (Example 5)
    [387] 5a. 1- (2- (6-Chloro-lH-indol-3-yl) -4- (lH-indol-4-yl) piperazine.
    [388] A solution of 2 g (0.5 g) of the compound was dissolved in cold acetic acid. Platinum catalyst (10% on charcoal, 10 mg) was added and the mixture was hydrogenated in a Parr apparatus under hydrogen atmosphere at 3 atm for 16 hours. Filtration and removal of the solvent gave the title compound (0.4 g) as a crystalline material.
    [389]
    [390] Pharmaceutical test
    [391] 5-HT 1A to measure the affinity of the compounds of this invention in the 5-HT 1A receptors as described in the test below receptor by measuring the inhibition of the binding of the radioligand.
    [392] Human 5-HT 1AAt the receptor 3Inhibition of H-5-CT binding
    [393] By this method, the HeLa cells trans Defect (HA7) (Fargin, A. et al, J. Biol. Chem., 1989, 264, 14848) 5- in the stably expressing the cloned human 5-HT 1A receptors in HT 1A agonist The inhibition by the drug on the binding of 3 H-5-carboxamidotrytamine ( 3 H-5-CT) was measured in vitro. Human 5-HT 1A receptor (40 세포 g of cell homogenate) was incubated in 50 mM Tris buffer (pH 7.7) in the presence of 3H-5-CT and 37 째 C for 15 minutes. Non-specific binding was measured by inclusion of 10 [mu] M methgergolin. The reaction was terminated by fast filtration through a TomtecCell Harvester Unifilter GF / B filter. The filter was counted in the Packard Top Counter. The obtained results are shown in Table 1.
    [394]
    [395] The compounds of the present invention were also tested for their effect on serotonin reuptake by the following test.
    [396] In rat brain synaptosomes 3Inhibition of H-5-HT reabsorption
    [397] Using this method, the ability of the drug to inhibit the accumulation of 3 H-5-HT in whole rat brain synaptosomes was measured in vitro. The assays were performed as described by Hyttel, J., Psychopharmacology 1978 , 60 ,
    [398]
    [399] The 5-HT 1A antagonistic activity of some of the compounds of the invention was evaluated in vitro in stably expressed cloned 5-HT 1A receptors in transfected HeLa cells (HA 7). In this test, the 5-HT 1A antagonistic activity was evaluated by measuring the ability of the compound to antagonize 5-HT induction of forskolin-induced cAMP accumulation. Pauwels, PJ et al., Biochem. Pharmacol . 1993 , 45 , 375.
    [400] Some of the compounds of the present invention are also described in Sanchez. C., et al., Eur. J. Pharmacol. , 1996 , 315 , pp. 245, were tested in vivo for effects on 5-HT 1A receptors. In this test, the antagonistic effect of the test compound was determined by measuring the ability of the test compound to inhibit 5-MeO-DMT induced 5-HT syndrome.
    [401] The compounds of the present invention have activity useful as serotonin reuptake inhibitors and have an antagonistic effect at the 5-HT 1A receptor. Thus, the compounds of the present invention are believed to be useful in the treatment of diseases and disorders responsive to inhibition of serotonin reuptake and antagonistic activity at the 5-HT 1A receptor. Diseases responsive to inhibition of serotonin reuptake are well known to those skilled in the art and include emotional disorders such as depression, psychosis, generalized anxiety disorder and anxiety disorders including panic disorder, obsessive-compulsive disorder, and the like.
    [402] As described above, the antagonistic activity of the compounds of the present invention at the 5-HT 1A receptor is expected to counterbalance the negative feedback mechanism induced by inhibition of serotonin reuptake. Thus, antagonistic activity at the 5-HT 1A receptor is expected to improve the effect of the compounds of the present invention on the serotonin reuptake inhibitory activity.
    [403] Thus, it is believed that the compounds as claimed herein will be useful as agents of rapid onset for the treatment of depression. Compounds may also be useful for the treatment of depression that does not respond to currently available SSRIs.
    [404] Pharmaceutical product
    [405] The pharmaceutical preparations of the present invention can be prepared by conventional methods in the art. For example: tablets may be prepared by mixing the active ingredient with ordinary adjuvants and / or diluents and then squeezing the mixture in a conventional tabletting machine. Examples of adjuvants or diluents include corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gum and the like. Any other adjuvant or diluent that is compatible with the active ingredient, usually used for purposes such as coloration, aroma, preservative, etc., may be used.
    [406] The injectable solution is prepared by dissolving the active ingredient and possibly additives in a part of the injectable solvent, preferably sterile water, adjusting the solution to the desired volume, disinfecting the solution, and filling into a suitable ampoule or vial. Any suitable additive conventionally used in the art, such as tonicity agents, preservatives, antioxidants, and the like, may be added.
    [407] The pharmaceutical compositions of the present invention or those made according to the present invention may be administered by any suitable route, for example, tablets, capsules, powders, syrups, etc., orally, or by injection, in the form of injectable solutions. In preparing such compositions, methods well known in the art may be used, and any pharmaceutically acceptable carriers, diluents, excipients, or other additives commonly used in the art may be used.
    [408] Conveniently, the compounds of the present invention are administered in unit dose form containing the compound in an amount of from about 0.01 mg to about 100 mg. The total daily dose is usually in the range of about 0.05-500 mg, most preferably about 0.1-50 mg of the active compound of the present invention.
    权利要求:
    Claims (18)
    [1" claim-type="Currently amended] 4-, 5-, 6-, or 7-indole or indoline derivatives substituted with A of formula I, or acid addition salts thereof.
    (I)

