US20220372013A2 - Piperidine-2,6-dione derivatives and crohn's disease treating - Google Patents

Piperidine-2,6-dione derivatives and crohn's disease treating Download PDF

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US20220372013A2
US20220372013A2 US16/464,228 US201716464228A US2022372013A2 US 20220372013 A2 US20220372013 A2 US 20220372013A2 US 201716464228 A US201716464228 A US 201716464228A US 2022372013 A2 US2022372013 A2 US 2022372013A2
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dione
pharmaceutically acceptable
acceptable salts
dioxopiperidin
isoindolin
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US20190352277A1 (en
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Hesheng Zhang
Guanghuai Zeng
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Tianjin Hemay Pharmaceutical SCI Tech Co Ltd
Ganzhou Hemay Pharmaceutical Co Ltd
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Tianjin Hemay Pharmaceutical SCI Tech Co Ltd
Ganzhou Hemay Pharmaceutical Co Ltd
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Assigned to TIANJIN HEMAY BIO-TECH CO., LTD reassignment TIANJIN HEMAY BIO-TECH CO., LTD ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ZENG, GUANGHUAI, ZHANG, HESHENG
Publication of US20190352277A1 publication Critical patent/US20190352277A1/en
Assigned to GANZHOU HEMAY PHARMACEUTICAL, CO., LTD, TIANJIN HEMAY PHARMACEUTICAL SCI-TECH CO., LTD reassignment GANZHOU HEMAY PHARMACEUTICAL, CO., LTD ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TIANJIN HEMAY BIO-TECH CO., LTD
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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells

Definitions

  • the present disclosure relates to organic chemistry and medicinal chemistry fields.
  • Crohn's disease is a chronic inflammatory autoimmune disease of the gastrointestinal tract (GI). Crohn's disease can affect any part of the digestive tract from the mouth to the anus. Under the microscope, Crohn's disease affects the entire intestinal wall (transmural injury). Chronic inflammation can cause fibrosis in the subgroup of patients with Crohn's disease, who have the complications including stenosis and fistula, and possibly need repeated surgery. Crohn's disease is associated with increased risk of gastrointestinal malignant tumour. It is found by the study on Crohn's disease that Crohn's disease is associated with TH1 (type 1 T helper cell) and TH17 (type 17 T helper cell) mediated cellular immunity.
  • TH1 type 1 T helper cell
  • TH17 type 17 T helper cell
  • the clinical manifestations of Crohn's disease are various and include gastrointestinal manifestations, systemic manifestations, parenteral manifestations, and complications.
  • Gastrointestinal manifestations mainly include diarrhea, abdominal pain, and bloody stool.
  • Systemic manifestations mainly include weight loss, fever, loss of appetite, fatigue, anemia, and the like. Growth retardation is commonly found in adolescent patients.
  • Common complications include fistula, abdominal abscess, intestinal stenosis, obstruction and perianal lesions.
  • Gastrointestinal bleeding and acute perforation are rare. The long course of disease can lead to cancer. Colonoscopy is generally manifested as segmental and asymmetric various mucosal inflammation, which has the characterized manifestation of non-continuous lesions, longitudinal ulcers and pebble-like appearance.
  • the histopathological changes of Crohn's disease mucosal biopsy samples include: (1) focal discontinuous infiltration of intrinsic membrane inflammatory cells; (2) fissuring ulcers; (3) aphthous ulcers; (4) abnormal crypt structure, glandular hyperplasia, individual crypt abscess, non-obvious reduction of mucus secretion, visible pyloric metaplasia or Paneth cell metaplasia; (5) non-cheese-like necrotic granuloma; (6) chronic inflammatory cell infiltration of lymphocytes and plasma cells, in which the inflammation at the bottom of lamina limba and submucosal layer is severe, and formation of lymph follicle is common; and (7) submucosal lymphatic dilatation; and (8) ganglion cell proliferation and/or ganglion inflammation.
  • Mildly active Crohn's disease is treated mainly with 5-aminosalicylic acids and budesonide. If the above treatment is ineffective, Crohn's disease is considered as moderately active. Moderately active Crohn's disease is preferably treated with hormone (such as dexamethasone). If the above treatment is ineffective or becomes dependent, combination with thioglycine or methotrexate will be considered. TNF- ⁇ monoclonal antibody can be used if the above hormone therapy and immunotherapy are ineffective or intolerable. Severely active Crohn's disease is treated mainly with systemic hormones, TNF- ⁇ monoclonal antibodies and surgery. Drugs for maintenance treatment for Crohn's disease in remission include 5-aminosalicylic acids, thioglycines and TNF- ⁇ monoclonal antibodies.
  • 5-aminosalicylic acid drugs such as sulfasalazine and mesalazine
  • sulfasalazine and mesalazine 5-aminosalicylic acid drugs
  • budesonide or azathiopurine can also be used, but only in a short term.
  • Monoclonal antibody drugs such as infliximab and adalimumab
  • infliximab may cause high blood pressure, chills, rash, fever, headache, eczema and so on.
  • infliximab is a chimeric antibody, it is possible to show antigenicity and sometimes cause acute hypersensitivity.
  • TNF- ⁇ inhibitors such as lenalidomide and thalidomide have been shown to be not effective in the treatment of Crohn's disease (C. Yang et, Aliment Pharmacol Ther 2015; 41:1079-7093.).
  • Crohn's disease is a chronic disease that requires a longer duration of drugs.
