WO2025031459A9 - Dérivé d'aza-ergoline, composition pharmaceutique associée et son utilisation - Google Patents

Dérivé d'aza-ergoline, composition pharmaceutique associée et son utilisation Download PDF

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WO2025031459A9
WO2025031459A9 PCT/CN2024/110706 CN2024110706W WO2025031459A9 WO 2025031459 A9 WO2025031459 A9 WO 2025031459A9 CN 2024110706 W CN2024110706 W CN 2024110706W WO 2025031459 A9 WO2025031459 A9 WO 2025031459A9
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compound
formula
solvate
pharmaceutically acceptable
acceptable salt
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WO2025031459A1 (fr
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李瑞鹏
弓雪莲
夏广新
李艳玲
王亚洲
田萧萧
高婧
巩万春
谢建树
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Shanghai Pharmaceuticals Holding Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • D 1-5 There are five subtypes of dopamine receptors (D 1-5 ), of which D 1 and D 5 are D 1 receptors, which are mainly coupled to G s proteins and increase intracellular cAMP levels after activation; D 2 , D 3 , and D 4 are D 2 receptors, which are mainly coupled to G i proteins and reduce intracellular cAMP levels after activation.
  • D 1 and D 5 are D 1 receptors, which are mainly coupled to G s proteins and increase intracellular cAMP levels after activation
  • D 2 , D 3 , and D 4 are D 2 receptors, which are mainly coupled to G i proteins and reduce intracellular cAMP levels after activation.
  • Different dopamine receptors have different expression levels and distributions in the central nervous system and play different physiological functions (Martel and McArthur, Front Pharmacol 2020, 11: 1003).
  • D2 receptor has been studied most extensively and in depth.
  • Clinically used drugs such as pramipexole, ropinirole, rotigotine, etc. are mainly used to treat Parkinson's disease and restless legs syndrome. These drugs mainly exert their therapeutic effects by activating dopamine D2 receptors, but they are also active on other dopamine receptors such as D3 .
  • Antipsychotic drugs such as haloperidol and olanzapine mainly exert their therapeutic effects by antagonizing D2 receptors, while the latest generation of drugs such as aripiprazole and cariprazine are partial agonists of dopamine D2 receptors (Frankel and Schwartz, Ther Adv Psychopharmacol 2017, 7(1): 29-41).
  • Dopamine D2 receptors have a certain degree of structural homology with other dopamine receptors, as well as other monoamine GPCRs such as 5-hydroxytryptamine (5-HT) receptors. This homology results in the fact that most drugs do not have target selectivity. Most of the antipsychotic drugs targeting dopamine D2 receptors mentioned above have a certain degree of affinity for 5-HT receptors, such as 5- HT2A receptors, and some drugs have an affinity for 5- HT2A receptors that is even stronger than their affinity for D2 receptors. The dual effects of D2 receptors and 5- HT2A receptors are the common characteristics of these drugs.
  • Krogsgaard-Larsen et al. reported a compound A with an aza-ergoline skeleton, wherein derivative A1 thereof has binding activity to 5-HT 6 receptors, derivative A2 has agonist activity to dopamine D 2 receptors, and A3 has partial agonist activity to dopamine D 2 receptors (Krogsgaard-Larsen et al., J. Med. Chem. 2014, 57, 5823-5828; WO2011088836; WO2011088838).
  • the target selectivity, in vivo activity and other drugability of the compound have not been reported.
  • CN114835709A discloses a series of azaergoline derivatives having the following structural formula I-10:
  • the technical problem to be solved by the present invention is that there are few existing compounds with affinity and agonistic activity to dopamine D2 receptors.
  • the present invention provides an azaergoline derivative, a pharmaceutical composition thereof and an application thereof.
  • the compound of the present invention has good affinity and agonistic activity to dopamine D2 receptors or D3 receptors.
  • the present invention provides a compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:
  • R1 is hydrogen or C1-6 alkyl
  • R2 is hydrogen or C1-6 alkyl
  • R3 and R4 satisfy the following conditions (1) or (2):
  • R 3 is hydrogen;
  • R 4 is hydrogen or C 1-6 alkyl;
  • Case (2) R 3 is C 2-6 alkyl; R 4 is hydrogen or C 1-6 alkyl.