    Wherein W is N, C, CH or COH, the dotted line represents a selective bond,
    Wherein A is a group having formula (IIA);
    (IIA)

    (In the formula, X is CR 1A, 1A CHR, N, NR 1B, O, or S, where R 1A is as defined for R 3 -R 9 below, R 1B R 10 is below Lt; / RTI >
    Y is CR 2A, CHR 2A, N, NR 2B, O, or S, where R 2A is as defined for R 3 -R 9 below, R 2B are as defined for R 10 below Is the same; And
    The dotted line represents a selective bond;
    X and Y are not both O or S)
    A is a group having the formula IIB; or
    (IIB)

    (In the formula, X is CR 1A, 1A CHR, N, NR 1B, O, or S, where R 1A is as defined for R 3 -R 9 below, R 1B R 10 is below Lt; / RTI >
    U is C, CH, or N; And
    The dotted line represents an optional bond)
    A is a group having the formula IIC;
    (IIC)

    Wherein U is C, CH, or N;
    Y is CR 2A, CHR 2A, N, NR 2B, O, or S, where R 2A is as defined for R 3 -R 9 below, R 2B are as defined for R 10 below Is the same; And
    The dotted line represents an optional bond)
    n is 0, 1, 2, 3, 4, or 5, and m is 0, 1, 2, 3, 4, or 5;
    Z is CH 2 , O, S, CO, SO, or SO 2 , and when n is 0, Z is CH 2 ;
    R 3 -R 9 and R 11 -R 12 are selected from the group consisting of hydrogen, halogen, cyano, nitro, C 1-6 -alk (in / phosphorus) yl, C 1-6 -alkoxy, C 1-6 -alkylthio, hydroxy, hydroxy -C 1-6 - alkyl, C 1-6 - alkoxycarbonyl, C 3-8 - cycloalkyl alk (en) yl, C 3-8 - cycloalkyl alk (en) yl -C 1-6 - alk (en / in) yl, C 1-6 - alkyl-carbonyl, phenyl-carbonyl, halogen substituted phenyl carbonyl as methylsulfonyl, methyl, trifluoromethyl trifluoromethyl sulfonyl oxy, C 1-6 - alkylsulfonyloxy, ≪ / RTI > aryl and heteroaryl,
    And / or two adjacent groups taken from R < 3 > -R < 9 > may together form a methylenedioxy group,
    And / or two adjacent groups R 7 -R 9 together may form a cyclopentyl or cyclohexyl ring which may be substituted with one or more methyl groups,
    And / or one of R 3 -R 9 may also be a -NR 13 R 14 group, wherein R 13 is as defined for R 10 below and R 14 is hydrogen, C 1-6 -alk / in) yl, C 3-8 - cycloalkyl alk (en) yl, C 3-8 - cycloalkyl alk (en) yl -C 1-6 - alk (en / in) yl, aryl, heteroaryl, aryl, -C 1-6 -alkyl, or heteroaryl-Ci- 6 -alkyl;
    R 10 is
    Hydrogen, C 1-6 - alk (en / in) yl, C 3-8 - cycloalkyl alk (en) yl, C 3-8 - cycloalkyl alk (en) yl -C 1-6 - alk (en / in) Aryl, heteroaryl, aryl-C 1-6 -alkyl, heteroaryl-C 1-6 -alkyl, acyl, thioacyl, C 1-6 -alkylsulfonyl, trifluoromethylsulfonyl, arylsulfonyl , Or heteroarylsulfonyl;
    R 15 VCO-, wherein V is O or S and R 15 is C 1-6 -alk (en / in), C 3-8 -cycloalk (en) yl, C 3-8 -cycloalk En-yl-C 1-6 -alk (en / in), aryl, or heteroaryl; or
    R 16 R 17 NCO- or R 16 R 17 NCS- group wherein R 16 and R 17 are independently selected from the group consisting of hydrogen, C 1-6 -alk (en / in), C 3-8 -cycloalk (En / yn) yl, heteroaryl, or aryl, or R 16 and R 17 are independently selected from C 3-8 -cycloalk (en) yl-C 1-6 -alk To form a pyrrolidinyl, piperidinyl, morpholinyl, or perhydroazepine group,
    [2" claim-type="Currently amended] 2. A compound according to claim 1, wherein A is a group having the formula (IIA).
    (IIA)