  • the above data show that there is no drug for long-term effective treatment of Crohn's disease, especially drug by oral administration. Therefore, there is a need for developing better target therapy with optimized chronic use for Crohn's disease, or drugs with better effectiveness or better safety.
  • DNBS Dinitrobenzene sulfonic acid
  • TNBS trinitrobenzene sulfonic acid
  • TNF- ⁇ inhibitors such as lenalidomide and thalidomide have been shown to be not effective in the treatment of Crohn's disease (C. Yang et, Aliment Pharmacol Ther 2015; 41:1079-7093.).
  • some embodiments disclose a piperidine-2,6-dione derivative of formula (I) and pharmaceutically acceptable salts thereof:
  • R 1 represents one or more substituents selected from the group consisting of H, halogen, —OH, —C 1-4 alkyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 and —NHCOC 1-4 alkyl;
  • R 2 represents —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 —;
  • R 3 represents —H or —C 1-4 alkyl.
  • R 4 represents one or more substituents selected from the group consisting of H, halogen, —C 1-4 alkyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 and —NHCOC 1-4 alkyl;
  • R 5 represents —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 —;
  • R 6 represents —S—, —SO—, —SO 2 —, —NH— or —N(C 1-4 alkyl)-;
  • R 7 represents —H or —C 1-4 alkyl.
  • R 8 represents one or more substituents selected from the group consisting of H, halogen, —C 1-4 alkyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 and —NHCOC 1-4 alkyl;
  • R 9 represents —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 —;
  • R 10 represents —O—, —S—, —SO—, —SO 2 —, —NH— or —N(C 1-4 alkyl)-;
  • R 11 represents —H or —C 1-4 alkyl
  • R 12 represents halogen or —C 1-4 alkyl.
  • some embodiments disclose a piperidine-2,6-dione derivative and pharmaceutically acceptable salts thereof, which are selected from the group consisting of:
  • some embodiments disclose a pharmaceutical composition
  • a pharmaceutical composition comprising the piperidine-2,6-dione derivative or pharmaceutically acceptable salts thereof as disclosed herein, and a pharmaceutically acceptable carrier, diluent or excipient.
  • some embodiments disclose a method for treating Crohn's disease, comprising administering a therapeutically effective amount of the piperidine-2,6-dione derivative or pharmaceutically acceptable salts thereof as disclosed herein, or a therapeutically effective amount of the pharmaceutical composition as disclosed herein to a subject in need thereof.
  • some embodiments disclose the piperidine-2,6-dione derivative and pharmaceutically acceptable salts thereof of as disclosed herein for treating Crohn's disease.
  • some embodiments disclose a pharmaceutical composition for treating Crohn's disease, comprising the piperidine-2,6-dione derivative or pharmaceutically acceptable salts thereof as disclosed herein, and a pharmaceutically acceptable carrier, diluent or excipient.
  • Crohn's disease can be mild Crohn's disease, moderate Crohn's disease, or severe Crohn's disease. According to the activity of disease, Crohn's disease can be divided into active Crohn's disease or Crohn's disease in remission.
  • the goal of treatment for Crohn's disease is to induce active Crohn's disease to enter the remission (i.e, induction of remission) and/or to maintain the disease in remission (i.e., maintenance of remission).
  • CDAI Crohn's disease activity index
  • the patient's disease was scored according to the Best CDAI calculation as described above. After scoring, the clinical remission corresponds to Crohn's disease in remission of the present disclosure, mild activity corresponds to mild Crohn's disease of the present disclosure, moderate activity corresponds to moderate Crohn's disease of the present disclosure, and severe activity corresponds to severe Crohn's disease of the present disclosure.
  • C 1 -C 4 alkyl describes an alkyl group, as defined below, having a total of 1 to 4 carbon atoms
  • C 3 -C 10 cycloalkyl describes a cycloaklyl group, as defined below, having a total of 3 to 10 carbon atoms.
  • the total number of carbon atoms in the shorthand notation does not include the carbons that may exist in the substituents of the groups described.
  • mammals means animals including, for example, dogs, cats, cows, sheep, horses, and humans. In some embodiments, mammals include humans.
  • patient means an animal, such as a human, a companion animal, such as a dog, cat and horse, and livestock, such as cattle, swine and sheep.
  • livestock such as cattle, swine and sheep.
  • patients are mammals, including both males and females.
  • patients are humans.
  • pharmaceutically acceptable means the carrier, vehicle, diluent, excipient and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isosmotic agent, solvent, or emulsifier, etc, which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or animals and have no side effects on preparing a pharmaceutical composition.
  • “Pharmaceutically acceptable salts” include both “pharmaceutically acceptable acid addition salts” and “pharmaceutically acceptable base addition salts”.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphanic acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid,
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited, to sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminium salts and the like. In some embodiments, inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and s basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, trometamol, purine, piperazine, piperidine, N-ethyl piperidine, polyamine resins and the like.
  • organic bases are isopropylamine, diethy
  • a solvent or a solvent mixture refers to any and all solvents
  • a solvent or a solvent mixture is organic solvents and water, which include, but are not limited to, water, methanol, ethanol, 2-propanol, n-butanol, iso-butanol, acetone, methylethylketone, ethylacetate, 1,4-dioxane, diethylether, MTBE, THF, acetonitrile, dichloromethane, chloroform, DMF, cyclohexane, cyclopentane, n-hexane, n-heptane, n-pentane, toluene, o-xylene, p-xylene, DMSO, pyridine, acetic acid, anisole, butylacetate, cumene, ethylformate, formic acid, iso-butylacetate, iso-propylacetate,
  • a “pharmaceutical composition” refers to a formulation of a compound of the present disclosure and a medium generally acceptable in the art for the delivery of the biologically active compound to mammals, e.g., humans.
