TW200406403A - S-(+)-3-{1-[2-(2,3-dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-6-chloro-1H-indole and acid addition salts thereof - Google Patents

Abstract

The present invention relates to the compound S-(+)-3-[1-[2-(2,3-Dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl]-6-chloro-1H-indole having the formula, or a pharmaceutically acceptable salt thereof and the use thereof for the preparation of a pharmaceutical composition for the treatment diseases and disorders responsive to 5-HT reuptake inhibition and/or diseases and disorders responsive to dopamine D4 receptor antagonism.

Description

200406403 Rose, Description of the invention: [Technical field to which the invention belongs] ⑽Compound η • ⑴⑴ · ⑽, 3_dihydro_iHi di-and earth) ethyl] _3,6-dihydro · 2ΗΙ di-4-yl] _6ι_1Η__, and "Legan's acceptable salts, and their use in the treatment-reuptake inhibition of reactive diseases or disorders and / or dopamine h receptor antagonism." M [PRIOR ART] BACKGROUND OF THE INVENTION The present invention relates to Regarding this compound, it has an antagonistic effect on dopamine receptors and an inhibitory effect on 5-HT reuptake. There is evidence that blocking 5-HT reuptake has antidepressant effects in patients ^ (Montgomery # A. Psychopharmacology The fourth generation of progress ^ ed: Meltzer HY, Raven Press, New York, 1995, PP 1043-1051), and today, for most depression, δ, the standard first-line treatment is 5-HT Reuptake inhibitor therapy (Berman et al., Heart Compilation / Shooting Brain ^ He:

Charney DS, Nestler EJ, Bunney BS, Oxford University

Press, Oxfold, 1999, 31, 419-432). Moreover, it is widely recognized that 5-HT reuptake inhibitors are effective in treating depression (Thase et al., Less expensive, 1996, 53, 777_784). 5-HT reuptake inhibitors can also be used to treat anxiety. Clinical studies have shown that 5-HT reuptake inhibitors have beneficial effects on generalized anxiety (see, for example, Rocca et al., Acta Psychiatr Scand, 1997, 200406403 95, 444-450). It is also widely accepted that 5-HT reuptake inhibitors are effective against panic anxiety / panic disorder (see e.g. Sheehan and

Harnett-Sheehan, / C / y / 7, Milk, 1996, 10, 51-58). The exact efficacy of 5-ΗΤ reuptake inhibitors is also confirmed in OCD (

McDougle, O / eds: Charney DS, Nestler EJ, Bunney BS, Oxford University Press, Oxford, 1999, 37, 5 1 8-533). Accumulated data suggest that the central 5-HT system is involved in the pathogenesis of post-traumatic stress disorder (

Charney Temple people, Lili yw / y, 1993, 50, 295-305). In line with this, '5-HT reuptake inhibitors have been shown to be effective in post-traumatic stress disorder, and these types of agents are often the first line of treatment for this disease (Rothbauni et al. ,, a⑽㈣

Are, 1996, 9, 865-871; Goddard et al., Mental illness, eds: Charney DS, Nestler EJ, Bunney BS?

Oxford University Press, Oxford, 1999, 39, 548-563). Not only that, clinical data indicate that blocking reuptake has a beneficial effect on the treatment of acute stress disorder (Roben et al., Jr Burn Care 1999, 20, 250-258). 5. HT reuptake inhibitors can also be used to treat phobias, especially social phobia / anxiety. Therefore, clinical studies have identified the role of the central 5-ΗΤ system in the physiology of phobias (

Potts et al., / Cavity is referred to as ca /, 1996, 11, Suppl 3, 43-48), and it is widely accepted that 5-HT reuptake inhibitors are effective in the treatment of social fear / anxiety (see for example van den Xin et al. 'Int Chn Psychopharmacol 10', 2, '5-23). 200406403 5-HT reuptake inhibitors are also effective in the treatment of impulse control disorders (Durst et al., Gaz, 2001, 15, 185_195; Honander et al., Psychiatr Clin North Am, ··,

