WO2020239073A1 - 一种并环化合物、其制备方法和用途 - Google Patents
一种并环化合物、其制备方法和用途 Download PDFInfo
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- WO2020239073A1 WO2020239073A1 PCT/CN2020/093279 CN2020093279W WO2020239073A1 WO 2020239073 A1 WO2020239073 A1 WO 2020239073A1 CN 2020093279 W CN2020093279 W CN 2020093279W WO 2020239073 A1 WO2020239073 A1 WO 2020239073A1
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- 0 CC*(C)C1C([*@@](*)C(C)=*C)*(C)C*(*)C1 Chemical compound CC*(C)C1C([*@@](*)C(C)=*C)*(C)C*(*)C1 0.000 description 15
- RDSIMGKJEYNNLF-UHFFFAOYSA-N Brc(cc1)cc2c1[s]cc2 Chemical compound Brc(cc1)cc2c1[s]cc2 RDSIMGKJEYNNLF-UHFFFAOYSA-N 0.000 description 1
- HQKXDCFSYKYITO-UHFFFAOYSA-N C(C1C(C2)CNC1)C2c1cccc2ccccc12 Chemical compound C(C1C(C2)CNC1)C2c1cccc2ccccc12 HQKXDCFSYKYITO-UHFFFAOYSA-N 0.000 description 1
- WHMKETHDPMCZCF-UHFFFAOYSA-N C1C(c2c(cccc3)c3ccc2)=CC2C1CNC2 Chemical compound C1C(c2c(cccc3)c3ccc2)=CC2C1CNC2 WHMKETHDPMCZCF-UHFFFAOYSA-N 0.000 description 1
- VECYYWDMWVGSEW-UHFFFAOYSA-N C1NCC(C2)C1CN2c1c[s]c2ccccc12 Chemical compound C1NCC(C2)C1CN2c1c[s]c2ccccc12 VECYYWDMWVGSEW-UHFFFAOYSA-N 0.000 description 1
- DSAMCIQNNUVVPE-UHFFFAOYSA-N C1NCC(CC2)C1CCN2c1cccc2c1[s]cc2 Chemical compound C1NCC(CC2)C1CCN2c1cccc2c1[s]cc2 DSAMCIQNNUVVPE-UHFFFAOYSA-N 0.000 description 1
- GNXMEDPJEBDXRE-UHFFFAOYSA-N CC(C)(C)OC(N1CC(CC(C2)(c3cccc4ccccc34)O)C2C1)=O Chemical compound CC(C)(C)OC(N1CC(CC(C2)(c3cccc4ccccc34)O)C2C1)=O GNXMEDPJEBDXRE-UHFFFAOYSA-N 0.000 description 1
- DIDQRACXWWEPDZ-UHFFFAOYSA-N CC(C)(C)OC(N1CC(CC(C2)O)C2C1)=O Chemical compound CC(C)(C)OC(N1CC(CC(C2)O)C2C1)=O DIDQRACXWWEPDZ-UHFFFAOYSA-N 0.000 description 1
- OYDIECGUBNPZFY-UHFFFAOYSA-N CC1SC=CC=C1 Chemical compound CC1SC=CC=C1 OYDIECGUBNPZFY-UHFFFAOYSA-N 0.000 description 1
- BMRWHMOKWQZVSY-UHFFFAOYSA-N CCCCNC(C)S Chemical compound CCCCNC(C)S BMRWHMOKWQZVSY-UHFFFAOYSA-N 0.000 description 1
- JKWIRLQJTXXTEP-UHFFFAOYSA-N CN(C1)CC(C2)C1CN2c1ccccc1F Chemical compound CN(C1)CC(C2)C1CN2c1ccccc1F JKWIRLQJTXXTEP-UHFFFAOYSA-N 0.000 description 1
- OSAMPQYJUNIRPD-UHFFFAOYSA-N CN(C1)CC(CC2)C1CCN2c1cc(cccc2)c2cc1 Chemical compound CN(C1)CC(CC2)C1CCN2c1cc(cccc2)c2cc1 OSAMPQYJUNIRPD-UHFFFAOYSA-N 0.000 description 1
- UMXFUKCRESMQIX-FRKPEAEDSA-N OC(/C=C(\C(O)=O)/[F]c(c1ccccc1cc1)c1N1CC(CNC2)C2C1)=O Chemical compound OC(/C=C(\C(O)=O)/[F]c(c1ccccc1cc1)c1N1CC(CNC2)C2C1)=O UMXFUKCRESMQIX-FRKPEAEDSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to a compound represented by the general formula (I), its stereoisomers or a pharmaceutically acceptable salt thereof, its preparation method, a pharmaceutical composition comprising it and its preparation treatment Application of drugs in central nervous system diseases.
- Depression is a widespread and persistent chronic disease, with a lifetime prevalence of approximately 16% worldwide.
- isoniazid and imipramine were accidentally discovered clinically to have antidepressant effects, and they became the first-generation drugs to treat depression.
- the monoamine hypothesis was put forward in pharmacological research, which believed that the hypofunction of serotoninergic (5-HT)rgic nerves, dopaminergic (DA)rgic nerves and noradrenalinergic (NA)rgic nerves in the brain is depression. The reason is that drugs that can improve the above-mentioned neurological function have antidepressant effects.
- the first-line therapeutic drugs currently in clinical use such as selective 5-HT reuptake inhibitors (SSRIs) and 5-HT and NA reuptake inhibitors (SNRIs), are drugs based on the monoamine hypothesis.
- SSRIs selective 5-HT reuptake inhibitors
- SNRIs 5-HT and NA reuptake inhibitors
- drugs on the market in the field of major depression only about 30-40% of patients respond to first-line treatment. These drugs still have no or low efficacy in more than 30% of patients. Therefore, it is still necessary to find new antidepressants with good curative effect, low side effects and broad therapeutic spectrum.
- An object of the present invention is to provide a fused ring compound represented by general formula (I), its stereoisomers or a pharmaceutically acceptable salt thereof.
- Another object of the present invention is to provide a method for preparing the compound represented by the general formula (I).
- Another object of the present invention is to provide a pharmaceutical composition containing a therapeutically effective amount of one or more compounds represented by the general formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof.
- Another object of the present invention is to provide a compound represented by the general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical composition for preparing prevention and/or treatment of central nervous system diseases Use in medicine.
- Another object of the present invention is to provide a method for preventing and/or treating central nervous system diseases, which is characterized in that a therapeutically effective amount of one or more compounds represented by the general formula (I), Its stereoisomer or its pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition.
- R 1 is hydrogen or C1-C20 alkyl; preferably hydrogen or C1-C10 alkyl; more preferably hydrogen or C1-C6 alkyl;
- n, p, q are each independently 0 or 1 or 2 or 3; preferably, m, n, p, and q are each independently 1 or 2; provided that m+p is 1, 2, 3, or 4 , N+q is 1, 2, 3, or 4 and m+p+n+q is 3, 4, 5, 6, or 7;
- X is CR 2 , N or C; when X is CR 2 or N, the one connected to X Represents a single bond, R 2 is hydrogen, hydroxyl or C1 ⁇ C6 alkoxy; when X is C, it is connected to X Represents a double bond;
- G ring is phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indenyl, monocyclic heterocyclic group or benzoheterocyclic group;
- the G ring is Moreover, the G ring is optionally substituted by one or more identical or different substituents, and the definition of the substituents on the G ring is the same as described above.
- the G ring is more preferably Moreover, the G ring is optionally substituted by one or more identical or different substituents, and the definition of the substituents on the G ring is the same as described above.
- the attachment position of the above-mentioned substituent can be any attachment position on the ring, for example, Substituents can represent among them, Indicates the connection location.
- X and R 1 are as defined above.
- R 1 is as described above.
- R 1 , X and G ring are as described above, and * indicates the binding site with G ring part.
- the invention relates to Compounds that are mixtures of enantiomers and where It is an enantiomerically rich or enantiomerically pure compound.
- the following shows the possible enantiomers of the groups S-9a, S-15a, S-18a and S-29a:
- Method 1 The compound represented by formula (II-a) is coupled with the compound represented by formula (III) to obtain the compound represented by formula (Ia), as shown in reaction formula 1:
- G ring, m, n, p, q, R 1 are the same as defined above;
- L 1 represents halogen, C1 ⁇ C6 alkylsulfonyloxy, benzenesulfonyloxy or naphthalenesulfonyloxy, the above C1 ⁇ C6 alkylsulfonyloxy, benzenesulfonyloxy, naphthalenesulfonyloxy can optionally be one or more selected from halogen, C1 ⁇ C6 alkyl, C1 ⁇ C6 alkoxy, nitro, hydroxyl , Amino and C1-C6 alkanoyl groups are further substituted;
- L 1 is preferably halogen, C1-C4 alkylsulfonyloxy, benzenesulfonyloxy, naphthalenesulfonyloxy, the above-mentioned C1-C4 alkylsulfonyl The
- Method 2 The compound represented by formula (II-b) is coupled with the compound represented by formula (III) to obtain the compound represented by formula (IV), and then the amino protecting group is removed to obtain the compound of formula (Ib).
- the alkylation reaction or the reductive amination reaction must be carried out to obtain the compound represented by formula (Ia), as shown in reaction formula 2:
- G ring, m, n, p, q have the same definition as above;
- R 1 is C1 ⁇ C20 alkyl,
- L 1 represents halogen, C1 ⁇ C6 alkylsulfonyloxy, benzenesulfonyloxy or naphthalenesulfonyl
- the oxy group, the above-mentioned C1-C6 alkylsulfonyloxy, benzenesulfonyloxy, and naphthalenesulfonyloxy may optionally be substituted by one or more selected from halogen, C1-C6 alkyl, C1-C6 alkoxy , Nitro, hydroxyl, amino and C1-C6 alkanoyl groups are further substituted;
- L 1 is preferably halogen, C1-C4 alkylsulfonyloxy, benzenesulfonyloxy, naphthalenesulfonyloxy, the
- PG is a substituted or unsubstituted benzyl group, an acyl type amino protecting group or an alkoxycarbonyl type amino protecting group, and the substituents on the benzyl group are independently selected from halogen, trifluoromethyl, C1-C6 alkyl, C1 One or more of ⁇ C6 alkoxy and nitro, preferably the acyl amino protecting group is formyl, acetyl, propionyl, benzoyl, haloacetyl, phthaloyl, and
- the alkoxycarbonyl amino protecting group is tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl,
- Method 3 The compound represented by formula (V) is coupled with the compound represented by formula (III) to obtain the compound of formula (VI), and then the amino protecting group is removed to obtain the compound of formula (Ic), optionally alkyl Chemical reaction or reductive amination reaction to obtain the compound represented by formula (If), as shown in reaction formula 3:
- G ring, m, n, p, q have the same definition as above;
- R 1 is C1 ⁇ C20 alkyl,
- L 1 represents halogen, C1 ⁇ C6 alkylsulfonyloxy, benzenesulfonyloxy or naphthalenesulfonyl
- the oxy group, the above-mentioned C1-C6 alkylsulfonyloxy, benzenesulfonyloxy, and naphthalenesulfonyloxy may optionally be substituted by one or more selected from halogen, C1-C6 alkyl, C1-C6 alkoxy , Nitro, hydroxyl, amino and C1-C6 alkanoyl groups are further substituted;
- L 1 is preferably halogen, C1-C4 alkylsulfonyloxy, benzenesulfonyloxy, naphthalenesulfonyloxy, the
- PG is a substituted or unsubstituted benzyl group, an acyl type amino protecting group or an alkoxycarbonyl type amino protecting group, and the substituents on the benzyl group are independently selected from halogen, trifluoromethyl, C1-C6 alkyl, C1 One or more of ⁇ C6 alkoxy and nitro, preferably the acyl amino protecting group is formyl, acetyl, propionyl, benzoyl, haloacetyl, phthaloyl, and
- the alkoxycarbonyl amino protecting group is tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl,
- the deamination of the protective group is carried out in the presence of acid or acidic silica gel
- the acid is selected from one or more of hydrochloric acid, hydrogen chloride gas, sulfuric acid, phosphoric acid, nitric acid, acetic acid, hydrobromic acid, hydroiodic acid, perchloric acid, trichloroacetic acid and trifluoroacetic acid;
- the reaction of the deamination protecting group is carried out in the presence or absence of a solvent, and the solvent is selected from water, dioxane, methanol, ethanol, n-propanol, isopropanol, tert-butanol, ethyl ether, N-methyl One or more of pyrrolidone, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, N,N-dimethylformamide, toluene, ethyl acetate, propyl acetate and butyl acetate;
- the compound (IV) or (VI) or its salt is dissolved in a solvent and reacted with the chloroformate A 2 OOCCl to remove the benzyl group.
- the product undergoes hydrolysis in the solvent to remove the acyl group to obtain the formula (Ib) or (Ic) ),
- a 2 is a halogenated or unsubstituted C 1 -C 6 alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group, and the substituent on the substituted phenyl group or the benzyl group is selected from fluorine One or more substituents in, chlorine, bromine, iodine, nitro, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; preferably, the A 2 is C 1 -C 4 alkyl , Substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, the substituent on the substituted phenyl or benzyl is selected from one or more substituents of fluorine, chlorine, bromine, iodine or nitro ; More preferably, the A 2 is methyl, ethyl, phenyl or benzyl,
- the reaction temperature for the deamination of the protective group is 0°C to 150°C, preferably 30°C to 100°C; the reaction time is 0.5 to 24 hours, preferably 1 to 12 hours;
- Method 4 The compound represented by formula (VII-a) and the compound represented by formula (X) undergo carbonyl addition reaction to obtain the compound represented by formula (VIII), and then the amino protecting group is removed to obtain the compound of formula (Id), As shown in Reaction 4:
- G ring, m, n, p, q are the same as defined above;
- L 2 represents Li, MgBr, MgCl, MgI, ZnBr, ZnCl or ZnI;
- PG is an acyl amino protecting group or an alkoxycarbonyl amino protecting group, preferably the acyl amino protecting group is formyl, acetyl, propionyl, benzoyl, haloacetyl, phthaloyl, and
- the alkoxycarbonyl amino protecting group is tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl,
- the deamination of the protective group is carried out in the presence of acid or acidic silica gel
- the acid is selected from one or more of hydrochloric acid, hydrogen chloride gas, sulfuric acid, phosphoric acid, nitric acid, acetic acid, hydrobromic acid, hydroiodic acid, perchloric acid, trichloroacetic acid and trifluoroacetic acid;
- the reaction of the deaminated protective group is carried out in the presence or absence of a solvent, and the solvent is selected from water, dioxane, methanol, ethanol, n-propanol, isopropanol, tert-butanol, diethyl ether, N-methyl One or more of pyrrolidone, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, N,N-dimethylformamide, toluene, ethyl acetate, propyl acetate and butyl acetate;
- the reaction temperature for the deamination of the protective group is 0°C to 150°C, preferably 30°C to 100°C; the reaction time is 0.5 to 24 hours, preferably 1 to 12 hours;
- Method 5 The compound represented by the formula (VII-a) and the compound represented by the formula (X) are subjected to a carbonyl addition reaction to obtain the compound represented by the formula (VIII), and then the protective group is simultaneously dehydrated and deaminoated to obtain the formula (Ie)
- the compound shown can optionally undergo an alkylation reaction or a reductive amination reaction to obtain a compound represented by formula (Ig), as shown in reaction formula 5:
- G ring, m, n, p, q are the same as defined above;
- R 1 is a C1-C20 alkyl group;
- L 2 represents Li, MgBr, MgCl, MgI, ZnBr, ZnCl or ZnI;
- PG is an acyl amino protecting group or an alkoxycarbonyl amino protecting group, preferably the acyl amino protecting group is formyl, acetyl, propionyl, benzoyl, haloacetyl, phthaloyl, and
- the alkoxycarbonyl amino protecting group is tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl,
- the simultaneous dehydration and deamination of the protecting group reaction is carried out in the presence of an acid; preferably, the acid is selected from hydrochloric acid, hydrogen chloride gas, sulfuric acid, phosphoric acid, nitric acid, acetic acid, hydrobromic acid, hydroiodic acid, perchloric acid, trichloro One or more of acetic acid and trifluoroacetic acid; the simultaneous dehydration and deamination of the protective group reaction is carried out in the presence or absence of a solvent, and the solvent is selected from water, dioxane, methanol, ethanol, n-propane Alcohol, isopropanol, tert-butanol, diethyl ether, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, N,N-dimethylformamide, toluene, ethyl acetate, propyl acetate and butyl acetate
- G ring, m, n, p, q are the same as defined above;
- R 1 is a C1-C20 alkyl group;
- L 2 represents Li, MgBr, MgCl, MgI, ZnBr, ZnCl or ZnI;
- the dehydration reaction is carried out in the presence of an acid; preferably, the acid is selected from hydrochloric acid, hydrogen chloride gas, sulfuric acid, phosphoric acid, nitric acid, acetic acid, hydrobromic acid, hydroiodic acid, perchloric acid, trichloroacetic acid and trifluoroacetic acid
- the dehydration reaction is carried out in the presence or absence of a solvent, and the solvent is selected from water, dioxane, methanol, ethanol, n-propanol, isopropanol, tert-butanol, and ether , One or more of N-methylpyrrolidone, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, N,N-dimethylformamide, toluene, ethyl acetate, propyl acetate and butyl acetate;
- Method 7 The compound represented by formula (Ie) or (Ig) is subjected to hydrogenation reduction reaction to obtain the compound represented by formula (Ic) or formula (If):
- G ring, m, n, p, q are the same as defined above.
- the hydrogenation reduction reaction is carried out in the presence of a reducing agent, and the reducing agent includes, but is not limited to: hydrogen/palladium carbon, hydrogen/Raney nickel, hydrogen/palladium hydroxide, and the like.
- the coupling reaction is carried out in the presence of a palladium catalyst and a base
- the palladium catalyst is palladium acetate (Pd(OAc) 2 ), two (triphenylphosphine) palladium dichloride ((Ph 3 P) 2 PdCl 2 ), bis(benzonitrile) palladium chloride ((PhCN) 2 PdCl 2 ), tetrakis(triphenylphosphine) palladium (Pd(PPh 3 ) 4 ), bis(triphenylphosphine) palladium acetate ((Ph 3 P) 2 Pd(OAc) 2 ), 1,2-two (Diphenylphosphino) ethane palladium dichloride ((PdCl 2 (dppe) 2 )), bis(1,2-bis(diphenylphosphine)ethane) palladium (Pd(dppe) 2 ), double (Dibenzylideneacetone)palladium (Pd(dba) 2 ), tris(dibenzylideneacetone
- the base is sodium bis(trimethylsilyl)amide, potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, potassium phosphate, sodium phosphate, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, potassium fluoride, One or more of sodium fluoride, tetrabutylammonium fluoride (TBAF), sodium acetate, potassium acetate, cesium carbonate, potassium carbonate and sodium carbonate,
- TBAF tetrabutylammonium fluoride
- the solvent used in the reaction includes water, dioxane, tetrahydrofuran, toluene, xylene, tert-butanol, acetone, N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, or the above solvents mixture;
- the reaction also optionally adds a ligand as a reaction accelerator, and the ligand is 2,2'-diphenylphosphino-1,1'-binaphthyl (BINAP), tri-tert-butyl (P( t-Bu) 3 ), 1,1'-bis-(diphenylphosphino)ferrocene (dppf), 2-dicyclohexylphosphorus-2,4,6-triisopropylbiphenyl (x-phos ), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (Xantphos), tri-tert-butylphosphine tetrafluoroborate or tris(2-methylphenyl)phosphine (P( o-tolyl) 3 ).
- BINAP 2,2'-diphenylphosphino-1,1'-binaphthyl
- P( t-Bu) 3 tri-tert-butyl
- the solvent for the carbonyl addition reaction is selected from one or more of tetrahydrofuran, diethyl ether, n-hexane, n-pentane, dioxane, and toluene, and the carbonyl addition reaction
- the reaction temperature is -80°C ⁇ 100°C, preferably -80°C ⁇ 30°C;
- the alkylation reaction is carried out in the presence of an alkylating reagent, and the alkylating reagent includes but is not limited to: methyl iodide, ethyl trifluoromethanesulfonate, ethyl iodide, ethyl bromide and the like.
- the reductive amination reaction is carried out in the presence of corresponding aldehydes/ketones and reducing agents, and the reducing agents include but are not limited to: sodium borohydride, potassium borohydride, sodium triacetoxyborohydride (NaBH(OAc) 3 ) , Tetramethyl triacetoxyammonium borohydride and sodium cyanoborohydride.