  • a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
  • “Therapeutically effective amount” refers to an amount of a compound or combination of compounds that ameliorates, attenuates or eliminates a particular disease or condition or a symptom of a particular disease or condition, or prevents or delays the onset of a particular disease or condition or a symptom of a particular disease or condition.
  • the amount of a compound of the present disclosure which constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • Treating” or “treatment” as used herein covers the treatment of the disease or condition of interest in a mammal, such as a human, having the disease or disorder of interest, and includes:
  • the terms “disease” and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians.
  • the compounds of the present disclosure or their pharmaceutically acceptable salt may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereoisomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or (D)- or (L)- for amino acids.
  • the present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and ( ⁇ ), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as HPLC using a chiral column.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present disclosure contemplates various stereoisomers and mixtures thereof.
  • substitution site of R 1 in formula (I) can be one of the sites numbered as 4, 5, 6 and 7 or a combination of several sites numbered as 4, 5, 6 and 7.
  • substitution site of R 4 in formula (II) can be one of the sites numbered as 4, 5, 6 and 7 or a combination of several sites numbered as 4, 5, 6 and 7.
  • substitution site of R 8 in formula (III) can be one of the sites numbered as 4, 5, 6 and 7 or a combination of several sites numbered as 4, 5, 6 and 7.
  • some embodiments disclose a piperidine-2,6-dione derivative of formula I) and pharmaceutically acceptable salts thereof:
  • R 1 represents one or more substituents selected from the group consisting of H, halogen, —OH, —C 1-4 alkyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 and —NHCOC 1-4 alkyl;
  • R 2 represents —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 —;
  • R 3 represents —H or —C 1-4 alkyl.
  • R 1 represents one or more substituents selected from the group consisting of —H, —F, —Cl, —Br, —OH, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —NHCH 3 , —NH 2 , —NHCH 2 CH 3 , —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —NHCOCH 3 and —NHCOCH 2 CH 3 ;
  • R 2 represents —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 —;
  • R 3 represents —H, —CH 3 or —CH 2 CH 3 .
  • R 1 represents one or more substituents selected from the group consisting of —H, —F, —OH, —CH 3 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 and —NH 2 ;
  • R 2 represents —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 —;
  • R 3 represents —H, —CH 3 or —CH 2 CH 3 .
  • piperidine-2,6-dione derivatives of formula (I) and pharmaceutically acceptable salts thereof which are selected from the group consisting of:
  • some embodiments disclose a piperidine-2,6-dione derivative of formula (II) and pharmaceutically acceptable salts thereof:
  • R 4 represents one or more substituents selected from the group consisting of H, halogen, —C 1-4 alkyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 and —NHCOC 1-4 alkyl;
  • R 5 represents —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 —;
  • R 6 represents —S—, —SO—, —SO 2 —, —NH— or —N(C 1-4 alkyl)-;
  • R 7 represents —H or —C 1-4 alkyl.
  • R 4 represents one or more substituents selected from the group consisting of —H, —F, —Cl, —Br, —OH, —CH 3 , —NHCH 3 , —NHCH 2 CH 3 , —NH 2 , —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —NHCOCH 3 and —NHCOCH 2 CH 3 ;
  • R 5 represents —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 —;
  • R 6 represents —S—, —SO—, —SO 2 —, —NH— or —N(CH 3 )—;
  • R 7 represents —H, —CH 3 or —CH 2 CH 3 .
  • R 4 represents —NH 2 or —NHCOCH 3 ;
  • R 5 represents —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 —;
  • R 6 represents —S—, —SO—, —SO 2 —, —NH— or —N(CH 3 )—;
  • R 7 represents —H, —CH 3 or —CH 2 CH 3 .
  • R 8 represents one or more substituents selected from the group consisting of H, halogen, —C 1-4 alkyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 and —NHCOC 1-4 alkyl;
  • R 9 represents —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 —;
  • R 10 represents —O—, —S—, —SO—, —SO 2 —, —NH— or —N(C 1-4 alkyl)-;
  • R 11 represents —H or —C 1-4 alkyl
  • R 12 represents halogen or —C 1-4 alkyl.
  • R 8 represents one or more substituents selected from the group consisting of —H, —F, —Cl, —Br, —OH, —CH 3 , —NHCH 3 , —NHCH 2 CH 3 , —NH 2 , —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2 , —NHCOCH 3 and —NHCOCH 2 CH 3 ;
  • R 9 represents —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 —;
  • R 10 represents —O—, —S—, —SO—, —SO 2 —, —NH— or —N(CH 3 )—;
  • R 11 represents —H, —CH 3 or —CH 2 CH 3 ;
  • R 12 represents halogen or —C 1-4 alkyl.
  • R 8 represents —NH 2 or —NHCOCH 3 ;
  • R 9 represents —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or —CH 2 CH 2 CH 2 CH 2 —;
  • R 10 represents —O—, —S—, —SO—, —SO 2 —, —NH— or —N(CH 3 )—;
  • R 11 represents —H, —CH 3 or —CH 2 CH 3 ;
  • R 12 represents halogen or —C 1-4 alkyl.
  • piperidine-2,6-dione derivatives and pharmaceutically acceptable salts thereof which are selected from the group consisting of:
  • some embodiments disclose a pharmaceutical composition
  • a pharmaceutical composition comprising the piperidine-2,6-dione derivative or pharmaceutically acceptable salts thereof as disclosed herein, and a pharmaceutically acceptable carrier, diluent or excipient.
