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WO2009052708A1 - 1-(3-amino-propyl)-pipéridin-4-yl-amides, compositions pharmaceutiques, leurs procédés de préparation et utilisations - Google Patents

1-(3-amino-propyl)-pipéridin-4-yl-amides, compositions pharmaceutiques, leurs procédés de préparation et utilisations Download PDF

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Publication number
WO2009052708A1
WO2009052708A1 PCT/CN2008/001769 CN2008001769W WO2009052708A1 WO 2009052708 A1 WO2009052708 A1 WO 2009052708A1 CN 2008001769 W CN2008001769 W CN 2008001769W WO 2009052708 A1 WO2009052708 A1 WO 2009052708A1
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Prior art keywords
propyl
piperidine
chloro
ethyl
acetyl
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Chinese (zh)
Inventor
Yaqiu Long
Dongzhi Feng
Li Chen
Renhai Chen
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Shanghai Institute of Materia Medica of CAS
SHANGHAI TARGETDRUG CO Ltd
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Shanghai Institute of Materia Medica of CAS
SHANGHAI TARGETDRUG CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a 1-(3-aminopropyl)piperidin-4-aminoamide compound, a pharmaceutical composition thereof, and a process for the preparation thereof and use thereof, which are useful as CCR5 antagonists.
  • Chemokines are a class of cytokines that direct the directed migration of lymphocytes and play an important role in inflammatory responses, leukocyte extravasation, tissue infiltration, tumorigenesis, and embryonic development. Chemokines are a large family of secretory signaling molecules with a molecular weight of approximately 8 to 14 kD. There are currently about 45 members of this family, and their common features are: Containing four conserved cysteines (Cys). The family is divided into four categories based on whether they contain other amino acids between the two Cys near the N-terminus: C-C, C-X-C, C-Xs-C, and C. Among them, CC (also known as ⁇ -chemokine) and CXC (also known as (X-chemokine)) are the two most important categories.
  • chemokines The function of chemokines in vivo is mediated through chemokine receptors.
  • the current standard nomenclature for chemokine receptors is characterized by their specific binding to chemokines (for example, if the ligand is a CC-like chemokine subfamily, it is named CCR).
  • the receptor for chemokines belongs to the 7-transmembrane G-protein coupled receptor family (GPCR), which has an N-terminus outside the cell and a C-terminus in the cell, containing seven very conserved Transmembrane regions. They bind to G proteins when bound to agonists, allowing extracellular signals to be delivered to the cells.
  • GPCR 7-transmembrane G-protein coupled receptor family
  • chemokine receptors can cause a series of intracellular Signaling and altering cell behavior, such as inhibition of adenylate cyclase (AC), mobilize intracellular calcium release, activate a series of protein kinases, direct cell-directed migration (chemotaxis), and affect cytokine release.
  • AC adenylate cyclase
  • chemotaxis direct cell-directed migration
  • chemokine receptors There are currently 19 chemokine receptors found, which are CCR1-11, CXCR1-6, XCR1, CX 3 CR1. Chemokine receptors are thought to be important mediators of inflammatory and autoimmune diseases (Gerard et al., Nature Immunology, 2, 108-15 (2001)), and therefore, modulators of chemokine receptors ( Including agonists and antagonists) can be used in a variety of diseases, such as inflammation or allergic diseases, allergic reactions, autoimmune diseases, inflammatory bowel disease, scleroderma, eosinophilic myositis, tumorigenesis and metastasis Wait.
  • diseases such as inflammation or allergic diseases, allergic reactions, autoimmune diseases, inflammatory bowel disease, scleroderma, eosinophilic myositis, tumorigenesis and metastasis Wait.
  • CCR5 As a member of the chemokine receptor family, CCR5, its endogenous agonist is RANTES, ⁇ -1 ⁇ ⁇ - ⁇ ⁇ , which is expressed in peripheral blood-derived dendritic cells, sputum lymphocytes, monocytes, giant Phagocytes and immune cells and inflammatory cells involved in maintaining long-term inflammatory responses. Therefore, regulation of CCR5 may regulate the recruitment of sputum cells to inflammatory response lesions, providing a new target for the treatment of inflammatory and autoimmune diseases.