- the reducing agents include but are not limited to: sodium borohydride, potassium borohydride, sodium triacetoxyborohydride (NaBH(OAc) 3 ) , Tetramethyl triacetoxyammonium borohydride and sodium cyanoborohydride.
- the stereoisomers of the compound of formula (I) include any enantiomers, diastereomers, tautomers, racemic mixtures, enantiomerically enriched mixtures and enantiomers thereof
- the racemic form can be decomposed into optical enantiomers by known methods.
- the diastereomeric salt can be separated using an optically active acid, treated with a base to release the optically active amine compound, and the racemate can be further resolved into
- the method of optical enantiomers is based on chromatography on an optically active substrate.
- racemic compounds of the present invention can also be decomposed into their optical pairs by fractional crystallization of d or l-(tartaric acid, mandelic acid or camphorsulfonic acid) salt. Enantiomer.
- the compounds of the present invention can also be decomposed by forming diastereomeric derivatives.
- the starting compound used in each of the above reaction formulas may be a suitable salt
- the suitable salt includes alkali metal salt and alkaline earth metal salt, such as sodium salt, potassium salt, calcium salt, magnesium salt, etc.; organic alkali salt such as pyridine salt , Triethylamine salt, etc.; inorganic acid salt such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.; organic acid salt such as formate, acetate, propionate , Glycolate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, picrate, Glutamate, methanesulfonate and benzenesulfonate, etc.;
- the starting compounds used in the above reaction formulas may include solvate forms, such as hydrates, alcoholates, and the like.
- the compound ring compound represented by the general formula (I) of the present invention and its stereoisomers also include its solvate forms, such as hydrates, alcoholates, etc., and the solvates are included in the scope of the present invention Inside.
- the pharmaceutically acceptable salt of the fused ring compound represented by the general formula (I) and its stereoisomers of the present invention means that the fused ring compound represented by the general formula (I) or its stereoisomer is treated with an appropriate acid , To convert them into therapeutically active non-toxic salt forms.
- salts such as hydrochloride, hydrobromide, hydroiodide, sulfate or hydrogen sulfate, nitrate, phosphate or acid phosphate, perchlorate, formate, acetate, Trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, succinate, glutarate, maleate, fumarate, milk Acid salt, malate, citrate, tartrate, picrate, glutamate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, water Salicylate, ascorbate, camphorate or camphorsulfonate, etc.
- alkali treatment can also be used to convert the salt form to the free base form.
- solvates include, for example, hydrates and alcoholates.
- Each target compound obtained by each reaction formula can be separated and purified from the reaction mixture by the following methods, for example: after the reaction mixture is cooled, the crude product is separated by methods such as filtration, extraction or concentration, and then passed through a conventional column such as Purification is carried out by chromatography, beating or recrystallization.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by the above general formula (I), its stereoisomers or pharmaceutically acceptable salts thereof and optionally a pharmaceutically acceptable carrier .
- the pharmaceutical composition can be used to treat or prevent central nervous system diseases.
- the present invention also provides a method for preparing a pharmaceutical composition, which comprises mixing the compound represented by the above general formula (I), its stereoisomer or its pharmaceutically acceptable salt with a pharmaceutically acceptable carrier.
- a pharmaceutically acceptable carrier for example, the active ingredient is mixed with common adjuvants and/or diluents, and then the mixture is compressed in a conventional tablet press to prepare tablets.
- compositions of the present invention a variety of pharmaceutical preparation forms can be selected according to the purpose of treatment, generally including: tablets, pills, capsules, granules, suspensions, solutions, creams, ointments, powders, suppositories, gas Sprays and injections, etc.
- the compound of the present invention is administered in a unit dosage form, which contains the compound in an amount of about 0.01 to 100 mg.
- the total daily dose is usually about 0.05 to 500 mg, most preferably about 0.1 to 50 mg of the active compound of the present invention.
- the present invention also provides the compound represented by the general formula (I) according to the present invention, its stereoisomers or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical composition for preparing prevention and/or treatment of central nervous system diseases Use in medicine.
- the present invention also provides a method for the treatment and/or prevention of central nervous system diseases, which method comprises administering to humans or animals the fused compound represented by general formula (I) of the present invention, its stereoisomers or Its pharmaceutically acceptable salt, or the above-mentioned pharmaceutical composition.
- the above-mentioned central nervous system diseases are selected from: mood disorders; mental disorders; mood disorders; depression; intrinsic depression; major depression; uncontrollable depression; dysthymic disorder; cyclic affective disorder; panic attack; panic sexual Disorders; Social Phobia; Obsessive-compulsive Disorders and Behavioral Disorders;impulsive Disorders; Post-traumatic Stress Disorders; Anxiety Disorders; Acute Stress Disorders; Hysteria; Anorexia nervosa; Sleep Disorders; Adaptive Disorders; Autism ; Neuropathic headache; Mania; Hyperactivity; Fibromyalgia; Neuropathic pain; Attention deficit/hyperactivity diseases and tics, etc.
- the sleep disorder is sleep apnea, insomnia, narcolepsy, and cataplexy; preferably, the central nervous system disease is selected from: depression; anxiety; obsessive-compulsive and behavioral disorders.
- the neuropathic pain includes, but is not limited to, postherpetic neuralgia, reflex sympathetic dystrophy/causalgia or nerve trauma, prosthetic pain, and peripheral neuropathy.
- the herpes is herpes zoster; the peripheral neuropathy is diabetic neuropathy or neuropathy caused by long-term use of alcohol.
- halogen generally refers to fluorine, chlorine, bromine and iodine; preferably fluorine, chlorine or bromine; more preferably fluorine or chlorine;
- the C1 ⁇ C20 alkyl group refers to a linear or branched saturated hydrocarbon group containing 1-20 carbon atoms.
- the meanings of the C1 ⁇ C10 and C1 ⁇ C6 alkyl groups can be deduced by analogy, for example, methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-ethylpropyl, isopentyl, neopentyl, isohexyl, 3-methylpentyl or n-hexyl Group, etc., preferably methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl or tert-butyl;
- the C1 ⁇ C20 alkoxy group refers to a straight or branched chain alkoxy group containing 1-20 carbon atoms, and the meaning of C1 ⁇ C10 and C1 ⁇ C6 alkoxy groups can be deduced by analogy, for example, methoxy, ethoxy, N-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, isopentoxy, neopentoxy, isohexoxy, 3 -Methylpentyloxy or n-hexoxy, etc., preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy.
- the present compounds have 5-HT 3 receptor with high affinity, thus treating diseases associated with 5-HT 3 receptor or by 5-HT 3 receptor of central nervous system disorders.
- the compound of the present invention has a high affinity for 5-HT transporter, and therefore can treat central nervous system diseases related to or affected by 5-HT transporter.
- the compound of the present invention has the characteristics of multi-target action, and simultaneously acts on the monoamine transporter/5-hydroxytryptamine receptor, etc., that is, it simultaneously acts on the 5-HT transporter, dopamine transporter, norepinephrine transporter, 5 At least two targets such as HT 3 receptor have high activity; from the results of pharmacological experiments, it can be seen that most of the compounds also have 5-HT transporter/5-HT 3 receptor effects.
- the characteristics of the multi-target action are beneficial to adjust the balance of neurotransmitters in the brain, and have a good curative effect on diseases of the central nervous system.
- the compound of the present invention has the characteristics of multi-target action, it can quickly take effect through the synergistic action of multiple targets and reduce the side effects caused by drugs.
- the compound of the present invention is not only strong in activity, but also effective in oral administration. It has the characteristics of low pharmacological dose and low toxic and side effects. It has curative effect on diseases of the central nervous system, especially for major depression (MDD), anxiety, obsessive-compulsive disorder, etc. The disease is effective.
- the compound of the present invention has the advantages of multi-target effect, lower pharmacodynamic dose, fewer side effects, better safety and tolerability, etc., and has good clinical applications. prospect.
- step 1
- the reaction solution was diluted with 150ml ethyl acetate, filtered, and the filter residue was washed with a small amount of ethyl acetate.
- the filtrate was washed with 300ml saturated sodium chloride solution.
- the organic phase was dried over anhydrous sodium sulfate and spin-dried to obtain 16g of brown oil.
- the oil was slurried by adding 100ml of ethanol. , A large amount of solids precipitate out, stir at room temperature for 2 hours to disperse the solids evenly, filter, and bake the filter cake at 50 degrees for 3 hours to obtain 1-b, a gray solid 15.2g, with a yield of 95.3%.
- step 1
- Example 1 The product of Example 1 (7.5g, 31.6mmol) was added to 120ml of ethyl formate, triethylamine (17.6ml, 126.6mmol, 4eq) was added, and the system was heated at 60°C for 3h. Dilute with 100ml ethyl acetate, wash the organic phase with 200ml saturated ammonium chloride solution, then wash with 200ml saturated sodium chloride solution, dry with anhydrous sodium sulfate and spin dry to obtain compound 2-a, light yellow solid 8.4g, yield 99.8%.
- step 1
- step 1
- step 1
- step 1
- step 1
- Dissolve compound 7-b in methanol add hydrochloric acid, stir at room temperature for 1 hour, after the reaction is complete, add water, add MTBE, discard the organic phase, separate the aqueous phase and adjust the pH to weakly alkaline, then add DCM for extraction, and then the organic phase It was washed once with brine, dried and concentrated to obtain an oily substance, which was converted into maleate in THF and dried to obtain the title compound as a pale yellow solid 920 mg.
- step 1
- step 1
- Dissolve the basic product in methanol dissolve 1.05eq of maleic acid in tetrahydrofuran, add dropwise to the methanol solution of the basic product, stir at room temperature for 5min, concentrate, add tetrahydrofuran for beating, stir at room temperature for 3h, filter, and bake the filter cake at 50°C for 3h , Get the title compound.
- the basic product was dissolved in methanol, 1.05 eq of oxalic acid was dissolved in tetrahydrofuran, added dropwise to the methanol solution of the basic product, stirred at room temperature for 5 min, concentrated, tetrahydrofuran was added for pulping, stirred at room temperature for 3 hours, filtered, and the filter cake was dried at 50 degrees for 3 hours to obtain Title compound.
- Example 12 Except that the basic product of Example 12 was used instead of the product of Example 1, 2-(benzo[b]thiophen-4-yl)-5-methyloctahydropyrrolo[3] was prepared in the same manner as in Example 2. ,4-c]pyrrole, using 40% hydrobromic acid aqueous solution instead of the maleic acid in tetrahydrofuran solution in Example 10, referring to Example 10 to form the hydrobromide salt to obtain the title compound.
- Example 14 Except that the basic product of Example 14 was used instead of the product of Example 1, 2-(benzo[b]thiophen-5-yl)-5-methyloctahydropyrrolo[3] was prepared in the same manner as in Example 2. ,4-c]pyrrole, using hydrogen chloride methanol solution instead of maleic acid in tetrahydrofuran solution in Example 10, and referring to Example 10 to form the hydrochloride to obtain the title compound.
- Example 24 Except that the basic product of Example 24 was used instead of the product of Example 1, 2-methyl-5-(naphthalene-1-yl)octahydropyrrolo[3,4-c] was prepared in the same manner as in Example 2. Pyrrole, referring to Example 11, was converted into oxalate to obtain the title compound.
- Example 27 Except that the basic product of Example 27 was used instead of the product of Example 1, 2-(2,3-dichlorophenyl)-5-methyloctahydropyrrolo[3,4] was prepared in the same manner as in Example 2.
- -c] pyrrole refer to Example 11 to form the oxalate to obtain the title compound.
- Example 10 Except that the basic product of Example 29 was used instead of the product of Example 1, 2-(6-fluoronaphthalen-2-yl)-5-methyloctahydropyrrolo[3, 4-c] pyrrole, refer to Example 10 to prepare the maleate to obtain the title compound.
- Example 10 Except that the basic product of Example 31 was used instead of the product of Example 1, 2-(1-fluoronaphthalene-2-yl)-5-methyloctahydropyrrolo[3, 4-c] pyrrole, refer to Example 10 to prepare the maleate to obtain the title compound.
- Example 33 Except that the basic product of Example 33 was used instead of the product of Example 1, 3-(5-methylhexahydropyrrolo[3,4-c]pyrrole-2(1H) was prepared in the same manner as in Example 2.
- -Base) isoquinoline refer to Example 10 to prepare the maleate to obtain the title compound.
- step 1
- Example 39 Except that the basic product of Example 39 was used instead of the product of Example 1, 2-methyl-6-(naphthalen-2-yl)decahydropyrrolo[3,4-d] was prepared in the same manner as in Example 2. Azepine was converted into oxalate according to Example 11 to obtain the title compound.
- a 5-(benzo[b]thiophen-6-yl)octahydrocyclopentane[c]pyrrole salt was prepared in the same manner as in Example 3 except that 6-bromobenzothiophene was used instead of 4-bromobenzothiophene Acid salt.
- a 5-(benzo[b]thiophen-7-yl)octahydrocyclopentane[c]pyrrole salt was prepared in the same manner as in Example 3 except that 7-bromobenzothiophene was used instead of 4-bromobenzothiophene Acid salt.
- a 6-(benzo[b]thiophen-5-yl)decahydrocycloheptane[c]pyrrole salt was prepared in the same manner as in Example 5 except that 5-bromobenzothiophene was used instead of 4-bromobenzothiophene Acid salt.
- a 6-(benzo[b]thiophen-6-yl)decahydrocycloheptane[c]pyrrole salt was prepared in the same manner as in Example 5 except that 6-bromobenzothiophene was used instead of 4-bromobenzothiophene Acid salt.
- Example 54 (60 mg) was dissolved in 1 mL of formaldehyde solution (40%) and stirred at 75°C for 4 hours. Add 2 equivalents of NaBH 4 to an ice-water bath, return to room temperature and react for 10 hours, dichloromethane/water layer, concentrate the organic phase, beaten with petroleum ether, and dry to obtain 45 mg of the title compound as a white solid.
- Example 57 (30 mg) was dissolved in 5 mL of acetic acid solution, and 5 mg 10% Pd/C was added. After hydrogen replacement, the reaction was performed at 25°C for 24 hours. Mass spectrometry showed that the raw materials had reacted. The reaction solution was filtered, and the acetic acid phase was basified with 5 ml 20% NaOH, layered with 10 ml DCM, and the organic layer was concentrated. In an ice water bath, 3 mL of HCl-dioxane was salted, the solid was filtered, and 5 mL of petroleum ether was slurried. After filtration and drying, 8 mg of the title compound was obtained as a white solid.
- Example 52 Except that the product of Example 52 was used instead of the product of Example 54, 5-(benzofuran-2-yl)-2-methyl-1,2,3,3a,4 was prepared in the same manner as in Example 57 , 6a-hexahydrocyclopentane[c]pyrrole, and then replaced the maleic acid in tetrahydrofuran solution in Example 10 with hydrogen chloride methanol solution, and converted into the hydrochloride salt in Example 10 to obtain the title compound.
- Example 59 (50 mg) was dissolved in 5 mL of acetic acid solution, and 5 mg 10% Pd/C was added. After hydrogen replacement, the reaction was performed at 25°C for 24 hours. Mass spectrometry showed that the raw materials had reacted.
- the reaction solution was filtered, and the acetic acid phase was basified with 5 ml 20% NaOH, layered with 10 ml DCM, and the organic layer was concentrated.
- 3 mL of HCl-dioxane was salted, the solid was filtered, and 5 mL of petroleum ether was slurried, filtered and dried to obtain 10 mg of the title compound as a white solid.
- Example 51 Except that the product of Example 51 was used instead of the product of Example 54, 5-(benzothiophen-2-yl)-2-methyl-1,2,3,3a,4 was prepared in the same manner as in Example 57 , 6a-hexahydrocyclopentane[c]pyrrole, using hydrogen chloride methanol solution instead of the maleic acid in tetrahydrofuran solution in Example 10, refer to Example 10 to form the hydrochloride to obtain the title compound.
- Example 61 (45 mg) was dissolved in 5 mL of acetic acid solution, 20 mg 10% Pd/C was added, and the reaction was performed at 25°C for 24 hours after hydrogen replacement. Mass spectrometry showed that the raw materials had reacted.
- the reaction solution was filtered, and the acetic acid phase was basified with 5 ml 20% NaOH, layered with 10 ml DCM, and the organic layer was concentrated.
- 3 mL of HCl-dioxane was salted, the solid was filtered, and 5 mL of petroleum ether was slurried, filtered and dried to obtain 5 mg of the title compound as a white solid.
- Example 64 Except that the basic product of Example 64 was used instead of the product of Example 1, 1-(benzothiophen-5-yl)-5-methyloctahydropyrrole [3,4-b] was prepared in the same manner as Example 2 ] Pyrrole, refer to Example 11 to form oxalate to obtain the title compound.
- Example 66 Except that the basic product of Example 66 was used instead of the product of Example 1, 2-(2,3-dimethylphenyl)-5-methyloctahydropyrrole [3,4] was prepared in the same manner as in Example 2 -c] pyrrole, refer to Example 11 to form oxalate to obtain the title compound.
- Example 69 Except that the basic product of Example 69 was used instead of the product of Example 1, 2-(6-fluorobenzothiophen-4-yl)-5-methyloctahydropyrrole [3, 4-c] pyrrole, refer to Example 11 to form the oxalate to obtain the title compound.
- Example 56 (50 mg) was dissolved in 1 mL of formaldehyde solution (40%) and stirred at 75°C for 4 hours. Add 2 equivalents of NaBH 4 to an ice-water bath, return to room temperature and react for 10 hours, dichloromethane/water layer, concentrate the organic phase, beaten with petroleum ether, and dry to obtain 40 mg of the title compound as a white solid.
- the intermediate 2-(2,3-dimethoxybenzene)octahydropyrrole was prepared in the same manner as in Example 1 except that 1-bromo-2,3-dimethoxybenzene was used instead of 2-bromonaphthalene [3,4-c]pyrrole. Then, this intermediate was used to replace the product of Example 1, and 2-(2,3-dimethoxybenzene)-5-methyloctahydropyrrole [3,4-c]pyrrole was prepared in the same manner as in Example 2.
- Using hydrogen chloride methanol solution instead of the maleic acid tetrahydrofuran solution in Example 10 refer to Example 10 to form the hydrochloride to obtain the title compound.
- Example 82 Except that the basic product of Example 82 was used instead of the product of Example 1, 2-(2-fluorophenyl)-5-methyloctahydropyrrolo[3,4-c] was prepared in the same manner as in Example 2. Pyrrole, referring to Example 11, was converted into oxalate to obtain the title compound.
- Example 84 Except that the basic product of Example 84 was used instead of the product of Example 1, 2-(2-ethoxyphenyl)-5-methyloctahydropyrrolo[3,4-] was prepared in the same manner as in Example 2.
- c] pyrrole refer to Example 11 to form oxalate to obtain the title compound.
- Example 87 Except that the basic product of Example 87 was used instead of the product of Example 1, 2-(5-fluoro-2-methoxyphenyl)-5-methyloctahydropyrrolo[ 3,4-c]pyrrole, refer to Example 11 to form oxalate to obtain the title compound.
- Example 35 6-(3,4-dichlorophenyl)-2-methyldecahydropyrrolo[3,4-d] acridine was prepared in the same manner as in Example 2. Enanthine was converted into hydrochloride by referring to Example 3 to obtain the title compound.
- Flexstation 3 uses Prism software to process the data after reading the board. The results are shown in Table 1.
- the preferred compounds of the invention display less than 200nM (IC 50) serotonin reuptake inhibitory concentration. More preferred compounds exhibit inhibitory concentrations below 100 nM, most preferred compounds exhibit inhibitory concentrations below 50 nM, and particularly interesting compounds exhibit serotonin reuptake inhibitory concentrations below 10 nM.
- the cell membrane was prepared from HEK293 cells expressing human recombinant 5-HT 3 receptor, the membrane concentration was 2.2 ⁇ g per well, the concentration of the isotope ligand 3H-BRL 43694 was 0.5 nM, and the concentration of the non-specific binding compound MDL 72222 was 10 ⁇ M.
- 5-HT 3 receptors are located in the postsynaptic membrane and regulate the inhibitory GABA interneurons in different brain regions to regulate the release of various neurotransmitters. Serotonin acts on 5-HT 3 receptors to reduce the release of various neurotransmitters. Therefore, antagonizing 5-HT 3 receptors causes de-inhibition, thereby increasing the release of neurotransmitters.