  • some embodiments disclose a method for treating Crohn's disease, comprising administering a therapeutically effective amount of the piperidine-2,6-dione derivative or pharmaceutically acceptable salts thereof as disclosed herein, or a therapeutically effective amount of the pharmaceutical composition as disclosed herein to a subject in need thereof.
  • Some embodiments disclose a method for treating Crohn's disease, comprising administering 1 mg-10 g of the piperidine-2,6-dione derivative or pharmaceutically acceptable salts thereof as disclosed herein to a subject in need thereof.
  • Some embodiments disclose a method for treating Crohn's disease, comprising administering 10 mg-3000 mg of the piperidine-2,6-dione derivative or pharmaceutically acceptable salts thereof as disclosed herein to a subject in need thereof.
  • Some embodiments disclose a method for treating Crohn's disease, comprising administering 100 mg-1000 mg of the piperidine-2,6-dione derivative or pharmaceutically acceptable salts thereof as disclosed herein to a subject in need thereof.
  • Some embodiments disclose a method for treating Crohn's disease, comprising administering 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg or 1000 mg of the piperidine-2,6-dione derivative or pharmaceutically acceptable salts thereof as disclosed herein to a subject in need thereof.
  • Some embodiments disclose a method for treating Crohn's disease, wherein the Crohn's disease is mild Crohn's disease, moderate Crohn's disease, severe Crohn's disease or Crohn's disease in remission.
  • Some embodiments disclose a method for treating Crohn's disease, wherein the subject in need thereof is a mammal.
  • Some embodiments disclose a method for treating Crohn's disease, wherein the subject in need thereof is human.
  • Some embodiments disclose of a method of maintenance treatment of Crohn's disease, comprising administering a therapeutically effective amount of the piperidine-2,6-dione derivative or pharmaceutically acceptable salts thereof as disclosed herein, or a therapeutically effective amount of the pharmaceutical composition as disclosed herein to a subject in need thereof.
  • Some embodiments disclose a method for treating Crohn's disease, wherein the piperidine-2,6-dione derivative or pharmaceutically acceptable salts thereof as disclosed herein, or the pharmaceutical composition comprising the piperidine-2,6-dione derivative or pharmaceutically acceptable salts thereof as disclosed herein is administered orally.
  • Some embodiments disclose a method for treating Crohn's disease, wherein the piperidine-2,6-dione derivative or pharmaceutically acceptable salts thereof as disclosed herein, or the pharmaceutical composition comprising the piperidine-2,6-dione derivative or pharmaceutically acceptable salts thereof as disclosed herein is administered orally in a solid or liquid formulation.
  • Exemplary examples of the solid formulation that can be used in the method for treating Crohn's disease as disclosed herein comprise, but are not limited to, a tablet, capsule and sugar-coated pill.
  • Exemplary examples of the tablet that can be used in the method for treating Crohn's disease as disclosed herein comprise, but are not limited to, a plain tablet, sugar-coated tablet and film-coated tablet.
  • Exemplary examples of the liquid formulation that can be used in the method for treating Crohn's disease as disclosed herein comprise, but are not limited to, a solution and suspension.
  • some embodiments disclose a piperidine-2,6-dione derivative and pharmaceutically acceptable salts thereof for treating Crohn's disease.
  • some embodiments disclose a pharmaceutical composition for treating Crohn's disease, comprising the piperidine-2,6-dione derivative or pharmaceutically acceptable salts thereof as disclosed herein, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the piperidine-2,6-dione derivatives as disclosed herein have good therapeutical effects.
  • the piperidine-2,6-dione derivatives as disclosed herein have better tolerance.
  • Some embodiments disclose a pharmaceutical composition
  • a pharmaceutical composition comprising the piperidine-2,6-dione derivative or pharmaceutically acceptable salts thereof as disclosed herein, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the route of administration of the piperidine-2,6-dione derivatives as disclosed herein to the mammals can be non-parenteral route.
  • the route of administration of the piperidine-2,6-dione derivatives as disclosed herein to the mammals can be oral route.
  • the route of administration of the piperidine-2,6-dione derivatives as disclosed herein to the mammals can be intrarectal route.
  • the piperidine-2,6-dione derivatives as described herein may be obtained in any suitable form such as tablet, capsule, powder, oral solution, suspension, rectal gel, rectal foam, rectal enema or suppository and the like.
  • exemplary examples of tablets comprise, but are not limited to, plain tablets, sugar-coated tablets and film-coated tablets.
  • a pharmaceutically acceptable carrier that can be used in the pharmaceutical composition of the present disclosure include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isosmotic agent, solvent or emulsifier, which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or animals.
  • Acceptable carriers or diluents for therapeutic use are well-known in the art, and are described, for example, in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa. (1990), which is incorporated herein by reference in its entirety.
  • compositions of the present disclosure may be administered by any means that achieve their intended purpose.
  • administration may be by oral, parenteral, topical, enteral, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal, transocular, subcutaneous, intraperitoneal, transdermal, or buccal routes.
  • the route of administration can be non-parenteral route, oral route and intrarectal route.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • Suitable dosage forms include, but are not limited to capsules, tablets, pellets, dragees, semi-solids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, solution, syrups, aerosols, suspension, emulsion, which can be produced according to methods known in the art.
