TWI308150B - Unique diazabicyclo alkane derivatives with nk1 antagonistic activity - Google Patents

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1308150 month r No. 92107414 patent application specification revision education, invention description:

[Minger J] The present invention relates to a unique group of diazabicycloalkane derivatives having the neurokinetic-N K! receptor antagonistic activity of interest. The present invention also relates to a method of preparing the novel compound, and to a pharmaceutical composition comprising a pharmacologically active amount of at least one of these compounds as an active ingredient. I: Prior Art 1 European Patent Application EP 0 655 442 discloses a piperidine derivative having a neurogenic agonistic activity. A new pulser derivative having this physiological activity is disclosed in EP 0 899 270, in which a series of 2-(3-tf-bendo D-methylmethyl)-1 -benzhydryl nitrogen having NK antagonistic activity is described. Base) ethyl)aminoguanidino)] piperazine derivatives. Surprisingly, it has now been found that 'when the piperazine ring is fused to its N-4 substituent 15 to give 1,4-diazabicyclo[4.3.0]pyroxene 1,4-diaza In the case of a bicyclo[4.4.0]decane or a fluorenyl-diazabicyclo[4.5.0]undecane derivative, the piperazine derivative is also an antagonist. C SUMMARY OF THE INVENTION The present invention relates to a compound of the formula (1): 1308150

Wherein -Rl represents a stylyl group, a 2-mercapto group, a 3-mercapto group, a 3-oxazolyl group or a benzo[b] °cephen-3-yl group. The group may be a halogen or a 1-3C alkane. Substituent substitution, 5 _R2 and R3 independently represent halogen, hydrazine, OCH3, CH3 and CF3, _R4, R5 and R6 independently represent hydrazine, OH, 0-(l-4C)alkyl, CH2〇H 'NH2 'di ( 1-3C) alkylamino, pyrrolidin-1-yl, piperidin-1-yl'morpholin-4-yl or morpholin-4 substituted by one or two methyl or methoxymethyl groups -yl, morpholine _4_ylamino, morpholine _4_ylmethyl, imidazolium hydrazino-yl, 10 thiophene-4-yl, U_dioxo-thiol _4_yl or 3 _Oxa-8-oxabicyclo[3.2.1]oct-8-yl; together may represent a keto group, a dioxane-2_ group or a 1,3-dioxolan-2-yl group, and X represents Ο or S, η has a value of 1 '2 or 3, 15 when η is equal to 1, 2 or 3, respectively, a is an asymmetric carbon atom 8a, 941〇a' and their pharmacologically acceptable salts. All of the compounds of the formula (1) in which the substituents on the asymmetric carbon atoms 3 and ν, and the substituents on the latent asymmetric carbon atoms 6 and 7 are in the R-configuration or the s-configuration are all in the present invention. 1308150 Prodrugs, i.e., compounds which are metabolized to a compound of formula (1) when administered to a human by any known route, are also within the scope of the invention. The invention particularly relates to compounds wherein R4, R5 or R6 represents a hydroxy or hydroxymethyl group, a typical example being 3,5-bis(trifluoromethyl)phenyl-[6-hydroxymethyl 3-(1Η-吲) Ind-3-ylmethyl)-5 hexahydrogen ratio [1,2-3]° bisazin-2-yl]-methanone (Compound 1 and its enantiomers, see below). Such a compound can be esterified to give a compound which can be metabolized to the compound of the formula (1). The invention particularly relates to compounds of formula (1) wherein R1 is 3-indenyl, R2 and R3 are CF3 groups at positions 3 and 5, X represents a keto group, and η 10 is 1 or 2, And 'a', R4, R5 and R6 have the meanings given above and include all possible stereoisomers listed above. More preferably, the compound of the present invention as described above, wherein R4 or R6 represents or contains one of 4-morpholinyl or hydroxymethyl groups, R5 is hydrogen, and the stereochemistry is 3R. The compound of the formula (1) and salts thereof can be obtained according to at least one of the following known methods for obtaining such a compound. Compounds of the invention wherein n = 1 and R4 and R5 are argon can be prepared by the general route described in Scheme 1. 1308150

Reaction Scheme 1 Thus, a binary carboxylic acid can be used as described in M. Bodanszky, A. Bodanszky The Practice of Peptide Synthesis, Springer-Verlag, 1994; ISBN: 50-387-57505-7 Acid II

Vinegar I (prepared according to the procedure of G. Cignnarella, G. Nathansohn J. 〇rg. Chem., 1961, 26, 1500) is coupled to a suitably protected amino acid to form the guanamine II. The protecting group in II (given as 'pg in the formula π) can be removed using known methods (TW Greene, PGM Wuts 10 Protective groups in organic synthesis, 3rd ed., John Wiley & Sons, 1999) . Subsequent cyclization gives the substituted diketoprazine, such that the chiral amino acid will result in the formation of diastereomers, and these diastereomers can be separated in this step using standard chromatography. The amino alcohol can be obtained by using a living hydride reagent such as a hydrogenated epoch to obtain an amino alcohol, which can be used with a suitable sulfhydryl group 10 1308150

The gas is deuterated under the conditions known in the art to obtain w. A detailed description of the conversion of an alcohol to a suitable leaving group, such as methyl vinegar, followed by reaction with an amine to give a compound & v, which is synthesized by this route is given in the following examples. 5 obtaining an ester prodrug of compound IV by deuteration with mercapto chloride in a solvent such as acetonitrile in the presence of a domain such as diisopropylethylamine at a temperature of 20 〇c to 8 (rc) (see Example 6) below.

Compounds of the invention wherein n = 1 and R6 = h can be prepared by the general route described in Scheme 2. Therefore, amino acid esters with appropriately protected 10 4-Zhaoqi acid bamboo organisms such as m. Bodanszky, A· Bodanszky The

Practice of Peptide Synthesis, Springer-Verlag, 1994; ISBN: The reaction of the standard peptide coupling method described in 〇-387-575〇5_7 gives the dipeptide VI. The protecting group in VI can be removed by a known method (T.W. Greene, P.G.M. Wuts Protective Groups in Organic Synthesis, 3rd ed., 15 J〇hn Wiley & Sons, 19"). Subsequent cyclization gives the substituted diketopiperazine νπ which can be achieved by stirring in a mixture of acetonitrile and piperidine. The hydroxyl group of YD is protected to the formamyl ether by standard methods such as those described in TW Greene, PGM. Wuts Protective Giroups in Organic Synthesis, John Wiley & Sons, 1999, followed by reduction with an active hydride reagent 20 such as hydrogenated lithium. Amino alcohol of W. The compound of the hydrazine is deuterated under standard conditions using a suitable hydrazine base gas to give IX. Conversion of the alcohol to a suitable leaving group, such as a mesylate, is followed by reaction with an amine to provide compound X. A detailed description of the synthesis of the compound by this route is given in Example 2 below. 11 1308150

Reaction Scheme 2 Compounds of the invention wherein n = 2 and R6 = H can be prepared by the general route outlined in Scheme 3. Thus, amino acid esters with 5-oxo-piperidine 5 -1,2-di-treatin 1-benzyl vinegar (H.C. Beyerman, P. Boekee Reel. Trav.