- 5-HT 3 antagonists can enhance the effect of SSRIs antidepressants. Animal experiments have shown that the combination of 5-HT 3 antagonist ondansetron and paroxetine can enhance the antidepressant effect of paroxetine.
- Ondansetron can partially prevent the inhibitory effect of paroxetine on the discharge of 5-HT neurons in the dorsal raphe nucleus and enhance paroxetine-induced extracellular 5-HT release in the hippocampus (Pharmacology, Biochemistry and Behavior 2015, 131, 136-142.).
- 5-HT system and other neurotransmitter systems such as cholinergic, dopaminergic, and glutamatergic systems interact in the control of learning and memory.
- the cerebral cortex and dorsal hippocampus are important structures related to memory.
- the excitement of 5-HTergic neurons can stimulate cholinergic neurons to release acetylcholine.
- 5-HT 3 R antagonists can inhibit the regulated release of 5-HT acetylcholine without affecting the steady-state release of acetylcholine and prevent cognitive impairment.
- Overexpression of 5-HT 3 R in mice has been shown to enhance learning, memory and concentration. It has been reported in the literature that ondansetron can improve the memory of patients and reduce cognitive impairment (Pharmacology&therapeutics, 2010, 128(1):146-169.).
- some of the compounds according to the present invention have 5-HTT/5-HT 3 receptor multi-target effects, which are conducive to regulating the balance of neurotransmitters in the brain and have a good effect on central nervous system diseases. . Therefore, the synergy of multiple targets can take effect quickly and reduce the side effects caused by drugs.
- mice C57BL/6 mice (Shanghai Xipuer-Bikai Experimental Animal Co., Ltd.), male, 6 weeks old, weighing 15-20g.
- ICR mice Shanghai Xipuer-Bikai Experimental Animal Co., Ltd.
- male, 6 weeks old weighing 20-25g. All ordered mice were kept in a standard environment for 2-3 weeks before experimenting.
- FST Forced swimming test
- the water level in the forced swimming equipment is 45cm and the water temperature is 25°C.
- the mice are placed in the experiment room to adapt to the environment for 1 hour.
- the mice were placed in the equipment for 6 minutes, and the whole process was recorded with a camera.
- the immobility time of the mice in the last 4 minutes was counted, and the result was expressed by mean ⁇ SD.
- Tail suspension test The tail of the mouse is fixed on the device with medical tape for 6 minutes. The whole process is recorded with a camera. When analyzing the data, only the immobility time of the mouse in the last 4 minutes is counted.
- test compounds at the following doses can significantly reduce the immobility time of mice, which has a significant difference compared with the blank group.
- po oral administration
- ip intraperitoneal administration
- FST forced swimming test
- TST tail suspension test.
- Test compound Effective dose (mg/kg) Compound of Example 1 5(po); FST Compound of Example 2 5(po); FST Compound of Example 7 10(ip); TST Compound of Example 10 10(ip); FST Compound of Example 11 10(ip); FST Compound of Example 12 3(ip); FST Compound of Example 13 5(ip); FST Compound of Example 14 3(ip); FST Compound of Example 15 2.5(po); FST Compound of Example 16 3(ip); FST Compound of Example 17 5(po); FST Compound of Example 19 10(ip); FST Compound of Example 21 3(ip); FST Compound of Example 22 10(ip); TST Compound of Example 25 10(ip); TST Compound of Example 28 10(ip); TST Compound of Example 29 5(po); FST Example 30 Compound 20(po); FST Compound of Example 31 20(po); FST
- Example 32 Compound of Example 32 20(po); FST Example 35 Compound 20(po); FST Compound of Example 36 10(ip); TST Compound of Example 37 10(ip); FST Example 38 Compound 10(ip); TST Example 39 Compound 10(ip); TST Example 41 Compound 10(ip); TST The compound of Example 50 10(ip); FST Example 55 Compound 5(po); FST Example 69 Compound 10(ip); FST Example 81 Compound 10(ip); FST B 20(po); FST Citalopram 20(po); FST
- the compound of the present invention is not only strong in activity, but also effective in oral administration. It has the characteristics of low pharmacological dose and small toxic and side effects. It has curative effect on diseases of the central nervous system, especially for severe depression (MDD), anxiety, obsessive-compulsive disorder and other diseases. it is good.
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Abstract
本发明涉及一种由通式（I）表示的并环化合物、其立体异构体或其药学上可接受的盐，其制备方法、药物组合物及其用途。本发明提供的化合物用于治疗、预防和/或控制各种神经系统障碍。本发明提供的化合物调节一种或多种单胺转运蛋白，抑制内源性单胺例如多巴胺、5-羟色胺和去甲肾上腺素的再摄取（例如从突触间隙），和/或调节5-HT3受体。
Description
本发明属于药物化学领域。具体而言，本发明涉及一种通式(I)所示的并环化合物、其立体异构体或其药学上可接受的盐，其制备方法，包含其的药物组合物及其在制备治疗中枢神经系统疾病的药物中的应用。
抑郁症是一种广泛的、持续发作的慢性疾病，全球范围内，其终身患病率约为16％。在二十世纪五十年代，临床上偶然发现异烟肼和丙米嗪具有抗抑郁效果，它们成为了治疗抑郁症的第一代药物。随后，药理学研究中提出了单胺假说，该假说认为脑内5-羟色胺(5-HT)能神经、多巴胺(DA)能神经和去甲肾上腺素(NA)能神经的功能低下是抑郁症产生的原因，能够改善上述神经功能的药物具有抗抑郁作用。目前临床上使用的一线治疗药物，如选择性5-HT再摄取抑制剂(SSRIs)和5-HT及NA再摄取抑制剂(SNRIs)等都是基于单胺假说的药物。尽管抗抑郁药的发展已取得了很大进展，在临床上仍存在许多需求，如药物的快速起效、防止复发、改善抑郁症患者的认知损伤等。尽管在重度抑郁领域有不少药物上市，但是仅约有30-40％的患者对一线治疗应答。这些药物仍对超过30％的患者没有疗效或疗效低下。因此，仍有必要寻找具有疗效好、副作用低、治疗谱宽的新型抗抑郁药。
发明内容
发明目的
本发明的一个目的是提供一种通式(I)所示的并环化合物、其立体异构体或其药学上可接受的盐。
本发明的另一个目的是提供一种上述通式(I)所示的并环化合物的制备方法。
本发明的再一个目的是提供包含治疗有效量的一种或多种上述通式(I)所示化合物、其立体异构体或其药学上可接受的盐的药物组合物。
本发明的又一个目的是提供通式(I)所示并环化合物、其立体异构体或其药学上可接受的盐，或者上述药物组合物在制备预防和/或治疗中枢神经系统疾病的药物中的用途。
本发明的又一个目的是提供一种预防和/或治疗中枢神经系统疾病的方法，其特征在于，向受试者施用治疗有效量的一种或多种上述通式(I)所示化合物、其立体异构体或其药学上可接受的盐，或者上述药物组合物。
根据本发明的一个方面，提供了一种由通式(I)表示的并环化合物、其立体异构体或其药学上可接受的盐：
其中：
R
1为氢或C1～C20烷基；优选氢或C1～C10烷基；更优选为氢或C1～C6烷基；
m,n,p,q各自独立地为0或1或2或3；优选地，m,n,p,q各自独立地为1或2；条件是m+p为1、2、3或4，n+q为1、2、3或4且m+p+n+q为3、4、5、6、或7；
X为CR
2，N或C；当X为CR
2或N时，与X相连的
表示单键，R
2为氢、羟基或C1～C6烷氧基；当X为C时，与X相连的
表示双键；
G环为苯基、联苯基、萘基、四氢萘基、二氢茚基、单环杂环基或苯并杂环基；
并且，G环非必须地被一个或多个相同或不同取代基取代；所述G环上的取代基为卤素、氧代(＝O)、羟基、卤代C1～C6烷基、C1～C6烷酰基、被C1～C6烷氧基取代的C1～C6烷基、C1～C6烷基或C1～C6烷氧基，优选地，所述G环上的取代基为卤素、氧代(＝O)、羟基、卤代C1～C4烷基、C1～C4烷酰基、被C1～C6烷氧基取代的C1～C4烷基、C1～C4烷基或C1～C4烷氧基，更优选地，所述G环上的取代基为卤素、氧代(＝O)、羟基、乙酰基、三氟甲基、甲氧基甲基、甲基、乙基、甲氧基或乙氧基。
优选地，G环为
且所述G环非必须地被一个或多个相同或不同取代基取代，所述G环上的取代基的定义与前述相同。
G环更优选为
且所述G环非必须地被一个或多个相同或不同取代基取代，所述G环上的取代基的定义与前述相同。
其中，上述取代基的连接位置可以是在环上的任何可以连接的位置，例如，
取代基可以表示
其中，
表示连接位置。
在优选实施方式中，本发明所述通式(I)表示的并环化合物中：
其中，X和R
1的定义如上所述。
在优选实施方式中，本发明所述通式(I)表示的并环化合物中：
其中，R
1的定义如上所述。
在优选实施方式中，本发明所述通式(I)表示的并环化合物中：
在通式(I)表示的并环化合物、其立体异构体或其药学上可接受的盐中，最优选如下化合物或其药学上可接受的盐：
根据本发明的另一个实施方式，其提供了一种通式(I)所示的并环化合物的制备方法，所述制备方法通过如下方法1-7之一进行，
方法1：式(II-a)所示的化合物与式(III)所示的化合物进行偶联反应得到式(Ia)所示的化合物，如反应式1所示：
其中，G环、m、n、p、q、R
1同上文定义的相同；L
1代表卤素、C1～C6烷基磺酰氧基、苯磺酰氧基或萘磺酰氧基，上述C1～C6烷基磺酰氧基、苯磺酰氧基、萘磺酰氧基可非必须地被一个或多个选自卤素、C1～C6烷基、C1～C6烷氧基、硝基、羟基、氨基和C1～C6烷酰基的基团进一步取代；L
1优选为卤素、C1～C4烷基磺酰氧基、苯磺酰氧基、萘磺酰氧基，上述C1～C4烷基磺酰氧基、苯磺酰氧基、萘磺酰氧基可非必须地被一个或多个选自卤素、C1～C4烷基、C1～C4烷氧基、硝基、羟基、氨基和C1～C4烷酰基进一步取代；L
1最优选为氯、溴、甲磺酰氧基、三氟甲磺酰氧基、苯磺酰氧基、萘磺酰氧基、甲基苯磺酰氧基、硝基苯磺酰氧基、氨基苯磺酰氧基、氯苯磺酰氧基、溴苯磺酰氧基或甲氧基苯磺酰氧基；
方法2：式(II-b)所示的化合物与式(III)所示的化合物进行偶联反应得到式(IV)所示的化合物，然后脱除氨基保护基得到式(Ib)化合物，非必须地进行烷基化反应或还原胺化反应得到式(Ia)所示的化合物，如反应式2所示：
其中，G环、m、n、p、q同上文定义相同；R
1为C1～C20烷基，L
1代表卤素、C1～C6烷基磺酰氧基、苯磺酰氧基或萘磺酰氧基，上述C1～C6烷基磺酰氧基、苯磺酰氧基、萘磺酰氧基可非必须地被一个或多个选自卤素、C1～C6烷基、C1～C6烷氧基、硝基、羟基、氨基和C1～C6烷酰基的基团进一步取代；L
1优选为卤素、C1～C4烷基磺酰氧基、苯磺酰氧基、萘磺酰氧基，上述C1～C4烷基磺酰氧基、苯磺酰氧基、萘磺酰氧基可非必须地被一个或多个选自卤素、C1～C4烷基、C1～C4烷氧基、硝基、羟基、氨基和C1～C4烷酰基进一步取代；L
1最优选为氯、溴、甲磺酰氧基、三氟甲磺酰氧基、苯磺酰氧基、萘磺酰氧基、甲基苯磺酰氧基、硝基苯磺酰氧基、氨基苯磺酰氧基、氯苯磺酰氧基、溴苯磺酰氧基或甲氧基苯磺酰氧基；
PG为取代或未取代的苄基、酰基类氨基保护基或烷氧羰基类氨基保护基，所述苄基上的取代基独立地选自卤素、三氟甲基、C1～C6烷基、C1～C6烷氧基和硝基中的一种或多种，优选所述酰基类氨基保护基为甲酰基、乙酰基、丙酰基、苯甲酰基、卤代乙酰基、邻苯二甲酰基，且所述烷氧羰基类氨基保护基为叔丁氧羰基、苄氧羰基、9-芴甲氧羰基，
方法3：式(V)所示的化合物与式(III)所示的化合物进行偶联反应得到式(VI)化合物，然后脱除氨基保护基得到式(Ic)化合物，非必须地进行烷基化反应或还原胺化反应得到式(If)所示的化合物，如反应式3所示：
其中，G环、m、n、p、q同上文定义相同；R
1为C1～C20烷基，L
1代表卤素、C1～C6烷基磺酰氧基、苯磺酰氧基或萘磺酰氧基，上述C1～C6烷基磺酰氧基、苯磺酰氧基、萘磺酰氧基可非必须地被一个或多个选自卤素、C1～C6烷基、C1～C6烷氧基、硝基、羟基、氨基和C1～C6烷酰基的基团进一步取代；L
1优选为卤素、C1～C4烷基磺酰氧基、苯磺酰氧基、萘磺酰氧基，上述C1～C4烷基磺酰氧基、苯磺酰氧基、萘磺酰氧基可非必须地被一个或多个选自卤素、C1～C4烷基、C1～C4烷氧基、硝基、羟基、氨基和C1～C4烷酰基进一步取代；L
1最优选为氯、溴、甲磺酰氧基、三氟甲磺酰氧基、苯磺酰氧基、萘磺酰氧基、甲基苯磺酰氧基、硝基苯磺酰氧基、氨基苯磺酰氧基、氯苯磺酰氧基、溴苯磺酰氧基或甲氧基苯磺酰氧基；
PG为取代或未取代的苄基、酰基类氨基保护基或烷氧羰基类氨基保护基，所述苄基上的取代基独立地选自卤素、三氟甲基、C1～C6烷基、C1～C6烷氧基和硝基中的一种或多种，优选所述酰基类氨基保护基为甲酰基、乙酰基、丙酰基、苯甲酰基、卤代乙酰基、邻苯二甲酰基，且所述烷氧羰基类氨基保护基为叔丁氧羰基、苄氧羰基、9-芴甲氧羰基，
在上述方法2和方法3中，
所述脱氨基保护基的反应在酸或酸性硅胶存在下进行；
所述酸选自盐酸、氯化氢气体、硫酸、磷酸、硝酸、醋酸、氢溴酸、氢碘酸、高氯酸、三氯乙酸和三氟乙酸中的一种或多种；
所述脱氨基保护基的反应在有或无溶剂存在下进行，所述溶剂选自水、二氧六环、甲醇、乙醇、正丙醇、异丙醇、叔丁醇、乙醚、N-甲基吡咯烷酮、四氢呋喃、乙腈、二氯甲烷、氯仿、N,N-二甲基甲酰胺、甲苯、乙酸乙酯、乙酸丙酯和乙酸丁酯中的一种或多种；
特别地，当PG为取代或未取代的苄基时，所述脱氨基保护基的反应为：
将化合物(IV)或(VI)或其盐溶解在溶剂中，与氯甲酸酯A
2OOCCl发生反应脱除苄基，产物在溶剂中发生水解反应脱除酰基得到式(Ib)或(Ic)，
A
2为被卤代或未取代的C
1-C
6烷基、取代或未取代的苯基、取代或未取代的苄基，所述取代的苯基或苄基上的取代基选自氟、氯、溴、碘、硝基、C
1-C
4烷基或C
1-C
4烷氧基中的一个或多个取代基；优选的，所述A
2为C
1-C
4烷基、取代或未取代的苯基、取代或未取代的苄基，所述取代的苯基或苄基上的取代基选自氟、氯、溴、碘或硝基中的一个或多个取代基；更优选的，所述A
2为甲基、乙基、苯基或苄基,
所述脱氨基保护基的反应温度为0℃～150℃，优选30℃～100℃；反应时间为0.5～24小时，优选1～12小时；
方法4：式(VII-a)所示的化合物与式(X)所示的化合物进行羰基加成反应得到式(VIII)所示的化合物，然后脱除氨基保护基得到式(Id)化合物，如反应式4所示：
其中，G环、m、n、p、q同上文定义相同；L
2代表Li、MgBr、MgCl、MgI、ZnBr、ZnCl或ZnI；
PG为酰基类氨基保护基或烷氧羰基类氨基保护基，优选所述酰基类氨基保护基为甲酰基、乙酰基、丙酰基、苯甲酰基、卤代乙酰基、邻苯二甲酰基，且所述烷氧羰基类氨基保护基为叔丁氧羰基、苄氧羰基、9-芴甲氧羰基，
所述脱氨基保护基的反应在酸或酸性硅胶存在下进行；
所述酸选自盐酸、氯化氢气体、硫酸、磷酸、硝酸、醋酸、氢溴酸、氢碘酸、高氯酸、三氯乙酸和三氟乙酸中的一种或多种；
所述脱氨基保护基的反应在有或无溶剂存在下进行，所述溶剂选自水、二氧六环、甲醇、乙醇、正丙醇、异丙醇、叔丁醇、乙醚、N-甲基吡咯烷酮、四氢呋喃、乙腈、二氯甲烷、氯仿、N,N-二甲基甲酰胺、甲苯、乙酸乙酯、乙酸丙酯和乙酸丁酯中的一种或多种；