  • Particularly suitable for oral use are ordinary tablets (plain tablets), sugar-coated tablet, film-coated tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal use are suppositories, suitable for parenteral use are solutions, or oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical use are ointments, creams or powders.
  • the compounds of the present disclosure may also be lyophilised and the resultant lyophilisates used, for example, for the preparation of injection preparations.
  • the preparations indicated may be sterilised and/or comprise assistants, such as lubricants, preservatives, stabilisers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes, flavours and/or a plurality of further active ingredients, for example one or more vitamins.
  • assistants such as lubricants, preservatives, stabilisers and/or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes, flavours and/or a plurality of further active ingredients, for example one or more vitamins.
  • a pharmaceutical composition of the present disclosure is formulated as tablet, solution, granule, patch, ointment, capsule, aerosol or suppository administered via parenteral, transdermal, mucosa, nasal, buccal, sublingual or oral route.
  • Preservatives may be provided in the pharmaceutical composition.
  • sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives.
  • antioxidants and suspending agents may be used.
  • alcohols, esters, sulfating aliphatic alcohols, and the like may be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicate, magnesium aluminate, methyl magnesium silicate aluminate, synthetic aluminum silicate, calcium carbonate, calcium bicarbonate, calcium hydrogenphosphate, calcium hydroxymethyl cellulose and the like may be used as excipients; magnesium stearate, tale, hardened oil may be used as smoothing agents; coconut oil, olive oil, sesame oil, peanut oil, soybean may be used as suspending agents or lubricants; cellulose acetate phthalate as a derivative of a carbohydrate such as cellulose or sugar, or methylacetate-methacrylate copolymer as a derivative of polyethylene may be used as suspending agents; and plasticizers such as ester phthalates and the like may be used as suspending agents.
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal or intraocular injections.
  • the compound can be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electromigrating) patches, and the like for prolonged and/or timed, pulsed administration at a predetermined rate.
  • compositions of the present disclosure may be manufacture in manner that is itself known, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or tabletting processes.
  • compositions for use in accordance with the present disclosure thus may be formulated by a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing the active compounds into preparation which can be used pharmaceutically. Proper formulation is dependent on the route of administration chosen. Any of the well-known techniques, carriers and excipients may be used as suitable and as understood in the art.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • Suitable excipients are, for example, water, saline, glucose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like.
  • the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like.
  • Physiologically compatible buffers include, but are not limited to, Hank's solution, Ringer's solution or physiological saline buffer. If desired, absorption enhancing preparations (such as liposomes) may be used.
  • the compound can be formulated readily by combining the active compound with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compound of the disclosure to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, ointments, suspensions, and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparation for oral use can be obtained by combining the active compound with solid excipient, optionally grinding a resultant mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, saccharose, mannitol or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solution, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added into the tablets or dagree coatings for identification or to characterizing different combinations of active compound doses.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, tale, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solution, and suitable organic solvents or solvent mixtures.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
  • the push-fit capsules can contain active ingredients in admixture with filler such as sugar, binders such as starches, and/or lubricants such as tale or magnesium stearate and, optionally, stabilizers.
  • the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oil, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the pharmaceutical composition of the present disclosure may comprise 0.1%-95% of the piperidine-2,6-dione derivatives as disclosed herein.
  • the pharmaceutical composition of the present disclosure may comprise 1%-70% of the piperidine-2,6-dione derivatives as disclosed herein.
  • composition or formulation to be administered may comprise some amount of the piperidine-2,6-dione derivatives as disclosed herein, which is effective to treat the disease/condition of a study subject to be treated.
  • At least one of the compounds of the present disclosure or the pharmaceutical compositions comprising at least one of the compounds of the present disclosure may be administered to the patient by any suitable means and/or by any means that topically delivers the compounds of the present disclosure.
  • methods of administration include, among others, (a) administration though oral pathways, which administration includes administration in capsule, tablet, granule, spray, syrup, or other such forms; (b) administration through non-oral pathways such as rectal, vaginal, intraurethral, intraocular, intranasal, or intrarticular, which administration includes administration as an aqueous suspension, an oily preparation or the like or as a drip, spray, suppository, salve, ointment or the like; (c) administration via injection, subcutaneously, intraperitoneally, intravenously, intramuscularly, intradermally, intraorbitally, intracapsularly, intraspinally, intrasternally, or the like, including infusion pump delivery; (d) administration locally such as by injection directly in the renal or cardiac area,
  • the most suitable route depends on the nature and severity of the condition to be treated.
  • a person having ordinary skill in the art also knows determination of methods of administration (buccal, intravenous, inhalation subcutaneous, rectal and the like), dosage form, suitable pharmaceutical excipients and other events regarding delivering the compound to a subject in need thereof.
  • compositions suitable for administration include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose.
  • the therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed.
  • the determination of effective dosage levels can be accomplished by one skilled in the art using routine pharmacological methods. Typically, human clinical applications of products are commenced at lower dosage levels, with dosage level being increased until the desired effect is achieved. Alternatively, acceptable in vitro studies can be used to establish useful doses and routes of administration of the compositions identified by the present methods using established pharmacological methods.
  • dosages may range broadly, depending upon the desired affects and the therapeutic indication. Typically, dosages may be between about 10 microgram/kg and 1000 mg/kg body weight, in some embodiments, between about 100 microgram/kg and 300 mg/kg body weight. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art.
  • the exact formulation, route of administration and dosage for the pharmaceutical compositions of the present disclosure can be chosen by the individual physician in view of the patient's condition.
  • the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient.