Chim. Pays-Bas, 1959, 78, 648) in, for example, M. Bodanszky, A.

Bodanszky The Practice of Peptide Synthesis, Springer-Verlag, 1994; ISBN: Reaction to the standard peptide coupling method described in 0-387-57505-7 to give the dipeptide XI 'The use of chiral amino acids will result in the formation of diastereomers 10 'And these diastereomers can be separated using standard chromatography in this (or subsequent) step. The ketone of the phantom is protected by a cyclic or acyclic ketal form as described, for example, in TW Greene, PGM Wuts Protective Groups in Organic Synthesis, John Wiley & Sons, 1999, to give a compound of formula XII, wherein A and B represents a cyclic or acyclic ketal. 15 This reaction can be carried out according to a conventional method generally known in the art. Under the conditions of reduction 12 1308150 (3⁄4, Pd/c), the oxygen-removing radicals are removed in a solvent such as methanol, followed by acid-catalyzed cyclization to give the two (four) „ Qin of the formula xm. Using an active hydride reagent such as hydrogenated brain county Xm gives an amine which can be deuterated under conditions generally known in the art to give oxime. For example, tw. 5 Greene, PGM Wuts Protective Groups in Organic Synthesis,

The method described by John Wiley & Sons, 1999, hydrolyzes ketals to form XV. Reductive amination with a suitable amine in a solvent such as ruthenium disulfide with a reducing agent such as diethylhydrazine hydrazine (10) affords the top compound. Alternatively, XVI can be prepared from XV by reducing the ketone XV to the alcohol XVII with a reducing agent such as triethyloxyboroxine in 10 solvents such as acetic acid. The alcohol can be converted to a leaving group (L) under conditions generally known in the art, such as gas, or oxime, to give XVIII. Substitution of the leaving group in XVIII with a suitable amine in a solvent such as acetonitrile affords the compound of formula νν. A detailed description of the synthesis of the compound by this route is given in the following Examples 3, 4 and 5. , ',. 13 1308150

HO

y^~v0_A

Γν VIII

Scheme 3 Intermediate M (Scheme 2), XIII (Scheme 3) and XVIII (Scheme 3) are novel compounds. The invention also relates to these novel compounds. 5 Suitable acid addition salts can be obtained by using inorganic acids such as hydrochloric acid, sulfuric acid, acid and nitric acid, or organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, Forming with toluenesulfonic acid, methanesulfonic acid and naphthalenesulfonic acid. The compound of the present invention of the formula (1) and salts thereof have ><>> antagonistic activity, and 10 shows good bioavailability. They are effective for the treatment of diseases in which neurokinins involved in interaction with NKi receptors, such as diseases involving neurokinesis-1 (=substance P), or diseases treated by the control of those systems. 14 1308150 For example, acute and chronic pain & vomiting, inflammatory diseases such as meningitis, arthritis, asthma, psoriasis and (sun) burns; stomach-intestinal disorders, especially irritable bowel syndrome, inflammatory bowel Disease (clonal disease), ulcerative colitis; bladder or gastrointestinal hyperactivity, urinary tract inflammation; allergic reactions such as 5 eczema and rhinitis; cardiovascular diseases such as hypertension, atherosclerosis, edema, angina 'Cluster headaches and migraine; skin diseases such as Zunma, lupus erythematosus and itching; respiratory disorders including chronic obstructive pulmonary disease, bronchospasm 'gas stagnation pneumonia, bronchitis, _ suction distress syndrome and cystic fibrosis, Various neoplastic diseases; psychiatric and/or neurological disorders such as psycho10 schizophrenia and other psychiatric disorders; mood disorders such as bipolar I disorders, bipolar II disorders and unipolar depression such as mild depression, seasonal affective disorder postpartum depression Symptoms, bad mood and severe depression; anxiety disorders including panic disorder (with or without square phobia), social phobia, compulsive Compulsory symptoms (chronic convulsions or schizophrenia with or without comorbidity), 15 stress disorders after trauma and general anxiety disorders; substance-related disorders, including the use of substances (eg dependence and Abuse) and substance-induced conditions (such as substance withdrawal); commonly developed conditions include autism and Rett (s); attention deficits and mitotic behavior disorders such as attention deficit hyperactivity; impulse control disorders such as attacks Behavior, pathological gambling; eating disorders such as neuropathic anorexia and bulimia nervosa, obesity; sleep disorders such as insomnia; convulsive disorders such as Tourette's disease; restless leg syndrome; conditions characterized by cognitive and memory impairment For example, Alzheimer's disease, ke-ya syndrome, Huntington's disease, Parkinson's disease and neurological rehabilitation (brain lesions after trauma). The antagonistic properties of the compounds of the invention were determined using the methods described below. 15 1308150 Pharmacological method Receptor binding of human 1^1^ receptor The affinity of the compound with the human NK! receptor was evaluated by radioreceptor binding assay. The membrane preparation was prepared from Chinese hamster ovary (CHO) connective tissue cells, 5 in which the human NK! receptor was stably expressed. The membrane was incubated with [3H]-substance p in the presence or absence of a specific concentration of compound diluted in a suitable buffer for 10 minutes at 25 ° C in the presence of an enzyme inhibitor. Separation of bound and unbound radioactivity was carried out by washing with a Whatman GF/B fiberglass filter and washing with a wash solution for two 5 seconds. The count of bound radioactivity was counted by liquid scintillation counting using a Betaplate 10 counter. The measured radioactivity is plotted against the concentration of the test compound and the substitution curve is calculated by four-parameter logistic regression to obtain the ICw value, which is the concentration of the replacement compound at which 50% of the radioligand is replaced. The affinity port & value is calculated by correcting the ICso value of the radioligand concentration, and its affinity for the human NK! receptor is calculated according to the 15 Cheng-Prusoff equation: pKi = -l 〇 g [IC5 〇 / (l +S/Kd)] where ICso is as described above, S is the concentration of [3H]-substance P used in the test, expressed in mol/L, and Kd is [3H]-substance P for human]^^ receptor The equilibrium dissociation constant (expressed in mol/L). 20 c AMP assay The role of the test compound in the formation of cyclic AMP (cAMP) was evaluated using CHO connective tissue cells stably expressing the cloned human NK! receptor. In addition to coupling with phospholipase C, the human NK! receptor also stimulates adenylate cyclase, which converts ATP to cAMP. For the test, the cells were raised in a 24-well plate with 16 1308150. Prior to the experiment, the medium was replaced with serum-free α-DMEM medium containing [3h]-adenine, which was taken up by the cells and sequentially converted into radiolabeled adenosine, AMP, ADP, and finally transformed. Radiolabeled ATP. After 2 hours, the cells were rinsed twice with phosphate buffered saline (pH 7.4) in the presence of 5 ImM isobutylphosphonium xanthine (ibmX; an inhibitor of phosphodiesterase which hydrolyzes cAMP to AMP). Subsequently, cells were stimulated with 10 nM of substance P in the presence of test compound in a suitable diluent for 20 minutes in PBS/IBMX. After the stimulation, the medium was aspirated and the cells were extracted with 5% tri-glycolic acid. Radiolabeled ATP and cAMP were recovered from the extract using continuous column chromatography. ATP can be recovered by separating the extract by ion exchange chromatography on a DOWEX 50WX4 column. The column was then placed on top of an alumina column and eluted with water. Recovery of cAMP was carried out by eluting the alumina column with 1 mM mM imidazole (pH 7.4). Both ATP and cAMP fractions were counted using liquid scintillation counting and the conversion ratio was calculated as follows: 15 v=[cAMP]*100%/([ATP]+[cAMP]). By compound concentration of cAMP The graph establishes a concentration_response relationship and calculates a 1<:5() value by four-parameter logistic regression. The antagonist potency (pA2) value pA2 = IC5 〇 / (l + [SP] / EC5 〇) was calculated using the following formula: wherein 试验: 5 试验 of the test compound was obtained from the concentration-effect relationship, and [SP] was the concentration of the substance P ( Expressed in mol/1; typically ΙΟηΜ), and EC5〇 is the potency of substance P in human clones>^& receptors. NKi agonist-induced gerbils in gerbils have demonstrated the ability of NK! antagonists to antagonize athlete's foot induced by nK i agonism 17 1308150 (Rupniak and Williams, 1994 (Eur. J. Pharmacol) 265:179); Bristow and Young, 1994 (Eur. J. Pharmacol. 254: 245)). Therefore, we used this model to evaluate the in vivo activity of the compounds of the invention. 5 Male gerbils (40-60 g; Charles River) received vehicle or test compound for 60 minutes prior to anesthesia with N2O (0-8 L/min), halothane (3%) and O2 (0.8 L/min) (ρ.ο·). Under successful anesthesia, the anesthetic was adjusted to N2O (0.6 L/min), fluorofibril (1.5%) and O2 (0.6 L/min), and the scalp was cut from the middle. GR 73632 was perfused into the ventricle space (from the front 囟 AP-0.5 mm, L-1.2 mm, vertical 10-4.5 mm). After the recovery from anesthesia (about 3-4 minutes), the ankle was recorded for 5 minutes. The predetermined standard for antagonism of this effect is defined as the inhibition of flavonoids for 25 minutes. The compounds of the present invention have high affinity for the receptor, and have a pKi value of 27_0 in the binding assay as described above. The compounds of the invention are also active in cAMP assay 15, and their pAa-values are consistent with their pKi values. Some of the compounds belonging to the present invention can penetrate the brain barrier, which can be confirmed by their activity in a gerbil foot lick test induced by a kinin agonist. This property makes them useful for the treatment of CNS disorders.