    Wherein X, Y, the dotted line and R 3 -R 6 are as defined in claim 1,
    [3" claim-type="Currently amended] 3. The compound according to claim 2, wherein A is a group represented by the formula

    ≪ / RTI >
    (Wherein R < 3 > -R < 6 > and the dotted line are as defined in claim 2)
    [4" claim-type="Currently amended] 4. The compound according to claim 3,

    ≪ / RTI >
    (Wherein R < 3 > -R < 6 > and the dotted line are as defined in claim 3)
    [5" claim-type="Currently amended] 2. A compound according to claim 1 having the formula II.
    (II)

    Wherein R 7 -R 12 , W, A, Z, n, m and the dotted line are as defined in claim 1,
    [6" claim-type="Currently amended] 6. Compounds according to any one of claims 1 to 5, wherein Z is CH 2 and n + m is 0, 1, 2, 3, 4, 5 or 6.
    [7" claim-type="Currently amended] 7. Compounds according to any one of claims 1 to 6, wherein W is N.
    [8" claim-type="Currently amended] 2. A compound according to claim 1 having the formula II.
    (II)

    Wherein R 7 -R 12 , W, Z, n, m and the dotted line are as defined in claim 1, and A is a group having the formula
    (IIA)

    (Wherein X, Y, the dotted line and R 3 -R 6 are as defined in claim 1)
    [9" claim-type="Currently amended] 9. A compound according to claim 8,

    ≪ / RTI >
    (Wherein R < 3 > -R < 6 > and the dotted line are as defined in claim 8)
    [10" claim-type="Currently amended] 10. Compounds of formula I according to claim 9,