  • human dosages for compounds have been established for at least some condition, the present disclosure will use those same dosages, or dosages that are between about 0.1% and 500%, in some embodiments, between about 25% and 250% of the established human dosage.
  • a suitable human dosage can be inferred from ED 50 or ID 50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
  • the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity).
  • the magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 2000 mg of each active ingredient, in some embodiments, between 1 mg and 2000 mg, e.g. 5 to 1500 mg.
  • an intravenous, subcutaneous, or intramuscular dose of each active ingredient of between 0.01 mg and 1000 mg, in some embodiments, between 0.1 mg and 1000 mg, e.g. 1 to 800 mg is used.
  • dosages may be calculated as the free base.
  • the composition is administered 1 to 4 times per day.
  • compositions of the disclosure may be administered by continuous intravenous infusion, in some embodiments, at a dose of each active ingredient up to 2000 mg per day.
  • each active ingredient up to 2000 mg per day.
  • the compounds disclosed herein in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the above-stated dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, in some embodiments, between 30-90% and in some embodiments, between 50-90%.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and in some embodiments, human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • a cell line such as a mammalian, and in some embodiments, human, cell line.
  • the results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • the toxicity of particular compounds in an animal model such as mice, rats, rabbits, or monkeys, may be determined using known methods.
  • the efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions comprising a compound of the disclosure formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • LPS lipopolysaccharide
  • PBS phosphate buffered saline
  • PBST 0.05% of Tween-20 in phosphate buffered saline
  • HRP horseradish peroxidase
  • TMB 3,3′,5,5′-tetramethylbenzidine
  • DSS dextra sulfate sodium
  • 5-ASA 5-aminosalicylic acid
  • CMC-Na sodium carboxymethyl cellulose
  • DNBS dinitrobenzenesulfonic acid
  • 1% CMC-Na 1% (weight/volume) of CMC-Na in water
  • DSS 1.6% (weight/volume) of DSS in water
  • DSS 0.9% (weight/volume) of DSS in water
  • mg/Kg milligram/kilogram
  • mg/Kg/d milligram/kilogram/day
  • ml/Kg milliliter/kilogram
  • Mean ⁇ SD Mean ⁇ standard deviation
  • cm 2 square centimeter
  • MPO myeloperoxidase
  • ⁇ L microliter
  • nm nanometer
  • OD value optical density value
  • the Chinese patent No. ZL200510013292.3 discloses the preparation process of 4-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione, which is incorporated herein by reference in its entirety.
  • the aqueous phase was back-extracted with ethyl acetate four times.
  • the organic phases were combined.
  • the combined organic phase was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered.
  • the organic phase was concentrated under reduced pressure to give a crude product.
  • the crude product was purified with silica gel column chromatography to give the title compound as a yellow solid (2.0 g) (HPLC purity: 95.53%). Yield: 49.2%.
  • 3-amino-3-methylpiperidin-2,6-dione hydrochloride was prepared in accordance with PCT Int. Appl., 2006081251, 3 Aug. 2006.
  • N-((benzyloxy)carbonyl)-glutamic anhydride was prepared in accordance with Archives of Pharmacal Research, 31(7), 834-837; 2008.
  • N,N′-carbonyldiiazole (23.4 g) was added into the above reaction solution in batch. The resultant solution was stirred at the room temperature over 72 hours until the reaction was complete. The solution was concentrated under reduced pressure. To the concentrate was added dichloromethane (500 mL). The resultant solution was washed with 1 N hydrochloric acid (250 mL), saturated aqueous solution of sodium bicarbonate (250 mL) and saturated aqueous solution of sodium chloride (250 mL).
  • N-((benzyloxy)carbonyl)-glutamic anhydride was used to prepare 1-(2-ethoxyethyl)-3-benzyloxyamido-2,6-piperidinedione as a brown oily crude product (17.2 g).
  • reaction solution was poured into saturated aqueous solution of ammonium chloride (400 mL).
  • the resultant solution was extracted with ethyl acetate (200 mL ⁇ 3).
  • the organic phases were combined.
  • the combined organic phase was dried over anhydrous sodium sulfate and filtered.
  • the filtrate was concentrated.
  • the residue was separated with column chromatography to give 4-nitro-2-(1-(3-methoxypropyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (1.211 g). Yield: 32.3%.
  • the Chinese patent No. ZL200510013292.3 discloses the preparation process of 4-amino-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione, which is incorporated herein by reference in its entirety.
  • Wistar rats male, body weight of 100-120 g.
  • mice 90 male Wistar rats were fasted for 40 hours. A 5% glucose injection was administered subcutaneously during fasting. 60 rats with normal conditions and moderate body weight were selected from the fasting rats. The animals were randomly divided into 6 groups according to the body weight: normal control group, model control group, sulfasalazine group (300 mg/Kg), and the compound in Example 27 groups consisting of 5, 15 and 30 mg/Kg dose groups. There were 10 rats in each group. The animals were anesthetized with ether. A specially made gavage device (made by a rat gavage device having the diameter of 2 mm, which was nested on a mouse gavage device having the diameter of 1 mm) was slowly inserted into the enteric cavity at 8 cm from the anus.
  • a specially made gavage device made by a rat gavage device having the diameter of 2 mm, which was nested on a mouse gavage device having the diameter of 1 mm
  • the model control group, the sulfasalazine group and the compound in Example 27 groups were administered with 0.5 mL of 50 mg/mL DNBS in 30% ethanol solution.
  • the normal control group was administered with 0.5 mL of 30% ethanol solution.