I: Embodiment J 2〇 The present invention is further illustrated by the following specific examples. Example 1 (See Scheme 1) Step 1 · To trans-pyrrolidine-2,5-dicarboxylate hydrochloride (42 g) and Να-oxycarbonyl-D-tryptophan (10 · 0 g) Add 1,3-diisopropylcarbodiimide (26 ml) in a mixture of acetonitrile (2 mL), and then add 18 1308150 4-dimethylaminopyridine (~ 20 mg). The resulting mixture was stirred at room temperature overnight, then diisopropylethylamine (2.5 mL) was added and stirring was continued for a day. The reaction was quenched with EtOAc (aq. The organic layer was dried (Na2SO4) filtered. The residue was purified by flash chromatography (Si02, EtOAc) to afford (2R,5R,2'R) and (2S,5S,2'R)l-[2-benzyloxycarbonylamino-3-(1Η-吲) A mixture of ind-3-yl)propanyl]-»pyrrolidine-2,5-dicarboxylic acid diethyl ester (8.25 g '90%). Rf 0.62 (EtOAc) ( Intermediates 1 and 2). Step 2: (2R, 5R, 2'R) and (2S, 5S, 2'R) 1-[2-benzyloxycarbonylamino 10 -3-(111-indol-3-yl)-propenyl A mixture of p-pyrrolidine-2,5-dicarboxylate (8.5 g), palladium on carbon (10%, ~250 mg) and ethanol (250 ml) was hydrogenated over H2 (latm) overnight. The catalyst was removed by filtration through celite and the residue was concentrated in vacuo. The two diastereomers obtained were separated by flash chromatography (SiO 2 , CH 2 Cl 2 / MeOH / NH 4 OH 95: 4.5: 0.5) to give 15 (311, 68, 8 & 8) -3- (out-吲哚-3) -ylmethyl)-1,4-dioxo-octahydro-pyrrolo[1,2-a]pyrazine-6-carboxylic acid ethyl ester (2.3 g) and (3R,6R,8aR)-3- (lH^W-3-ylmethyl)-1,4-dioxo-octahydro-pyrrolo[l,2-a]pyrazine-6-carboxylic acid ethyl ester (1.75 g) (intermediate 3 and 4). Step 3: Add (3R,6R,8aR)-3-(lH-indol-3-ylindenyl)-l,4-dioxo to 20 suspensions of hydrogenated lithium (1.2 g) in ml) a solution of octahydro-o to ^I and [l,2-a] ° -6-oleic acid ethyl ester (1.75 g) in THF (50 mL). The resulting mixture was heated under reflux for 3 hr. then a mixture of water (3 mL) and THF (30 mL) was then added dropwise </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; After cooling to room temperature, 19 1308150 was added diisopropylethylamine (4 mL) and 3,5-bis(trifluoromethyl)benzamide (24 mL) and stirring was continued overnight. Ethyl acetate was added and the mixture was extracted with sodium bicarbonate (5% aqueous). The organic layer was dried (Na.sub.2.sub.4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Si.sub.2, CH.sub.2Cl.sub.2/MeOH/H. )- 6-Methyl-3-(1Η-indol-3-ylmethyl)-hexahydro"• 比略和[1,2-小比呼_2_yl]-methanone (1.49 g). MH+ 526; Rf 0.20 (EtOAc) (Compound 1). Step 4: (3,5-Bis(trifluoromethyl)phenyl)-[(3R,6R,8aR)-6 hydroxymethyl-3-(1Η-0丨丨0-3-ylmethyl) Hexahydropyrolo[i,2_a]n is exemplified by _2_yl]-10 ketone (1.30 g), triphenylphosphine (1.2 g), carbon tetrachloride (4 ml), and acetonitrile (40 ml) The mixture was heated at 70 ° C for 6 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was purified by ion exchange chromatography on a strong cation exchange (SCX) column to give 3,5-bis(trifluoromethyl)phenyl-[(3R,6R,8aR)_6_ gas fluorenyl-3-(111 -°丨0-3-ylindolyl)-hexahydro&gt;1 to 11 and [1,2_&amp;] „比„_2_ 15 base]-fluorenone (1.06 g) (intermediate 5) . Step 5: To (3,5-bis(trifluoromethyl)phenyl)-[(3R,6R,8aR)-6-gasmethyl-3-(1Η-π弓布朵-3-ylfluorenyl) - hexahydro 0 to each [i, 2_a]n than 嗓_2_yl]-fluorenone (1.06 g) in dimethylformamide (15 ml), morpholine (5 ML). The resulting mixture was heated at 120 ° C for 6 hours. After cooling to room temperature, ethyl acetate and 5% aqueous sodium hydrogencarbonate were added, and the layers were separated. The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography (Si.sub.2, EtOAc/MeOH/H.sub.HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH (lH-Indol-3-ylmethyl)_6_(Merlin-4-ylmethyl)-hexahydro 0-haha [l,2-a]D is 0-0-2-yl]--- (4〇7 mg). Rf 20 1308150 0.46 (MTBE / MeOH / NH4OH 95: 4.5: 0.5) (Compound 2). The following compound 3 can be obtained in a similar manner; MH+ 595, Rf 0.71 (CH2Cl2/MeOH/NH4OH 90:10:1). 5 Compound 4; Rf 0.38 (CH2Cl2/MeOH/NH4OH 90:10:1). 