TWI274584B - New 2,3-diaryl-pyrazolidine derivatives as neurotensin degrading enzyme inhibitors - Google Patents

Abstract

The invention relates to a group of novel 2,3-diaryl-pyparazolidine derivatives having formula (1). The symbols used in formula (1) have the meanings given in the specification. The compounds have inhibiting activity on enzymes which degrade the neuropeptide neurotensin and can be used for the treatment of affections and diseases caused by disturbances of the neurotensin mediated transmission.

Description

1274584 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明The enzyme of neurotensin has an inhibitory activity of a 2,3·diaryl-σ ratio smoldering derivative. 5 ^ C SUMMARY OF THE INVENTION 3 It has been found that the compound of the formula (1) and its salt have neurotensin-degrading enzyme inhibitory activity:

Wherein, hydrogen, dentate, hydroxyl or i_3c alkoxy-S2 is hydrogen or halogen - S3 is hydrogen, halogen, hydroxy or K3C alkoxy-S4 is hydrogen, halogen or optionally hydroxy, idC alkane An oxy group, an amino group, an alkyl group having a fluorene-duplex mono- or dialkylamino group, a fluorenyl group or a 1-3C sulfane 15 group substituted; an alkyl group of X6C representing a nitrogen or a carbon - when X is a nitrogen Y represents nitrogen or oxygen, or when X is carbon, γ is nitrogen - R3 and R4 are each independently hydrogen or 1-3C alkyl 1274804 玖, invention description - when X is carbon or nitrogen, Rs is Hydrogen or 1 which may be substituted by halogen, CN, CF3, thiol, 1-3C alkoxy, 1-3C sulfonylalkyl, amino, alkyl having 1-3C mono- or dialkylamino -6C alkyl group, when hydrazine is carbon, R5 represents 1-6C alkoxy group, Wei group or UC sulphur group 5-R'5 is hydrogen or 1-3C alkyl group - R6 is hydrogen or 3C's alkyl group - R7 is hydrogen or 1-3C alkyl group - Rs and R6 or R, 5 and R0 together form a 3-7 membered ring group which can be substituted by lower alkyl, pixel, CN or CF3 And R5+r,5 together form a ring of 3_7 10 7L, and, Z2 and Z3 represent a carbon atom, or B is a nitrogen atom The heart and heart are carbon atoms, or Z々z3 is a carbon atom, 22 is a nitrogen atom, or Z々Z2 is a carbon atom, z3 is a nitrogen atom, and -A is a gas group that can be halogen, CF3, (iv) or burned oxygen. A (1) cyclofilament system composed of a 4_1 () element ring substituted with a ke, cn, 15 by a hydroxy group.

More eight compounds are also inhibited by Thimet etp. peptidase EC • 15# / spirulina Ec 3 4 24 16, both enzymes will destroy the neuronal neurotoxin. Since the neurotensin-degrading activity of these enzymes is inhibited, the level of endogenous god 20 by the blood pressure-lowering hormone will increase, and it is a disease caused by a disorder of neurotensin level. Beneficial effect. The compounds of the present invention were able to effectively inhibit the above enzymes in the range of 5 pastes (P1C50 values) according to the method described in the literature BiGChenum 42i-426 and Em. LBlGchem m 269-276. 1274584 发明, DESCRIPTION OF THE INVENTION The compounds of the present invention can be used to treat lesions and disorders caused by neurotensin-mediated progression disorders, such as peripheral disorders such as blood pressure regulation and gastric emptying, neurological disorders such as Parkin eating

To the rickets, and the middle of the nervous system (CN disorder such as anxiety, depression #, mental "other mental abnormalities. The compound of formula (1) can be prepared according to at least one of the following four methods a, b, wd. The starting compound of the method is a substituted 2,3-diaryl-anthracene, one of the structures shown in the figure of the lower brother:

,, lit

Cr VI

F VH

F X Fig. 1 The fragment U-A of the 化 () morph can have the 10 structure of the group shown in Figure 2:

1274584 发明, invention description · Figure 1 = start. ratio. The scorch derivative can be obtained by the method of Scheme i. Scheme 1 is illustrated in Example 5:

Method A:

The compound referred to in Table A can be prepared according to the synthesis method of the compound A23/A24. Upon completion of step i, two diastereomers are formed which, after completion of step iii, can be separated by chromatography to the enantiomerically pure diastereomers A23 and A24, see scheme a.