Christenson and Crow, / CV // 7 / ^ 7 仏 5 ", 1996, Suppl 8 42_47). In particular, inhibiting 5-HT reuptake can reduce aggressive behavior, which may be a positive effect derived from serotonic dysfunction, which is related to aggressive behavior against itself or others (review

Walsh & Dman ^ Acta Psychiatr Scand, 2001, 104, 84-91) 〇 Both clinical and preclinical studies indicate that the central 5-HT system is involved in cognitive functions. For example, the damage to the 54-cm tip caused by the drug can be clearly seen from the decrease in the reuptake position of 5-HT, which has been implicated in the memory loss of animals and humans (Morgan et al. 30-36). Blockage of 5-HT reuptake has also been shown to improve cognitive function in older patients with depression (Meltzer et al. Neuropsychopharmacology ^ 1998, 18, 407-430). Finally, treatment with agents that increase serotoninic nerve conduction has also been reported to improve cognitive deficits in patients with schizophrenia (Sumiyosn et al., Kung Gong / Li iWy, 2001, 158, 1722-1725) . These findings collectively teach that 5-HT reuptake inhibitors are effective in treating cognitive disorders. 5-HT reuptake inhibitors have previously been described to be effective in treating premenstrual syndromes (see, for example, Enksson et al .: Neuropsychopharmacology ^^ 12? 167.176). Several research results support the identification of serotonin mechanisms involving drug abuse, enhancement of 200406403, and subjective effects (see, for example, W a 1 h h rt? Η · waish and Cunningham, 1997, 13〇, 41_58). Therefore, several human studies have shown that blocking 5-HT reuptake can attenuate the subjective effects of psychomotor stimuli (eg, coca bases) (Walsh et al., / 〇 · 刀 W⑽ 如 凡 1994, 14, 396_4〇 7). 5-h Ding reuptake inhibitors can also be used to treat alcohol abuse (see Sellers et al., / 1991, 52, 49_54). Thus, 5-HT reuptake inhibitors may be beneficial in treating drug abuse. 5-HT reuptake inhibitors have been shown to be effective in the treatment of bulimia nervosa and anorexia nervosa (see Kaye et al., Wanchuan Naikou, 1998, 44, 825-83δ). Clinical studies have indicated that treatment with 5-HT reuptake inhibitors has been shown to be superior to placebo in reducing the frequency of overeating (Goldstein et al., Copies / Public Health, 1995, 166, 660-666). Moreover, published data teaches that fHT reuptake inhibitors can improve outcomes and prevent relapses in people with anorexia nervosa (

Kaye et al., Price 1998, 44, 825-838). Therefore, it seems clear that 5-HT reuptake inhibitors can be used for drug treatment of eating disorders including bulimia and anorexia. Finally, clinical studies have pointed out that the pharmacology of 5-HT reuptake inhibitors has a beneficial role in entering obesity. Because of & treatment with a 5Ητ reuptake inhibitor has been reported to effectively cause obese men and women Significant weight loss (RlCCa et al., / Office C / / from 1996, 19, 727-733 'Lawton et al., And, 1995, 3, 345-356). 5-HT transporter and dopamine A Receptor compound

10 200406403 has a more beneficial effect on depression and negative symptoms in patients with schizophrenia. Case No. W98 / 28293 describes a series of substituted indene or indole compounds having a role at the dopamine receptor. The described compounds are believed to be useful in treating a range of psychiatric and neurological disorders, including the positive and negative symptoms of schizophrenia and other psychiatric disorders. This application contains 3 acridine 1H-D in the form of an oxalate salt of B-do-3-yl) ethyl] -3,6 · dihydro-2H-pyridin-4-yl] -6-chloroport Disclosure of the racemate, and the compounds (+) and hydrazone, which are closely related to it and have an ethylamidine group instead of hydrogen at position 1, of the 2,3-dihydroindole. Today we have found that +) [Bu [2 gas 2% dihydro] H-indol-3-yl) ethyl] -3,6 · dihydro-2H-pyridyl] j chloride_ΙΗ- 昭Udo and its pharmaceutically acceptable salts have an effective 5-HT reuptake inhibitory effect in addition to its effect on the dopamine D4 receptor.