2 (See Scheme 2) Step 1: At 0 ° C, to N, 9-fluorenylmethoxycarbonyl _L_trans _4_hydroxyproline (1 〇 · 2 g), D-color ammonia Acid methyl ester hydrochloride (8.1 g), and benzotriazol-1-yloxy-tris (° ratio 11 fen) squamous hexafluorophosphate (15 g) in acetonitrile (2 〇〇 10 10) Add diisopropylethylamine (15 ml) to the mixture in liter. The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo, taken up in ethyl acetate, extracted twice with water and twice with 2 EtOAc. The organic layer was dried (NaJO4) &quot;transition&quot; and concentrated in vacuo. The residue was dissolved in acetonitrile (2 mL), and β bottom bit (25 ml) was added. After 2 hours at room temperature, 1_(9Η-芴-9-yl group formed by filtration and removal of 15) Base)-piperidine' and the residual solution was allowed to stand for 72 hours. The crystal material formed was collected by filtration to give (3R,7R,8aS)-7-carbyl-3-(1Η-indol-3-ylmethyl)-hexahydropyrrolodione (7.4 g) (intermediate) 6). Step 2: to (3R,7R,8aS)-7-pyridyl-3-(1Η-π丨1111_3_基甲)_20 hexahydro 0 piroxime [1,2-3]0 Adding imidazole (1.7 g) and gasified t-butyl diphenyl fluorite (4.35 ml) to a solution of dimethyl-1,4-di(2.5 g) in dimethylformamide (3 ml) . The resulting mixture was stirred at room temperature overnight and then partitioned between water and ethyl acetate. The dried organic layer was filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc EtOAc) eluting Methyl hexahydro 0 is more than [l,2-a]D is -1,4-diyl (4.6 g, 99%) (Intermediate 7). Step 3: To lithium aluminum hydride (1.8 g (3R,7R,8aS)-7-(tert-butyldiphenylcarbamoyloxy)-3-(1 Ηΐ5 -3-ylmethyl)-six was added to a suspension of THF (120 ml) 1 〇 略 略 [i, 2-a] 0 to 0-Q-1,4-dione (4.6 g) in THF (35 ml). The obtained mixture was heated to reflux overnight, then water (1.8) A mixture of hexanes and THF (3 mL), followed by aq. (1 ml) and 10 TtiF (2 ml), add diisopropylethylamine (5 ml) and 3,5-bis(trifluoromethyl)benzamide (2 ml) and The mixture was stirred overnight at room temperature. The mixture was extracted with water, dried, filtered and concentrated in vacuo. 〇2, MTBE/Xinyuan 2:1) Purification, 3,5-bis (Sanxiang Jiamei) benzoic acid (311,711,8&amp;8)-2-(3,5-bis(trifluoromethyl) Benzene oxime)_3_(11^15吲哚ylmethyl)-octahydropyrrolo[1,2_a]pyrazin-7-yl ester (4.2 g, 65%). MH+ 752 ( Intermediate 8). Step 4: 3,5-Bis(trifluoromethyl)benzoic acid (3R,7R,8aS)_2_(3,5-bis(difluoromethyl)benzylidene)-3-(1Η-吲哚_3-ylmethyl&gt; octahydropyrrolo[l,2-a]t-Qin-7-yl vinegar (4.2 g)' 1,4-dioxane (45 ml), methyl 20 alcohol ( Mixture of 12 ml) and 4M sodium hydroxide (aq. EtOAc) (3 mL). , 3,5-bis(trifluoromethyl)phenyl-[(3R,7R,8aS)-7_transcarbyl_3 sen_tetramethylmethyl)hexahydro- 0-pyrrolo[1,2_a ]°Biazinyl]-methylnet (4 g) (Compound 5). 22 13〇8i5° Step 5a: to 3,5-bis(trifluoromethyl)phenyl-[(3R,7R,8aS)- 7-carbyl-3-(1Η-indol-3-ylmethyl)hexahydropyrrolo[l,2-a]pyrazin-2-yl]-methanone (〇·54 g) To a solution of ethyl acetate (2 mL) was added diisopropylethylamine (2 mL) and dichloromethane (0.2 mL). The resulting mixture was stirred at room temperature for 5 overnight and concentrated in vacuo. Morpholine (4 ml) was added to the residue, and the mixture was stirred at 95 ° C for 4 hr. Excess morpholine was removed in vacuo and the residue was purified using preparative HPLC to afford 3,5-bis(trifluoromethyl)phenyl-[(3R,7S,8aS)-3-(lH-indol-3-yl) Methyl)_7_(morpholin-4-yl)-hexahydropyrrolo[l,2-a]pyrazine-2-yl]-methanone (81 mg). MH+ 581 (compound 6). 10 Steps North: to 3,5-bis(trifluoromethyl)phenyl-[(3R,7R,8aS)-7-hydroxy-3-(1Η-indol-3-ylmethyl)hexahydropyrrole [1,2-a]pyrazin-2-yl]-methanone (0.68 g) in dimethylformamide (20 ml), diisopropylethylamine (2 ml) and methanesulfonate Chlorine (0.2 ml). The resulting mixture was stirred at room temperature for 1 hour, then a brominated planer (excess) was added, and the mixture was stirred at 95 ° C for 5 hours. The intermediate bromide was separated by partitioning between water and ethyl acetate. The organic layer was concentrated and purified by chromatography. Morpholine (4 ml) was added to the bromide, and the mixture was heated at 95 ° C for 4 hr. Excess morpholine was removed in vacuo and the residue was purified using