  • CCR5 deletion protects mice from DSS-induced severe Inflammation and mucosal damage (Andres et al., Journal of Immunology, 164, 6303-12 (2000)); in mice, TCR-779, a small molecule antagonist of CCR5, inhibits collagen-induced arthritis (Yang et al) , European Journal of Immunology, 32, 2124-32 (2002) ) o Therefore, antagonists of CCR5 can be used in the treatment of the following diseases: asthma and local disorders (such as local dermatitis, local allergies), rheumatoid arthritis , arteriosclerosis, psoriasis, sarcoidosis and other fibrotic diseases, autoimmune diseases (such as multiple sclerosis, inflammatory bowel disease).
  • asthma and local disorders such as local dermatitis, local allergies
  • rheumatoid arthritis arteriosclerosis
  • psoriasis psoriasis
  • sarcoidosis and other fibrotic diseases
  • autoimmune diseases such
  • CD 8+ T cells are associated with chronic obstructive pulmonary disease (COPD) (Cosio et al., Chest, 121, 160S-165S, (2002)), therefore, CCR5 is antagonistic.
  • Anti-agents may also be used in the treatment of COPD.
  • chemokine receptors may also be important receptors for certain parasites and viral invasion cells.
  • the Duffy receptor is a receptor for Plasmodium to enter red blood cells, and people who lack Duffy receptors are less susceptible to malaria. More importantly, several chemokine receptors are involved in the invasion of HIV, known as the co-receptor of HIV into the host.
  • CCR5 and CXCR4 are the major co-receptors of HIV entry, and CCR3 may also be involved in the entry of some HIV.
  • CCR5 is a co-receptor of macrophage tropism (M-tropic) HIV-1 and CXCR4 is a T cell tropism (T-tropic) co-receptor of HIV-1. Therefore, CCR5 plays an important role in the spread of HIV.
  • the substances that regulate CCR5 can affect the spread of M-tropic HIV-1 in the human population and control the disease in the early stage.
  • chemokines RANTES, ⁇ -1 ⁇ and ⁇ -1 ⁇ which bind to CCR5, were found to inhibit HIV infection by inhibiting the entry of HIV-1 into the cell.
  • Some small molecule compounds that bind to CCR5 and antagonize CCR5 function are also very effective in inhibiting HIV invading cells in vitro.
  • the present inventors have extensively and intensively studied a compound having CCR5 antagonistic activity, and have designed and synthesized a compound of the formula I.
  • the test results show that these compounds are potent CCR5 antagonists, can be used as an entry inhibitor of HIV virus, and can be developed into an anti-AIDS drug, on the basis of which the present invention has been completed.
  • Another object of the present invention is to provide a process for the preparation of the above compounds.
  • a further object of the invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula I or a pharmaceutically acceptable salt thereof.
  • a further object of the present invention is to provide the use of such compounds as CCR5 antagonists in the manufacture of a medicament for the treatment of diseases mediated by CCR5.
  • NR6COOR 7 NR6S0 2 R 7 , COOR 7 , COR 7 , CONR ⁇ S0 2 R 7 , S0 2 NR6R 7 , OR? and OCOR 7 ;
  • G is OCO, CO, NR 7 CO or S0 2 ;
  • R 2 is an unsubstituted or substituted group of 1 to 3 substituents: phenyl, benzyl, naphthyl or C 5 -C 1 () aromatic heterocyclic group, said heterocyclic ring includes 1- 3 heteroatoms selected from N, 0 and S, the substituents being selected from the group consisting of the following atoms or groups: CC 6 alkyl, dC 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6- block, C 3 -C 7 cycloalkyl, dC 6 alkyl fluorenyl, halogen, fluorenyl, hydroxy, CF 3 , CN, N0 2 , NR6R 7 , NR6S0 2 R 7 , COOR 7 , COR 7 , CONR6R 7 , S0 2 R 7 , OR?