  • the animals were inverted in anesthesia for 15 minutes after the gavage device was removed.
  • the day when the model was prepared was the first day of the experiment.
  • the corresponding drug or the corresponding volume of 1% CMC-Na was administered once per day.
  • the body weights were recorded and the stool characteristics were scored.
  • colon tissues were taken from the animals to observe the results of each index.
  • Example 27 The compound in Example 27 and sulfasalazine: Preparation Method: Suspended with 1% CMC-Na, and prepared when it was needed.
  • the frozen tissue was ground into powder in liquid nitrogen. An appropriate amount of the powder was weighed and was added into 50 mM potassium phosphate solution (containing 0.5% cetyltrimethylammonium bromide) to give a 25 mg/mL solution. The resultant solution was homogenized by an electric homogenizer. 1 mL of suspension was centrifuged to give a supernatant. 7 ⁇ L of the supernatant was added into a 96-well plate and 200 ⁇ L of o-dianisidine mixture (containing 0.167 mg/mL o-dianisidine and 0.0006% H 2 O 2 potassium phosphate buffer). OD values of the resultant solution at 0, 30, 60, and 90 s were detected at 450 nm of the microplate reader.
  • results of colonic tissue-related indexes showed that compared with the normal control group, the colon of the model control group was significantly shortened, the colon tissue was abnormally proliferated and the colon weight was increased. At the same time, the MPO activity of colon tissue was significantly increased, the colon had a larger area of ulcer injury. Sulfasalazine as positive drug at the dose of 300 mg/Kg reduced the colon abnormal proliferation and reduced the colon weight, and had some improvement on colonic ulcers with the reduction of the ulcer area by 60%.
  • the compound in Example 27 at the dose of 5 mg/Kg, 15 mg/Kg and 30 mg/Kg reduced the adhesion degree of colons, reduced the weight of colon tissue and the ulcer degree, and reduced the MPO activity of colon tissue, and thus showed a certain dose effect and a good therapeutic effect without the weight loss of animals.
  • the compound in Example 27 at the dose of 30 mg/Kg reduced the ulcer degree of colon with a reduction of the ulcer area by about 80%, while the MPO activity of colon tissue was significantly reduced (P ⁇ 0.05), of which the therapeutic effects are better than those of sulfasalazine as positive drug at the dose of 300 mg/Kg.
  • mice 110 male Wistar rats were fasted for 40 hours.
  • a 5% glucose injection (10 mL/Kg) was administered subcutaneously during fasting.
  • 48 rats with normal conditions and moderate body weight were selected from the fasting rats.
  • the animals were randomly divided into 5 groups according to the body weight: normal control group, model control group, sulfasalazine group (300 mg/Kg), dexamethasone group (0.1 mg/Kg), the compound in Example 26 group (30 mg/kg) and the compound in Example 27 group (30 mg/kg), with 8 rats in each group.
  • the animals were anesthetized with isoflurane.
  • a specially made gavage device (made by a rat gavage device having the diameter of 2 mm, which was nested on a mouse gavage device having the diameter of 1 mm) was slowly inserted into the enteric cavity at 8 cm from the anus.
  • the model control group, the compound in Example 26 group and the compound in Example 27 group were administered with 0.5 mL of 50 mg/mL DNBS in 30% ethanol solution.
  • the normal control group was administered with 0.5 mL of 30% ethanol solution.
  • the animals were inverted in anesthesia for 15 minutes after the gavage device was removed.
  • the day when the model was prepared was the first day of the experiment. After 4 hours of DNBS induction, the corresponding drug or the corresponding volume of 1% CMC-Na was administered once per day.
  • the animals were euthanized to observe the results of each index so as to score the colon adhesion degree, measure the length of colon and ulcer area, weigh colon and calculate the colon weight to length ratio.
  • Example 26 The compound in Example 26 and Example 27, sulfasalazine and dexamethasone: Preparation Method: Suspended with 1% CMC-Na, and prepared when it was needed.
  • Levene's Test for homogeneity of data was performed with Spss. Where the data were homogeneous (P>0.05), one-way ANOVA LSD test was performed. Where the analysis of variance was significant (P ⁇ 0.05), Dunnett's multiple comparison (parameter method) was performed. Where the results of Levene's Test were significant (P ⁇ 0.05), Kruskal-Wallis nonparametric test was performed. Where the results of Kruskal-Wallis nonparametric test were significant (P ⁇ 0.05), Mann-Whitney U test was performed for pairwise comparison.
  • Colon indexes showed that the area of colonic ulcer and the weight of colon of model control group were significantly higher than those of normal control group (P ⁇ 0.05), and the colon was significantly shortened. Compared with model control group, there was significant reduction in the area of colonic ulcer in each administration group (P ⁇ 0.05).
  • the animals were anesthetized with ether after 40 hours fasting. A specially made gavage device was slowly inserted into the enteric cavity at 8 cm from the anus.
  • the model control group and each test group were administered with 0.5 mL of 50 mg/mL DNBS in 30% ethanol solution.
  • the normal control group was administered with 0.5 mL of 30% ethanol solution.
  • the animals were inverted in anesthesia for 15 minutes. The day when the model was prepared was day 0 of the experiment. After 4 hours of DNBS induction, the corresponding drug or the corresponding volume of 1% CMC-Na was administered once per day. On day 7 of the experiment, the animals were euthanized to score the colon adhesion degree, measure the length of colon and ulcer area, weigh colon and calculate the colon weight to length ratio.
  • the pathological changes of the colon (adhesion, hyperplasia and ulcer) in the animals can be effectively relieved by the treatment in each experimental group.