所述脱氨基保护基的反应温度为0℃～150℃，优选30℃～100℃；反应时间为0.5～24小时，优选1～12小时；
方法5：式(VII-a)所示的化合物与式(X)所示的化合物进行羰基加成反应得到式(VIII)所示的化合物，然后同时脱水脱氨基保护基得到式(Ie)所示的化合物，非必须地进行烷基化反应或还原胺化反应得到式(Ig)所示的化合物，如反应式5所示：
其中，G环、m、n、p、q同上文定义相同；R
1为C1～C20烷基；L
2代表Li、MgBr、MgCl、MgI、ZnBr、ZnCl或ZnI；
PG为酰基类氨基保护基或烷氧羰基类氨基保护基，优选所述酰基类氨基保护基为甲酰基、乙酰基、丙酰基、苯甲酰基、卤代乙酰基、邻苯二甲酰基，且所述烷氧羰基类氨基保护基为叔丁氧羰基、苄氧羰基、9-芴甲氧羰基，
所述同时脱水脱氨基保护基反应在酸存在下进行；优选地，所述酸选自盐酸、氯化氢气体、硫酸、磷酸、硝酸、醋酸、氢溴酸、氢碘酸、高氯酸、三氯乙酸和三氟乙酸中的一种或多种；所述同时脱水脱氨基保护基的反应在有或无溶剂存在下进行，所述溶剂选自水、二氧六环、甲醇、乙醇、正丙醇、异丙醇、叔丁醇、乙醚、N-甲基吡咯烷酮、四氢呋喃、乙腈、二氯甲烷、氯仿、N,N-二甲基甲酰胺、甲苯、乙酸乙酯、乙酸丙酯和乙酸丁酯中的一种或多种；
方法6：式(VII-b)所示的化合物与式(X)所示的化合物进行羰基加成反应得到式(Ih)所示的化合物，然后经脱水反应得到式(Ig)所示的化合物，如反应式6所示：
其中，G环、m、n、p、q同上文定义相同；R
1为C1～C20烷基；L
2代表Li、MgBr、MgCl、MgI、ZnBr、ZnCl或ZnI；
所述脱水反应在酸存在下进行；优选地，所述酸选自盐酸、氯化氢气体、硫酸、磷酸、硝酸、醋酸、氢溴酸、氢碘酸、高氯酸、三氯乙酸和三氟乙酸中的一种或多种；所述脱水反应在有或无溶剂存在下进行，所述溶剂选自水、二氧六环、甲醇、乙醇、正丙醇、异丙 醇、叔丁醇、乙醚、N-甲基吡咯烷酮、四氢呋喃、乙腈、二氯甲烷、氯仿、N,N-二甲基甲酰胺、甲苯、乙酸乙酯、乙酸丙酯和乙酸丁酯中的一种或多种；
方法7：式(Ie)或(Ig)所示的化合物经氢化还原反应分别得到式(Ic)或式(If)所示的化合物：
其中，G环、m、n、p、q同上文定义的相同。
所述氢化还原反应在还原剂存在下进行，所述还原剂包括但不限于：氢气/钯炭、氢气/雷尼镍、氢气/氢氧化钯等。
在上述方法1至方法3中，所述偶联反应在钯催化剂和碱存在下进行，
所述钯催化剂为醋酸钯(Pd(OAc)
2)、二(三苯基膦)二氯化钯((Ph
3P)
2PdCl
2)、双(苯甲腈)氯化钯((PhCN)
2PdCl
2)、四(三苯基膦)钯(Pd(PPh
3)
4)、双(三苯基膦)醋酸钯((Ph
3P)
2Pd(OAc)
2)、1,2-二(二苯基膦基)乙烷二氯化钯((PdCl
2(dppe)
2))、双(1,2-双(二苯基膦)乙烷)钯(Pd(dppe)
2)、双(二亚芐基丙酮)钯(Pd(dba)
2)、三(二亚苄基丙酮)二钯(Pd
2(dba)
3)、[1,3-双(二苯基膦基)丙烷]二氯化钯(PdCl
2(dippp))和[1,1'-双(二苯基膦)二茂铁]二氯化钯(Pd(dppf)Cl
2)；
所述碱为双(三甲硅基)氨基钠、叔丁醇钾、叔丁醇钠、碳酸铯、磷酸钾、磷酸钠、甲醇钠、乙醇钠、氢氧化钾、氢氧化钠、氟化钾、氟化钠、氟化四丁基铵(TBAF)、醋酸钠、醋酸钾、碳酸铯、碳酸钾和碳酸钠中的一种或多种，
优选地，该反应使用的溶剂包括水、二氧六环、四氢呋喃、甲苯、二甲苯、叔丁醇、丙酮、N,N-二甲基甲酰胺、二甲基亚砜、乙腈，或上述溶剂的混合物；
优选地，该反应还非必须地加入配体作为反应促进剂，所述配体为2,2'-二苯膦基-1,1'-联萘(BINAP)、三叔丁基(P(t-Bu)
3)、1,1'-二-(二苯膦基)二茂铁(dppf)、2-二环己基磷-2,4,6-三异丙基联苯(x-phos)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(Xantphos)、三叔丁基膦四氟硼酸盐或三(2-甲基苯基)膦(P(o-tolyl)
3)。
在上述方法4至方法6中，所述羰基加成反应的溶剂选自四氢呋喃、乙醚、正己烷、正戊烷、二氧六环、甲苯中的一种或多种，所述羰基加成反应的反应温度为-80℃～100℃，优选-80℃～30℃；
在上述方法2、方法3和方法5中：
所述烷基化反应在烷基化试剂存在下进行，所述烷基化试剂包括但不限于：碘甲烷、三氟甲磺酸乙酯、碘乙烷、溴乙烷等。
所述还原胺化反应在相应的醛/酮、还原剂存在下进行，所述还原剂包括但不限于：硼氢化钠、硼氢化钾、三乙酰氧基硼氢化钠(NaBH(OAc)
3)、四甲基三乙酰氧硼氢化铵和氰基硼氢化钠等。
式(II-a)、式(II-b)、式(III)、式(V)、式(X)、式(VII-a)、式(VII-b)化合物是商业上可得 到的化合物或者是按照技术上已知的方法制备或按照相似化合物的合成方法制备。
所述式(I)化合物的立体异构体包括其任何对映异构体、非对映异构体、互变异构体、外消旋混合物、对映体富集的混合物和对映纯形式，外消旋形式可以通过已知的方法分解为旋光对映体，例如，使用旋光活性酸分离非对映体盐，用碱处理释放旋光活性的胺化合物，另外的解析外消旋物成为旋光对映体的方法基于旋光活性基质上的层析法，本发明外消旋化合物还可以通过d或l-(酒石酸，苦杏仁酸或樟脑磺酸)盐分级结晶被分解为它们的旋光对映体。本发明化合物也可以通过形成非对映体衍生物分解。
上述各反应式中使用的起始化合物可以是适合的盐，所述合适的盐包括碱金属盐和碱土金属盐，如钠盐、钾盐、钙盐、镁盐等；有机碱盐如吡啶盐、三乙胺盐等；无机酸盐如盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐如甲酸盐、乙酸盐、丙酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、丁二酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、苦味酸盐、谷氨酸盐、甲磺酸盐和苯磺酸盐等；
此外，上述各反应式中使用的起始化合物可以包括溶剂合物形式，如水合物、醇合物等。
本发明通式(I)所示的并环化合物及其立体异构体也同样包括其溶剂合物形式，如水合物、醇合物等，并且所述的溶剂合物包括在本发明的范围内。
本发明通式(I)所示的并环化合物及其立体异构体的药学上可接受的盐是指通式(I)所示的并环化合物或其立体异构体用适当的酸处理，把它们转化成治疗活性的非毒性的盐形式。所述的盐例如盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐或硫酸氢盐、硝酸盐、磷酸盐或酸式磷酸盐、高氯酸盐、甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、丙酮酸盐、羟乙酸盐、乙二酸盐、丙二酸盐、丁二酸盐、戊二酸盐、马来酸盐、富马酸盐、乳酸盐、苹果酸盐、柠檬酸盐、酒石酸盐、苦味酸盐、谷氨酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、水杨酸盐、抗坏血酸盐、樟脑酸盐或樟脑磺酸盐等。相反，也可以用碱处理把盐形式转化成游离碱形式。
上述所用的术语“药学上可接受的盐”也包括它们的溶剂合物，并且所述的溶剂合物包括在本发明的范围内。溶剂合物的例子有，例如，水合物、醇合物等。
由各反应式获得的各目标化合物可以通过以下方法将其从反应混合物中分离和纯化，例如：反应混合物在冷却后经过如过滤、萃取或浓缩等方法分离出粗产物，接着通过常规的如柱层析法、打浆法或重结晶法来进行纯化。
本发明还提供一种药物组合物，其包含治疗有效量的上述通式(I)所示的并环化合物、其立体异构体或其药学上可接受的盐和任选的可药用载体。所述药物组合物可用于治疗或者预防中枢神经系统疾病。
本发明还提供一种制备药物组合物的方法，包括将上述通式(I)所示的并环化合物、其立体异构体或其药学上可接受的盐与可药用载体混合。例如：使活性成分与普通辅助剂和/或稀释剂混合，随后在常规的压片机中压缩该混合物可以制备片剂。
在本发明的药物组合物中，根据治疗目的可以选择多种药物制剂形式，一般包括：片剂、丸剂、胶囊剂、颗粒剂、混悬液、溶液、霜剂、软膏、粉剂、栓剂、气雾剂和注射剂等。方便地，本发明化合物以单位剂型给药，其中包含约0.01到100毫克量的该化合物。 总日剂量通常约为0.05到500毫克，最优选约0.1到50毫克本发明活性化合物。
本发明还提供根据本发明的通式(I)所示并环化合物、其立体异构体或其药学上可接受的盐，或者上述药物组合物在制备预防和/或治疗中枢神经系统疾病的药物中的用途。
本发明还提供一种用于治疗和/或预防中枢神经系统疾病的方法，这种方法包括向人或动物施用上述本发明的通式(I)表示的并环化合物、其立体异构体或其药学上可接受的盐，或者上述药物组合物。
上述中枢神经系统疾病选自：情感紊乱；精神紊乱；情绪紊乱；抑郁症；内因性抑郁症；重性抑郁症；难控制的抑郁症；情绪恶劣性障碍；循环情感性障碍；恐慌发作；惊恐性障碍；社交恐惧症；强迫性观念与行为病症；冲动性病症；创伤后精神紧张性障碍；焦虑症；急性应激障碍；癔病；神经性厌食症；睡眠障碍；适应性障碍；自闭症；神经性头痛；狂躁症；多动症；纤维肌痛；神经性疼痛；注意力缺乏/亢进类疾病和抽动症等。优选地，所述睡眠障碍是睡眠呼吸暂停、失眠、发作性睡病、猝倒；优选地，所述中枢神经系统疾病选自：抑郁症；焦虑症；强迫性观念与行为病症。
所述神经性疼痛包括但不限于疱疹后神经痛、反射交感性营养不良/灼痛或神经创伤、假肢痛和周围神经病。优选地，所述疱疹是带状疱疹；所述周围神经病是糖尿病性神经病变或长期服用酒精引起的神经病。
在通式(I)中的各基团的定义如下：
术语卤素通常是指氟、氯、溴及碘；优选为氟、氯或溴；更优选为氟或氯；
C1～C20烷基指含有1-20个碳原子的直链或支链的饱和烃基，C1～C10和C1～C6烷基的含义以此类推，例如，甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1-乙基丙基、异戊基、新戊基、异己基、3-甲基戊基或正己基等，优选为甲基、乙基、正丙基、异丙基、丁基、异丁基或叔丁基；
C1～C20烷氧基指含有1-20个碳原子的直链或支链烷氧基，C1～C10和C1～C6烷氧基的含义以此类推，例如，甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基、异戊氧基、新戊氧基、异己氧基、3-甲基戊氧基或正己氧基等，优选为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基。
本发明化合物具有以下有益效果：
1)本发明化合物具有5-HT
3受体高亲和力，因此能够治疗与5-HT
3受体相关或受5-HT
3受体影响的中枢神经系统疾病。
2)本发明化合物具有5-HT转运体高亲和力，因此能够治疗与5-HT转运体相关或受5-HT转运体影响的中枢神经系统疾病。
3)本发明化合物具有多靶点作用的特性，同时作用于单胺转运体/5-羟色胺受体等，即，同时对5-HT转运体、多巴胺转运体、去甲肾上腺素转运体、5-HT
3受体等至少两个靶点具有高活性；由药理实验结果可见，大部分化合物同时具有5-HT转运体/5-HT
3受体作用。该多靶点作用的特性有利于调节脑内神经递质平衡，对中枢神经系统类疾病具有较好疗效。
4)由于本发明化合物具有多靶点作用的特性，可以通过多靶点的协同作用快速起效并减少药物引起的副作用。
5)本发明化合物不仅活性强，而且口服有效，具有药效剂量低、毒副作用小等特点，对中枢神经系统领域的疾病具有疗效，尤其对重度抑郁症(MDD)、焦虑症、强迫症等疾病 疗效好。
总之，本发明化合物与现有抗抑郁药物相比，具有多靶点作用、更低的药效剂量、更少的毒副作用、更好的安全性和耐受性等优点，具有良好的临床应用前景。
下列制备例、实施例和药理活性测试实施例进一步阐明本发明，但并不限制本发明的范围。
实施例1：2-萘-2-基八氢吡咯[3,4-c]吡咯
步骤1：
2-溴代萘1-a(10.7g，52mmol，1.1eq)，六氢吡咯并[3,4-c]吡咯-2(1H)-甲酸叔丁酯(10g，47mmol，1eq)加入150mL甲苯，甲苯溶液中加入Pd
2(dba)
3(2.16g，2.36mmol，0.05eq)，BINAP(2.35g，3.78mmol，0.08eq)，叔丁醇钾(7.9g，70.8mmol，1.5eq)，反应N
2保护，外温105度加热10h。150ml乙酸乙酯稀释反应液，过滤，少量乙酸乙酯洗涤滤渣，滤液加入300ml饱和氯化钠溶液洗涤，有机相无水硫酸钠干燥，旋干，得到褐色油状物16g，油状物加入100ml乙醇打浆，大量固体析出，室温搅拌2h固体分散均匀，过滤，滤饼50度烘3h，得到1-b，灰色固体15.2g，收率95.3％。
步骤2：
化合物1-b(15.2g)加入100ml甲醇中，加入80ml浓盐酸，室温搅拌2h。反应液加500ml水稀释，400ml甲基叔丁基醚萃取除去小极性杂质，水相使用200ml 5M NaOH溶液调pH至9，加入600ml二氯甲烷萃取，有机相加入300ml饱和氯化钠溶液洗涤，无水硫酸钠干燥，旋干，得到黄色固体10.8g。ESI-MS(m/z):239.17[M+H]
+.HPLC>95％.
实施例2：2-甲基-5-(萘-2-基)八氢吡咯[3,4-c]吡咯
步骤1：
实施例1的产物(7.5g，31.6mmol)加入120ml甲酸乙酯中，加入三乙胺(17.6ml，126.6mmol，4eq)，体系外温60度加热3h。100ml乙酸乙酯稀释，有机相使用200ml饱和氯化铵溶液洗涤，接着使用200ml饱和氯化钠溶液洗涤，无水硫酸钠干燥，旋干，得到化合物2-a，淡黄色固体8.4g，收率99.8％。
步骤2：
化合物2-a(8.4g，31.6mmol)加入120ml干燥四氢呋喃中，加入1M硼烷四氢呋喃溶液(63.2ml，63.2mmol，2eq)，反应液逐渐溶清，N
2保护下外温68度2h。反应液冰浴，7.9ml盐酸(3eq)溶于100ml甲醇，滴加到反应液中，产生大量气泡，反应液外温68度加热10h。旋干反应液，残液加水80ml，水相用20ml 5M NaOH溶液调pH至9，加入200ml DCM萃取，有机相加入200ml饱和氯化钠溶液洗涤，无水硫酸钠干燥，旋干，得到固体8g。ESI-MS(m/z):253.35[M+H]
+.HPLC>95％.
实施例3：5-(苯并[b]噻吩-4-基)八氢环戊烷[c]吡咯盐酸盐
步骤1：
0℃下向3-a(2.27g，10mmol)及三乙胺(1.01g，10mmol)的二氯甲烷(30mL)溶液滴加二氯亚砜(1.2g，10mmol)，滴加完毕后升到20℃反应5小时。加入水淬灭反应，分液，有机层浓缩并柱层析(EA:PE＝1:15至1:5)得到化合物3-b(1.25g，收率60％)。
步骤2：
0℃下向双联硼酸频哪醇酯(2.54g，10mmol)、氯化亚铜(25mg，0.25mmol)及配体xantphos(145mg，0.25mmol)的THF(30mL)溶液加叔丁醇钾(1.12g，10mmol)，氮气保护，加完毕后升到20℃反应30min后滴加3-b(1.23g,5mmol)的THF(2mL)溶液；室温反应过夜。反应液直接加硅胶拌样过柱(EA:PE＝1:15至1:5)得到化合物3-c(800mg，收率48％)。
步骤3：
化合物3-c(340mg，1mmol)、4-溴苯并噻吩(213mg，1mmol)、碳酸铯(326mg，1mmol)及dppfPdCl
2(73.2mg，0.1mmol)的二氧六环(10mL)溶液在氮气保护下80℃反应过夜。反应液直接加硅胶拌样过柱(EA:PE＝1:15至1:5)得到化合物3-d(40mg，收率12％)。
步骤4：
化合物3-d(66mg，0.2mmol)溶于甲醇(1mL)，加入4N HCl甲醇溶液(1mL)，室温反应1h。反应液浓缩干加入甲基叔丁基醚打浆得到标题化合物，类白色固体40mg。
1H NMR(400MHz,CD
3OD)δ7.88(d,1H),7.69(d,1H),7.54(d,1H),7.46(d,1H),7.23(t,1H),3.28(m,2H),3.20(m,2H),3.08(m,1H),2.90(m,2H),2.39(m,2H),1.37(m,2H).ESI-MS(m/z):244.20[M+H]
+.
实施例4：5-(苯并噻吩-5-基)八氢环戊烷[c]吡咯盐酸盐
步骤1：
化合物4-a(340mg，1mmol)、5-溴苯并噻吩(213mg，1mmol)、碳酸铯(326mg，1mmol)及dppfPdCl
2(73.2mg，0.1mmol)加入二氧六环(10mL)中，氮气保护80℃反应过夜。反应液直接加硅胶拌样过柱(EA:PE＝1:15至1:5)得到化合物4-b(43mg，收率14％)。
步骤2：
将化合物4-b(66mg，0.2mmol)溶于甲醇(1mL)，加入4N盐酸甲醇溶液(1mL)，室温反应1h。反应液浓缩干加入甲叔醚打浆得到标题化合物，类白色固体38mg。
1H NMR(400MHz,CD
3OD)δ8.00(d,1H),7.81(d,1H),7.62(d,1H),7.43(dd,1H),7.33(d,1H),3.28(m,2H),3.20(m,2H),3.09(m,1H),2.90(m,2H),2.40(m,2H),1.37(m,2H).ESI-MS(m/z):244.20[M+H]
+.
实施例5：6-(苯并[b]噻吩-4-基)十氢环庚烷[c]吡咯盐酸盐
步骤1：
0℃下向化合物5-a(2.55g，10mmol)及三乙胺(1.01g，10mmol)的二氯甲烷(30mL)溶液滴加二氯亚砜(1.2g，10mmol)，滴加完毕后升到20℃反应5小时。加入水淬灭反应，分液，有机层浓缩并柱层析(EA:PE＝1:15至1:5)得到化合物5-b(1.5g，收率55％)。
步骤2：
0℃下向双联硼酸频哪醇酯(2.54g，10mmol)、氯化亚铜(25mg，0.25mmol)及配体xantphos(145mg，0.25mmol)的THF(30mL)溶液加叔丁醇钾(1.12g，10mmol)，氮气保护，加完后升到20℃反应30min后滴加化合物5-b(1.37g,5mmol)的THF(2mL)溶液；室温反应过夜。反应液直接加硅胶拌样过柱(EA:PE＝1:15至1:5)得到化合物5-c(900mg，收率50％)。
步骤3：
化合物5-c(360mg，1mmol)、4-溴苯并噻吩(213mg，1mmol)、碳酸铯(326mg，1mmol)及dppfPdCl
2(73.2mg，0.1mmol)的二氧六环(10mL)溶液在氮气保护下80℃反应过夜。反应液直接加硅胶拌样过柱(EA:PE＝1:15至1:5)得到化合物5-d(45mg，收率13％)。
步骤4：
化合物5-d(74mg，0.2mmol)溶于甲醇(1mL)，加入4N盐酸甲醇溶液(1mL)，室温反应1h。反应液浓缩干加入甲基叔丁基醚打浆得到标题化合物，类白色固体48mg。
1H NMR(400MHz,CD
3OD)δ7.90(d,1H),7.70(d,1H),7.56(d,1H),7.47(d,1H),7.24(t,1H),3.52(m,3H),2.87(dd,2H),2.53(m,2H),1.89(m,6H),1.56(m,2H).ESI-MS(m/z):272.28[M+H]
+.
实施例6：2-(萘-2-基)十氢吡咯[3,4-d]吖庚因马来酸盐
步骤1：
化合物6-a(200mg，0.66mmol，1eq)，2-溴代萘(137mg，0.66mmol，1eq)，Pd
2(dba)
3(30mg，0.033mmol，0.05eq)，BINAP(33mg，0.053mmol，0.08eq)，叔丁醇钾(222mg，1.98mmol，3eq)加入5ml二氧六环中，氮气保护，外温105度加热8h。过滤，乙酸乙酯洗涤滤饼，滤液水洗，饱和氯化钠洗，干燥，旋干，硅胶柱层析得到化合物6-b粗品，油状物153mg。
步骤2及步骤3：
化合物6-b(153mg，0.43mmol，1eq)溶于氯仿，加入1-氯乙基氯甲酸乙酯(93μl，0.86mmol，2eq)，外温70度加热4h。旋干反应液，加入甲醇，70度加热回流1h。加水，加入1ml浓盐酸，甲叔醚除杂，水相调pH至9，DCM萃取，有机相饱和食盐水洗，干燥，旋干，柱层析，得到固体95mg，THF中成马来酸盐，烘干得到标题化合物，白色固体98mg。
1H NMR(400MHz,DMSO-d
6)δ8.46(br,2H),7.73(d,1H),7.70(d,1H),7.63(d，1H),7.34(t,1H),7.15(t,1H),7.06(dd,1H),6.79(d,1H),6.02(s,2H),3.70(dd,2H),3.37(m,2H),3.00(m,4H),2.70(br,2H),2.00-1.79(m,4H).ESI-MS(m/z):267.37[M+H]
+.