  • dC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 block, C 3 -C 7 cycloalkyl, dC 6 alkoxy or dC 6 alkyl fluorenyl may be optionally substituted by a hydrazine, a hydroxy group, an amino group, a C 3 -Cv cycloalkyl group, a cyano group or a decyl group;
  • X is not present, 0, CO or NH;
  • R4 is an unsubstituted or substituted group of 1-3 substituents: dC 6 alkylene, dC 6 alkoxy dC 6 alkylene, dC 6 alkylenecarbonyl, dC 6 alkyleneoxy, a c 2 -c 6 alkenylene group or a c 2 -c 6 subunit group, said substituent being selected from the group consisting of: dC 6 alkyl, dC 6 alkoxy, halogen, amino, nitro, nitrile Base, thiol and hydroxy;
  • R 5 is an unsubstituted or substituted group of 1 to 3 substituents: 8 cycloalkyl, adamantyl, phenyl, phenol, benzyl, naphthyl, C 5 -C 1Q aromatic heterocyclic Or a C 4 -C 7 saturated heterocyclic group, said heterocyclic ring comprising 1-3 heteroatoms selected from N, 0 and S, said substituent being selected from the group consisting of the following atoms or groups: dC 6 alkane Base, dC 6 alkoxy, halogen, fluorenyl, hydroxy, CF 3 , CN, N0 2 , NR6R 7 , NReCOR ⁇ NReCOOR ⁇ NR6S0 2 R 7 , COOR 7 , COR 7 , CONR6R 7 , S0 2 R 7 , S0 2 NR6R 7 , OR? and OCOR 7 , and NR ⁇ R? can together form a cyclic amine
  • R6 is hydrogen, hydroxy or CC 6 alkyl
  • the heterocyclic ring includes 1 to 3 hetero atoms selected from N, 0 and S, and the substituent is selected from the group consisting of dC 6 alkyl, dC 6 alkoxy dC 6 alkyl, halogen , amino, nitro, thiol, hydroxy, CN and CF 3 .
  • the compound of the invention is a compound of formula II below:
  • R 3 is hydrogen, dC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 block or C 3 -C 7 cycloalkyl, wherein dC 6 alkyl is optionally halogen, hydroxy , dC 4 alkoxy, c 3 -c 7 cycloalkyl, cyano, decyl, amino, nitro Or a dc 4 alkyl thiol group;
  • R3 is a C1-C4 fluorenyl group
  • X is not present
  • R4 is dC 4 alkylene
  • R 5 is an unsubstituted or substituted group of 1 to 3 substituents: phenyl, phenol, naphthyl, adamantyl, morpholinyl, piperazinyl, piperidinyl, pyrrolyl, thienyl , imidazolyl, triazolyl, tetrazolyl, furyl, pyranyl or fluorenyl, quinolyl, benzopyranyl, benzothienyl, benzofuranyl, benzimidazolyl or benzo a triazolyl group, the substituent is selected from the group consisting of lower-C 4 alkyl, dC 4 alkoxy, halogen, hydroxy, CF 3 , NO 2 , NR 6 R 7 , NR 6 COR 7 , S0 2 R 7 , S0 2 NR6R 7 , OR 7 and B OCOR 7 , and NR6R 7 may together form a cyclic amine, wherein R
  • R 8 is hydrogen, halogen or CrC 4 alkyl
  • R 9 is hydrogen or halogen.
  • a pharmaceutically acceptable salt of the 1-(3-aminopropyl)piperidin-4-aminoamide compound of the present invention which is a compound of the present invention and hydrochloric acid, tartaric acid, hydrazine according to a pharmaceutically conventional salt formation method a salt formed from an acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, sulfuric acid or methanesulfonic acid.
  • R 2 , R 3 , R 4 and R 5 are as defined above;
  • P is a common protecting group for an amino group, such as tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl (Bn), 9-fluorenylmethoxycarbonyl (Fmoc), CH 3 CO or CH 3 OCO.
  • the preparation of the primary or secondary amine compound in the above step c), i.e., the intermediate 4-N-substituted-4-aminopiperidine compound, is as follows.
  • R 3 is defined as above; and! ⁇ is a common protecting group for amino groups, such as Boc, Cbz, Bn, Fmoc, CH 3 CO or CH 3 OCO; etc.; 1-N-protected 4-piperidone is protected by reductive amination to give - piperidine VII, via 4 - an amino protecting group (to give compound VIII), and compound VIII via a 1-amino deprotecting group to give the intermediate 4-N-substituted-4-aminopiperidine IX.