The compound of Table B can be prepared by the synthetic method represented in Scheme B.1: 10 1274584 发明, Invention Description

The reaction steps in Scheme B.1 are identical to the reaction steps i and i i described in the scenario. Method C: 5 The compounds in Table c can be prepared according to the procedures of Schemes C2 and C8: + #述的合成化合物

The compound cores mentioned in Table D were prepared according to the method for synthesizing compound D1 shown in the scheme: 1274584 发明, description of the invention

The reaction steps i and ϋ in Scheme D·1 are the same as the reaction steps iii and iv described in Scheme c. [Embodiment] 5 The compound of the formula (1) and its plurality of intermediates are now described in more detail in the following examples in the manner of A-D. Example 1 Step i (Scheme A.11) 4 g (14 5 mmol^^^1·7 g (14·3 mol) of N-Boc- under stirring at room temperature under a nitrogen atmosphere L-alanine and 3.8 g (18.4 mmol) of DCC (dicyclohexylcarbodiimide) were added to 5 ml of dry acetonitrile to form a precipitate immediately, and stirring was continued overnight. The thin layer chromatography of the reaction mixture was not observed. Two points of the 8-shaped type, including two possible diastereomers in the two points. After the enthalpy, the sulphide is removed. About 2 gram of the dioxide is added to the filtrate and under vacuum at 15 The obtained powder was placed on top of a dry column of silica dioxide and then eluted with an eluent (eluent··dichloromethane/methanol 98/2). The portion of the column is absorbed and absorbed in 12 1274584 玖, the invention describes the sterol. The slurry is filtered, the residue is washed once with decyl alcohol, the sterol fraction is combined and concentrated under vacuum, and the resulting The residue is dissolved in a methane, dried over magnesium sulfate, filtered to remove the desiccant and evaporated in vacuo to remove solvent Approximately 5 g (80%) of the crude product was isolated. 5 Step oxime (Scheme A.1): 5 g (about 10 mmol) of the product obtained in the step oxime was dissolved in 1 mL of trifluoroacetic acid / stirring. Stirring was continued for 2 hours in a solution consisting of two gas methane/water (70/25/5). The reaction mixture was then concentrated under vacuum, and the resulting residue was dissolved in di-methane, then the solution was saturated. The aqueous solution of 10 and potassium carbonate was treated with water and brine, and finally dried over magnesium sulfate. The desiccant was removed by filtration and the solvent was removed by evaporation in vacuo to give 4 g of crude amine (about 1%). Iii (square A.1: 〇_5〇克〇.44 mmol at room temperature under a nitrogen atmosphere with stirring) The crude amine obtained in the 15 step oxime was suspended in 1 mL of acetonitrile and then 0.26 g (1.44 mmol) of 2-adamantyl isocyanate was added and the reaction was continued for 2 hours. About 2 g of cerium oxide was added to the reaction mixture and concentrated under vacuum, and the resulting powder was placed in dry Si〇2. The top of the column is then eluted with the eluent ( Deliquoring: ethyl acetate/petroleum ether 1/t), separately collected 2 column fractions containing diastereomers and absorbed in methanol. The two suspensions obtained were separately filtered, each residue Washing with methanol once, 'combining the corresponding methanol fractions of each diastereomer and concentrating in vacuo, then dissolving each residue in dichloromethane and drying the two solutions with magnesium sulfate. After removing the desiccant and removing the solvent in vacuo, 1274584 rose, the invention stated that each of the two solids containing one diastereomer: 0·16 g of Α23 (21%) 'melting point 14 (M ° C and 0.22 g of Α24 (29%), melting point 145_8 t. Note: Compound A12 has been prepared in enantiomerically pure form. The intermediate after the step 方案 (Scheme A1) is separated to give the enantiomer, and then the step "丨 ( Scheme A w. The (+) · enantiomer of A12 is eut〇mer.