  • the compound shown in Formula I is a compound shown in Formula Ia:
  • the compound as shown in Formula I is a compound as shown in Formula Ib or Ib', preferably a compound as shown in Formula Ib;
  • the compound as shown in formula I is a compound as shown in formula Ic or Ic', preferably a compound as shown in formula Ic;
  • the C1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
  • the C 1-6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
  • the C 1-6 alkyl in R 4 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, such as methyl or ethyl.
  • the C2-6 alkyl in R3 is ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, such as ethyl.
  • R 1 is hydrogen
  • R2 is hydrogen
  • R 4 is hydrogen, methyl or ethyl.
  • R 3 is hydrogen
  • R 4 is hydrogen, methyl or ethyl
  • R 3 is ethyl
  • R 4 is hydrogen, methyl or ethyl.
  • R 3 is ethyl
  • R 4 is hydrogen, methyl or ethyl
  • R 3 is hydrogen; R 4 is hydrogen or C 1-6 alkyl; for example, R 3 is hydrogen; R 4 is C 1-6 alkyl.
  • R 3 is a C 2-6 alkyl group
  • R 4 is hydrogen or a C 1-6 alkyl group.
  • the compound shown in Formula I is a compound shown in Formula Ia:
  • R1 is hydrogen; R2 is hydrogen; R3 is ethyl; R4 is hydrogen, methyl or ethyl.
  • the compound as shown in formula I is any of the following compounds:
  • the compound shown in Formula 1 is Preferably, the for
  • the filler is a chromatographic column with amylose-tris(3-chloro-5-methylcarbamate) bonded to the surface of silica gel or cellulose-tris(3,5-dichlorophenylcarbamate) bonded to the surface of silica gel;
  • the mobile phase includes an alcohol solvent (such as methanol) and a nitrile solvent (such as acetonitrile); or the mobile phase includes an alkane solvent (such as cyclohexane) and an alcohol solvent (such as methanol);
  • chromatographic column CHIRALPAKIG, 2.5cm*25cm*10 ⁇ m
  • a compound having a negative optical rotation value preferably, a compound having an optical rotation value of -60.20° under the following test conditions;
  • test conditions are: measurement temperature: 20°C; sample concentration: 1 mg/ml; selected wavelength: 589 nm; dilution solvent: methanol; instrument: automatic polarimeter Rudolph V Plus.
  • the compound shown in Formula 2 is Preferably, the for
  • the filler is a chromatographic column with amylose-tris(3-chloro-5-methylcarbamate) bonded to the surface of silica gel or cellulose-tris(3,5-dichlorophenylcarbamate) bonded to the surface of silica gel;
  • the mobile phase includes an alcohol solvent (such as methanol) and a nitrile solvent (such as acetonitrile); or the mobile phase includes an alkane solvent (such as cyclohexane) and an alcohol solvent (such as methanol);
  • the The compound with a retention time of 17.43 min under the following conditions is:
  • a compound having a negative optical rotation value preferably, a compound having an optical rotation value of -60.00° under the following test conditions;
  • test conditions are: measurement temperature: 20°C; sample concentration: 1 mg/ml; selected wavelength: 589 nm; dilution solvent: methanol; instrument: automatic polarimeter Rudolph V Plus.
  • the compound shown in Formula 3 is Preferably, the for
  • the chromatographic column is a chromatographic column whose filler is a silica gel surface bonded with amylose-tris(3-chloro-5-methylcarbamate) or a silica gel surface bonded with cellulose-tris(3,5-dichlorophenylcarbamate);
  • the mobile phase includes an alcohol solvent (such as methanol) and a nitrile solvent (such as acetonitrile); or the mobile phase includes an alkane solvent (such as cyclohexane) and an alcohol solvent (such as methanol);
  • the The compound with a retention time of 8.06 min under the following conditions is:
  • the A compound having a negative optical rotation value preferably, a compound having an optical rotation value of -52.43° under the following test conditions;
  • test conditions are: measurement temperature: 20°C; sample concentration: 1 mg/ml; selected wavelength: 589 nm; dilution solvent: methanol; instrument: automatic polarimeter Rudolph V Plus.