  • ⁇ is a common protecting group for amino groups, such as Boc, Cbz, Bn, Fmoc, CH 3 CO or CH 3 OCO; etc.
  • 1-N-protected 4-piperidone is protected by reductive amination to give - piperidine VII, via 4 - an amino protecting group (to give compound VIII), and compound VIII via a 1-amino deprotecting group to give the intermediate 4-N-substituted-4-aminopiperidine IX.
  • a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of formula I, or a pharmaceutically acceptable salt thereof, and further comprising a pharmaceutically acceptable carrier, Protease inhibitors and/or reverse transcriptase inhibitors may also be included.
  • a compound of formula I or a pharmaceutically acceptable salt of the invention as an antagonist of CCR5, for the manufacture of a medicament for the treatment of a disease mediated by CCR5.
  • COPD chronic obstructive pulmonary disease
  • Step 6 1-Acetyl-N-(3-chlorophenyl)-N-(3-(4-(N-ethyl-2-phenylacetamido)-1-piperidinyl)propyl) Piperidine-4-carboxamide (Compound 1)
  • Step 1 1-Benzylpiperidinyl-4-ethylcarbamic acid tert-butyl ester
  • Step 2 N-(4-piperidinyl)-N-ethylformic acid tert-butyl ester
  • Step 4 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-chloropropyl)-4-piperidinecarboxamide
  • N-(3-chloropropyl)-3-chloro-4-methylaniline (18.64 g, 85.9 mmol) was dissolved in dichloromethane (350 mL) with stirring, and three were added to the solution under ice cooling.
  • Ethylamine 47.9 mL, 343.6 mmol
  • 1-acetyl-4-piperidinecarbonyl chloride 48.72 g, 257.7 mmol
  • Step 5 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-N-ethylcarbamic acid tert-butyl ester-1-piperidinyl)propyl Piperidine-4-carboxamide
  • Step 6 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-ethylamine-1-piperidinyl)propyl)piperidine-4-methyl Amide
  • Step 5 The product of Step 5 (9.4 g, 16.63 mmol) was dissolved in tetrahydrofuran (40 mL) with stirring, and 4N hydrochloric acid (40 mL) was added dropwise to the solution at room temperature, then the mixture was stirred at 40 ° C. hour. Thereafter, the THF in the solution was evaporated, the aqueous phase was extracted with ethyl acetate (60 mL), and then the pH of the solution was adjusted to 10 with a 2N sodium hydroxide solution. The aqueous phase was extracted three times with dichloromethane (30 mL). EtOAc (EtOAc m. Purification, the next step can be directly carried out.
  • Step 7 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-phenylacetamido)-1- Piperidinyl)propyl) piperidine-4-carboxamide (compound 2)
  • the 1-adamantylacetic acid was used in place of the phenylacetic acid, and the reaction was carried out in the same manner as in the step 7 of Example 2 to give a white foam (96 mg, yield 78%).
  • Ethyl phenylacetate (3.35 g, 20 mmol) was dissolved in dry carbon disulfide (15 mL), and the obtained mixture was cooled in ice-cooled, and anhydrous aluminum trichloride (6.67 g, 50 mmol) was slowly added while stirring. Thereafter, acetyl chloride (1.85 mL, 26 mmol) was added while stirring at 0 ° C, and the mixture was refluxed for 12 hours and then quenched with crushed ice. The mixture was diluted with EtOAc (EtOAc)EtOAc. The residue is placed in a freezer and then the solid obtained by filtration is the product. Ethyl 4-acetylacetophenone was recrystallized from petroleum ether to give white crystals (500 mg, yield 12%).
  • Step 3 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-acetylphenyl))acetamide -1-piperidinyl)propyl)piperidine-4-carboxamide (compound 18)
  • Step 3 4-G-pyrrolidinyl)sulfonylphenylacetic acid
  • Step 4 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-(l-pyrrolidinyl))) Acylphenyl)acetamido)-1-piperidinyl)propyl)piperidine-4-carboxamide (compound 23)
  • step 2 dimethylamine was used in place of pyrroline, and the reaction was carried out in the same manner as in Steps 2, 2, and 3 of Example 23 to obtain white needle crystals (450 mg, yield 53%).