The resolution of the intermediate after step ii (Scheme A.1) was carried out using a 10 Chirac el CD column (25 x 5 cm2, 20μ, eluent: n-hexane/ethanol oxime I). 14 1274584 玖, Invention Description The compounds in Table A were prepared by the same method: Table A R3, R4, R6, R7, S2, S4 = HX? Y = N Compound carbazole:): R5 r5. YR7A Note Melting Point A1 IHH 1 See Appendix 1 A2 II HH 1 See Appendix 2 A3 II HH 2 See Appendix 3 A4 III HH 3 153-5 A5 III HH 4 > 220 A6 II HH 5 185-8 A7 II HH 4 120-5 A8 II HH 6 130-3 A9 III HH 6 195-8 A10 IV HH 7 241-2 All III HH 7 >280 A12 III HH 8 [a ]+94 164-5 A13 II HH 8 135-40 A14 II HH 9 105- 10 A15 III HH 8 168-71 A16 IHH 7 208-210 A17 II HH 7 115-120 A18 VHH 7 See Appendix 4 A19 IHH 8 140-5 A20 III Me H 8 Diastereomer 125-145 A21 III Me H 8 132-150 A22 IHH 10 See Appendix 5 A23 II Me H 8 Diastereomer 140-3 A24 II Me H 8 145-8 A25 II Et H 8 Diastereomer 145-8 A26 II Et H 8 155-8 A27 II nBut H 8 122-5 A28 II iBut H 8 122-5 A29 II HH 10 See Appendix 6 A30 VI HH 8 221-3 A31 XHH 8 208-210 A32 VIII HH 8 145-165 A33 II nPr H 8 110 -130 15 1274584 玖, Invention Description Example 2 Step-out (Scheme Π.Π: 0.20 g (0.67 mmol) of triphosgene was dissolved in 1 mL of dry dichloromethane, and added thereto by 〇 in 45 minutes. 7 g (2.0 Torr). The reaction mixture was stirred while stirring a solution of the 5oxazolidine derivative and 42 ml (2 - 4 mmol) of diisopropylethylamine. Then, a solution of 0.33 g (2.03⁄4 mol) of methyl-2-amylamine and 0.42 ml (2.4 mol) of diisopropylethylamine in 5 ml of dry methylene chloride was added to the reaction mixture over 5 minutes. . The reaction mixture was allowed to react overnight, then the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate. The resulting solution was treated with aq. The desiccant was removed by filtration and the solvent was removed in vacuo to give an oil, which was separated by flash column chromatography (Si.sub.2, eluent: methane/methanol 99/1). The eluate was then removed in vacuo to give an oil which crystallised with stirring in diisopropyl ether solvent. The crystals were filtered and dried in air to give 69 g (yield: 184-6) of hexane (64%). Note: The methyladamantanamine used can be easily prepared by standard reductive amination using NaBH(OAc)3 as a reducing agent from 2-adamantanone and methylamine hydrochloride. 16 1274584 玖, Invention Description The compounds in Table B were prepared in the same manner: Table B R3, R4, R5, R5, S25S4 = H 4 匕 吼 坐 烧 X X Υ r6 r7 yr7a Melting point B1 III Ν Ν Η nPr 11 132-4 B2 III Ν Ν Η Me 12 184-6 B3 III Ν Ν Me Η 4 222-4 B4 III Ν Η Me 13 140-2 B5 III Ν 0 Η 14 110-2 B6 II Ν 0 Η 15 142 -4— B7 II Ν 0 Η 14 135-8 B8 I Ν 0 Η 14 141-3 B9 I Ν 0 Η 15 151-4