CI \) / We have also found that this compound is compared with its corresponding compound having an acetamidine group at position 1, 2, dihydro-chaotuo; 5-image isomers (ie, the above-mentioned (+)-Mirror image isomers) have more ideal properties for pharmaceutical use. 200406403 For example, compared with 2,3_dichloral pain, it has the corresponding s & yl group at position 1 Half-life and distribution volume of mirror isomers, tritiated. The half-life of the substance in the human body seems to be longer, and the volume of distribution in the human body seems to be smaller. The results of these studies indicate that the compounds of the present invention have better stability in vivo. Furthermore, the compounds of the present invention are based on 2,3-dihydro. The number 3 position has the corresponding 3_mirror isomer of the ethyl alcohol group in the human body's metabolite '. Therefore, it is more convenient to use the compound of the present invention for pharmaceutical production. In vitro studies have shown that the dopamine receptor is a xiaodao transporter. This compound is more effective than its corresponding racemate and its corresponding S_ mirror image isomer with acetamidine at the 2,3 dihydro__ position. Is effective. : Only so, preliminary research points out that the compound is a safe drug for use. [Summary of the Invention] SUMMARY OF THE INVENTION Therefore, the present invention relates to a compound having the following chemical formula (+ \ ο Γι, compound S-4 '^ ⑽, 3 · dihydro · 1Η · horor_3_yl) ethyl] _3,6 ^ Benzene, chloro-1, -indole or a pharmaceutically acceptable salt thereof, and its use for 5-QT reuptake to inhibit reactive diseases and disorders.

Η (I) 12 200406403 The compound can also be used to treat dopamine D4 receptor antagonistic disease or disorder. 5-HT reuptake inhibitory reactive diseases and disorders are snoring, dysentery, and other affective disorders, including generalized anxiety disorder: panic disorder, obsessive-compulsive disorder, acute stress disorder, post-traumatic stress disorder, or social anxiety disorder ' Eating disorders' such as bulimia, anorexia and obesity, phobias, psychosis, premenstrual syndrome, cognitive disorders, and motor control disorders, including aggressive behavior and substance abuse. , Dopamine D4 Receptor-Responsive Diseases or Disorders are Psychiatry, Positive and Negative Disorders of Schizophrenia, ADHD, and L-Dopa-induced Parkinson's Movement Disorders . In particular, the compounds of the present invention are useful for treating the positive and negative symptoms of schizophrenia without causing side effects of the extrapyramidal system (eXtraPyramidal) and for treating anxiety. [Embodiment] The detailed compound of the present invention + q-# 4,3_ monol-iH-indD-Dol-3-yl) ethyl] · 3,6-monohydro-2H-D specific ice group]- The racemic system of 6-Education μl-8 Lice_1H-Indica was first uncovered in the case of WO 98/28293. This case covers dopamine. 4 Receptor affinity compounds] A case. Although some compounds disclosed in the WO98 / 28293 case have been beneficial to # φ. It is said that the compound can act on the 5 and 5HT2a and / or have a reuptake inhibitory effect, but the application has Not mentioned considering 3 Yang · (2,3_4 · 1Η ___ 3_yl) ethyl] _3,6_dichloro_ 2Η | Ding-4-yl] -6-chloro] Η__ and its mirror isomers for this Under the influence of 13 200406403 and 5-HT transporter. Now we have unexpectedly found the compound S _ (+) H [2_12'3 monohydro-1H'Ddolidyl) ethyl] -3,6-dihydro-2H-Dttidin-4-yl] Winter Chlorine 1 Η-orthogonal B is a very effective inhibitor of D-reuptake. Therefore, the use of this compound for the treatment of 5-ht reuptake inhibiting responsive diseases or disorders has been described this month. Additional forms of the compounds of the present invention exist which have the benefits of several pharmaceutical compositions. For example, take solid unit dosage forms, such as capsules containing the base in a drug or oil phase. The advantage is that its free base is crystallized. Regarding the formulation of the medicine containing the compound, 'a crystalline base can be formulated into an oral tablet' and can be formulated into an organic phase. The compound of formula (1) can be prepared by reduction ( + M1_ tertiary · butoxycarbonyl-2,3 · monohydro-1Η-indole-3-yl) acetic acid, and then replace the hydroxyl group of the produced alcohol with a halogen group, and then (3, Budihydro-2Η-pyridinyl)-1''indole reaction to produce a Boc-protected analog of a compound of formula ⑴ can be obtained by deprotecting the Boc-analog using difluoroacetic acid to obtain the formula 〇) of compounds. Compounds (+ Hl-tertiary-butoxyquinyl; 2,3 · dihydro-ιη -_- 3-yl) acetic acid and 6-chloroj (3mrudinjyl) -1Η-Indodol can be as W Prepared according to the description in the case No. 98/28293. Suitable salts of the compound of the present invention can be suitably reacted by reacting the compound with a pre-calculated amount of an organic or inorganic acid in a water-miscible solvent, and then separating the salt by concentration and cooling, Or = Inverse reaction with an excess of organic or inorganic acid in a water-immiscible solvent, the salt will be automatically separated and prepared. ~