  • Step 2 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-( 3-(4-(N-ethyl-2-(4-N,N-dimethylamine) Acylphenyl)acetamido)-1-piperidinyl)propyl)piperidine-4-carboxamide (compound 24)
  • Compound 25 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-(1-piperidinyl))sulfonate Acylphenyl)acetamido)-1-piperidinyl)propyl)piperidine-4-carboxamide
  • Step 1 4-(1-piperidinyl)sulfonylphenylacetic acid
  • Step 2 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-(l-piperidinyl))sulfonate Acylphenyl)acetamido)-1-piperidinyl)propyl)piperidine-4-carboxamide (compound 25)
  • Step 1 4-(1-morpholinyl)sulfonylphenylacetic acid
  • Step 2 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-morpholinylsulfonylphenyl)) Acetylamino)-1-piperidinyl)propyl)piperidine-4-carboxamide (Compound 26)
  • Step 1 4-n-propylamine sulfonylphenylacetic acid
  • Step 2 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-n-propylaminesulfonylphenyl)) Amido)-1-piperidinyl)propyl)piperidine-4-carboxamide (Compound 27)
  • Step 1 4-tert-butylamine sulfonylphenylacetic acid
  • Step 2 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-tert-butylaminesulfonylphenyl)acetamide) -1-piperidinyl) propyl) piperidine-4-carboxamide (compound 28)
  • Step 5 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-(4-methanesulfonylphenyl)acetamide) -1-piperidinyl) propyl) piperidine-4-carboxamide (compound 29)
  • Step 1 1-acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-chloroacetamido)-1-piperidinyl ) propyl) piperidine-4-carboxamide
  • Step 2 1-Acetyl-N-(3-chloro-4-methylphenyl)-N-(3-(4-(N-ethyl-2-morpholinacetamide)-1-piperidinyl ) propyl)-4-piperidinecarboxamide (compound 30)
  • Example 42 Compound 42: NG-HN-3-chloro-4-methylphenyl)benzenesulfonamido)propyl)piperidin-4-yl)-N-ethyl-2-phenylacetamide
  • CCR5 belongs to the G-protein coupled receptor (GPCR) family.
  • GPCR G-protein coupled receptor
  • the development of drug development technology for GPCR is relatively complete, and the experimental techniques such as receptor ligand binding method, GTPyS binding method and Ca 2+ flow detection method are widely used in drug screening related to chemokine receptors.
  • the compounds of the present invention were tested for CCR5 inhibitory activity by suction filtration [ 35 S]GTP Y S binding assay, SPA-WGA method [ 35 S]GTP Y S binding assay and calcium influx assay.
  • the G protein is activated.
  • the G protein is a trimer composed of a ct subunit and a ⁇ subunit. Since (the ability of the subunit to bind to GTP depends on the action of CCR5 and the agonist, the amount of GTP bound to the a subunit can be measured to reflect the agonist's ability to activate CCR5.
  • GTPyS In the GTPyS binding assay, in order to rule out GTP hydrolysis due to GTPase The amount of GTP that binds to the G protein does not accurately reflect the activation of CCR5, and for the convenience of detection, GTPyS, a structural analog of 35 S-labeled GTP, is substituted for GTP, and GTPyS binds to the activated ct subunit but cannot be hydrolyzed.
  • the subunit binds to GDP; after CCR5 is activated, the ⁇ subunit binds to GTPyS, and GTPyS irreversibly binds to the ⁇ subunit. Therefore, the ⁇ subunit binds to [ 35 S]-GTP Y S
  • the amount reflects the extent to which CCR5 is activated by the agonist. When an antagonist is added, it will reduce the ability of the agonist to activate CCR5.
  • the free G protein-bound [ 35 S]-GTP Y S can be isolated by membrane filtration, which is called the suction filtration GTPyS experiment.
  • SPA Scintillation Proximity Assay
  • [ 35 S]-GTPyS is called the SPA-WGA method [ 35 S]GTP Y S binding experiment.
  • the principle of SPA technology is: Subatomic particles released by the decay process of radioactive atoms, such as beta rays (electrons), can stimulate the microspheres to emit light at a distance close enough to be detected by the photometric instrument. The energy of such rays in an aqueous phase solution is mostly absorbed by the solvent and the propagation distance is very limited. Therefore, if the luminescent microspheres are attached to the cell membrane by wheat germ agglutinin (WGA), only the [ 35S ]-GTP Y S bound to the G protein has a sufficiently short distance to excite the microspheres to illuminate, thereby reflecting the receptor. Activation.