preparative HPLC to afford 3,5-bis(trifluoromethyl)phenyl-[(3 s, 7 艮8aS)-3-(lH-indole-3- Benthyl)-7-(morpholin-4-yl)-hexahydropyrrolo 20 U,2-a]pyrazin-2-yl]-fluorenone (101 mg). MH+ 581 (compound 7). Compounds 8 and 9 can be obtained in a similar manner. Example 3 (See Scheme 3) Step 1: To a solution of 5-oxo-andnithyl-1,2-dicarboxylic acid 1-benzyl ester (93_5 g) in acetonitrile (1 L) was added diisopropyl A solution of carbodiimide (53 ml) in acetonitrile (50 23 1308150 mL) was then cooled to 5 °. To the obtained suspension, D-tryptophan oxime hydrochloride (85.5 g) was added portionwise, and a solution of diisopropylethylamine (58.6 ml) in acetonitrile (50 ml) was added dropwise. The resulting mixture was stirred at rt for 18 h then filtered and concentrated in vacuo. The residue was dissolved in methylene chloride (EtOAc) (EtOAc) (EtOAcjjjjjjjjjjjjjjjjjjjjjjjjj -[2-(lH-indol-3-yl)·ι_methoxycarbonyl-ethylaminoindenyl]-5-oxo-piperidine-1-carboxylic acid benzyl ester (intermediates 9 and 10) Mixture (171.2 g) 'This mixture can be used directly in the next step. Step 2: (2R, 2'R)· and (2S, 2'R)-2-[2-(lH-吲哚,3-yl)10-methoxycarbonyl-ethylcarbamoyl]_5_ a mixture of oxalic acid (18 gram) and 1,3-propanediol (87 ml) in acetonitrile (1.5 ml) was heated at 40 ° C. 20 hours. The solvent was then removed in vacuo and the residue was purified using flash chromatography eluting eluting eluting eluting eluting eluting Indole-3-yl)-1-oxocarbonyl-ethyl-15aminodecyl]-1,5-dioxa-8-aza-spiro[5.5]undecane-8-carboxylic acid benzyl Mixture of esters (118 g). MH+ 536, Rf 〇.〇7 (CH2Cl2/MeOH 99:1) ( Intermediates 11 and 12). Step 3: To (9R,2'R)- and (9S,2'R)_9_[2-(lH-n-bend-3-yl)-1-methoxycarbonyl-ethylcarbamoyl l · a solution of a mixture of 1,5-dioxa-8-azaspiro[5·5]undecane-8-carboxylic acid benzyl vinegar (92.8 g) in methanol (1 L), added 10%/ Carbon (~5 grams). The resulting mixture was hydrogenated with H2 (latm) at room temperature overnight. The catalyst was removed by hydrazine, and the residual solution was concentrated in vacuo to give (2R,9,R) and (π,9'3)-2-&quot;,5·dioxa-8·aza - 24 1308150 (69.0 g) of a mixture of spiro[5_5]undecane-9-carbonylamino]-3-(1Η-indol-3-yl)-propionic acid methyl ester. Rf〇.24 (CH2Cl2/MeOH/NH4OH 92:7.5:0.5) (Intermediate 13 and H) ° Step 4: (2R,9'R) and (2R,9,S)-2-[(l, 5-mixture (69.0 g) of 5-dioxa-8-aza-spiro[5.5]decahydrocarbyl)-amino]-3-(111-indol-3-yl)-propionic acid methyl ester and Acetic acid (9 ml) was heated to reflux in acetonitrile (900 mL). After cooling to room temperature, the mixture was concentrated to about one-third of the original volume. The precipitate formed was collected by filtration to give (3R,9aS)-3-(lH-indol-3-ylmethyl)-hexahydrospiro[2H-pyrido[l,2-a]pyrazine-1,4 -Dione-7,2'-[1,3]dioxane] (23.7 g; Rf 0.34 (Et20/Me0H 10 9:1)). The filtrate was concentrated and the residue was purified by flash chromatography (EtOAc EtOAc EtOAc EtOAc 2Η-»比唆[l,2-a]pyrazine-1,4-dione-7,2'-[1,3]dioxane] (20.6 g; Rf 0.18 (Et2O/MeOH) 9:1) (Intermediate 15). Step 5: To a suspension of 15 (1,6 g) of 1:1 (500 ml) of hydrogenation hour, add (3R,9aR)-3-(lH-0).弓)-3-ylmethyl)_hexahydrospiro[2h_ 0 than bite [l,2-a].Biazine-1,4-di-7,2'-[1,3]dioxo A solution of heterocyclohexane] (2 〇 6 g) in THF (100 mL), EtOAc (EtOAc) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; )-3-( 1Η-. 哚-3-ylmethyl)_ octanitrospiro[2Η_ 吼. Ding [l,2-a;h azine-7,2'-[1,3]dioxo Heterocyclohexane] (19 7 g, Rf 〇.l6 (CH2Cl2/MeOH/NH4〇H92: 7.5:0.5)) Body 16), the product can be directly used in the next step. 25 1308150 Step 6: To (3R, called 3 Pe(4) 3-ylmethyl)_ octahydrospiro [2H_ t and [U-a (d) to dioxin Add 2,5-bis(trifluoromethyl)benzamide under the armpits at room temperature by adding diiso-diethylamine (9.6 ml) to a solution of bismuth (ΐ9·7 g) in a gas. The chlorine was brewed (1 G ml). The obtained mixture was concentrated at room temperature (4) overnight, and the column was colored and purified by column chromatography (ship, CH2Cl2/Me〇H/NH4〇H 96:3.75: ().25). 3R9aR) 2_ [3,5·bis(trifluoromethyl)benzyl]-3 sen, 哚 曱 ) ) _ 八 2 2 2 2 2 2 2 2 2 2 2 2 2 U U U U U U