  • the compound shown in Formula 4 is Preferably, the for
  • the filler is a chromatographic column with amylose-tris(3-chloro-5-methylcarbamate) bonded to the surface of silica gel or cellulose-tris(3,5-dichlorophenylcarbamate) bonded to the surface of silica gel;
  • the mobile phase includes an alcohol solvent (such as methanol) and a nitrile solvent (such as acetonitrile); or the mobile phase includes an alkane solvent (such as cyclohexane) and an alcohol solvent (such as methanol);
  • the The compound with a retention time of 7.08 min under the following conditions is:
  • test conditions are: measurement temperature: 20°C; sample concentration: 1 mg/ml; selected wavelength: 589 nm; dilution solvent: MeOH; instrument: automatic polarimeter Rudolph V Plus.
  • the compound shown in Formula 5 is Preferably, the for
  • the filler is a chromatographic column with amylose-tris(3-chloro-5-methylcarbamate) bonded to the surface of silica gel or cellulose-tris(3,5-dichlorophenylcarbamate) bonded to the surface of silica gel;
  • the mobile phase includes an alcohol solvent (such as methanol) and a nitrile solvent (such as acetonitrile); or the mobile phase includes an alkane solvent (such as cyclohexane) and an alcohol solvent (such as methanol);
  • the The compound with a retention time of 8.70 min under the following conditions is:
  • a compound having a negative optical rotation value preferably, a compound having an optical rotation value of -57.43° under the following test conditions;
  • test conditions are: measurement temperature: 20°C; sample concentration: 1 mg/ml; selected wavelength: 589 nm; dilution solvent: MeOH; instrument: automatic polarimeter Rudolph V Plus.
  • the present invention also provides a pharmaceutical composition, comprising substance A and pharmaceutical excipients, wherein substance A is a compound as shown in Formula I according to any one of the present invention, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for preparing a compound as shown in Formula I, which is the following method 1 or method 2:
  • Method 1 comprises the following steps: in a solvent, in the presence of a base, reacting a compound represented by formula I-S1 and a compound represented by formula I-S2 as shown in the following formula to obtain the compound represented by formula I;
  • R 1 , R 2 , R 3 and R 4 are as defined in any one of the present invention; and R 3 and R 4 are not H at the same time;
  • Method 2 comprises the following steps: in a solvent, in the presence of a base and an amide condensation reagent, reacting a compound as shown in formula I-S1 and a The compound represented by S2' is subjected to the reaction shown in the following formula to obtain the compound represented by the formula I;
  • R 1 , R 2 , R 3 and R 4 are as defined in any of the present invention.
  • the operation and conditions of the reaction are conventional operations and conditions for such reactions in the art.
  • the solvent may be N,N-dimethylformamide
  • the base may be triethylamine
  • the reaction temperature may be room temperature
  • the compound represented by formula I may be compound 1.
  • the operation and conditions of the reaction are conventional operations and conditions for such reactions in the art.
  • the solvent may be N,N-dimethylformamide;
  • the base may be triethylamine;
  • the molar ratio of the base to the compound represented by formula I-S1 may be 5:1
  • the amide condensation reagent may be N,N-carbonyldiimidazole (CDI)
  • the molar ratio of the amide condensation reagent to the compound represented by formula I-S1 may be 2:1
  • the molar ratio of the compound represented by formula I-S2' to the compound represented by formula I-S1 may be 2:1;
  • the reaction temperature may be room temperature, and the compound represented by formula I may be compound 2, 3, 4 or 5.
  • the method for preparing the compound of formula I also includes a method for preparing the compound of formula I-S1, which comprises the following steps: in a solvent, in the presence of a deprotection agent, the compound of formula I-S1-1 is subjected to a deprotection reaction as shown in the following formula to obtain the compound of formula I-S1,
  • R t is an amine protecting group, such as tert-butyloxycarbonyl (-Boc).
  • the solvent may be methanol
  • the deprotection reagent may be hydrogen chloride
  • the molar ratio of the hydrogen chloride to the compound represented by the formula I-S1-1 may be 14:1
  • the reaction temperature may be the reflux temperature of the solvent
  • the hydrogen chloride and methanol participate in the deprotection reaction in the form of a hydrogen chloride methanol solution (for example, the molar concentration of hydrogen chloride is 4 mol/L).