Note: In the case of B3 (R0 = methyl), the intermediate required after the step is called Scheme ^) can be prepared analogously to step i or oxime of Scheme A.1. 5 Example 3 ^Step i (Scheme CH: 16 g (160 mmol) of succinic anhydride was dissolved in dry diethyl ether, and then the gram dissolved in B_ was added dropwise to the detonate anhydride solution under stirring. π. After the dropwise addition is completed, the reaction mixture is heated to reflux temperature 10 and the reaction is continued overnight. The formed precipitate is filtered, and the residue is washed twice with B-, dried in air to give 45. 6 g (75%) of the desired intermediate. Panong ilL scheme cn: 4.5 g (12 mmol) of the intermediate 15 obtained in the step of argon and 7.9 g (61 mmol, 5.1 equivalents) under a nitrogen atmosphere Diisopropylethylamine was dissolved in 5 liters of dry dichloromethane, and the resulting solution was cooled to 17 1274584 搅拌 under stirring, invention 41, and then 〇·9 gram (7.0 mM) was added thereto. Molar) 1 - hydroxyaza. stupid triazole and 4.20 g (15 Torr) of 2-chloro-dimethylimidazolium rust hexafluorophosphate. Then add 2·丨9 g to the reaction mixture (丨5 毫2 moles of amino-adamantane and reacted at room temperature for 1 hour. 5 Add about 4 grams of cerium oxide The reaction mixture was poured into a reaction mixture under vacuum and the resulting powder was added to the top of a dry column (si02), followed by elution with an eluent (eluent: ethyl acetate/petroleum ether/丨) The fraction containing the product was collected and absorbed in sterol, the resulting slurry was filtered, and the residue was washed once with decyl alcohol. The methanol solution was combined and concentrated under 10 vacuum, and then the residue was dissolved. In di-methane, the resulting solution was dried over magnesium sulfate. After removing the solvent and removing the solvent in vacuo, 2.0 g of solid C2 (32%), m.p. The gram (60 mmol) succinic anhydride suspension 15 floated in 35 liters of a stupid, and then added thereto 2.07 g (18 亳mol) of hydroxy-butanediamine, 〇.73 g (6 亳 mole) The dimethylaminopyridine, gram (8 mmol) of dry tert-butanol and gram (18 mmol) of triethylamine are heated to reflux temperature and reacted overnight. The reaction mixture is cooled and passed to the reaction mixture. Add acetic acid, the solution is used separately The recommended sample is treated with a solution of 2 citric acid and brine, and then the organic portion is dried with magnesium sulfate, the desiccant is removed and the solvent is removed under vacuum to obtain a smudged oil. Crystallization in hexanes gave 4. 4 g (42%) of the desired monoester. Disk iv (18 1274584 玖, invention shows that this step is carried out according to the procedure described in the literature "Synthesis (2000) ρ1369-7Γ) The 2-position methylation reaction of mono-tert-butyl succinate was carried out by reaction with diisopropyl amination clock and mercapto iodide in tetrahydrofuran at -78 °C. The isolated yield of 2-mercapto-succinic acid mono-tert-butyl ester reached 60 〇/〇. 5 骤 v ( 方 方 方 方 方 方 方 方 方 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在Then, the solution was cooled to 4. 〇. 9 g (6.4 mmol) of 1-yl-7-aza-benzotriazole and 4 g (15 mmol of methyl meth 10) were added thereto. Sodium cadmium hexafluorophosphate, then added 4. j g (14 mmol) of hydrazine without increasing the temperature, and reacted at room temperature overnight. About 3 g of yttrium (si〇^ was added to the reaction mixture) And concentrated under vacuum, the obtained powder was added to the baking sheet of the drying column (SiO 2 ), and then eluted with an eluent (eluent: ethyl acetate / petroleum _ 1/4), and the product containing the product was collected. Part of the column and sucked it in sterol, filtered the resulting liquid, and the residue was washed once with alcohol. The sterol fraction was combined and concentrated under vacuum, and the resulting residue was dissolved in dichloromethane. In the hospital, the obtained solution was dried with magnesium sulfate, and the intermediate was reduced. 20 Step vi (Part: The following method was carried out in the middle of t-butyl vinegar Hydrolysis reaction (obtained in step v): 3 g (6.4 mmol) of tert-butyl was dissolved in 3 q ml of dry dichlorohydrazine, and then 1 ml of trifluoroacetic acid was added dropwise thereto. After 2 hours, the reaction was completed. The reaction mixture was concentrated under vacuum, and the residue was dissolved in 19 1 274 584 玖, and a small amount of diethyl ether was invented and placed on top of a short column (dry Si 2 ), followed by an ethyl bond. The elution was carried out. The eluate containing the product was concentrated under vacuum, the residue was stirred overnight in petroleum ether, filtered to collect crystals, and the crystals were dried in air to obtain 2 g (80%). Intermediate. 5 Step vii (Fanghuang Cl): 2.17 g (5.3 mmol) of the intermediate prepared in the step "Steps and 4. 7 ml (27 mmol, 5.1 equivalents) of diisopropyl B under a nitrogen atmosphere. The base amine was dissolved in 25 ml of dry digas institute, and the resulting solution was cooled to 4 ° C under the drop. Then, 42 g (31 mmol) of hydrazine-hydroxyaza-benzo(7) tris And 1.85 g (6.6 亳mol) of 2_chloro-u-dimercaptoimidazolium hexafluorodislate 1 gram (6. 6 moles) of 2-amino-adamantane was added to the reaction mixture and allowed to react at room temperature for 1 hour. About 4 grams of cerium oxide was added to the reaction mixture and concentrated under vacuum. The obtained powder was added to the top of a drying column (Si〇2), and then 15 was eluted with an eluent (eluent: ethyl acetate/petroleum ether 1/2), and the diastereoisomers were collected separately. The part of the column is taken up in methanol and the resulting two slurries are separately filtered and each residue is washed once with methanol. The corresponding methanol knives of each diastereomeric racemate are combined and Concentration was carried out under vacuum, and each residue was separately dissolved in dioxane gas and dried over magnesium sulfate. The desiccant was removed and the solvent was removed in vacuo to afford two solids, each solid containing one of the possible diastereomeric racemates, respectively, 1.08 g of C8 (37%) active racemate, melting point 23 8-4 CTC, and 1.09 g (3 7%) of another pharmacologically inactive racemate with a melting point of 125-30 ° C (not listed in Table C). 20 1274584 发明, inventive description The compound of Table C is obtained by a similar method: Table C R3, H4, R5, R5,, S2, S4 = HX=c, Y=N Compound mouth ratio σ sitting r6 R7 YR7A Melting point Cl III HH 8 210-2 C2 II HH 8 90-4 C3 II HH 7 230-2 C4 IHH 8 160-4 C5 IHH 7 1 198-202 C6 VII HH 7 208-210 C7 VII HH 8 215-7 C8 III Me H 8 238-240 C9 IX HH 8 147-150 Example 4 Step iii (French D.1): 5 0.92 g (4.9 mmol) of the intermediate obtained in the step and 4.4 ml under a nitrogen atmosphere. (25 mmol, 5.1 eq.) Diisopropylethylamine was dissolved in 15 liters of dry dioxane, and the resulting solution was cooled to 4 °C with stirring. Then, 0.45 g (3.3 mmol) of 1-hydroxy-7-aza-benzotriazole and 2.1 g (7.5 mmol) of 2-chloro-1,3-dimercaptoimidazolium hexafluorophosphate 10 salt were added. Next, 1 g of 8 g (7.2 mmol) of 2-amino-Golden J was added to the reaction mixture and reacted at room temperature for 1 hour. This reaction mixture was used in the next step iv. H poly iv (Scheme D.1): To the reaction mixture of step iii was added 45 ml of dry di 15 chlorodecane and 11 liters (143 mmol) of trifluoroacetic acid under stirring, and stirring was continued for 24 hours. The reaction mixture was concentrated under vacuum and the residue was dissolved in a small portion of <RTI ID=0.0>>> The product-containing eluate was concentrated under vacuum to give the desired acid intermediate of EtOAc (yield: 67%). Step v (square D/η: 5) Under stirring, 〇·87 g (3.28 mmol) of decyl-succinic acid monodecylamine (step iv) was dissolved in 15 ml of dry dichloromethane, and the solution was It was cooled to 4 ° C. Then, 3 g (2.2 mol) of hydroxyazepine-benzodiazepine and 1.40 g (5 mM) of 2-chloro-indole, 3-dimethyl group were added thereto. Imidazoline rust hexafluorophosphate' was then added to a solution of 33 g (4·8 〇亳mol 10 ) 温度 without increasing the temperature, and reacted overnight at room temperature. About 3 g of yttrium (Si〇2) was added. To the reaction mixture and concentration under vacuum, the obtained powder was added to a dry column (top of SiOJ, and then eluted with an eluent (eluent: ethyl acetate/oil shout 1:1). The portion of the column of the diastereomeric racemate was taken up in methanol. The two slurries obtained were separately filtered and each residue was washed once with methanol, 'merging each diastereomeric The phase of the racemate