14 200406403 Pharmacological analysis " Compound S- (+) -3- [1- [2- (2,3-dihydro-1HH3-yl) ethyl l · 3'6 monol-2H-pyridine j Kib 6-Chloro_1H • indole has been widely recognized and trusted to measure the affinity of 5_HT reuptake inhibition and dopamine h receptor. [3Η] ΥΜ′ΐ5 " Inhibition of binding to specific receptors 1 > 4.2 The Chinese hamster ovary (CH0) cell line was produced in the laboratory using standardized and stable transfection technology. Cells were collected, sentenced, and sliced into 5 mM MgC12, 5 Zanxian TA, 5 KC1, and 1.5 yuan. 2 of 5 "MTris, pH 7 4. Clozapine (p 1 ne) (1 G 卩 μ) was used as a non-specific-displacement agent. The homogenized product was accompanied by the test compound and ηM [3 coffee_Q9i5 2 2 in Incubate under starvation for 60 minutes. 1 GF / B filter was vacuum filtered to terminate the test, and counted using a Wallac Trilux. In this test, the compound of the present invention has " -IIi, and its corresponding external The racemate has a KI value of 4.5 nM, and in this experiment, the corresponding s _ (+)-mirror isomer with an acetamyl group at the i position of dihydro-_ has a KI value of 4.4. Large 3 [Η] 5-Ητ uptake of mouse whole brain synaptosomes. Using this formula * 'The drug inhibits the emperor] The ability of 3 cells to accumulate to rat synaptosomes is measured in vitro. This test was performed as described in Person 1978, 60, 13. In this test, S-⑴-3- [ι_ [2_ (2,3 · Dihydroxan-indole_3_yl) ethyl] -3,6 -Dihydro-2Η-pyridin-4-yl μ6_chloro-1Η_indole has an IC5 value of 53-15 200406403. In this test, it was found at 2,3-dihydro_ind1]. Corresponding S-(+) · mirror isomers with acetyl groups at position 1, Ic 50 value of 8.7 0 Functional dopamine D4 test The compounds of the present invention were also analyzed by the functional test described in Gazl et al., Part p. 1999, 128, 613-629. In this test, The compounds, racemates, and corresponding s _ (+) _ mirror isomers having an ethanoyl group at the 1-position of 2,3_dihydro_Allodol have been shown to be unacceptable for dopamine D4. Example S- (+) -3- [M2_ (2,3-dihydro_1Η · indolyl) ethyl] _3,6_dihydro-2Η-pyridin-4-yl] -6 · Chloro-1Η-Indodol M + M1-tertiary-butoxycarbonyl_2,3_dihydro_1Η々 丨 late) acetic acid (Compound 33a of WO 98/28293) (7.4 g) Dissolved in tetrahydrofuran (100 mL) and then added to a suspension of LiAlH4 (3.0 g) in tetrahydrofuran (250 mL) at 5 ° C. Water (6 mL), 15% NaOH (3 mL) were added sequentially. ) And water (15 mL) to suppress the reaction, then Mg SO * was added. The mixture was stirred at room temperature for 30 minutes, filtered and concentrated under vacuum. Flash chromatography (heptane / ethyl acetate) 1: 1) The residue was purified to obtain a colorless oil (5.4 g). The crude oil (5.4 g) , A mixture of diethylamine (3.4 mL) and tetrahydrofuran (1000 mL) was cooled (50 c), and then tetrahydrofuran (50 mL) containing methanesulfonium gas (1.7 mL) was added below. Solution. The resulting mixture was stirred at room temperature for 30 minutes and filtered-concentrated under vacuum. 