实施例7：6-(苯并噻吩-5-基)十氢吡咯[3,4-d]吖庚因马来酸盐
步骤1：
将820mg原料7-a、1.1eq原料5-溴苯并噻吩、0.05eq Pd
2(dba)
3，0.08eq BINAP混合于甲苯中，室温下搅拌5min，再加入2eq叔丁醇钾，氮气置换三次，80℃反应过夜。滤除不溶物，滤渣用乙酸乙酯洗，合并滤液，食盐水洗，干燥、浓缩后硅胶柱层析得产物870mg，用少量二氯甲烷打浆得到化合物7-b，白色固体780mg。
步骤2：
将化合物7-b溶于甲醇中，加入盐酸，室温下搅拌1h，反应毕，加水，加MTBE，弃去有机相，水相分出调pH至弱碱性，再加DCM萃取，有机相再用食盐水洗一次，干燥浓缩得油状物，于THF中成马来酸盐，烘干得标题化合物，淡黄色固体920mg。
1H NMR(400MHz,DMSO-d
6)δ8.66(d,2H),7.75(d,1H),7.62(d,1H),7.26(d,1H),7.19(d,1H),6.99(dd,1H),6.09(s,2H),3.83(dd,2H),3.35(brs,2H),3.18(ddd,2H),2.77(d,2H),2.56(q,2H),1.66-1.85(m,4H).ESI-MS(m/z):273.28[M+H]
+.
实施例8：5-(萘-1-基)八氢环戊烷[c]吡咯盐酸盐
步骤1：
取500mg 1-溴代萘溶解到5mL THF，氮气保护，外温-80度冷却，控制内温小于-70度将1.05eq.n-BuLi(2.5M)滴加至1-溴代萘的THF溶液中，-70度搅拌1h以形成8-b，控制内温小于-70度将0.8eq.原料8-a(溶解于3mL THF)滴加至反应中，缓慢升温至-40度搅拌12h。氯化铵水溶液淬灭后，乙酸乙酯/水分层，浓缩乙酸乙酯相得粗品8-c。
步骤2：
粗品8-c溶解到5mL甲醇中，加入2mL浓盐酸，65度回流1h。降温至室温，丙酮浓缩置换两次，再用丙酮打浆，过滤烘干后得到140mg 8-d。
步骤3：
取90mg化合物8-d溶解到5mL醋酸溶液中，加入20mg 10％Pd/C，氢气置换后25度反应24h。过滤反应液，用5ml 20％NaOH碱化醋酸相，10mL DCM分层，浓缩有机相。冰水浴，加入3mL HCl-二氧六环成盐，过滤固体，5mL石油醚打浆，过滤烘干后得到26mg标题化合物，白色固体。ESI-MS m/z 238.32[M+H]
+.
实施例9：5-(3,4-二氯苯基)-1,2,3,3a,4,6a-六氢环戊烷[c]吡咯盐酸盐
步骤1：
500mg 3,4-二氯溴苯9-b(1eq)加入到5ml新蒸的THF中，氮气保护下降温至-80度。滴加丁基锂溶液(2.5M，1.1eq)，体系溶清。在此温度下加入含300mg 9-a的2ml THF溶液(0.6eq)中，然后自然升温至室温反应。用氯化铵淬灭反应体系，乙酸乙酯和水萃取，干燥、浓缩柱层析得到90mg中间体9-c。
步骤2：
将中间体9-c加入到2ml甲醇中，加入1ml浓盐酸，加热回流3小时。浓缩体系至干，加入丙酮打浆得到42mg标题化合物，白色片状晶体。
1H NMR(400MHz,CD
3OD)δ7.66(d,1H),7.51(d,1H),7.45(dd,1H),6.17(m,1H),3.81(m,1H),3.57-3.26(m,4H),3.15(m,2H),2.74(m,1H).
实施例10：2-(苯并[b]噻吩-7-基)八氢吡咯并[3,4-c]吡咯马来酸盐
除了以7-溴代苯并[b]噻吩代替2-溴代萘以外，以与实施例1相同的方式制备2-(苯并[b]噻吩-7-基)八氢吡咯并[3,4-c]吡咯。
将碱式产物用甲醇溶解，1.05eq马来酸溶于四氢呋喃中，滴加入碱式产物的甲醇溶液中，室温搅拌5min，浓缩，加入四氢呋喃打浆，室温搅拌3h，过滤，滤饼50度烘3h，得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ8.77(s,2H),7.72(d,1H),7.46(d,1H),7.43(d,1H),7.29(t,1H),6.77(d,1H),6.02(s,2H),3.47-3.60(m,4H),3.27-3.37(m,2H),3.03-3.15(m,4H).ESI-MS(m/z):245.22[M+H]
+.
实施例11：2-(苯并[b]噻吩-7-基)-5-甲基八氢吡咯并[3,4-c]吡咯草酸盐
除了以实施例10的碱式产物代替实施例1的产物以外，以与实施例2相同的方式制备2-(苯并[b]噻吩-7-基)-5-甲基八氢吡咯并[3,4-c]吡咯。
将碱式产物用甲醇溶解，1.05eq草酸溶于四氢呋喃中，滴加入碱式产物的甲醇溶液中，室温搅拌5min，浓缩，加入四氢呋喃打浆，室温搅拌3h，过滤，滤饼50度烘3h，得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ9.59(brs,2H),7.72(d,1H),7.47(d,1H),7.44(d,1H),7.29(t,1H),6.79(d,1H),3.64(dd,2H),3.52(dd,2H),3.24(t,2H),3.13(m,2H),3.01(m,2H),2.80(s,3H).ESI-MS(m/z):259.27[M+H]
+.
实施例12：2-(苯并[b]噻吩-4-基)八氢吡咯并[3,4-c]吡咯马来酸盐
除了以4-溴代苯并[b]噻吩代替2-溴代萘以外，以与实施例1相同的方式制备碱式产物，参照实施例10成马来酸盐，得到2-(苯并[b]噻吩-4-基)八氢吡咯并[3,4-c]吡咯马来酸盐。
1H NMR(400MHz,DMSO-d
6)δ8.78(s,2H),7.67(d,1H),7.64(d,1H),7.55(d,1H),7.24(t,1H),6.76(d,1H),6.02(s,2H),3.51(dd,2H),3.43(dd,2H),3.23(dd,2H),3.04-3.20(m,4H).ESI-MS(m/z):245.21[M+H]
+.
实施例13：2-(苯并[b]噻吩-4-基)-5-甲基八氢吡咯并[3,4-c]吡咯氢溴酸盐
除了以实施例12的碱式产物代替实施例1的产物，以与实施例2相同的方式制备2-(苯 并[b]噻吩-4-基)-5-甲基八氢吡咯并[3,4-c]吡咯，采用40％氢溴酸水溶液代替实施例10中的马来酸的四氢呋喃溶液，参照实施例10成氢溴酸盐，得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ9.80(d,1H),7.56-7.72(m,3H),7.26(t,1H),6.82(dd,1H),3.89(td,1H),3.61(dd,1H),3.20-3.55(m,5H),2.92-3.11(m,3H),2.87(dd,3H).ESI-MS(m/z):259.30[M+H]
+.
实施例14：2-(苯并[b]噻吩-5-基)八氢吡咯并[3,4-c]吡咯马来酸盐
除了以5-溴代苯并[b]噻吩代替2-溴代萘以外，以与实施例1相同的方式制备碱式产物，参照实施例10成马来酸盐，得到2-(苯并[b]噻吩-5-基)八氢吡咯并[3,4-c]吡咯马来酸盐。
1H NMR(400MHz,DMSO-d
6)δ8.78(s,2H),7.79(d,1H),7.65(d,1H),7.29(d,1H),7.08(d,1H),6.88(dd,1H),6.01(s,2H),3.44-3.52(m,2H),3.39(dd,2H),3.26-3.30(m,2H),3.07-3.17(m,4H).ESI-MS(m/z):245.18[M+H]
+.
实施例15：2-(苯并[b]噻吩-5-基)-5-甲基八氢吡咯并[3,4-c]吡咯盐酸盐
除了以实施例14的碱式产物代替实施例1的产物，以与实施例2相同的方式制备2-(苯并[b]噻吩-5-基)-5-甲基八氢吡咯并[3,4-c]吡咯，采用氯化氢甲醇溶液代替实施例10中的马来酸的四氢呋喃溶液、参照实施例10成盐酸盐，得到标题化合物。
1H NMR(400MHz,CD
3OD)δ8.06(m,3H),7.73(t,1H),7.63(dd,1H),7.43(t,1H),3.97(m,4H),3.85(d,1H),3.75(m,1H),3.65-3.46(m,3H),3.43(dd,1H),3.01(d,3H).ESI-MS(m/z):259.23[M+H]
+.
实施例16：2-(3,4-二氯苯基)八氢吡咯并[3,4-c]吡咯
除了以1-溴-3,4-二氯苯代替2-溴代萘以外，以与实施例1相同的方式制备2-(3,4-二氯苯基)八氢吡咯并[3,4-c]吡咯。
1H NMR(400MHz,MeOH-d
4)δ7.29(d,1H),6.84(d,1H),6.65(dd,1H),3.59(m,2H),3.42(m,2H),3.33(m,2H),3.27-3.18(m,4H).ESI-MS(m/z):257.29[M+H]
+.
实施例17：2-(3,4-二氯苯基)-5-甲基八氢吡咯并[3,4-c]吡咯
除了以实施例16的产物代替实施例1的产物，以与实施例2相同的方式制备2-(3,4-二氯苯基)-5-甲基八氢吡咯并[3,4-c]吡咯。
1H NMR(400MHz,CDCl
3)δ7.20(d,1H),6.67(d,1H),6.44(dd,1H),3.37(t,2H),3.14(dd,2H),2.97(m,2H),2.70(t,2H),2.46(dd,2H),2.33(s,3H).ESI-MS(m/z):271.24[M+H]
+.
实施例18：2-(苯并呋喃-4-基)八氢吡咯并[3,4-c]吡咯盐酸盐
除了以4-溴苯并呋喃代替2-溴代萘，以与实施例1相同的方式制备2-(苯并呋喃-4-基)八氢吡咯并[3,4-c]吡咯，采用氯化氢甲醇溶液代替实施例10中的马来酸的四氢呋喃溶液、参照实施例10成盐酸盐得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ9.46(d,2H),7.84(d,1H),7.16(d,1H),7.13(t,1H),6.98(d,1H),6.41(d,1H),3.40-3.60(m,6H),3.06-3.15(m,4H).ESI-MS(m/z):229.19[M+H]
+.
实施例19：2-(苯并[b]噻吩-6-基)八氢吡咯并[3,4-c]吡咯马来酸盐
除了以6-溴苯并[b]噻吩代替2-溴代萘以外，以与实施例1相同的方式制备2-(苯并呋喃-4-基)八氢吡咯并[3,4-c]吡咯，参照实施例10成马来酸盐得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ8.83(s,2H),7.69(d,1H),7.35(d,1H),7.25(d,1H),7.18(d,1H),6.85(dd,1H),6.02(s,2H),3.48(m,2H),3.40(dd,2H),3.33(m,2H),3.05-3.17(m,4H).ESI-MS(m/z):245.39[M+H]
+.
实施例20：2-(苯并呋喃-7-基)八氢吡咯并[3,4-c]吡咯
除了以7-溴苯并呋喃代替2-溴代萘以外，以与实施例1相同的方式制备2-(苯并呋喃-7-基)八氢吡咯并[3,4-c]吡咯。
1H NMR(400MHz,DMSO-d
6)δ7.90(d,1H),7.03(m,2H),6.86(d,1H),6.51(d,1H),3.56(m,2H),3.24(dd,2H),2.94(m,2H),2.78(m,2H),2.62(m,2H).ESI-MS(m/z):229.34[M+H]
+.
实施例21：2-(苯并呋喃-5-基)八氢吡咯并[3,4-c]吡咯马来酸盐
除了以5-溴苯并呋喃代替2-溴代萘以外，以与实施例1相同的方式制备2-(苯并呋喃-7-基)八氢吡咯并[3,4-c]吡咯，参照实施例10成马来酸盐，得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ8.78(s,2H),7.86(d,1H),7.43(d,1H),6.86(d,1H),6.81(dd,1H),6.76(dd,1H),6.02(s,2H),3.47(m,2H),3.37(m,2H),3.22(m,2H),3.05-3.15(m,4H).ESI-MS(m/z):229.27[M+H]
+.
实施例22：2-(苯并[b]噻吩-2-基)八氢吡咯并[3,4-c]吡咯马来酸盐
除了以2-溴苯并[b]噻吩代替2-溴代萘以外，以与实施例1相同的方式制备2-(苯并[b]噻吩-2-基)八氢吡咯并[3,4-c]吡咯，参照实施例10成马来酸盐，得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ8.81(s,2H),7.68(d,1H),7.45(d,1H),7.21(td,1H),7.03(t,1H),6.09(s,1H),6.02(s,2H),3.37-3.49(m,4H),3.33(m,2H),3.09-3.20(m,4H).ESI-MS(m/z):245.18[M+H]
+.
实施例23：2-(苯并[b]噻吩-3-基)八氢吡咯并[3,4-c]吡咯马来酸盐
除了以3-溴苯并[b]噻吩代替2-溴代萘以外，以与实施例1相同的方式制备2-(苯并[b]噻吩-3-基)八氢吡咯并[3,4-c]吡咯，参照实施例10成马来酸盐，得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ8.73(s,2H),7.96(dd,1H),7.91(dd,1H),7.38(m,2H),6.78(s,1H),6.02(s,2H),3.50(m,2H),3.26-3.46(m,2H),3.17(d,2H),3.01-3.11(m,4H).ESI-MS(m/z):245.18[M+H]
+.
实施例24：2-(萘-1-基)八氢吡咯并[3,4-c]吡咯马来酸盐
除了以1-溴代萘代替2-溴代萘以外，以与实施例1相同的方式制备2-(萘-1-基)八氢吡咯并[3,4-c]吡咯，参照实施例10成马来酸盐，得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ8.73(s,2H),8.15(m,1H),7.89(m,1H),7.59(d,1H),7.52(m,2H),7.42(t,1H),7.11(d,1H),6.01(s,2H),3.57(m,2H),3.28(d,2H),3.19(dd,2H),3.09(d,4H).ESI-MS m/z 239.27[M+H]
+.
实施例25：2-乙基-5-(萘-2-基)八氢吡咯并[3,4-c]吡咯草酸盐
除了以乙酸乙酯代替甲酸乙酯，以与实施例2相同的方式制备2-乙基-5-(萘-2-基)八 氢吡咯并[3,4-c]吡咯，参照实施例11成草酸盐，得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ7.75(d,1H),7.72(d,1H),7.68(d,1H),7.36(m,1H),7.18(m,2H),6.92(d,1H),3.59(br,2H),3.51(m,2H),3.32(m,2H),3.13(m,6H),1.2(t,3H).ESI-MS m/z 267.40[M+H]
+.
实施例26：2-甲基-5-(萘-1-基)八氢吡咯并[3,4-c]吡咯草酸盐
除了以实施例24的碱式产物代替实施例1的产物，以与实施例2相同的方式制备2-甲基-5-(萘-1-基)八氢吡咯并[3,4-c]吡咯，参照实施例11成草酸盐，得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ8.18(m,1H),7.88(m,1H),7.59(d,1H),7.52(m,2H),7.41(t,1H),7.11(d,1H),3.62(br,2H),3.28(d,2H),3.08(m,6H),2.86(s,3H).ESI-MS m/z 253.33[M+H]
+.
实施例27：2-(2,3-二氯苯基)八氢吡咯并[3,4-c]吡咯马来酸盐
除了以1-溴-2,3-二氯苯代替2-溴代萘以外，以与实施例1相同的方式制备2-(2,3-二氯苯基)八氢吡咯并[3,4-c]吡咯，参照实施例10成马来酸盐，得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ8.67(s,2H),7.29(m,2H),7.10(dd,1H),6.01(s,2H),3.53(m,2H),3.34(d,2H),3.00(m,6H).ESI-MS m/z 257.23[M+H]
+.
实施例28：2-(2,3-二氯苯基)-5-甲基八氢吡咯并[3,4-c]吡咯草酸盐
除了以实施例27的碱式产物代替实施例1的产物，以与实施例2相同的方式制备2-(2,3-二氯苯基)-5-甲基八氢吡咯并[3,4-c]吡咯，参照实施例11成草酸盐，得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ7.29(m,2H),7.10(dd,1H),3.58(m,2H),3.32(d,2H),3.00(m,6H),2.77(s,3H).ESI-MS m/z 271.23[M+H]
+.
实施例29：2-(6-氟萘-2-基)八氢吡咯并[3,4-c]吡咯马来酸盐
除了以2-溴-6-氟萘代替2-溴代萘以外，以与实施例1相同的方式制备2-(6-氟萘-2- 基)八氢吡咯并[3,4-c]吡咯，参照实施例10成马来酸盐，得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ8.88(s,2H),7.76(d,1H),7.74(d,1H),7.52(dd,1H),7.28(td,1H),7.19(dd,1H),6.95(d,1H),6.02(s,2H),3.43(m,6H),3.12(m,4H).ESI-MS m/z 257.31[M+H]
+.
实施例30：2-(6-氟萘-2-基)-5-甲基八氢吡咯并[3,4-c]吡咯马来酸盐
除了以实施例29的碱式产物代替实施例1的产物以外，以与实施例2相同的方式制备2-(6-氟萘-2-基)-5-甲基八氢吡咯并[3,4-c]吡咯，参照实施例10成马来酸盐，得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ7.76(dt,2H),7.53(dd,1H),7.29(td,1H),7.24(dd,1H),7.01(d,1H),6.02(s,2H),3.54(m,4H),3.24(m,6H),2.84(s,3H).ESI-MS m/z 271.29[M+H]
+.
实施例31：2-(1-氟萘-2-基)八氢吡咯并[3,4-c]吡咯马来酸盐
除了以2-溴-1-氟萘代替2-溴代萘以外，以与实施例1相同的方式制备2-(1-氟萘-2-基)八氢吡咯并[3,4-c]吡咯，参照实施例10成马来酸盐，得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ8.83(s,2H),7.86(m,2H),7.67(d,1H),7.51(m,1H),7.35(m,1H),7.25(t,1H),6.02(s,2H),3.49(m,6H),3.10(m,4H).ESI-MS m/z 257.25[M+H]
+.
实施例32：2-(1-氟萘-2-基)-5-甲基八氢吡咯并[3,4-c]吡咯马来酸盐
除了以实施例31的碱式产物代替实施例1的产物以外，以与实施例2相同的方式制备2-(1-氟萘-2-基)-5-甲基八氢吡咯并[3,4-c]吡咯，参照实施例10成马来酸盐，得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ7.89(d,1H),7.86(d,1H),7.68(d,1H),7.52(m,1H),7.37(m,1H),7.28(t,1H),6.02(s,2H),3.60(m,2H),3.31(br,6H),3.13(br,2H),2.85(s,3H).ESI-MS m/z 271.33[M+H]
+.
实施例33：3-(六氢吡咯并[3,4-c]吡咯-2(1H)-基)异喹啉马来酸盐
除了以3-溴-异喹啉代替2-溴代萘以外，以与实施例1相同的方式制备3-(六氢吡咯并[3,4-c]吡咯-2(1H)-基)异喹啉，参照实施例10成马来酸盐，得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ8.96(s,1H),8.85(s,2H),7.86(d,1H),7.66(d,1H),7.53(m,1H),7.24(m,1H),6.69(s,1H),6.07(s,2H),3.52(m,6H),3.14(m,4H).ESI-MS m/z 240.32[M+H]
+.
实施例34：3-(5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)异喹啉马来酸盐
除了以实施例33的碱式产物代替实施例1的产物以外，以与实施例2相同的方式制备3-(5-甲基六氢吡咯并[3,4-c]吡咯-2(1H)-基)异喹啉，参照实施例10成马来酸盐，得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ8.98(s,1H),7.87(d,1H),7.67(d,1H),7.54(t,1H),7.26(t,1H),6.75(s,1H),6.06(s,2H),3.48(m,6H),2.85(s,3H),2.77(m,2H),2.50(m,2H).ESI-MS m/z 254.41[M+H]
+.
实施例35：6-(3,4-二氯苯基)十氢吡咯并[3,4-d]吖庚因
步骤1：
将800mg原料7-a、1.1eq原料3,4-二氯溴苯、0.05eq Pd
2(dba)
3，0.08eq BINAP混合于甲苯中，室温下搅拌5min，再加入2eq叔丁醇钾，氮气置换三次，80℃反应过夜。滤除不溶物，滤渣用乙酸乙酯洗，合并滤液，食盐水洗，干燥、浓缩后硅胶柱层析得产物35-a 850mg。
步骤2：
将化合物35-a溶于甲醇中，加入盐酸，室温下搅拌1h，反应毕，加水，加MTBE，弃去有机相，水相分出调pH至弱碱性，加DCM萃取，有机相再用食盐水洗一次，干燥浓缩、柱层析得标题化合物，白色固体。ESI-MS(m/z):285.22[M+H]
+.