Racemic D1, smelting behavior: melting at 80-2t remelting at 125-8 °C. And 〇·4〇g (23%) of the active base melt, solidified at 100 ° C, ?? ! 274584 玖, the invention description of the compound of Table D was obtained by a similar method. Table D ---~~__ R3, R4Rs \SX=CY=N >2?S4 = H ——-- J\ ? 1 1>| Compound ° ratio. Sit-fired r5 r6 YR7A ------ Note----- Melting point D1 II Me H 8 80-2/125^ D2 II nBut H 8 Diastereomer 80-1/150^? D3 II nBut H 8 210-2 D4 II iBut H 8 ' --------— 155-8 D5 II Et H 8 diastereomer 90-2/125^ D6 II Et H 8 90-2/ 155^7 Example 5 The 2,% diaryl-5 pyrazolidines I to X used as starting materials in the above Examples 1-4 were prepared as follows: Step i (Scheme will be 16.9 g of acetic acid and 2.3 ml of water) The mixture was cooled (ice/water)' and then 6. 8 ml of concentrated sulfuric acid was carefully added thereto. U.3 g (82 mmol) was added portionwise to the cooled solution under an air atmosphere and vigorous stirring. 1 )) 2-fluorophenyl hydrazine. Then keep the temperature below 25, and add 1 〇. gram (82 mmol) 2 qi styrene and 2 46 g (8) mmol to the obtained solution. a mixture of oligomeric roads. The reaction may accumulate ((10) for a period of time (4). Mix vigorously overnight at room temperature. Under cooling conditions, add 50 ml of water to it, iron detox 7 π ± $ l ..., dip with ether. The remaining aqueous phase is made up of 1 5 50% hydrazine emulsified sodium aqueous solution, and then extracted with two liters of B knife. "Do not wash with water 3 times and brine! Two owes, finally with sulphuric acid Drying in the town, removing the desiccant by filtration and removing the solvent under vacuum to obtain ι 6 23 1274584 玖, invention gram (75%) crude oil, which was not purified, should be carried out under a nitrogen atmosphere at -20 ° C. Preservation to avoid oxidation of the pyrrolidine ring.