16 200406403 The residue was dissolved in acetone (100 mL), LiBr (8.9 g) was added and boiled under heating for 2 hours. The mixture was filtered under vacuum, reduced, and the residue was purified by flash chromatography (heptane / ethyl acetate 4: 1) to give a colorless oil (5.9 g). The crude oil (4 ()) was then dissolved in methyl ethyl ketone (100 mL), and then added dropwise to butyl g j ml 1 v 6-chloro-3- (3,6-dihydropyridine-4) -Based) -1Η-indole (34 A TEA (8.6 mL) in a mixture. The resulting mixture was heated under reflux for 4 hours and 12 hours, concentrated under vacuum and flash chromatography (acetic acid / ethanol / Triethylamine 2 0: 2: 1) was purified to obtain a crude product (3.9 g); 不 不 丨 · 非 非 / z 1 ″. The crude product was dissolved in two Chloromethane (Kansha / tetrahydrofuran (25 mL) mixture and cooled (trifluoroacetic acid (3GmL) was added. The mixture was shattered at room temperature into :: 'and then poured into an ice / water mixture. Aqueous ammonia The aqueous layer was made and dried: and extracted with ethyl acetate. The organic layer was washed with brine: MgS04) and concentrated in vacuo. The residue was processed by the instantaneous method (ethyl acetate / ethanol ~ based). Amine 100: 4: 4) was purified, and said:-crude target product 'which was under ethyl acetate and subsequent ethanol :: 2 to obtain a pure target product (. 5 g). Analysis result: mirror image Passed !: > 98%. 16Q p ΐττ alcohol), mp 166- b9C; hnmrodmso, (m, 1H); 2.40-2.55 (m, 4H); 2.60-2.70 (m, 2H); 3.05-3 15 5 3.15-3.25 (m, 1H) · 3 / f ihv S An 夂 55 (t, 1H), 5.40 (s, 1H); 61〇iH); 6.50 (d, 1H); 6.55 (t 1HV 6 90 (t lux lh), 6.9U (t , 1H); 7.00-7.05 2H); 7.40-7.45 (m, 2H); 7.80 (d, 1H); 11.25 (s? 1H) o 200406403 Formulations The pharmaceutical formulations of the present invention can be based on the conventional knowledge in this field Prepared by the method. So 'the active ingredients can be mixed with common adjuvants and / or fillers and diluents' and then the mixture is compressed into tablets using a conventional tableting machine. Examples of adjuvants, diluents or fillers include: Horse's pavilion powder, talc, magnesium stearate, gelatin, lactose, gums and the like. Any other adjuvants or additives commonly used for purposes such as coloring, flavoring, preservatives, etc. may be used provided they are compatible with the active ingredient. Alternatively ' capsules containing a compound of the present invention in an organic and / or oil phase can be used. > The main shot solution can be prepared by dissolving the active ingredient and possible additives in a part of the injection solvent, preferably sterile water. The solution can be rounded to the desired volume, the solution can be sterilized and Fill it into suitable bottles, vials and vials. Any suitable additives conventionally used in the field can be added, such as tonicity agents, preservatives, antioxidants, and the like. The daily dose of the compound of the present invention can be determined according to the disease or disorder to be treated. A suitable mother's daily dose is 0.1-500 mg, more preferably 1-150 mg ', more preferably 5-100 mg, and still more preferably 10 -50 mg, even more appropriate and 20-30 mg, depending on the condition being treated. 18