  • WGA wheat germ agglutinin
  • CHO (Chinese Hamster Ovary Cell) Permanent Cell Line (CHO-CCR5) expressing CCR5 was lysed with lysis buffer (5 mM Tris-HCl, H 7.5, 5 mM EDTA and 5 mM EGTA) and centrifuged at 15,000 x g for 10 min. .
  • the cell membrane was resuspended in reaction buffer (5 mM Tris-HCl, pH 7.5, 5 mM MgCl 2 , 1 mM EGTA, 100 mM NaCl), and Bio-Rad's Bioford legal protein was used.
  • a GTPyS binding experiment was carried out in a reaction buffer, wherein the reaction system was ⁇ , containing 1 ( ⁇ g membrane protein, 40 ⁇ GDP, 0.5 nM [ 35 S]-GTPyS (1200 Ci/mmol), after adding the compound to be tested. After shaking and mixing, the reaction tube was incubated at 30 ° C for 1 hour. After the reaction was completed, the tube was placed on ice, diluted with PBS to stop the reaction, and immediately vacuum filtered with a GF/C filter. The radioactive activity is added to the scintillation fluid and measured by a liquid scintillation counter. This is the filtered GTPyS experimental method.
  • the previous steps of the SPA-WGA assay are the same as the GTPyS assay, except that after the reaction is terminated by adding PBS to the reaction, the reaction system is added.
  • the SPA-WGA microspheres were further added with the compound to be tested, and the system was mixed, incubated at 30 ° C for 1 hour, and then partially stopped on ice. Centrifugation at room temperature, 1000 rpm, 15 min, followed by measurement using a liquid scintillation counter.
  • the bound radioactivity was determined using a liquid scintillation counter.
  • the basal was determined without agonists and the non-specific was determined in the presence of 10 ⁇ of non-isotopic GTPyS.
  • IC 5Q is a compound that inhibits ⁇ RA TES (a cytokine that has a strong chemotactic effect on mononuclear-macrophages) caused by [ 35 S]-GTP Y S binding 50%, concentration curve from compound Get it on.
  • ⁇ RA TES a cytokine that has a strong chemotactic effect on mononuclear-macrophages
  • the highest CPM value or RFU value under the action of the agonist RANTES is 100%
  • the background CPM value or the RFU value is 0%
  • the antagonist is obtained.
  • concentration of the compound is 1 ⁇ and the CCR5 ability of the antagonistic assay is less than 90%
  • a virtual concentration is required for the convenience of mapping.
  • the virtual point is: when the compound is 1 mM, its antagonistic Compound
  • the CCR5 capacity is 100%.
  • Invitrogen's Fluo-4 calcium dye is a commonly used fluorescent dye for Ca 2+ detection, and signal detection can usually be done using the FlexStation or FLIPR of the molecular device.
  • the present invention achieves activation of the G q signaling pathway by the G l/() protein-coupled CCR5 receptor by overexpressing the G q family protein-G16 in a CHO-CCR5 stable cell line.
  • the cells were cultured in serum-free medium 4 hours before the start of the experiment, and the cells were digested with 0.04% EDTA-PBS and washed once with HBSS (Hank's Balanced Salt Solution) buffer.
  • the cells were resuspended in HBSS containing 2.5 mM Probenecid, and a premixed mixture of Fluo-4 AM (fluorescent dye) and Cremophor EL (polyoxyethylene castor oil) was added to the cell suspension. After mixing well, the reaction was carried out in a 37 ° C incubator for 40 min, then centrifuged at 800 rpm for 3 min, the supernatant was discarded, and 5 mL of HBSS was used to wash the cells twice.
  • the compound inhibited CCR5 by more than 50% at a concentration of nM; "one" indicates that the compound did not exhibit CCR5 antagonistic activity at a concentration of 300 nM.
  • the activity data listed in Table 1 fully shows that the screening results obtained by the three experimental methods are mutually validated and very consistent.
  • the compounds of the present invention are all high activity antagonists of the chemokine receptor CCR5, of which 30 compounds are against CCR5.