  • the method for preparing the compound of formula I-S1 also includes a method for preparing the compound of formula I-S1-1, which comprises the following steps: in a solvent, in the presence of a base, reacting the compound of formula IA and the compound of formula IC as shown in the following formula to obtain the compound of formula I-S1-1,
  • R t is an amine protecting group, such as tert-butyloxycarbonyl (-Boc);
  • R s is a hydroxy protecting group, such as p-toluenesulfonyl (-Ts).
  • the solvent may be a mixed solvent of tetrahydrofuran and dimethyl sulfoxide, for example, the volume ratio of tetrahydrofuran to dimethyl sulfoxide is 4:1;
  • the base may be potassium carbonate;
  • the molar ratio of the base to the compound represented by formula I-A may be 4:1, and the molar ratio of the compound represented by formula I-C to the compound represented by formula I-A may be 2:1;
  • the reaction temperature may be 60°C.
  • the present invention provides a compound (an intermediate for preparing a compound represented by formula I), wherein the compound is any of the following compounds:
  • the present invention also provides a use of the substance A or the pharmaceutical composition in the preparation of a dopamine D2 receptor agonist or a D3 receptor agonist.
  • the dopamine D 2 receptor is a dopamine D 2 L receptor and/or a dopamine D 2 S receptor, such as a dopamine D 2 L receptor.
  • the present invention also provides a use of the substance A or the pharmaceutical composition in the preparation of a drug for treating and/or preventing diseases associated with dopamine D2 receptors or D3 receptors.
  • the dopamine D2 receptor-related disease can be selected from one or more of neurodegenerative diseases, mental disorders and metabolic diseases related to mental disorders, such as Parkinson's disease, Alzheimer's disease, dementia, schizophrenia, bipolar disorder, depression, attention deficit hyperactivity disorder, restless legs syndrome, Huntington's disease, male erectile dysfunction, prolactinoma or drug addiction.
  • neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, dementia, schizophrenia, bipolar disorder, depression, attention deficit hyperactivity disorder, restless legs syndrome, Huntington's disease, male erectile dysfunction, prolactinoma or drug addiction.
  • the present invention also provides an application of the substance A or the pharmaceutical composition in preparing a drug for treating and/or preventing a disease.
  • the disease may be selected from one or more of neurodegenerative diseases, mental disorders and metabolic diseases related to mental disorders.
  • the disease is preferably Parkinson's disease, Alzheimer's disease, dementia, schizophrenia, bipolar disorder, depression, attention deficit hyperactivity disorder, restless legs syndrome, Huntington's disease, male erectile dysfunction, prolactinoma or drug addiction.
  • stereoisomer refers to cis-trans isomers or optical isomers. These stereoisomers can be obtained by chiral separation by introduction of raw materials or separation, purification and enrichment by chiral separation.
  • single stereoisomer means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
  • trans-trans isomers in the present invention is caused by the fact that the single bonds of the carbon atoms of cyclohexane cannot rotate freely. It is the trans isomer.
  • alkyl refers to a straight or branched chain alkyl group having a specified number of carbon atoms (e.g., C 1-6 or C 2-6 ).
  • Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.
  • pharmaceutically acceptable salt refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base.
  • a base addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent.
  • an acid addition salt can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.
  • solvate refers to a substance formed after crystallization of a compound with a solvent. Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.
  • solvate of a pharmaceutically acceptable salt refers to a substance formed by combining a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base and a solvent, wherein the pharmaceutically acceptable salt has the same meaning as the term “pharmaceutically acceptable salt” above, and the solvent is stoichiometric or non-stoichiometric.
  • Pharmaceutically acceptable salt solvates include, but are not limited to, hydrochloride monohydrate.
  • pharmaceutical excipients refers to excipients and additives used in the production of drugs and the preparation of prescriptions. It is all substances contained in drug preparations except active ingredients. Please refer to the Pharmacopoeia of the People's Republic of China (2015 Edition) Part IV, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).
  • treat refers to any of the following: (1) alleviating one or more biological manifestations of a disease; (2) interfering with one or more points in the biological cascade that initiates a disease; or (3) slowing the progression of one or more biological manifestations of a disease.
  • prevention refers to reducing the risk of developing a disease.
  • patient refers to any animal that has been or is about to be treated, preferably a mammal, most preferably a human. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc.
  • the reagents and raw materials used in the present invention are commercially available.
  • the positive and progressive effect of the present invention is that the compounds of the present invention have good affinity and agonistic activity to dopamine D2 receptors or D3 receptors.