24 1274584 玖, invention instructions

25 1274584 玖, invention instructions

t diagram simple description 3 (none) [the main components of the diagram represent the symbol table] (none) 26

Claims (1)

Pick up, apply for patent scope 1 · A compound of formula (1): Perimeter revision Revision period: July 1995. ΠΑ El repair (more} original Wherein -S1 is hydrogen, halogen, hydroxy or 1-3C alkoxy; -§2 is hydrogen or _; -S3 is hydrogen, halogen, hydroxy or alkoxy; -S4 is ruthenium, ruthenium or An alkyl group of UC optionally substituted by a hydroxy group, an alkoxy group, an amino group, a thiol group having a mono- or dialkylamino group having 1 to 3 C, a thiol group or H; -X represents nitrogen or carbon; - When X is nitrogen, γ represents nitrogen or oxygen, or when it is carbon again, γ φ is nitrogen; • R3 and R4 are each independently hydrogen or 1-3C alkyl; - when X is carbon or nitrogen When R5 is hydrogen or may be substituted by halogen, CN, CF3, a trans group, a 1-3C alkoxy group, a sulfonyl group of uc, an amino group, an alkyl group, a mono- or dialkylamino group having UC 1-6C alkyl group, or when X is carbon, R5 represents a 1-6C alkoxy group, a fluorenyl group or a 1-3C sulfanyl group; -R'5 is a hydrogen or a K3C alkyl group; 27 1274584 , the scope of the patent application - R6 is hydrogen or 1-3C alkyl; seven seven is hydrogen or 1-3C alkyl; -R5 and R0 together or R'5 and &together; can be formed by low-grade alkyl, hydrazine a CN-7 or CF3 substituted 3-7 membered ring group, together with r5 + ruler '5, can form a 3-7 membered ring. 'Ζ#Ζ3 indicates carbon, or Z! is nitrogen, Z2*Z3 is carbon, or ZjaZ3 is carbon, Z2 is nitrogen, or Ζ3σΖ2 is carbon, Z3 is nitrogen; •A is derived from halogen, eh, uc a (poly)cycloalkyl system consisting of a 4-10 membered ring substituted with alkoxy, CN, hydroxy or thiol, and pharmaceutically acceptable salts thereof. 2. A process for the preparation of a compound according to claim 1 which is characterized in that the compound is prepared according to one of the following schemes: In this synthesis, after completion of step i, two diastereomers are formed which, after completion in step iii, can be chiraled with Chiralcel CD (25 x 5 cm2, 2 〇/i, eluent: hexane/ethane 4/1) Separation into enantiomerically pure diastereomers by column chromatography; 28 1274584 Pickup, patent application scope Scheme B In the synthesis, the reaction steps i and ii are the same as those of the scheme A; Option C 29 1274584 Pick up, apply for patent scope In this synthesis, reaction steps i and ii are the same as steps m and iv of Scheme C, respectively. 3. A composition of music comprising at least one of the compounds described in the scope of the patent application as an active ingredient. 4. Use of a compound as described in claim 1 for the preparation of a pharmaceutical composition for the treatment of diseases and diseases caused by neurotensin-mediated delivery. 10 5. Use of a compound as described in the patent application for the preparation of a pharmaceutical composition for the treatment of psychosis. μ 6·2 The use of the compound described in claim 1 for the treatment of a pharmaceutical composition for the treatment of Parkinson's disease. The use of pharmacy compositions for depression. 8_ ^ as claimed in the scope of patents! The use of the compound described in the preparation of the pharmaceutical composition of Yin. , ~ therapy 30 15