  • the inhibitory activity of the receptor IC 5Q reached the nM level
  • the IC 5Q of the 5 compounds reached the level of 10 nM
  • the IC 5Q of the 8 compounds reached at least the level of 100 nM.
  • H4DA5 cell model (operating under P3 laboratory conditions)
  • H4DA5 cells Hela cells express human CD4, CCR5 receptor and reporter gene Ltr-lacZ,
  • H4DA5 cells Place the appropriate number of H4DA5 cells on a 96-well plate and incubate overnight.
  • the H4DA5 cell model experiments showed that the compound of the present invention is a CCR5 antagonist capable of inhibiting virus replication in a cell model, and its inhibitory activity EC 5Q is listed in Table 2 below, and the structures of the corresponding compounds are shown in Table 1.
  • the activity data listed in Table 2 shows that the compounds of the present invention have potent inhibitory effects on viral replication at the cellular level, wherein the inhibitory activity of five compounds against the H4DA5 cell model reaches the nM level of EC 5Q , and five compounds against H4DA5 cells.
  • inhibitory activity EC 5Q model reaches ⁇ level of inhibitory activity of compounds 4
  • EC 5Q H4DA5 cell model reaches ⁇ level.
  • the compound of the present invention is a potent CCR5 antagonist and can be used as a therapeutic agent for CCR5-mediated diseases such as HIV-1 virus invasion inhibitor, autoimmune disease, asthma, rheumatoid arthritis, chronic obstructive pulmonary disease, etc. .

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Abstract

La présente invention concerne des 1-(3-amino-propyl)-pipéridin-4-yl-amides ayant la formule suivante, leurs sels pharmaceutiquement acceptables, leurs compositions et leurs procédés de préparation. Ces composés ou leurs sels pharmaceutiquement acceptables qui peuvent être utilisés en tant qu'antagonistes de CCR5 sont utilisés pour préparer des médicaments pour le traitement de maladies induites par CCR5 ou d'une infection par le VIH, de l'asthme, de la polyarthrite rhumatoïde, de maladies auto-immunes ou d'une pneumopathie chronique obstructive (COPD).
PCT/CN2008/001769 2007-10-18 2008-10-20 1-(3-amino-propyl)-pipéridin-4-yl-amides, compositions pharmaceutiques, leurs procédés de préparation et utilisations Ceased WO2009052708A1 (fr)

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CN101768139B (zh) * 2010-01-15 2011-11-30 浙江大学 哌嗪类衍生物及制备方法和用途
CN101812054B (zh) * 2010-04-30 2014-01-22 北京工业大学 1-乙酰基-n-苯基-n-(3-(4-(3-苯基-1-h-吡唑-5-基)哌啶-1-基)丙基)-4-酰胺衍生物及其制备方法
CN101921224B (zh) * 2010-05-21 2012-01-18 中国人民解放军军事医学科学院生物工程研究所 1-（3-氨基丙基）哌嗪-4-氨基酰胺类化合物及其制备方法与应用
CN102311380B (zh) * 2010-09-07 2014-05-07 浙江大学 哌啶-4-羧基酰胺类衍生物及制备方法和用途
CN104402883B (zh) * 2014-10-24 2016-04-27 艾琪康医药科技（上海）有限公司 4，4-二氟金刚烷甲酰胺衍生物、药物组合物及其制备方法和用途
CN109336795B (zh) * 2018-11-22 2020-12-25 利尔化学股份有限公司 3-三氟甲基苯硫酚及3-甲硫基三氟甲苯的制备方法
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WO2002076948A1 (fr) * 2001-03-22 2002-10-03 Astrazeneca Ab Nouveaux derives piperidines utilises en tant que modulateurs de recepteurs des chimiokines
WO2003080574A1 (fr) * 2002-03-25 2003-10-02 Astrazeneca Ab Derives de piperidine ou 8-aza-bicyclo[3.2.1]oct-3-yle convenant comme modulateurs de l'activite des recepteurs de la chimiokine (plus paritculierement ccr5)
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CN103130709B (zh) * 2011-11-22 2017-04-12 常州亚邦制药有限公司 具有抗hiv活性的3‑氨基丙酸哌啶酰胺类化合物，合成方法及用途

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