    ≪ / RTI >
    (Wherein R < 3 > -R < 6 > and the dotted line are as defined in claim 9)
    [11" claim-type="Currently amended] 11. Compounds according to any one of claims 1 to 10, wherein Z is CH 2 , n + m is 0, 1, 2, 3, 4, 5 or 6, R 3 -R 9 and R 11 -R 12 is hydrogen, halogen, cyano, nitro, C 1-6 - alkyl, C 1-6 - alkoxy, hydroxy, hydroxy -C 1-6 - alkyl, C 1-6 - alkoxycarbonyl and trifluoromethyl and , And R < 10 > is hydrogen.
    [12" claim-type="Currently amended] A compound according to any one of claims 8 to 11, wherein W is N.
    [13" claim-type="Currently amended] 2. The compound according to claim 1, wherein the compound is
    1- (2- (3-benzofuranyl) ethyl) -4- (1H-indol-4-yl) piperazine,
    1- (3-benzofuranylmethyl) -4- (1H-indol-4-yl) piperazine,
    1- (2- (5-fluoro-3-benzofuranyl) ethyl) -4- (lH-indol-4- yl) piperazine,
    1- (4- (5-fluoro-3-benzofuranyl) -1-butyl) -4- (lH-indol-
    1- (2- (lH-indol-3-yl) ethyl) -4- (lH-indol-4- yl) piperazine,
    1- (3- (lH-indol-3-yl) -1-propyl) -4- (lH-indol-
    1- (4- (1H-indol-3-yl) -1-butyl) -4- (1H-
    1- (3- (5-fluoro-3-benzofuranyl) -l-propyl) -4- (lH-indol-
    (2- (2-methyl-4,5,6,7-tetrafluoro-3-benzofuranyl) ethyl) -4- (1H-
    1- (2- (3-indazolyl) ethyl) -4- (lH-indol-4- yl) piperazine,
    1- (2- (6-Chloro-3-indazolyl) ethyl) -4- (lH-indol-4- yl) piperazine,
    L- (2- (7-Cyano-lH-indol-3-yl) ethyl) -4- (lH-
    L- (2- (6-chloro-lH-indol-3-yl) ethyl) -4- (lH-indol-
    L- (2- (4-chloro-lH-indol-3-yl) ethyl) -4- (lH-indol-
    (2- (5-fluoro-lH-indol-3-yl) ethyl) -4- (lH-
    4- (1H-indol-4-yl) -1,2,3,6-tetrahydropyridine,
    4- (1H-indol-4-yl) -1,2,3,6-tetrahydropyridine,
    L- (2- (7-Bromo-lH-indol-3-yl) ethyl) -4- (lH-indol-
    L- (l-allyl-lH-indol-4-yl) -4-
    Yl) -4- (2- (5-fluoro-lH-indol-3-yl) ethyl) piperazine,
    (L- (6-chloro-lH-indol-3-yl) ethyl) piperazine,
    (L-benzyl-lH-indol-4-yl) -4-
    (L-benzyl-lH-indol-4-yl) -4-
    L- (2- (6-chloro-lH-indol-3-yl) ethyl) -4- (l-
    L- (2- (lH-indol-3-yl) ethyl) -4- (1-propargyl-lH-indol-
    L- (2- (5-fluoro-lH-indol-3-yl) ethyl) -4- (l-propargyl-
    1 - (2- (5-Bromo-1 H-indol-3-yl) ethyl) -4- (1-propargyl-
    4- (2- (lH-indol-3-yl) ethyl) piperazine, l-
    (2- (5-bromo-1H-indol-3-yl) ethyl) -4- (lH- indol-
    L- (2- (5-chloro-lH-indol-3-yl) ethyl) -4- (lH- indol-
    4- (6-hydroxymethyl-1 H-indol-4-yl) piperazine,
    4- (6-hydroxymethyl-1 H-indol-4-yl) piperazine,
    4- (6-hydroxymethyl-1 H-indol-4-yl) piperazine,
    1- (3- (6-fluoro-1,2-benzisoxazol-3-yl)
    1- (2- (lH-indol-3-yl) ethyl) -4- (6-methoxycarbonyl-lH-indol-
    4- (6-methoxycarbonyl-lH-indol-4-yl) piperazine,
    1- (2- (5-Fluoro-3-benzofuranyl) ethyl) -4- (6-methoxycarbonyl-lH-indol-
    (5-fluoro-3-benzofuranylmethyl) -4- (lH-indol-4-yl) piperazine,
    (3-cyano-lH-indol-4-yl) -4- (2- (lH-
    4- (2- (5-fluoro-3-benzofuranyl) ethyl) piperazine,
    4- (3-cyano-lH-indol-4-yl) piperazine,
    L- (2- (3-benzofuranyl) ethyl) -4- (3-cyano-lH-indol-4- yl) piperazine,
    4- (2- (5-methyl-3-benzofuranyl) ethyl) piperazine,
    4- (2- (4-methyl-3-benzofuranyl) ethyl) piperazine,
    Propyl) -4- (1H-indol-4-yl) -1,2,3,6-tetrahydropyridine,
    1- (2- (5-chloro-3-benzofuranyl) ethyl) -4- (lH-indol-4- yl) piperazine,
    4- (2- (6-methyl-3-benzofuranyl) ethyl) piperazine,
    1- (2- (7-chloro-3-benzofuranyl) ethyl) -4- (lH-indol-4- yl) piperazine,
    4- (3-cyano-lH-indol-4-yl) piperazine,
    (2- (6-chloro-lH-indol-3-yl) -4- (lH- indol- 4- yl) piperidine,
    (2- (5-chloro-lH-indol-3-yl) ethyl) -4- (lH-
    L- (2- (7-Bromo-lH-indol-3-yl) ethyl) -4- (lH-indol-
    L- (2- (4-chloro-lH-indol-3-yl) ethyl) -4- (lH-indol-
    4- (lH-indol-4-yl) piperazine, l- (2-
    4- (2- (5-methyl-lH-indol-3-yl) ethyl) piperazine,