实施例36：6-(苯并[b]噻吩-7-基)十氢吡咯并[3,4-d]吖庚因马来酸盐
除了以7-溴-苯并[b]噻吩代替5-溴苯并噻吩以外，以与实施例7相同的方式制备6-(苯并[b]噻吩-7-基)十氢吡咯并[3,4-d]吖庚因马来酸盐。
1H NMR(400MHz,DMSO-d
6)δ8.69(s,2H),7.71(d,1H),7.50(d,1H),7.43(d,1H),7.30(t,1H),6.94(d,1H),6.02(s,2H),3.49(m,4H),3.08(m,2H),2.85(m,2H),2.66(m,2H),1.90(m,4H).ESI-MS m/z 273.29[M+H]
+.
实施例37：6-(2,3-二氯苯基)十氢吡咯并[3,4-d]吖庚因马来酸盐
除了以1-溴-2,3-二氯苯代替5-溴苯并噻吩以外，以与实施例7相同的方式制备6-(2,3-二氯苯基)十氢吡咯并[3,4-d]吖庚因马来酸盐。
1H NMR(400MHz,DMSO-d
6)δ8.66(s,2H),7.26(m,2H),7.13(dd,1H),6.02(s,2H),3.43(m,2H),3.23(m,2H),2.91(m,2H),2.81(m,2H),2.63(m,2H),1.86(m,4H).ESI-MS m/z 285.38[M+H]
+.
实施例38：6-(苯并[b]噻吩-4-基)十氢吡咯并[3,4-d]吖庚因马来酸盐
除了以4-溴-苯并[b]噻吩代替5-溴苯并噻吩以外，以与实施例7相同的方式制备6-(苯并[b]噻吩-4-基)十氢吡咯并[3,4-d]吖庚因马来酸盐。
1H NMR(400MHz,DMSO-d
6)δ8.69(s,2H),7.69(d,1H),7.55(d,1H),7.37(d,1H),7.24(t,1H),6.87(d,1H),6.02(s,2H),3.45(m,4H),3.05(m,2H),2.85(m,2H),2.66(m,2H),1.93(m,4H).ESI-MS m/z 273.47[M+H]
+.
实施例39：6-(萘-2-基)十氢吡咯并[3,4-d]吖庚因马来酸盐
除了以2-溴代萘代替5-溴苯并噻吩以外，以与实施例7相同的方式制备6-(萘-2-基)十氢吡咯并[3,4-d]吖庚因马来酸盐。
1H NMR(400MHz,DMSO-d
6)δ8.75(s,2H),7.72(d,1H),7.68(d,1H),7.63(d,1H),7.33(td,1H),7.26(dd,1H),7.16(td,1H),7.00(d,1H),6.01(s,2H),3.90(m,2H),3.30(m,4H),2.78(m,2H),2.56(m,2H),1.76(m,4H).ESI-MS(m/z):267.27[M+H]
+.
实施例40：2-甲基-6-(萘-2-基)十氢吡咯并[3,4-d]吖庚因草酸盐
除了以实施例39的碱式产物代替实施例1的产物，以与实施例2相同的方式制备2-甲基-6-(萘-2-基)十氢吡咯并[3,4-d]吖庚因，参照实施例11成草酸盐，得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ7.69(m,3H),7.31(m,2H),7.17(t,1H),7.04(d,1H),4.01(m,2H),3.52(m,2H),3.17(m,2H),2.72(m,7H),1.78(m,4H).ESI-MS(m/z):281.36[M+H]
+.
实施例41：2-(苯并[b]噻吩-4-基)十氢吡咯并[3,4-d]吖庚因马来酸盐
除了以4-溴-苯并[b]噻吩代替2-溴代萘以外，以与实施例6相同的方式制备2-(苯并[b]噻吩-4-基)十氢吡咯并[3,4-d]吖庚因马来酸盐。
1H NMR(400MHz,DMSO-d
6)δ8.73(s,1H),8.37(s,1H),7.62(d,1H),7.58(d,1H),7.40(d,1H),7.19(t,1H),6.60(d,1H),6.04(s,2H),3.72(m,2H),3.38(m,2H),3.01(m,4H),2.65(m,2H),1.90(m,4H).ESI-MS m/z 273.39[M+H]
+.
实施例42：2-(3,4-二氯苯基)十氢吡咯并[3,4-d]吖庚因马来酸盐
除了以1-溴-3,4-二氯苯代替2-溴代萘以外，以与实施例6相同的方式制备2-(3,4-二氯苯基)十氢吡咯并[3,4-d]吖庚因马来酸盐。
1H NMR(400MHz,DMSO-d
6)δ8.31(br,1H),7.34(d,1H),6.70(d,1H),6.52(dd,1H),6.02(s,2H),3.53(m,2H),3.33(m,2H),2.94(m,4H),2.65(m,2H),1.85(m,4H).ESI-MS m/z 285.38[M+H]
+.
实施例43：2-(苯并[b]噻吩-7-基)十氢吡咯并[3,4-d]吖庚因马来酸盐
除了以7-溴-苯并[b]噻吩代替2-溴代萘以外，以与实施例6相同的方式制备2-(苯并[b]噻吩-7-基)十氢吡咯并[3,4-d]吖庚因马来酸盐。
1H NMR(400MHz,DMSO-d
6)δ8.73(s,1H),8.39(s,1H),7.68(d,1H),7.40(d,1H),7.36(d,1H),7.24(t,1H),6.64(d,1H),6.03(s,2H),3.79(m,2H),3.38(m,2H),3.00(m,4H),2.67(m,2H),1.89(m,4H).ESI-MS m/z 273.40[M+H]
+.
实施例44：5-(苯并[b]噻吩-6-基)八氢环戊烷[c]吡咯盐酸盐
除了以6-溴苯并噻吩代替4-溴苯并噻吩以外，以与实施例3相同的方式制备5-(苯并[b]噻吩-6-基)八氢环戊烷[c]吡咯盐酸盐。
1H NMR(400MHz,CD
3OD)δ8.07(d,1H),7.73(d,1H),7.57(d,1H),7.47(dd,1H),7.35(d,1H),3.28(m,2H),3.20(m,2H),3.09(m,1H),2.90(m,2H),2.40(m,2H),1.37(m,2H).ESI-MS m/z 244.20[M+H]
+.
实施例45：5-(苯并[b]噻吩-7-基)八氢环戊烷[c]吡咯盐酸盐
除了以7-溴苯并噻吩代替4-溴苯并噻吩以外，以与实施例3相同的方式制备5-(苯并[b]噻吩-7-基)八氢环戊烷[c]吡咯盐酸盐。
1H NMR(400MHz,CD
3OD)δ7.83(d,1H),7.65(d,1H),7.50(m,2H),7.28(t,1H),3.28(m,2H),3.20(m,2H),3.09(m,1H),2.90(m,2H),2.40(m,2H),1.37(m,2H).ESI-MS m/z 244.22[M+H]
+.
实施例46：6-(苯并[b]噻吩-5-基)十氢环庚烷[c]吡咯盐酸盐
除了以5-溴苯并噻吩代替4-溴苯并噻吩以外，以与实施例5相同的方式制备6-(苯并[b]噻吩-5-基)十氢环庚烷[c]吡咯盐酸盐。
1H NMR(400MHz,CD
3OD)δ8.02(d,1H),7.82(d,1H),7.64(d,1H),7.45(dd,1H),7.35(d,1H),3.52(m,3H),2.87(dd,2H),2.53(m,2H),1.89(m,6H),1.56(m,2H).ESI-MS m/z 272.27[M+H]
+.
实施例47：6-(苯并[b]噻吩-6-基)十氢环庚烷[c]吡咯盐酸盐
除了以6-溴苯并噻吩代替4-溴苯并噻吩以外，以与实施例5相同的方式制备6-(苯并[b]噻吩-6-基)十氢环庚烷[c]吡咯盐酸盐。
1H NMR(400MHz,CD
3OD)δ8.08(d,1H),7.75(d,1H),7.58(d,1H),7.48(dd,1H),7.36(d,1H),3.53(m,3H),2.87(dd,2H),2.52(m,2H),1.89(m,6H),1.56(m,2H).ESI-MS m/z 272.29[M+H]
+.
实施例48：5-(苯并噻吩-7-基)-1,2,3,3a,4,6a-六氢环戊烷[c]吡咯盐酸盐
除了以7-溴苯并噻吩代替3,4-二氯溴苯以外，以与实施例9相同的方式制备5-(苯并噻吩-7-基)-1,2,3,3a,4,6a-六氢环戊烷[c]吡咯盐酸盐。
ESI-MS m/z 242.27[M+H]
+.
实施例49：5-(苯并[b]噻吩-2-基)八氢环戊烷[c]吡咯-5-醇
除了以2-溴苯并噻吩代替3,4-二氯溴苯以外，以与实施例9中的化合物9-c的相同的制备方法制备中间体49-a。
取该中间体110mg加入到3ml甲苯中，加入550mg酸性硅胶，加热回流过夜。浓缩溶剂，柱层析得产物50mg。用石油醚打浆得到26mg标题化合物，类白色固体。
1H NMR(400MHz,CDCl
3)δ7.81(d,1H),7.69(d,1H),7.28(m,2H),7.17(s,1H),3.06(d,2H),2.97-2.82(m,4H),2.49(dd,2H),2.07(d,2H).ESI-MS m/z 260.14[M+H]
+.
实施例50：5-(苯并噻吩-2-基)八氢环戊烷[c]吡咯盐酸盐
除了以2-溴苯并噻吩代替4-溴苯并噻吩以外，以与实施例3相同的方式制备5-(苯并噻吩-2-基)八氢环戊烷[c]吡咯盐酸盐。
1H NMR(400MHz,CD
3OD)δ7.78(d,1H),7.70(d,1H),7.28(m,2H),7.15(s,1H),3.46(m,1H),3.40-3.24(m,4H),3.08(m,2H),2.55(m,2H),1.69(m,2H).ESI-MS m/z 244.24[M+H]
+.
实施例51：5-(苯并噻吩-2-基)-1,2,3,3a,4,6a-六氢环戊烷[c]吡咯盐酸盐
除了以2-溴苯并噻吩代替3,4-二氯溴苯以外，以与实施例9相同的方式制备5-(苯并噻吩-2-基)-1,2,3,3a,4,6a-六氢环戊烷[c]吡咯盐酸盐。
1H NMR(400MHz,DMSO-d
6)δ9.62(br,1H),9.15(br,1H),7.91(m,1H),7.81(m,1H),7.35(m,3H),5.99(m,1H),3.67(m,1H),3.43-3.24(m,2H),3.17(m,2H),3.10-2.93(m,2H),2.77(m,1H).ESI-MS m/z 242.25[M+H]
+.
实施例52：5-(苯并呋喃-2-基)-1,2,3,3a,4,6a-六氢环戊烷[c]吡咯盐酸盐
除了以2-溴苯并呋喃代替3,4-二氯溴苯以外，以与实施例9相同的方式制备5-(苯并呋喃-2-基)-1,2,3,3a,4,6a-六氢环戊烷[c]吡咯盐酸盐。
1H NMR(400MHz,DMSO-d
6)δ9.30(br,2H),7.63(d,1H),7.56(d,1H),7.31(t,1H),7.24(t,1H),6.88(s,1H),6.18(m,1H),3.71(m,1H),3.34(m,2H),3.18(m,2H),2.99(m,2H),2.69(m,1H).ESI-MS m/z 226.21[M+H]
+.
实施例53：5-(苯并呋喃-2-基)八氢环戊烷[c]吡咯-5-醇
除了以2-溴苯并呋喃代替3,4-二氯溴苯以外，以与实施例9中的化合物9-c的相同的制备方法制备中间体53-a。
取该中间体120mg和600mg酸性硅胶溶解到3.5mL甲苯中，升温至90度反应1h，过柱得到纯品并用石油醚50度热打浆，过滤烘干后得到15mg标题化合物，淡黄色固体。
1H NMR(400MHz,CDCl
3)δ7.53(d,1H),7.43(d,1H),7.21(m,2H),6.69(s,1H),3.23 (d,2H),3.01(d,4H),2.57(dd,2H),2.03(d,2H).ESI-MS m/z 244.14[M+H]
+.
实施例54：5-(萘-2-基)-1,2,3,3a,4,6a-六氢环戊烷[c]吡咯盐酸盐
除了以2-溴代萘代替3,4-二氯溴苯以外，以与实施例9相同的方式制备5-(萘-2-基)-1,2,3,3a,4,6a-六氢环戊烷[c]吡咯盐酸盐。
1H NMR(400MHz,CD
3OD)δ7.85(m,4H),7.76(dd,1H),7.48(m,2H),6.24(m,1H),3.86(m,1H),3.60-3.24(m,5H),3.20(dd,1H),2.91(d,1H).
实施例55：5-(萘-2-基)八氢环戊烷[c]吡咯盐酸盐
除了以2-溴代萘代替4-溴苯并噻吩以外，以与实施例3相同的方式制备5-(萘-2-基)八氢环戊烷[c]吡咯盐酸盐。
1H NMR(400MHz,DMSO-d
6)δ9.33(br,1H),7.82(m,4H),7.59(dd,1H),7.47(m,2H),3.32(m,1H),3.15(m,4H),2.92(m,2H),2.29(m,2H),1.72(m,2H).ESI-MS m/z 238.23[M+H]
+.
实施例56：5-(萘-1-基)-1,2,3,3a,4,6a-六氢环戊烷[c]吡咯二盐酸盐
除了以1-溴代萘代替3,4-二氯溴苯以外，以与实施例9相同的方式制备5-(萘-1-基)-1,2,3,3a,4,6a-六氢环戊烷[c]吡咯二盐酸盐。
1H NMR(400MHz,DMSO-d
6)δ9.31(br,2H),7.95-7.83(m,4H),7.77(dd,1H),7.50(m,2H),6.28(d,1H),3.70(br,1H),3.40(dd,1H),3.33(dd,1H),3.23-3.05(m,3H),2.99(dd,1H),2.81(d,1H).ESI-MS m/z 236.32[M+H]
+.
实施例57：2-甲基-5-(萘-2-基)-1,2,3,3a,4,6a-六氢环戊烷[c]吡咯
取实施例54(60mg)溶解到1mL甲醛溶液(40％)中，75度搅拌4h。冰水浴加入2当量NaBH
4，恢复至室温反应10h，二氯甲烷/水分层，浓缩有机相，石油醚打浆，烘干后得到45mg标题化合物，白色固体。
ESI-MS m/z 250.39[M+H]
+.
实施例58：2-甲基-5-(萘-2-基)八氢环戊烷[c]吡咯盐酸盐
取实施例57(30mg)溶解到5mL醋酸溶液中，加入5mg 10％Pd/C，氢气置换后25度反应24h，质谱显示原料反应完。过滤反应液，并用5ml 20％NaOH碱化醋酸相，10mL DCM分层，浓缩有机层。冰水浴，3mL HCl-二氧六环成盐，过滤固体，5mL石油醚打浆，过滤烘干后得到8mg标题化合物，白色固体。
ESI-MS m/z 252.43[M+H]
+.
实施例59：5-(苯并呋喃-2-基)-2-甲基-1,2,3,3a,4,6a-六氢环戊烷[c]吡咯盐酸盐
除了以实施例52的产物代替实施例54的产物以外，以与实施例57相同的方式制备5-(苯并呋喃-2-基)-2-甲基-1,2,3,3a,4,6a-六氢环戊烷[c]吡咯，然后采用氯化氢甲醇溶液代替实施例10中的马来酸的四氢呋喃溶液、参照实施例10成盐酸盐得到标题化合物。
ESI-MS m/z 240.39[M+H]
+.
实施例60：5-(苯并呋喃-2-基)-2-甲基八氢环戊烷[c]吡咯盐酸盐
取实施例59(50mg)溶解到5mL醋酸溶液中，加入5mg 10％Pd/C，氢气置换后25度反应24h，质谱显示原料反应完。过滤反应液，并用5ml 20％NaOH碱化醋酸相，10mL DCM分层，浓缩有机层。冰水浴，3mL HCl-二氧六环成盐，过滤固体，5mL石油醚打浆，过滤烘干后得到10mg标题化合物，白色固体。
ESI-MS m/z 242.36[M+H]
+.
实施例61：5-(苯并噻吩-2-基)-2-甲基-1,2,3,3a,4,6a-六氢环戊烷[c]吡咯盐酸盐
除了以实施例51的产物代替实施例54的产物以外，以与实施例57相同的方式制备5-(苯并噻吩-2-基)-2-甲基-1,2,3,3a,4,6a-六氢环戊烷[c]吡咯，采用氯化氢甲醇溶液代替实施例10中的马来酸的四氢呋喃溶液、参照实施例10成盐酸盐得到标题化合物。
ESI-MS m/z 256.23[M+H]
+.
实施例62：5-(苯并噻吩-2-基)-2-甲基八氢环戊烷[c]吡咯盐酸盐
取实施例61(45mg)溶解到5mL醋酸溶液中，加入20mg 10％Pd/C，氢气置换后25度反应24h，质谱显示原料反应完。过滤反应液，并用5ml 20％NaOH碱化醋酸相，10mL DCM分层，浓缩有机层。冰水浴，3mL HCl-二氧六环成盐，过滤固体，5mL石油醚打浆，过滤烘干后得到5mg标题化合物，白色固体。
ESI-MS m/z 258.31[M+H]
+.
实施例63：5-(3,4-二氯苯基)八氢环戊烷[c]吡咯盐酸盐
除了以1-溴-3,4-二氯苯代替4-溴苯并噻吩以外，以与实施例3相同的方式制备5-(3,4-二氯苯基)八氢环戊烷[c]吡咯盐酸盐。
1H NMR(400MHz,CD
3OD)δ7.73(d,1H),7.45(m,2H),3.47(m,2H),3.37(m,1H),3.05(m,2H),2.93(m,2H),1.96(m,2H),1.82(m,2H).ESI-MS m/z 256.27[M+H]
+.
实施例64：1-(苯并噻吩-5-基)八氢吡咯[3,4-b]吡咯马来酸盐
除了以5-溴苯丙噻吩代替2-溴代萘，并以六氢吡咯并[3,4-b]吡咯-5(1H)-甲酸叔丁酯代替六氢吡咯并[3,4-c]吡咯-2(1H)-甲酸叔丁酯以外，以与实施例1相同的方式制备1-(苯并噻吩-5-基)八氢吡咯[3,4-b]吡咯，参照实施例10成马来酸盐得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ8.88(s,2H),7.80(d,1H),7.66(d,1H),7.29(d,1H),7.03(d,1H),6.81(d,1H),6.01(s,2H),4.29(t,1H),3.62(m,1H),3.48(m,1H),3.33(m,1H),3.19(m,4H),2.17(m,1H),1.94(m,1H).ESI-MS(m/z):245.21[M+H]
+.
实施例65：1-(苯并噻吩-5-基)-5-甲基八氢吡咯[3,4-b]吡咯草酸盐
除了以实施例64的碱式产物代替实施例1的产物，以与实施例2相同的方式制备1-(苯并噻吩-5-基)-5-甲基八氢吡咯[3,4-b]吡咯，参照实施例11成草酸盐得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ9.50(brs,2H),7.79(d,1H),7.65(d,1H),7.29(d,1H),7.02(d,1H),6.80(d,1H),4.34(m,1H),3.59(m,1H),3.47(m,1H),3.24(m,5H),2.72(s,3H),2.15(m,1H),1.95(m,1H).ESI-MS(m/z):259.22[M+H]
+.
实施例66：2-(2,3-二甲基苯基)八氢吡咯[3,4-c]吡咯马来酸盐
除了以1-溴-2,3-二甲基苯代替2-溴代萘以外，以与实施例1相同的方式制备2-(2,3-二甲基苯基)八氢吡咯[3,4-c]吡咯，参照实施例10成马来酸盐得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ8.68(s,2H),7.02(t,1H),6.87(m,2H),6.02(s,2H),3.52(m,2H),2.98(m,6H),2.86(m,2H),2.21(s,3H),2.16(s,3H).ESI-MS(m/z):217.23[M+H]
+.