Rf0.35 (CH2Cl2/MeOH/NH4OH 96:3.75: 〇.25) (,t^^ 10) 〇10 15 20 Step 7: (3R,9aR)_2-[3,5-bis(trifluoromethyl) Benzyl sulfhydryl]-3-(1H-called budo-3. fluorenyl)-octahydrospiro [2H" than bite [i, 2_ small than -7'2 - [1,3] _ Oxacyclohexyl κ 3 〇 · 0 g) in a mixture of acetic acid (15 〇 ml) and _ salt 酉 (150 ml) at 4 〇. (: heating for three days. After cooling to room temperature, add two gas Methane (75 ml) and 2 sodium hydroxide (aq., η (9) mL). The layers were separated and the aqueous layer was extracted twice with hexanes. The combined organic layers were washed with water and concentrated in vacuo. Si〇2, CH2C12/Me〇H 98:2) Purified to give (3R,9aR)_2_[3,5-bis(trifluoromethyl)benzylidene]-3-(1Η-吲哚_3_ Methyl) _ octahydro 2H_pyridine and u, 2. pyrazine -7-one (21.7 g) ° R_f 〇 2 (CH 2 CI 2 / Me 〇 H 98: 2) (Compound 11). 8: to (3R,9aR)-2-[3,5-bis(trifluoromethyl)benzylidene]_3_(1H-indol-3-ylmethyl)-octahydro-2H-pyridinium[丨, 2-a]pyrazine-7-one (5.6 g) in acetic acid (75 ml) suspension was added triethyl hydrazine Sodium borohydride (6 78 g). The mixture was stirred at room temperature for one hour, then poured into water and basified with 2M sodium hydroxide (aq). The precipitate formed was collected by filtration, 26 1308150 washed with water , suspended in toluene and concentrated in vacuo to give 3,5-bis(tributenyl)phenyl-[(3R,7S,9aR)-7-hydroxy-3-(1Η-indenyl)- Octahydropyridinium pyridine [l,2-a]° -2--2-yl]-methanone (5.7 g). Rf 0.35 (CH2C12 / MeOH 9:1) (Compound 12). 5 Step 9: To 3 , 5_bis(trifluoromethyl)phenyl-[(3R,7S,9aR)-7-hydroxy-3-(1Η-indol-3-ylmethyl)-octahydroindole than bite [l, To a suspension of 2-a]D-pyridinyl]-methanone (3.85 g) in acetonitrile, add carbon tetrabromide (1. 6 g) and triphenylphosphine (9.18 g) to give the mixture in the chamber. The mixture was stirred overnight. The formed precipitate was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si </ </ RTI> <RTIgt; </RTI> <RTIgt; -[(3 ft, 9&amp;11)-7-bromo-3-(1-decyl-3-ylmethyl)-octahydro 11-pyridyl[1,2-&amp;] phenazine-2- Base]-methanone (3. 5 grams). MH+ 588, Rf 0.38 (CH2Cl2/MeOH 97:3) ( Intermediate 17). Step 10: 3,5-Bis(trifluoromethyl)phenyl-[(3R,9aR)_7-bromo-15·3_(1Η-吲哚_3·ylmethyl)-octahydropyridinium [1, A mixture of 2-a]pyrazin-2-yl]-fluorenone (2.94 g) and morphine (ο. % ml) in acetonitrile (ml) was heated at 8 ° C for 40 hours. After cooling to room temperature, the mixture was concentrated in vacuo and purified title crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj [(3R,7R,9aR) 3_(1H_ 2〇吲°木基methyl)-7-morpholin-4-yl-octahydropyrido[i,2-a]pyrazin-2-yl]- Steel (1.6 g, Rf 〇.33 (CH2Cl2/MeOH/NH4OH 92:7.5: 0.5)) (Compound 13) and 3,5-bis(trifluoromethyl)phenyl-[(3R,7S,9aR)- 3-(lH-indol-3-ylmethyl)_7_morpholine_4_yl_octahydropyrido[nypyrazin-2-yl]fluorenone (1.28 g 'Rf〇27(CH2Cl2/MeOH/) NH4OH 92: 7.5: 0.5)) (Compound 27 14). 1308150 Compounds 15-23 and 33-40 can be obtained in a similar manner. Example 4 (see Scheme 3) (3R,9aR)-2-[3,5-bis(trifluoromethyl)benzimidyl]-3_(ΐΗ_°弓丨°5 -3-基甲))- octahydro-2-indole-pyrido[l,2-a]pyrazine-7-one (0.785 g 'see step I-7 of Example 3), pyrrolidine (0.107 g), acetic acid (0·09 g) A mixture of sodium triethyloxyborohydride (0.47 g) in 1,2-dichloroethane (60 ml) was stirred at room temperature for three days. The resulting mixture was poured into water, basified with sodium bicarbonate (5% aqueous) and extracted with dichloromethane. The organic layer was concentrated and the residue was purified by column chromatography (SiO2, CH.sub.2Cl.sub.2/MeOH/NH. 9aR)-3-(lH-indol-3-ylmethyl)-7-npyrrolidine-1_yl-octahydropyrido[i,2-a]pyridazin-2-yl]-methanone (0.20 g, Rf0.23 (CH2Cl2/MeOH/NH4OH 92: 7.5: 0.5)) (Compound 24) and 3,5-bis(trifluoromethyl)phenyl-[(3R,7S,9aR)-3- (lH-Indole-3-15-methyl)-7-°pyrrolidin-1-yloctahydrogen. Bis-[1,2-a]pyrazin-2-yl]-methanone (0.48 g, Rf 0.15 (CH2Cl2 / MeOH / NH4OH 92: 7.5: 0.5)) (Compound 25). Compounds 26-28 can be obtained in a similar manner. Example 5 (see Scheme 3) 20 Step 1: At 5 ° C 'to (3R,7S,9aR)-(3-pyrylhydroxy-octahydro.bipyridyl[l,2-a]» a mixture of zirconyl)-(3,5-bis(trifluoromethyl)phenyl ketone (3 3 g, similar to that prepared in steps 1-8 of Example 3) in di-methane (1 mL) Diisopropylethylamine (24 ml) and sulfonium sulfonate (8 ml) were added. The resulting mixture was stirred at room temperature for 15 min and concentrated in vacuo. Res. 28 1308150 column chromatography (8 丨〇 2 , (:112(:12/]^〇1^95:5) was purified to obtain oxime sulfonic acid (3 ft, 73 such as 11)-3-benzyl-2-(3,5-bis(trifluoromethyl) Benzyl hydrazino)-octahydroacridino[l,2-a]pyrazin-7-yl ester (3.8 g). Rf 〇.67 (CH2Cl2/MeOH 95:5) ( Intermediate 18). Step 2: 曱Sulphonic acid (3R,7S,9aR)-3-benzyl-2-(3,5-bis(trifluoromethyl)benzoquinone)-octahydrogen is bitten and [l, 2 -a]e a mixture of 噃-7-yl ester (1_97 g) and morpholine (0.44 ml) and acetonitrile (50 ml) at 40 ° C for 40 hours. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was chromatographed with ^02, (: by 0:12/]^011/:^1140 11 980:18.75:1.25) Purification to give 10 3,5-bis(trifluoromethyl)phenyl-[(3R,7R,9aR)-3-benzyl-7-morpholin-4-yl·octahydro Pyrido[1,2-a]pyrazin-2-yl]-methanone (0.97 g, Rf 0.24 (CH2C12/MeOH/NH4OH 96:3.75:0.25)) (Compound 29) and 3,5-bis (III) Fluorinyl) phenyl-[(3R,7S,9aR)-3-pyryl-7-morphin-4-yl-octahydro-11 ratio bite [i,2_a]pyrazin-2-yl]- Ketone (0.75 g, Rf 0.15 (CH2Cl2 / MeOH / NH4OH 15 96: 3.75: 0.25)) (Compound 30). The following compound compounds 31 and 32, compound 41 can be obtained in a similar manner; Rf 0.11 (CH2Cl2/MeOH/ NH4OH (96: 3.75: 0.25)) Compound 42; Rf 0.06 (CH2Cl2/MeOH/NH4OH (96: 3.75: 0.25)) 20 Compound 43; Rf 0.08 (CH2Cl2/MeOH/NH4OH (96:3.75:0.25)) Compound 44; Rf 0.05 (CH 2 Cl 2 / MeOH / NH 4 OH (96: 3.75: 0.25)) Compound 45, 46, 55, 56, 58 and 59 Compound 57; Rf 0.10 (CH2Cl2/MeOH/NH4OH (98:1.85) :0.15)) Example 6 (ester prodrug) 29 1308150 to (3,5-bis(trifluoromethyl)phenyl H(3R,6R,8aR)-6- via methyl- at room temperature 3-(lH-^I丨丨π丨-3-ylmethyl)-hexahydrogen ratio 1^ each [l,2-a]° ratio °Qin-2-yl]-fluorenone (0 52 g) in acetonitrile (40 mL) was added diisopropyl ethylamine (0.17 ml) and acetyl gas (0.8 ml) in acetonitrile (10 mL). The resulting mixture was stirred at room temperature overnight. The residue was purified by hydrazine chromatography (Si 〇 2 ' CH 2 Cl 2 /Me 〇H 97:3) to give 2-(3,5-bis(trifluoromethyl)phenylhydrazinyl)-3-( 1Η-Indol-3-ylmethyl)-hexahydropyrrolo[1,2-a]pyrazine-6-ylmethyl ester (0.32 g). Rf 0.33 (CH2C12/