  • the animals were anesthetized with ether after 72 hours fasting. A specially made gavage device was slowly inserted into the enteric cavity at 8 cm from the anus.
  • the model control group and each test group were administered with 0.5 mL of 50 mg/mL DNBS in 30% ethanol solution.
  • the normal control group was administered with 0.5 mL of 30% ethanol solution.
  • the animals were inverted in anesthesia for 15 minutes. The day when the model was prepared was day 0 of the experiment. After 4 hours of DNBS induction, the corresponding drug or the corresponding volume of 1% CMC-Na was administered once per day. On day 7 of the experiment, the animals were euthanized to score the colon adhesion degree, measure the length of colon and ulcer area, weigh colon and calculate the colon weight to length ratio.
  • Example 13 TABLE 13 Grouped Table DNBS Clysis Administration Number DNBS Concentration Volume Administration Dose Administration of Groups Solvent (mg/ml) (ml/rat) Route (mg/Kg) Regimen Animals Normal 30% 0 0.5 — — — 8 Control Group ethanol Model Control 50 0.5 i.g — qd ⁇ 7 Group Example 27 30 Example 8 Example 14 Example 24 Example 5 Example 23 Example 10 Example 2 Example 12 Note: The drug in the experiment was suspended with 1% CMC-Na to prepare a 3 mg/mL of homogenous suspension. The administration volume was 10 mL/Kg. i.g: intragastric administration. qd ⁇ 7: once per day, a total of 7 times.
  • the pathological changes of the colon (adhesion, hyperplasia and ulcer) in the animals can be effectively relieved by the treatment in each experimental group.
  • mice The mice were fasted one day before the experiment. On the day of the experiment, 6 mice (ICR mice, body weight of 19-21 g, three females and three males) were selected in each experiment group. First of all, one female and one male were selected to orally give 1000 mg/Kg, and observed for 5-10 minutes. If there were no obvious side effects, the remaining 4 animals were orally given the same dose, and observed for 10-15 minutes. If no animal died, the animals were placed in a box to balancedly feed for 7 days. The state was observed and the body weight was recorded daily. The animal grouping plan and the initial dose of the drug were shown in the table below:
  • Nervous system response tremor, spasm, convulsion, ataxia, posture abnormality, etc.
  • Autonomic nerve exophthalmos, salivation, tears, urination (hematuria), diarrhea, piloerection, breathing, etc.
  • Example 11 Male Abnormality was not observed in 7 days of the test Female Decrease of activity was observed in one animal after administration but activity was recovered within 3 minutes. Abnormality was not observed in all the animals from day 2 to 7.
  • Example 20 Male Decrease of activity was observed in one animal 11 minutes after administration but activity was recovered later. Abnormality was not observed in all the animals from day 2 to 7.
  • Example 17 Male Motor dysfunction in two animals was observed 30 minutes after administration and function was recovered later. Abnormality was not observed in all the animals from day 2 to 7.
  • Female Motor dysfunction in one animal was observed 10 minutes after administration and function was recovered later.
  • the body weight of the animals in each group had a trend of increase with slight fluctuations.
  • Each compound had no side effects on the change of the body weights of the mice at the dosage of 1000 mg/Kg.

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CN108727319A (zh) * 2018-09-05 2018-11-02 常州大学 一种3-硝基邻苯二甲酸酐的制备方法
CN109293631B (zh) * 2018-11-30 2020-05-08 常州制药厂有限公司 3-氨基-n-(2，6-二氧代-3-哌啶基)-邻苯二甲酰亚胺化合物的制备方法
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CN100488959C (zh) * 2003-03-27 2009-05-20 天津和美生物技术有限公司 水溶性的酞胺哌啶酮衍生物
EP1663223B1 (fr) * 2003-09-17 2014-01-01 The Government of the United States of America, as represented by the Secretary of the Department of Health and Human Services Analogues du thalidomide comme inhibiteurs de tnf-alpha
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CN100383139C (zh) * 2005-04-07 2008-04-23 天津和美生物技术有限公司 可抑制细胞释放肿瘤坏死因子的哌啶-2，6-二酮衍生物
CN1961876A (zh) * 2005-11-08 2007-05-16 北京恩华医药研究院 邻苯二甲酰亚胺衍生物在制备抗新血管生成的药物中的用途
WO2011160042A2 (fr) * 2010-06-18 2011-12-22 Makoto Life Sciences, Inc. Modulateurs de prpk-tprkb et leurs utilisations
CN105246480A (zh) 2013-04-02 2016-01-13 细胞基因公司 使用4-氨基-2-(2,6-二氧代-哌啶-3-基)-异吲哚啉-1,3-二酮治疗和控制中枢神经系统癌症的方法和组合物
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US20240132466A1 (en) 2024-04-25
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CA3049161C (fr) 2023-03-07
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EP3546449A1 (fr) 2019-10-02
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US20190352277A1 (en) 2019-11-21
US11485724B2 (en) 2022-11-01
CA3045703A1 (fr) 2018-05-31
US20220306600A1 (en) 2022-09-29
CN108101887A (zh) 2018-06-01
EP3546450A1 (fr) 2019-10-02
AU2017366515A1 (en) 2019-06-13
JP7143295B2 (ja) 2022-09-28
EP3546449A4 (fr) 2020-06-10
CA3049161A1 (fr) 2018-05-31
WO2018095378A1 (fr) 2018-05-31
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JP7143296B2 (ja) 2022-09-28
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