实施例67：2-(2,3-二甲基苯基)-5-甲基八氢吡咯[3,4-c]吡咯草酸盐
除了以实施例66的碱式产物代替实施例1的产物，以与实施例2相同的方式制备2-(2,3-二甲基苯基)-5-甲基八氢吡咯[3,4-c]吡咯，参照实施例11成草酸盐得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ7.02(t,1H),6.87(m,2H),3.59(m,2H),2.82-3.06(m,8H),2.80(s,3H),2.21(s,3H),2.17(s,3H).ESI-MS(m/z):231.30[M+H]
+.
实施例68：2-(4-氟苯并[b]噻吩-6-基)八氢吡咯[3,4-c]吡咯二盐酸盐
除了以6-溴-4-氟苯并[b]噻吩代替2-溴代萘，以与实施例1相同的方式制备2-(4-氟苯并[b]噻吩-6-基)八氢吡咯[3,4-c]吡咯，采用氯化氢甲醇溶液代替实施例10中的马来酸的四氢呋喃溶液、参照实施例10成盐酸盐得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ9.51(brs,2H),7.40(d,1H),7.27(d,1H),6.99(s,1H),6.65(dd,1H),3.34-3.50(m,6H),2.98-3.18(m,4H).ESI-MS(m/z):263.18[M+H]
+.
实施例69：2-(6-氟苯并噻吩-4-基)八氢吡咯[3,4-c]吡咯二盐酸盐
除了以4-溴-6-氟苯并噻吩代替2-溴代萘，以与实施例1相同的方式制备2-(6-氟苯并噻吩-4-基)八氢吡咯[3,4-c]吡咯，采用氯化氢甲醇溶液代替实施例10中的马来酸的四氢呋喃溶液、参照实施例10成盐酸盐得到标题化合物。
1H NMR(400MHz,CD
3OD)δ7.57(d,1H),7.47(d,1H),7.25(dd,1H),6.63(dd,1H),3.65(m,2H),3.55(m,2H),3.18-3.36(m,6H).ESI-MS(m/z):263.13[M+H]
+.
实施例70：2-(6-氟苯并噻吩-4-基)-5-甲基八氢吡咯[3,4-c]吡咯草酸盐
除了以实施例69的碱式产物代替实施例1的产物，以与实施例2相同的方式制备2-(6-氟苯并噻吩-4-基)-5-甲基八氢吡咯[3,4-c]吡咯，参照实施例11成草酸盐得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ7.63(m,2H),7.41(dd,1H),6.59(dd,1H),3.57(m,2H),3.49(m,2H),3.24(m,2H),3.12(m,4H),2.81(s,3H).ESI-MS(m/z):277.24[M+H]
+.
实施例71：2-甲基-5-(萘-1-基)-1,2,3,3a,4,6a-六氢环戊烷[c]吡咯
取实施例56(50mg)溶解到1mL甲醛溶液(40％)中，75度搅拌4h。冰水浴加入2当量NaBH
4，恢复至室温反应10h，二氯甲烷/水分层，浓缩有机相，石油醚打浆，烘干后得到40mg标题化合物，白色固体。
ESI-MS m/z 250.44[M+H]
+.
实施例72：2-(3,6-二甲氧基萘-2-基)-5-甲基八氢吡咯[3,4-c]吡咯二盐酸盐
除了以2-溴-3,6-二甲氧基萘代替2-溴代萘以外，以与实施例1相同的方式制备中间体2-(3,6-二甲氧基萘-2-基)八氢吡咯[3,4-c]吡咯。然后以该中间体代替实施例1的产物，以与实施例2相同的方式制备2-(3,6-二甲氧基萘-2-基)-5-甲基八氢吡咯[3,4-c]吡咯，采用氯化氢甲醇溶液代替实施例10中的马来酸的四氢呋喃溶液、参照实施例10成盐酸盐得到标题化合物。
1H NMR(400MHz,CD
3OD)δ8.13(m,1H),7.77(m,1H),7.45(m,1H),7.25(br,1H),7.08(m,1H),4.10(s,3H),4.15-3.96(m,4H),3.91(s,3H),3.84(m,2H),3.65-3.38(m,4H),3.02(m,3H).ESI-MS(m/z):313.43[M+H]
+.
实施例73：2-(2,3-二甲氧基苯)-5-甲基八氢吡咯[3,4-c]吡咯二盐酸盐
除了以1-溴-2,3-二甲氧基苯代替2-溴代萘以外，以与实施例1相同的方式制备中间体2-(2,3-二甲氧基苯)八氢吡咯[3,4-c]吡咯。然后以该中间体代替实施例1的产物，以与实施例2相同的方式制备2-(2,3-二甲氧基苯)-5-甲基八氢吡咯[3,4-c]吡咯，采用氯化氢甲醇溶液代替实施例10中的马来酸的四氢呋喃溶液、参照实施例10成盐酸盐得到标题化合物。
1H NMR(400MHz,CD
3OD)δ7.40(d,1H),7.19(t,1H),7.11(t,1H),6.96(d,1H),4.05-3.81(m,10H),3.76(m,2H),3.55(m,1H),3.40(m,2H),3.19(m,1H),2.99(m,3H),.ESI-MS(m/z):263.38[M+H]
+.
实施例74：2-(苯并[d][1,3]二恶英-4-基)-5-甲基八氢吡咯[3,4-c]吡咯二盐酸盐
除了以4-溴-苯并[d][1,3]二恶英代替2-溴代萘以外，以与实施例1相同的方式制备中间体2-(苯并[d][1,3]二恶英-4-基)八氢吡咯[3,4-c]吡咯。然后以该中间体代替实施例1的产物，以与实施例2相同的方式制备2-(苯并[d][1,3]二恶英-4-基)-5-甲基八氢吡咯[3,4-c]吡咯， 采用氯化氢甲醇溶液代替实施例10中的马来酸的四氢呋喃溶液、参照实施例10成盐酸盐得到标题化合物。
1H NMR(400MHz,CD
3OD)δ6.83(m,1H),6.70(t,1H),6.63(d,1H),5.97(d,2H),3.95(dd,1H),3.77(t,2H),3.69(d,1H),3.50-3.35(m,4H),3.28(m,1H),3.14(m,1H),2.95(m,3H).ESI-MS(m/z):247.31[M+H]
+.
实施例75：2-(1,3-二氟萘基-2-基)-5-甲基八氢吡咯[3,4-c]吡咯二盐酸盐
除了以2-溴-1,3-二氟萘代替2-溴代萘以外，以与实施例1相同的方式制备中间体2-(1,3-二氟萘基-2-基)八氢吡咯[3,4-c]吡咯。然后以该中间体代替实施例1的产物，以与实施例2相同的方式制备2-(1,3-二氟萘基-2-基)-5-甲基八氢吡咯[3,4-c]吡咯，采用氯化氢甲醇溶液代替实施例10中的马来酸的四氢呋喃溶液、参照实施例10成盐酸盐得到标题化合物。
1H NMR(400MHz,CD
3OD)δ7.93(d,1H),7.78(d,1H),7.48(m,2H),7.41(d,1H),3.99(m,1H),3.63-3.39(m,6H),3.30(m,1H),3.12(m,1H),2.95(m,4H).ESI-MS(m/z):289.32[M+H]
+.
实施例76：2-(3-氟萘基-2-基)-5-甲基八氢吡咯[3,4-c]吡咯二盐酸盐
除了以2-溴-3-氟萘代替2-溴代萘以外，以与实施例1相同的方式制备中间体2-(3-氟萘基-2-基)八氢吡咯[3,4-c]吡咯。然后以该中间体代替实施例1的产物，并以盐酸代替马来酸，以与实施例2相同的方式制备2-(3-氟萘基-2-基)-5-甲基八氢吡咯[3,4-c]吡咯，采用氯化氢甲醇溶液代替实施例10中的马来酸的四氢呋喃溶液、参照实施例10成盐酸盐得到标题化合物。
1H NMR(400MHz,CD
3OD)δ7.75(d,1H),7.71(d,1H),7.49(dd,1H),7.39(t,1H),7.33(t,1H),7.28(dd,1H),4.00(dd,1H),3.64(m,3H),3.44(dd,1H),3.34(m,1H),3.22(m,2H),3.06(dd,1H),3.00-2.90(m,4H).ESI-MS(m/z):271.32[M+H]
+.
实施例77：5-(苯并[b]噻吩-4-基)八氢吡咯并[3,4-b]吡咯盐酸盐
除了以4-溴苯丙噻吩代替2-溴代萘，以六氢吡咯并[3,4-b]吡咯-1(2H)-甲酸叔丁酯代替六氢吡咯并[3,4-c]吡咯-2(1H)-甲酸叔丁酯，以与实施例1相同的方式制备5-(苯并[b]噻吩-4-基)八氢吡咯并[3,4-b]吡咯，采用氯化氢甲醇溶液代替实施例10中的马来酸的四氢呋喃 溶液、参照实施例10成盐酸盐得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ9.79(brs,1H),9.39(brs,1H),7.62(m,2H),7.46(d,1H),7.21(t,1H),6.70(d,1H),4.62(m,1H),3.97(m,1H),3.36(m,3H),3.11(m,2H),2.97(m,1H),2.03(m,2H).ESI-MS(m/z):245.17[M+H]
+.
实施例78：2-([1,1'-联苯]-2-基)八氢吡咯并[3,4-c]吡咯盐酸盐
除了以2-溴-1,1'-联苯代替2-溴代萘，以与实施例1相同的方式制备2-([1,1'-联苯]-2-基)八氢吡咯并[3,4-c]吡咯，采用氯化氢甲醇溶液代替实施例10中的马来酸的四氢呋喃溶液、参照实施例10成盐酸盐得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ9.21(brs,1H),9.09(brs,1H),7.49(m,4H),7.35(t,1H),7.28(td,1H),7.15(dd,1H),7.04(m,2H),3.32(m,2H),2.78(m,4H),2.69(m,2H),2.61(m,2H).ESI-MS(m/z):265.26[M+H]
+.
实施例79：2-(2-(甲氧基甲基)苯基)八氢吡咯并[3,4-c]吡咯二盐酸盐
除了以1-溴-2-(甲氧基甲基)苯代替2-溴代萘，以与实施例1相同的方式制备2-(2-(甲氧基甲基)苯基)八氢吡咯并[3,4-c]吡咯，采用氯化氢甲醇溶液代替实施例10中的马来酸的四氢呋喃溶液、参照实施例10成盐酸盐得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ9.23(brs,2H),7.33(m,1H),7.24(m,1H),7.02(m,2H),4.44(s,2H),3.47(m,2H),3.32(s,3H),3.06(m,2H),2.96(m,6H).ESI-MS(m/z):233.29[M+H]
+.
实施例80：2-(3-甲氧基苯基)-5-甲基八氢吡咯并[3,4-c]吡咯草酸盐
除了以1-溴-3-甲氧基苯代替2-溴代萘以外，以与实施例1相同的方式制备中间体2-(3-甲氧基苯基)八氢吡咯[3,4-c]吡咯。然后以该中间体代替实施例1的产物，以与实施例2相同的方式制备2-(3-甲氧基苯基)-5-甲基八氢吡咯并[3,4-c]吡咯，参照实施例11成草酸盐得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ7.08(t,1H),6.29(td,2H),6.20(t,1H),3.71(s,3H),3.53(m,2H),3.35(m,2H),3.14(m,4H),3.02(m,2H),2.76(s,3H).ESI-MS(m/z):233.30[M+H]
+.
实施例81：2-甲基-5-(4-(三氟甲基)苯基)八氢吡咯并[3,4-c]吡咯草酸盐
除了以1-溴-4-(三氟甲基)苯代替2-溴代萘以外，以与实施例1相同的方式制备中间体2-(4-(三氟甲基)苯基)八氢吡咯[3,4-c]吡咯(ESI-MS(m/z):257.32[M+H]
+)。然后以该中间体代替实施例1的产物，以与实施例2相同的方式制备2-甲基-5-(4-(三氟甲基)苯基)八氢吡咯并[3,4-c]吡咯，参照实施例11成草酸盐得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ7.50(d,2H),6.75(d,2H),3.50(m,2H),3.42(m,2H),3.36(m,2H),3.17(m,2H),3.08(m,2H),2.76(s,3H).ESI-MS(m/z):271.21[M+H]
+.
实施例82：2-(2-氟苯基)八氢吡咯并[3,4-c]吡咯马来酸盐
除了以1-溴-2-氟苯代替2-溴代萘以外，以与实施例1相同的方式制备2-(2-氟苯基)八氢吡咯并[3,4-c]吡咯，参照实施例10成马来酸盐得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ8.72(s,2H),7.11(m,1H),7.06(m,1H),6.85(m,2H),6.01(s,2H),3.48(m,2H),3.35(m,2H),3.20(m,2H),3.02(m,4H).ESI-MS(m/z):207.18[M+H]
+.
实施例83：2-(2-氟苯基)-5-甲基八氢吡咯并[3,4-c]吡咯草酸盐
除了以实施例82的碱式产物代替实施例1的产物，以与实施例2相同的方式制备2-(2-氟苯基)-5-甲基八氢吡咯并[3,4-c]吡咯，参照实施例11成草酸盐得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ7.09(m,2H),6.88(m,2H),3.55(m,2H),3.36(d,2H),3.08(m,4H),2.97(m,2H),2.77(s,3H).ESI-MS(m/z):221.28[M+H]
+.
实施例84：2-(2-乙氧基苯基)八氢吡咯并[3,4-c]吡咯马来酸盐
除了以1-溴-2-乙氧基苯代替2-溴代萘以外，以与实施例1相同的方式制备2-(2-乙氧基苯基)八氢吡咯并[3,4-c]吡咯，参照实施例10成马来酸盐得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ8.66(s,2H),6.88(m,3H),6.77(dd,1H),6.02(s,2H),4.01(m,2H),3.53(m,2H),3.36(d,2H),2.94(m,6H),1.37(t,3H).ESI-MS(m/z):233.26[M+H]
+.
实施例85：2-(2-乙氧基苯基)-5-甲基八氢吡咯并[3,4-c]吡咯草酸盐
除了以实施例84的碱式产物代替实施例1的产物，以与实施例2相同的方式制备2-(2-乙氧基苯基)-5-甲基八氢吡咯并[3,4-c]吡咯，参照实施例11成草酸盐得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ6.89(m,2H),6.85(m,1H),6.78(dd,1H),4.01(m,2H),3.73(m,2H),3.41(m,2H),3.02(m,2H),2.82(s,3H),2.50(m,4H),1.38(t,3H).ESI-MS(m/z):247.30[M+H]
+.
实施例86：2-甲基-5-(邻甲苯基)八氢吡咯[3,4-c]吡咯草酸盐
除了以邻溴甲苯代替2-溴代萘以外，以与实施例1相同的方式制备中间体2-甲基-5-(邻甲基苯基)八氢吡咯[3,4-c]吡咯(ESI-MS(m/z):203.34[M+H]
+)。然后以该中间体代替实施例1的产物，以与实施例2相同的方式制备2-甲基-5-(邻甲苯基)八氢吡咯[3,4-c]吡咯，参照实施例11成草酸盐得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ8.23(brs,2H),7.12(m,2H),6.95(m,2H),3.62(m,2H),3.08(d,2H),2.97(m,4H),2.85(m,2H),2.79(s,3H),2.28(s,3H).ESI-MS(m/z):217.31[M+H]
+.
实施例87：2-(5-氟-2-甲氧基苯基)八氢吡咯并[3,4-c]吡咯马来酸盐
除了以1-溴-2-甲氧基-5-氟苯代替2-溴代萘以外，以与实施例1相同的方式制备2-(5-氟-2-甲氧基苯基)八氢吡咯并[3,4-c]吡咯，参照实施例10成马来酸盐得到标题化合物。
ESI-MS(m/z):237.20[M+H]
+.
实施例88：2-(5-氟-2-甲氧基苯基)-5-甲基八氢吡咯并[3,4-c]吡咯草酸盐
除了以实施例87的碱式产物代替实施例1的产物，以与实施例2相同的方式制备2-(5-氟-2-甲氧基苯基)-5-甲基八氢吡咯并[3,4-c]吡咯，参照实施例11成草酸盐得到标题化合物。
1H NMR(400MHz,DMSO-d
6)δ9.71(brs,2H),6.90(dd,1H),6.66(ddd,1H),6.58(dd,1H),3.76(s,3H),3.59(m,2H),3.38(d,2H),2.97(m,6H),2.77(s,3H).ESI-MS(m/z):251.31[M+H]
+.
实施例89：6-(2,3-二氯苯基)十氢吡咯并[3,4-d]吖庚因盐酸盐
除了以2,3-二氯溴苯代替2-溴代萘以外，以与实施例6相同的方式制备6-(2,3-二氯苯基)十氢吡咯并[3,4-d]吖庚因，参照实施例3成盐酸盐，得到标题化合物。
1H NMR(400MHz,Methanol-d
4):δ7.66(dd,J＝8.1,1.3Hz,1H),7.54(dd,J＝8.1,1.3Hz,1H),7.22(t,J＝8.1Hz,1H),3.65(d,J＝7.7Hz,1H),3.62(d,J＝7.7Hz,1H),3.55(d,J＝6.6Hz,1H),3.52(d,J＝6.6Hz,1H),3.11–2.95(m,4H),2.79(m,2H),2.11–2.02(m,2H),1.95(m,2H).ESI-MS(m/z):285.35[M+H]
+
实施例90：6-(2,4-二氯苯基)十氢吡咯并[3,4-d]吖庚因盐酸盐
除了以2,4-二氯溴苯代替2-溴代萘以外，以与实施例6相同的方式制备6-(2,4-二氯苯基)十氢吡咯并[3,4-d]吖庚因，参照实施例3成盐酸盐，得到标题化合物。
1H NMR(400MHz,Methanol-d
4):δ7.68(d,J＝8.6Hz,1H),7.59(d,J＝2.4Hz,1H),7.27(dd,J＝8.6,2.4Hz,1H),3.65(d,J＝7.7Hz,1H),3.62(d,J＝7.7Hz,1H),3.56(d,J＝6.5Hz,1H),3.52(d,J＝6.5Hz,1H),3.13–2.95(m,4H),2.81(m,2H),2.12–1.91(m,4H).ESI-MS(m/z):285.35[M+H]
+.
实施例91：6-(3,4-二氯苯基)-2-甲基十氢吡咯并[3,4-d]吖庚因盐酸盐
除了以实施例35代替实施例1的产物，以与实施例2相同的方式制备6-(3,4-二氯苯基)-2-甲基十氢吡咯并[3,4-d]吖庚因，参照实施例3成盐酸盐，得到标题化合物。
ESI-MS(m/z):299.30[M+H]
+.HPLC:95.99％.
实施例92 7-(5-甲基六氢吡咯[3,4-c]吡咯-2(1H)-基)-3,4-二氢喹啉-2(1H)-酮二盐酸盐
以5-溴-3,4-二氢喹啉-2(1H)-酮和2-甲基八氢吡咯[3,4-c]吡咯为原料，参照实施例1步骤的方法制备7-(5-甲基六氢吡咯[3,4-c]吡咯-2(1H)-基)-3,4-二氢喹啉-2(1H)-酮，参照实施例3成盐酸盐，得到标题化合物。
1H NMR(400MHz,Methanol-d
4):δ7.06(m,3H),3.94(m,1H),3.73(d,J＝11.8Hz,1H),3.70–3.30(m,8H),3.03–2.89(m,5H),2.56(m,2H).
ESI-MS(m/z):272.34[M+H]
+.
实施例93 5-(5-甲基六氢吡咯[3,4-c]吡咯-2(1H)-基)-3,4-二氢喹啉-2(1H)-酮二盐酸 盐
以2-氧代-1,2,3,4-四氢喹啉-5-基三氟甲烷磺酸酯和2-甲基八氢吡咯[3,4-c]吡咯为原料，参照实施例1步骤的方法制备5-(5-甲基六氢吡咯[3,4-c]吡咯-2(1H)-基)-3,4-二氢喹啉-2(1H)-酮，参照实施例3成盐酸盐，得到标题化合物。
1H NMR(400MHz,Methanol-d
4):δ6.95(t,J＝8.0Hz,1H),6.49(dd,J＝8.2,1.0Hz,1H),6.37(dd,J＝7.9,1.0Hz,1H),3.93(m,1H),3.73(d,J＝11.9Hz,1H),3.70–3.34(m,8H),2.97(d,3H),2.89(t,J＝7.7Hz,2H),2.52(t,J＝7.7Hz,2H).ESI-MS(m/z):272.33[M+H]
+.