MeOH 97:3) (Compound 47). The following compound compound 48 can be obtained in a similar manner; Rf 0.50 (CH 2 Cl 2 / MeOH 97:3) Compound 49; Rf 0.51 (CH 2 Cl 2 / MeOH 97:3) Compound 50; Rf 0.50 (CH 2 Cl 2 / MeOH 97:3) Compound 51 ; Rf 0.12 (CH 2 Cl 2 / MeOH 98: 2) 15 Compound 52; Rf 0.47 (CH 2 Cl 2 / MeOH 95: 5) Compound 53; Rf 0.21 (CH 2 Cl 2 / MeOH 97: 3) Compound 54 as exemplified by compound 1-59 The compound of the invention has a high affinity for the &gt;^^ receptor, and has a pi-value of 20 W·0 in the binding assay as described above. As described in detail in the examples given, this compound has been used as a synthetic intermediate for other compounds, the compounds of the invention are active in the cAMP assay, their pAr&gt; values and their ρκ The values are the same. Some of the compounds belonging to the present invention can permeate the blood-brain barrier, as evidenced by their activity in the gerbil-foot lick test induced by neurokinin agonists 30 1308150. This property makes them useful for the treatment of CNS disorders 5 |N&gt; 3 90 - D; :t-· κ 5 00 . «Λ N&gt; CT 簦〇〇Ο 簦〇〇Ο Ο 〇Ο Ο Ο ο ο Ο C Ο Ο XI Ο 〇Ο Ο XXI m u&gt; iv I u&gt; 4 # w U) * 53⁄4 Thai m Ϊ w X * Ui XU) &lt;3* IW 4 * U) iwk ¥ 1 •Ϊ&amp;w;ki I * Ui 4 UJ&gt; ά u&gt; ▲ 4&gt; UJ sk ?〇B u» 6 Τί 'U» u» 9 hu» u» nwn 53 w Π *Ί3 S UJ Π &lt;7 u&gt; h Λ iS ? Vj 〇w UJ 6 u&gt;&lt;hu&gt; 6 u» Π U) &lt;so u&gt; 〇.§ 'Νί h W1 ό V» ή π iS «-Λ Λ 1-Λ (S π ΚΛ 6 U1 UJ ό *T ! w Υ» 6 ν·Λ Π ;? KJr Λ π ί-Λ (S ίΙΡ Ui n ^T5 %Λ h &lt;y ί-Λ B u* h J1 Kf\ h *vs w W1 k V» hy Ln Q %#» &gt; 1, ψ # f N3 V “ HB playing k 禹A 1 1 蝌A 1 f 议 t J* 典 f 呶 wife 争¥ m #i # •k ο 6 RS ft o Φ Φ f # Ftto K o ^s. n Π ? • 'w* b 〇5 5= oa: woo 5* ow bj Ϊ3^ 〇neb ρϋ w K&gt;κ&gt;K&gt;K&gt;N&gt;N&gt;N&gt;K&gt;ts&gt;κ&gt; Ni - one - one - one - 3 3» on ζΛ 5 « ? acupoints? Q po 7〇5*3 W ζ/i &lt;7\ t/3 ρσ is ζΛ I/l 涔ζ ζ/5 7S 7〇ίΛ ρσ ?〇?c V3 C/5 ζΛ JW ?c pd 00 CO C/5 7S φ » 31 1308150 cr u&gt; 00 UJ UI V» U) u&gt;U&gt; to U) K O〇 U Λ U U U U 〇 〇 U U 〇 〇 〇 〇 〇 〇 ) i 〇 〇 i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i u&gt; U) Ά ?ΰ 舛 &u&gt; i* U) &lt;ni U) «·% yj &lt;ni UJ U) * s * * I * * i * * I i * 蝌m ίκ 3-Cl Π μ π Π Ui h u&gt; ή Μ ή u&gt; ή ή (SU) fS u&gt; ή u&gt; ή Ο u&gt; n U) 〇Ui ή cS u&gt; ό u&gt; u* τι Ul ή KJ\ η Ln η KJ \ n &lt;S ή ή &lt;-h &lt;S &lt;-Λ η ΚΑ η (-Λ &lt;s η * n &lt;-r* &lt;s V-fl ό t-ft ή ή U) y 7 J1 U) Morpholin-4-ylcis--3,5-dimethyl - "4Μ-yl-trans-3,5-dimethyl-morpholine. 4-yloxa-8-azabicyclo[3.2.1]oct-8-yl; 5-octyl (methoxy) Methyl)-morpholine&gt;4-yl 1 i,5-bis(methoxymethyl)-morpho-4-yl 3-methylmethylmethyl-morphin-4-yl 1,1-di Oxygen 琉 琉 _ _ 4- base 1,1-dioxo-thiophene-4-yl oxalin-4-ylmorpholin-4-ylmorpholin-4-yloridine *4-based?淋4- 4-aminoaminodiethylnitrodihexylamino °tb Luotong·1·基吼洛坑-1_基 Imidazole-1-yl?〇κ&gt; to Κ) Ν&gt; to to S&gt; Κ) Κ S Ν) to to to ts&gt; to to Ν&gt; ?〇P3 方?〇?〇?〇73 U) is ?β穴?〇?〇?〇X 5〇Os is 〇〇?σ (/1 ? 〇UipO 7S 〇〇V3?〇ζΠ (/3 hole οι ?〇〇〇?α C/3 ?〇05 c/a ?S ?β Ρΰ !» Pi ζΛ C/5 ?〇5〇5〇?〇32 1308150 Ό Οι Οθ UJ 〇\ U\ Ut Ui u&gt; Ι-Λ LA έ ί: 6 Ο Ο 〇〇Ο Ο 0 〇Ο 〇Ο ο Ο 〇〇〇〇Ο Stupid [b]thiophene-3-ylindole Benzo[b]porphin-3-yl 3- »5l&quot; Killing 4-Fluoro-Based 4-Fluoro-Based 3-&quot;5-Budyl 3-&quot;丨哚基基3-4丨哚基3-&quot;5丨嘴基3-吲嗦基3-.5卜朵基3-吲哚基3-&quot;5丨哚基3-^1哚基1 L-based 3-β弓1哚基3-»引&quot;朵基3-吲哚基3-CF3 3-CF3 2-CF3 3-CF3 3-CF3 3-CF3 3-CF3 3-CF3 3-CF3 3-CF3 3-CF3 3-CF3 3-CF3 3-CF3 3-CF3 3-CH3 3-CH3 3- C1 5-CF3 ! 5-CF3 5-CF3 5-CF3 5-CF3 5-CF3 5-CF3 5-CF3 5-CF3 5-CF3 5-CF3 5-CF3 5-CF3 ^Γΐ 5-CH3 5-CH3 5 -CI 吗淋~4-基吗淋-4_基i morpholine-4-ylmorpholin-4-yloxaline~4-yl 1 淋 -4--4-ylmorpholine _4- morpholine*4 - morpholine 4-ylmorpholine 4-yl CH2OCOCH2N(CH3)2 η EE ΙΟ ο X Cooling ch2ococh2ococh3 CH2〇CO(CH2)2CH3 CH2OCO(CH2)sCH3 CH2OCO(CH2)3CH3 CH2〇COC(CH3)3 K2OCOCH3 ts&gt; K) KJ to — - — MX* - one S) N3 K) Ν&gt;Ν&gt; is 5〇so ?〇?σ ?〇73 C/3 C/1 square ζΛ ?ζΛ ?〇S « ΙΛ ?α ?ΰ ?σ 33 1308150 [Simple description of the diagram] (none) [The main components of the diagram represent the symbol table] (none) 34