    4- (2- (6-methyl-lH-indol-3-yl) ethyl) piperazine,
    4- (2- (7-methyl-lH-indol-3-yl) ethyl) piperazine,
    1- (2- (4,5-Dichloro-3-benzofuranyl) ethyl) -4- (lH-indol-4- yl) piperazine,
    1- (2- (5-bromo-3-benzofuranyl) ethyl) -4- (lH-indol-4- yl) piperazine,
    L- (2- (4-chloro-lH-indol-3-yl) ethyl) -4- (lH-indol-
    4-yl) -1- (2- (5-methyl-1H-indol-3-yl) ethyl) piperidine,
    4- (lH-indol-4-yl) -1- (2- (lH-indol-3- yl) ethyl) piperidine,
    4- (3- (4-methyl-3-benzofuranyl) -1-propyl) piperazine,
    4- (1H-indol-4-yl) -1- (3- (4-methyl-3- benzofuranyl)
    1- (3- (4-Chloro-3-benzofuranyl) -l-propyl) -4- (lH-indol-
    4- (6-chloro-lH-indol-4-yl) piperazine,
    4- (6-fluoro-lH-indol-4-yl) piperazine,
    4- (6-cyano-lH-indol-4-yl) piperazine,
    L- (2- (6-chloro-lH-indol-3-yl) ethyl) -4-
    L- (2- (6-chloro-lH-indol-3-yl) ethyl) -4- (7-
    4- (2-cyano-lH-indol-4-yl) piperazine,
    L- (2- (6-chloro-lH-indol-3-yl) ethyl) -4- (lH-indolin-
    L- (2- (6-Chloro-lH-indol-3-yl) ethyl) -4- (lH- indol-6-yl)
    1- (2- (6-chloro-lH-indol-3-yl) ethyl) -4- (lH- indol-
    Lt; RTI ID = 0.0 > pharmaceutically < / RTI > acceptable acid addition salts thereof.
    [14" claim-type="Currently amended] 14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent.
    [15" claim-type="Currently amended] A compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of disorders or diseases responsive to the inhibition of serotonin reuptake and the antagonism of 5-HT 1A receptors ≪ / RTI >
    [16" claim-type="Currently amended] 13. A compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of an emotional disorder such as depression, psychosis, generalized anxiety disorder and anxiety disorder including panic disorder and obsessive compulsive disorder The use of their acid addition salts.
    [17" claim-type="Currently amended] 14. A method of treating a living animal comprising a human, comprising administering to a living animal comprising a human according to any one of claims 1 to 13 or a pharmaceutically acceptable acid addition salt thereof in a therapeutically effective amount. A method for the treatment of disorders or diseases responsive to inhibition of serotonin reuptake and antagonism of the 5-HT 1A receptor.
    [18" claim-type="Currently amended] 13. A method of treating depression, psychosis, generalized anxiety disorder, depression, psychosis, generalized anxiety disorder or depression in a living animal including a human, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable acid addition salt thereof. And anxiety disorders, including panic disorders, and obsessive-compulsive disorders.
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    同族专利:
    公开号 | 公开日
    EA004248B1|2004-02-26|
    US20020128272A1|2002-09-12|
    HK1044339A1|2002-10-18|
    YU78100A|2003-04-30|
    PL344978A1|2001-11-19|
    AR018899A1|2001-12-12|
    EA200100056A1|2001-06-25|
    BR9911843A|2001-03-20|
    CZ20004780A3|2001-08-15|
    CN1336925A|2002-02-20|
    ZA200007157B|2001-11-22|
    US6391882B1|2002-05-21|
    TR200003858T2|2001-06-21|
    SK19412000A3|2001-07-10|
    IS5731A|2000-11-24|
    ID27976A|2001-05-03|
    IL139962D0|2002-02-10|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1998-06-19|Priority to DKPA199800820
    1998-06-19|Priority to DK82098
    1999-06-14|Application filed by 피터슨 존 메이달, 하. 룬트벡 아크티에 셀스카브
    1999-06-14|Priority to PCT/DK1999/000326
    2001-07-28|Publication of KR20010071513A
    优先权:
    申请号 | 申请日 | 专利标题
    DKPA199800820|1998-06-19|
    DK82098|1998-06-19|
    PCT/DK1999/000326|WO1999067237A1|1998-06-19|1999-06-14|4,5,6 and 7-indole and indoline derivatives, their preparation and use|
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