药理实验
1.5-HTT再摄取活性测试
根据文献(Journal of Neuroscience Methods,2008,169(1):168-176)的记载，采用基于荧光的非放射性高通量筛选体系进行化合物的5-HTT再摄取活性测试。该测试按照Molecular Devices公司关于他们的神经递质转运蛋白摄取测定试剂盒(Neurotransmitter transporter uptake assay kit)的说明书进行。
具体操作如下：
1)第一天将每孔20μl含有20000个HEK293-hSERT细胞种到384孔板中，37℃孵育过夜。
2)第二天，阳性对照化合物和测试化合物用0.1％BSA缓冲液稀释。
3)将细胞板从孵育箱中取出，从孔中吸取细胞培养介质，每个孔加入25μl测试溶液。阴性对照孔中加入25μl含有BSA的缓冲溶液，阳性对照孔中加入25μl阳性溶液。
4)37℃孵育30min，然后每孔加入25μl染液，37℃孵育30min。
5)Flexstation 3读板后利用Prism软件处理数据，结果见表1。
表1：
| 化合物 | IC 50 |
| 1 | <10nM |
| 2 | <10nM |
| 6 | <200nM |
| 7 | <10nM |
| 8 | <200nM |
| 9 | <200nM |
| 10 | <50nM |
| 11 | <50nM |
| 12 | <50nM |
| 13 | <50nM |
| 14 | <10nM |
| 15 | <10nM |
| 16 | <10nM |
| 17 | <10nM |
| 19 | <10nM |
| 21 | <50nM |
| 22 | <50nM |
| 23 | <200nM |
| 26 | <200nM |
| 27 | <50nM |
| 28 | <200nM |
| 29 | <10nM |
| 30 | <10nM |
| 31 | <10nM |
| 32 | <10nM |
| 35 | <10nM |
| 36 | <10nM |
| 37 | <10nM |
| 38 | <10nM |
| 39 | <10nM |
| 41 | <10nM |
| 42 | <10nM |
| 43 | <50nM |
| 48 | <50nM |
| 50 | <200nM |
| 51 | <50nM |
| 52 | <200nM |
| 54 | <50nM |
| 55 | <10nM |
| 56 | <50nM |
| 57 | <50nM |
| 59 | <50nM |
| 61 | <50nM |
| 62 | <50nM |
| 64 | <50nM |
| 65 | <50nM |
| 66 | <50nM |
| 67 | <200nM |
| 68 | <200nM |
| 69 | <200nM |
| 70 | <50nM |
| 71 | <50nM |
| 75 | <100nM |
| 76 | <50nM |
| 81 | <50nM |
| 89 | <10nM |
| 90 | <50nM |
| 93 | <200nM |
| 阳性对照西酞普兰 | 6.45nM |
在以上测定中，优选的本发明化合物显示低于200nM(IC
50)血清素再摄取抑制浓度。更优选的化合物显示低于100nM的抑制浓度，最优选的化合物显示低于50nM的抑制浓度，特别令人感兴趣的化合物显示低于10nM的血清素再摄取抑制浓度。
2. 5-HT
3受体亲和力活性测试
细胞膜由表达了人重组5-HT
3受体的HEK293细胞制备，膜浓度每孔2.2μg，同位素配体3H-BRL 43694的浓度为0.5nM，非特异性结合化合物MDL 72222的浓度为10μM。
1)将1μl的待测化合物转移到分析板中，以及1μl连续稀释的阳性对照MDL 72222和1μl的DMSO阴性对照。
2)铺板，将100μl膜储备液加入到测试板中。
3)加入100μl同位素标记的配体3H-BRL 43694。
4)密封测试板，在常温下孵育1小时。
5)将50μl洗涤剂0.3％聚乙烯亚胺加入到每个孔中，在室温下浸泡Unifilter-96GF/C过滤板至少30min。
6)当结合实验结束后，用GF/C过滤板过滤反应液混合物，然后用冷缓冲液洗4次。
7)在50℃条件下干燥过滤板。
8)干燥后，用密封胶带封闭过滤板底部，加入50μl闪烁液(Perkin Elmer Microscint 20 cocktail)。用密封膜封闭过滤板顶部。
9)用Perkin Elmer MicroBeta2读数仪计数过滤板上捕获的3H，用GraphPad Prism 5软件分析数据，结果见表2。
表2：
根据表2可以看出，本发明化合物具有5-HT
3受体高亲和力，可用于治疗5-HT
3受体相关的中枢神经系统类疾病。5-HT
3受体位于突触后膜，调节不同脑区抑制性GABA中间神经元从而调节各种神经递质的释放。血清素作用于5-HT
3受体能降低各种神经递质的释放，因此，拮抗5-HT
3受体引起去抑制，从而增加神经递质的释放。5-HT
3拮抗剂能够增强SSRIs类抗抑郁药的效果。动物试验表明，将5-HT
3拮抗剂昂丹司琼和帕罗西汀合用能够增强帕罗西汀的抗抑郁效果。昂丹司琼能够部分阻止帕罗西汀对中缝背核5-HT神经元放电的抑制作用，并增强帕罗西汀诱导的海马细胞外5-HT释放(Pharmacology,Biochemistry and Behavior 2015,131,136-142.)。
抑郁症患者常伴有慢性疼痛。慢性躯体疼痛与抑郁症紧密关联，而且其严重程度与抑郁症严重程度呈正相关。纤维肌痛是一个以广泛疼痛为特征的慢性疼痛疾病。临床证据表明，5-HT3R拮抗剂格拉司琼、昂丹司琼和托烷司琼可显著减少纤维肌痛(Arthritis Res Ther,2006,8(4),212.)，因此预期具有5-HT
3R拮抗作用的抗抑郁药物能够缓解抑郁症患者的疼痛病症。
大量研究证据表明5-HT能系统和其他神经递质系统如胆碱能、多巴胺能、谷氨酸能系统在控制学习和记忆方面存在相互作用。大脑皮质和背侧海马都是与记忆有关的重要结构。5-HT能神经元的兴奋可刺激胆碱能神经元释放乙酰胆碱。5-HT
3R拮抗剂可以在不影响乙酰胆碱稳态释放的前提下，抑制5-HT的调节释放乙酰胆碱，阻止认知损伤。将老鼠的5-HT
3R过度表达已被证明可增强学习记忆和注意力。有文献报道昂丹司琼能改善患者记忆力，降低认知功能损害(Pharmacology&therapeutics,2010,128(1):146-169.)。
根据以上实施例可以看出，根据本发明的部分化合物具有5-HTT/5-HT
3受体多靶点作用，有利于调节脑内神经递质平衡，对中枢神经系统类疾病具有较好疗效。因此，可以通过多靶点的协同作用快速起效并减少药物引起的副作用。
3.体内药效试验(小鼠强迫游泳模型)
实验动物：C57BL/6小鼠(上海西普尔-必凯实验动物有限公司)，雄性，6周，体重15-20g。ICR小鼠(上海西普尔-必凯实验动物有限公司)，雄性，6周，体重20-25g。所有订购小鼠在标准环境下饲养2-3周后再进行实验。
强迫游泳实验(Forced swimming test,FST):强迫游泳设备中水位为45cm，水温25℃，实验开始前将小鼠置于实验房间适应环境1h。实验开始时将小鼠置于设备中，时长6min，整个过程用摄像头记录，分析数据时只统计最后4min小鼠的不动时间，其结果用mean±SD表示。
悬尾实验(Tail suspension test,TST):用医用胶布将小鼠尾部固定在设备上，时长6min，整个过程用摄像头记录，分析数据时只统计最后4min小鼠的不动时间。
结果采用单因素方差分析进行统计。受试化合物在以下剂量(表3)均可显著降低小鼠不动时间，与空白组相比具有显著性差异。po:口服给药；ip:腹腔给药。FST:强迫游泳实验；TST:悬尾实验。
表3：
| 测试化合物 | 有效剂量(mg/kg) |
| 实施例1的化合物 | 5(po)；FST |
| 实施例2的化合物 | 5(po)；FST |
| 实施例7的化合物 | 10(ip)；TST |
| 实施例10的化合物 | 10(ip)；FST |
| 实施例11的化合物 | 10(ip)；FST |
| 实施例12的化合物 | 3(ip)；FST |
| 实施例13的化合物 | 5(ip)；FST |
| 实施例14的化合物 | 3(ip)；FST |
| 实施例15的化合物 | 2.5(po)；FST |
| 实施例16的化合物 | 3(ip)；FST |
| 实施例17的化合物 | 5(po)；FST |
| 实施例19的化合物 | 10(ip)；FST |
| 实施例21的化合物 | 3(ip)；FST |
| 实施例22的化合物 | 10(ip)；TST |
| 实施例25的化合物 | 10(ip)；TST |
| 实施例28的化合物 | 10(ip)；TST |
| 实施例29的化合物 | 5(po)；FST |
| 实施例30的化合物 | 20(po)；FST |
| 实施例31的化合物 | 20(po)；FST |
| 实施例32的化合物 | 20(po)；FST |
| 实施例35的化合物 | 20(po)；FST |
| 实施例36的化合物 | 10(ip)；TST |
| 实施例37的化合物 | 10(ip)；FST |
| 实施例38的化合物 | 10(ip)；TST |
| 实施例39的化合物 | 10(ip)；TST |
| 实施例41的化合物 | 10(ip)；TST |
| 实施例50的化合物 | 10(ip)；FST |
| 实施例55的化合物 | 5(po)；FST |
| 实施例69的化合物 | 10(ip)；FST |
| 实施例81的化合物 | 10(ip)；FST |
| 度洛西汀 | 20(po)；FST |
| 西酞普兰 | 20(po)；FST |
本发明化合物不仅活性强，而且口服有效，具有药效剂量低、毒副作用小等特点，对中枢神经系统领域的疾病具有疗效，尤其对重度抑郁症(MDD)、焦虑症、强迫症等疾病疗效好。
Claims (10)
- 一种由通式(I)表示的化合物、其立体异构体或其药学上可接受的盐：
其中：R 1为氢或C1～C20烷基；优选氢或C1～C10烷基；更优选为氢或C1～C6烷基；m,n,p,q各自独立地为0或1或2或3；优选地，m,n,p,q各自独立地为1或2；条件是m+p为1、2、3或4，n+q为1、2、3或4且m+p+n+q为3、4、5、6、或7；X为CR 2，N或C；当X为CR 2或N时，与X相连的表示单键，R 2为氢、羟基或C1～C6烷氧基；当X为C时，与X相连的
表示双键；
G环为苯基、联苯基、萘基、四氢萘基、二氢茚基、单环杂环基或苯并杂环基；并且，G环非必须地被一个或多个相同或不同取代基取代；所述G环上的取代基为卤素、氧代(＝O)、羟基、卤代C1～C6烷基、C1～C6烷酰基、被C1～C6烷氧基取代的C1～C6烷基、C1～C6烷基或C1～C6烷氧基，优选地，所述G环上的取代基为卤素、氧代(＝O)、羟基、卤代C1～C4烷基、C1～C4烷酰基、被C1～C6烷氧基取代的C1～C4烷基、C1～C4烷基或C1～C4烷氧基，更优选地，所述G环上的取代基为卤素、氧代(＝O)、羟基、乙酰基、三氟甲基、甲氧基甲基、甲基、乙基、甲氧基或乙氧基。 - 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中，G环为
且所述G环非必须地被一个或多个相同或不同取代基取代，所述G环上的取代基的定义与权利要求1中相同。
- 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中，所述G环为且所述G环非必须地被一个或多个相同或不同取代基取代，所述G环上的取代基的定义与权利要求1中相同。
- 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中，为选自式S-1至S-41的基团：
其中，X和R 1的定义与权利要求1中相同。 - 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中，为选自式S-1a至S-41a的基团：
其中，R 1的定义与权利要求1中相同。 - 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中，所述化合物选自如下化合物：
- 一种并环化合物的制备方法，所述制备方法通过如下方法1-7之一进行，方法1：式(II-a)所示的化合物与式(III)所示的化合物进行偶联反应得到式(Ia)所示的化合物，如反应式1所示：
其中，G环、m、n、p、q、R 1与权利要求1中定义的相同；L 1代表卤素、C1～C6烷基磺酰氧基、苯磺酰氧基或萘磺酰氧基，上述C1～C6烷基磺酰氧基、苯磺酰氧基、萘磺酰氧基可非必须地被一个或多个选自卤素、C1～C6烷基、C1～C6烷氧基、硝基、羟基、氨基和C1～C6烷酰基的基团进一步取代；L 1优选为卤素、C1～C4烷基磺酰氧基、苯磺酰氧基、萘磺酰氧基，上述C1～C4烷基磺酰氧基、苯磺酰氧基、萘磺酰氧基可非必须地被一个或多个选自卤素、C1～C4烷基、C1～C4烷氧基、硝基、羟基、氨基和C1～C4烷酰基进一步取代；L 1最优选为氯、溴、甲磺酰氧基、三氟甲磺酰氧基、苯磺酰氧基、萘磺酰氧基、甲基苯磺酰氧基、硝基苯磺酰氧基、氨基苯磺酰氧基、氯苯磺酰氧基、溴苯磺酰氧基或甲氧基苯磺酰氧基；方法2：式(II-b)所示的化合物与式(III)所示的化合物进行偶联反应得到式(IV)所示的化合物，然后脱除氨基保护基得到式(Ib)化合物，非必须地进行烷基化反应或还原胺化反应得到式(Ia)所示的化合物，如反应式2所示：
其中，G环、m、n、p、q与权利要求1中定义相同；R 1为C1～C20烷基，L 1代表卤素、C1～C6烷基磺酰氧基、苯磺酰氧基或萘磺酰氧基，上述C1～C6烷基磺酰氧基、苯磺酰氧基、萘磺酰氧基可非必须地被一个或多个选自卤素、C1～C6烷基、C1～C6烷氧基、硝基、羟基、氨基和C1～C6烷酰基的基团进一步取代；L 1优选为卤素、C1～C4烷基磺酰氧基、苯磺酰氧基、萘磺酰氧基，上述C1～C4烷基磺酰氧基、苯磺酰氧基、萘磺酰氧基可非必须地被一个或多个选自卤素、C1～C4烷基、C1～C4烷氧基、硝基、羟基、氨基和C1～C4烷酰基进一步取代；L 1最优选为氯、溴、甲磺酰氧基、三氟甲磺酰氧基、苯磺酰氧基、萘磺酰氧基、甲基苯磺酰氧基、硝基苯磺酰氧基、氨基苯磺酰氧基、氯苯磺酰氧基、溴苯磺酰氧基或甲氧基苯磺酰氧基；PG为取代或未取代的苄基、酰基类氨基保护基或烷氧羰基类氨基保护基，所述苄基上的取代基独立地选自卤素、三氟甲基、C1～C6烷基、C1～C6烷氧基和硝基中的一种或 多种，优选所述酰基类氨基保护基为甲酰基、乙酰基、丙酰基、苯甲酰基、卤代乙酰基、邻苯二甲酰基，且所述烷氧羰基类氨基保护基为叔丁氧羰基、苄氧羰基、9-芴甲氧羰基，方法3：式(V)所示的化合物与式(III)所示的化合物进行偶联反应，然后脱除氨基保护基得到式(Ic)化合物，非必须地进行烷基化反应或还原胺化反应得到式(If)所示的化合物，如反应式3所示：
其中，G环、m、n、p、q与权利要求1中定义相同；R 1为C1～C20烷基，L 1代表卤素、C1～C6烷基磺酰氧基、苯磺酰氧基或萘磺酰氧基，上述C1～C6烷基磺酰氧基、苯磺酰氧基、萘磺酰氧基可非必须地被一个或多个选自卤素、C1～C6烷基、C1～C6烷氧基、硝基、羟基、氨基和C1～C6烷酰基的基团进一步取代；L 1优选为卤素、C1～C4烷基磺酰氧基、苯磺酰氧基、萘磺酰氧基，上述C1～C4烷基磺酰氧基、苯磺酰氧基、萘磺酰氧基可非必须地被一个或多个选自卤素、C1～C4烷基、C1～C4烷氧基、硝基、羟基、氨基和C1～C4烷酰基进一步取代；L 1最优选为氯、溴、甲磺酰氧基、三氟甲磺酰氧基、苯磺酰氧基、萘磺酰氧基、甲基苯磺酰氧基、硝基苯磺酰氧基、氨基苯磺酰氧基、氯苯磺酰氧基、溴苯磺酰氧基或甲氧基苯磺酰氧基；PG为取代或未取代的苄基、酰基类氨基保护基或烷氧羰基类氨基保护基，所述苄基上的取代基独立地选自卤素、三氟甲基、C1～C6烷基、C1～C6烷氧基和硝基中的一种或多种，优选所述酰基类氨基保护基为甲酰基、乙酰基、丙酰基、苯甲酰基、卤代乙酰基、邻苯二甲酰基，且所述烷氧羰基类氨基保护基为叔丁氧羰基、苄氧羰基、9-芴甲氧羰基，方法4：式(VII-a)所示的化合物与式(X)所示的化合物进行羰基加成反应得到式(VIII)所示的化合物，然后脱除氨基保护基得到式(Id)化合物，如反应式4所示：
其中，G环、m、n、p、q与权利要求1中定义相同；L 2代表Li、MgBr、MgCl、MgI、ZnBr、ZnCl或ZnI；PG为酰基类氨基保护基或烷氧羰基类氨基保护基，优选所述酰基类氨基保护基为甲 酰基、乙酰基、丙酰基、苯甲酰基、卤代乙酰基、邻苯二甲酰基，且所述烷氧羰基类氨基保护基为叔丁氧羰基、苄氧羰基、9-芴甲氧羰基，方法5：式(VII-a)所示的化合物与式(X)所示的化合物进行羰基加成反应得到式(VIII)所示的化合物，然后同时脱水脱氨基保护基得到式(Ie)所示的化合物，非必须地进行烷基化反应或还原胺化反应得到式(Ig)所示的化合物，如反应式5所示：
其中，G环、m、n、p、q同上文定义相同；R 1为C1～C20烷基，L 2代表Li、MgBr、MgCl、MgI、ZnBr、ZnCl或ZnI；PG为酰基类氨基保护基或烷氧羰基类氨基保护基，优选所述酰基类氨基保护基为甲酰基、乙酰基、丙酰基、苯甲酰基、卤代乙酰基、邻苯二甲酰基，且所述烷氧羰基类氨基保护基为叔丁氧羰基、苄氧羰基、9-芴甲氧羰基，方法6：式(VII-b)所示的化合物与式(X)所示的化合物进行羰基加成反应得到式(Ih)所示的化合物，然后经脱水反应得到式(Ig)所示的化合物，如反应式6所示：
其中，G环、m、n、p、q同上文定义相同；R 1为C1～C20烷基；L 2代表Li、MgBr、MgCl、MgI、ZnBr、ZnCl或ZnI；方法7：式(Ie)或(Ig)所示的化合物经氢化还原反应分别得到式(Ic)或式(If)所示的化合物：
其中，G环、m、n、p、q同上文定义的相同。 - 一种药物组合物，其包含治疗有效量的上述通式(I)所示的化合物、其立体异构体或其药学上可接受的盐和任选的可药用载体。
- 权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，或者权利要求 8所述的药物组合物在制备预防和/或治疗中枢神经系统疾病的药物中的用途。
- 根据权利要求9所述的用途，其中，所述中枢神经系统疾病选自：情感紊乱；精神紊乱；情绪紊乱；抑郁症；内因性抑郁症；重性抑郁症；难控制的抑郁症；情绪恶劣性障碍；循环情感性障碍；恐慌发作；惊恐性障碍；社交恐惧症；强迫性观念与行为病症；冲动性病症；创伤后精神紧张性障碍；焦虑症；急性应激障碍；癔病；神经性厌食症；睡眠障碍；适应性障碍；自闭症；神经性头痛；狂躁症；多动症；纤维肌痛；神经性疼痛；注意力缺乏/亢进类疾病和抽动症等，优选地，所述睡眠障碍是睡眠呼吸暂停、失眠、发作性睡病、猝倒；优选地，所述中枢神经系统疾病选自：抑郁症；焦虑症；强迫性观念与行为病症，优选地所述神经性疼痛包括但不限于疱疹后神经痛、反射交感性营养不良/灼痛或神经创伤、假肢痛和周围神经病，优选地，所述疱疹是带状疱疹；所述周围神经病是糖尿病性神经病变或长期服用酒精引起的神经病。
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| DE4338396A1 (de) * | 1993-11-10 | 1995-05-11 | Basf Ag | N-Substituierte Azabicycloalkan-Derivate, ihre Herstellung und Verwendung |
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