Claims (1)

130815 f Patent application No. 92107414............................... Please. Patent encirclement not 3 ^5X11.19 Pick up, apply for patent scope : Announcement | &amp; Year / / Month Day Repair (More) Original 1. A compound of the general formula (1): Wherein -R1 represents phenyl, 3-, indenyl or benzo[b]thiophen-3-yl, the group is unsubstituted or substituted by a halogen or an alkyl group of CrC3, and -R2 and R3 independently represent a halogen, hydrazine, CH3 or CF3, -R4 represents hydrazine, hydrazine H, CH2OH, NH2, bis(1-3C)alkylamino, pyrrole-1-yl, D is acyl-1-yl, morpholine _4·yl or one Or morpholino-4-yl substituted with two methyl or methoxymethyl groups, morpholine-4-amino, morpholine-4-ylmethyl, benzo-l-yl' thiophene _ 4_yl, oxothiomorpholino or 3_oxaazabicyclo[3_2.1]octyl-8-yl; -R5 represents hydrogen, or _R4 and R5_ may represent a keto group, 1, a 3-dioxa-2-yl group or a 1, 3-dioxolan-2-yl group, R represents hydrogen 'M-linyl-4-ylmethyl or CH2〇H, wherein the CH2OH group can be an organic acid Esterification, 35 1308150 η has a value of 1 or 2, when the number is equal to 1 or 2, a is an asymmetric carbon atom 8_a, our pharmacologically acceptable salt 'and includes all possible stereoisomers' The substituents on the asymmetric carbon atoms 3 and 'a, and on the latent asymmetric carbon atoms 6 and 7 are in the R-configuration or in the S-configuration. 2. If you apply for a patent scope! A compound of formula (1) wherein the aryl group 'R2 and R3 are Cf3 groups at positions 3 and 5, or 2, and 乂, R4, R and R have the meaning as defined in the scope of the patent application, And includes all possible stereoisomers listed in item 1 of the scope of the patent application. 3. A compound of the formula 第) according to claim 2, wherein R5 is hydrogen and the stereo configuration is 3R, and a, R4 and R6 have the meanings as defined in the scope of the patent application. 4. A compound of the formula (2) Wherein R1 'R2 and R3 have the meanings given in the scope of the patent application, and L represents a leaving group' such compounds can be used in the synthesis of a compound having the formula (1). 5. A pharmaceutical composition for treating a disease in which a neuropathy involving interaction with a receptor is involved, or a disease treated by controlling those receptors, comprising at least one of a pharmacologically active amount The compound claimed in one of claims 1-3 is used as an active ingredient. 36 1308150 Such as Shen μ special fiber 驿, 2 or 3 lion compound preparation - the use of pharmacy composition 'is used to treat diseases involving neurokinins interacting with cis receptors, or by controlling those receptors For diseases treated, the diseases are selected from acute and chronic pain, vomiting, inflammatory diseases, meningitis, arthritis, oxen, burns and sun burns, stomach and bowel disorders, and bowel syndrome. Human intestinal disease, ulceration, inflammation, occupational or stomach riding Wei disease, urinary tract inflammation, allergic reaction, wet therapy and rhinitis, cardiovascular disease, hypertension, atherosclerosis, edema, angina, Cluster headaches and migraine, skin diseases, #麻疗, lupus erythematosus and itching, respiratory disorders, chronic obstructive pulmonary disease, bronchospasm, bronchial pneumonia, bronchitis, respiratory syndrome and no fibrosis, various facial tumor diseases , psychiatry and / or nervous system disorders, schizophrenia and other psychiatric disorders, mood disorders 'bipolar I' bipolar _ disease and monopolar stagnation, mild inconvenience, seasonal affective disorder, New Zealand t disease, Bad money and serious (4), anxiety, panic with square phobia 'panic disorder without square phobia, social phobia, compulsive coercion with chronic convulsions or schizophrenic disorders Symptoms, compulsive obsessive-compulsive disorder with chronic convulsions or schizophrenic disorders, post-traumatic stress disorder and general anxiety disorder, substance-related disorders, dependence and abuse, substance-induced disorders, Substance withdrawal, general development of the disease, autism and Rett's disease, attention deficit and sub-behavior loss, attention to lack of activity hyperactivity, impulsive control disorder, aggressive behavior, pathological gambling, eating disorders, obesity, Sleep disorders, convulsive disorders, restless leg syndrome, conditions characterized by cognitive and memory impairments 'Alzheimer's disease' Ke-Ya syndrome' Huntington's disease, Parkinson's disease and neurological rehabilitation, and post-traumatic brain lesions. 37