  • Figure 1 is a three-dimensional structural ellipsoid diagram of compound S-A.
  • Figure 2 is a three-dimensional structural ellipsoid diagram of compound R-A.
  • peak1 (front peak) t R 2.55 min
  • peak2 (back peak): t R 2.83 min.
  • Cultivate single crystals by evaporation method weigh 10 mg of compound S-A product in 10 mL of dichloromethane, then add 1 mL of methanol. Place the test tube at room temperature to slowly evaporate and crystallize.
  • Test conditions CuK ⁇ radiation, ⁇ / ⁇ scanning
  • the direct method (Shelxs97) was used to analyze the crystal structure.
  • the least square method is used to correct the structural parameters and determine the atomic types, and the geometric calculation method is used to obtain the position of hydrogen atoms.
  • the chemical formula of the asymmetric unit is finally determined to be C13H15N3, the calculated molecular weight is 213.28, and the calculated crystal density is 1.305g/cm3.
  • the absolute configuration of the compound in the crystal can be determined as shown in Figure 1. In the crystalline state, the molecules are stabilized in space by van der Waals forces and hydrogen bonds.
  • Cultivate single crystals by evaporation method weigh 10 mg of compound R-A product in 10 mL of dichloromethane, then add 1 mL of methanol. Place the test tube at room temperature to slowly evaporate and crystallize.
  • Test conditions CuK ⁇ radiation, ⁇ / ⁇ scanning
  • the crystal structure was analyzed by direct method (Shelxs97).
  • the least square method is used to correct the structural parameters and determine the atomic types, and the geometric calculation method is used to obtain the position of hydrogen atoms.
  • the chemical formula of the asymmetric unit is finally determined to be C13H15N3, the calculated molecular weight is 213.28, and the calculated crystal density is 1.329g/cm3.
  • Step 1 Add trans-2-(4-aminocyclohexyl)ethyl acetate hydrochloride C3 (2.00 g, 9.0 mmol), solvent dichloromethane (20 ml) and triethylamine (3.10 g, 30.6 mmol) to the reaction flask, then add methylcarbamoyl chloride (1.26 g, 13.5 mmol) at 0-5°C, protect with nitrogen, and stir at room temperature for 8 hours.
  • reaction solution is washed with water (20 ml) and saturated brine (20 ml) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated to dryness and slurried with methyl tert-butyl ether (15 ml) to obtain the target compound D1 (1.69 g, yield 77.5%) as a white solid.
  • Step 2 Add D1 (0.50 g, 2.06 mmol) and solvent tetrahydrofuran (5 ml) to the reaction flask, start stirring, then add sodium borohydride (0.63 g, 16.5 mmol), heat to reflux, and stir for 1 hour. Then cool to room temperature, slowly drop methanol (1 ml), and reflux for 16 hours. After the reaction is completed, add water (1 ml) to quench the reaction, then add 0.5 ml hydrochloric acid and stir for 1 hour.
  • Step 3 D2 (0.35 g, 1.75 mmol), solvent dichloromethane (3.5 ml) and triethylamine (0.53 g, 5.24 mmol) were added to the reaction flask. After cooling to 0-5°C, p-toluenesulfonyl chloride (0.48 g, 1.75 mmol) was added and stirred at room temperature for 12 h.
  • the reaction solution was washed with water (3.5 ml), dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, slurried with methyl tert-butyl ether (3.5 ml) for 12 h, filtered and dried in vacuo to obtain the target product D3 (0.52 g, 83.5%) as a white solid.
  • Step 4 Add intermediate A (100 mg, 0.47 mmol), intermediate D3 (220 mg, 0.61 mmol) and K 2 CO 3 (0.19 g, 1.41 mmol) to the reaction flask in sequence, and then add solvent THF (6 mL) and DMSO (2 ml). The reaction system was heated and stirred at 60°C for 16 hours. After the reaction, the solvent was removed and purified by rapid silica gel column chromatography (eluent: 0-10% methanol/dichloromethane) to obtain compound 1-1 (170 mg, 92%) as an off-white solid.
  • Step 1 Add intermediate SA (10 g, 46.89 mmol), intermediate C8 (37.30 g, 93.77 mmol) and K 2 CO 3 (25.88 g, 187.5 mmol) to the reaction flask in sequence, and then add solvent THF (80 mL) and DMSO (20 ml). Heat the reaction system at 60° C. with stirring for 16 hours.