Claims (1)

200406403 Scope of patent application: 1 ’# Compound with formula s_ (+) _3_n_ [2_ (2,3-Diqi D bow 丨 D flower’ or its pharmaceutically acceptable salts 2. If a compound of the town A _ member of the scope of the application for a patent, wherein the compound is S— [+) q ″ π Maqi, then R [[2 一 (2,3—Diazo_1Η— _ 朵 j 土 一 ， k hydrogen—2ΗΙ 定 —4- 基] -6-chloro-1 1 Η_ _. Dingzhong any 1 azepine composition, which contains the compound as described in any one of the scope of the patent application 1 to 2 And release agent. "I have accepted the acceptable carrier, filler or dilute 4_-uses such as patent application compounds, which are used to anti-reactive diseases and production of any of 2 items,- A medicinal composition for treating dopamine h receptor antagonistic development and premature obstruction. 5. Uses such as those in the scope of patent application, which are any one of 2 to 2 allergic diseases „Therapeutic 5-HT reuptake inhibiting facial composition. 6 · If a patent application, reactive disease or disorder, use & 丨 dopamine receptors are positive and negative for psychiatric and schizophrenia Xiangzheng 19 200406403: Movement :: Obstacles, 1--7-7. For the purpose of applying for the scope of patent application No. 6, where the dopa cavity ~ subject Antagonistic reactive diseases and disorders are the positive symptoms of psychiatric disorders and schizophrenia. / ', The second application of the scope of patent application, which ... T reuptake inhibits the reaction 丨 sickness and disorders, sensory disorders, * Including wide ...: anxiety and other emotions., R. ^ S panic anxiety, panic anxiety, obsessive-compulsive disorder, strip stress disorder, trauma, private ^ mental stress 4 social stress or social anxiety Disease, diet such as anorexia, anorexia, premenstrual syndromes, awareness of obstacles ^ Divine deterrence and drug abuse. Early obstacles' impulsive control obstacles, including attack 9 5 Yong M: The use of λ members, in which 5-ΗΤ reuptake inhibits reactive diseases or disorders ^ * uptake 1 0 ·-a method used for Λ 夕 碍 ，, D ^ D4 receptors Antagonistic response to a disease or disorder: Pharmacology ::::::: Applicable patents, item 1, category I to individuals in need. U. A method for treating 5 -Ητ $ ister, which is included in Reuptake Inhibition of Reactive Diseases or Disorders Pharmaceutically Acceptable: Class Please refer to the compound in the scope of patent No. 1 or ...] individuals in need. 12. If the patent application is for a body-responsive disease or disorder ... Method in which dopamine ~ affected by symptoms, cognitive impairment, ΑΙ) Ηη π? Disease Positive and negative dyskinesias of schizophrenia. Caused by Xiba treatment of Parkinson's disease 20 200406403 13. If a patent application covers a body-reactive disease or disorder as a symptom. Method 12 Psychiatry and Psychiatric Score ' Dopamine D4 schizophrenia positive and negative 14 · If you apply for patent scope No. 丨 1 Inhibition of reactive diseases or disorders ... ", where 5-HT re-writes emotional disorders, including: anxiety, anxiety, and other acute plant strength disorders Sexual anxiety, panic anxiety, obsessive-compulsive disorder, premature dysfunction, post-traumatic stress disorder, such as bulimia Γ plant " premature dysfunction or social anxiety, 'beige disease, anorexia and obesity Depression, premenstrual signs # ^ W fear, mental breakdown, cognitive impairment, aggressive behavior and substance abuse. Work obstacles, which include 15. Inhibition of reactive diseases or obstacles such as the scope of application for patents is anxiety. ， Zhongli re-ingestion 21 200406403 (1) Designated representative map: (1) The designated representative map in this case is: (none) map. (2) Brief description of the component representative symbols in this representative map: None. If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention. CI 6