  • Measurement temperature 25°C
  • sample concentration 1 mg/ml
  • selected wavelength 589 nm
  • dilution solvent MeOH
  • Step 2 Add M1 (10 g, 22.83 mmol) and 4 mol/L methanolic hydrogen chloride solution (80 ml) to the reaction flask, start stirring, heat to reflux, and stir for 5 hours. Then cool to room temperature and filter. The filter cake is freed with aqueous sodium carbonate solution.
  • the preparation method is as in Example 1.
  • the preparation method is as in Example 1.
  • the preparation method is as in Example 1.
  • the preparation method is as in Example 1.
  • Compound (-)-I-10 is prepared according to Example 10 in patent application CN114835709A.
  • Plasmids and CHO cells are routine in the art.
  • Reaction system 100 ⁇ L cell membrane, 1 ⁇ L test compound, 100 ⁇ L corresponding isotope.
  • the vector plasmid was transfected into CHO cells using liposome transfection method.
  • Cell membrane preparation dilute D 2 L and D 3 cell membranes with Assay buffer (50 mM Tris-HCl, pH 7.4). The final concentrations of cell membranes are as follows:
  • Isotope preparation dilute the corresponding isotope with Assay buffer.
  • the final isotope concentration of the experimental system is as follows:
  • the starting concentration of compound 1-2 was 1000nM, the starting concentration of compound 5-2 was 10000nM, the starting concentration of compound (-)-I-10 was 1000nM, and the starting concentration of positive compound 7-OH-DPAT (Sigma, H8653) was 1 ⁇ M; for D3 receptor, the starting concentration of 1-2 was 1000nM, the starting concentration of compound 5-2 was 10000nM, the starting concentration of (-)-I-10 was 10000nM, and the starting concentration of positive compound NGB2904 (Sigma, SML0066) was 0.1 ⁇ M; transfer 1 ⁇ L of nonspecific binding compound to the experimental plate as nonspecific binding well Low control (LC), transfer 1 ⁇ L of DMSO to the experimental plate as total binding well High control (HC).
  • LC nonspecific binding well Low control
  • HC total binding well High control
  • reaction plate After the reaction plate is incubated, use a cell collector to collect the reaction solution onto the GF/C filter plate, wash it 4 times with wash buffer, and dry it in a 50°C oven for 1 hour.
  • Both D 2 L receptor and D 2 R receptor can be retrieved through commonly used biological databases (such as NCBI, National Center for Biotechnology Information, US National Center for Biotechnology Information).
  • Plasmids and HEK 293T cells are routine in the art.
  • 6-cm dishes were transfected with 1 ⁇ g of dopamine D 2 L or D 2 R receptor, 1 ⁇ g of G ⁇ i1 containing C-terminal algal luciferase (G ⁇ i1 ), 1 ⁇ g of G ⁇ 3 , 1 ⁇ g of G ⁇ 9 containing C-terminal green fluorescent protein (G ⁇ 9 ), and 16 ⁇ L of PEI.
  • the confluent cells were digested and the amount of cells from a confluent 6-cm culture dish was plated on a 96-well plate, with 100 ⁇ L of culture medium per well.

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Abstract

La présente invention concerne un dérivé d'aza-ergoline, une composition pharmaceutique de celle-ci et son utilisation. La présente invention concerne un composé tel que représenté dans la formule I, un sel pharmaceutiquement acceptable de celui-ci, un solvate de celui-ci, ou un solvate du sel pharmaceutiquement acceptable de celui-ci. Le composé de la présente invention présente une bonne affinité et une bonne activité agoniste vis-à-vis du récepteur D2 ou D3 de la dopamine.
PCT/CN2024/110706 2023-08-08 2024-08-08 Dérivé d'aza-ergoline, composition pharmaceutique associée et son utilisation Pending WO2025031459A1 (fr)

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CN114835709B (zh) * 2021-02-01 2023-10-20 上海科技大学 氮杂麦角林类衍生物及其制备方法和应用
CN115772175A (zh) * 2021-09-07 2023-03-10 中国科学院分子细胞科学卓越创新中心 噻吩并环化合物及其制备方法和应用

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