WO2018095378A1 - 哌啶-2,6-二酮衍生物以及克罗恩氏病的治疗 - Google Patents

哌啶-2,6-二酮衍生物以及克罗恩氏病的治疗 Download PDF

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WO2018095378A1
WO2018095378A1 PCT/CN2017/112669 CN2017112669W WO2018095378A1 WO 2018095378 A1 WO2018095378 A1 WO 2018095378A1 CN 2017112669 W CN2017112669 W CN 2017112669W WO 2018095378 A1 WO2018095378 A1 WO 2018095378A1
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dione
pharmaceutically acceptable
isoindoline
dioxapiperidin
acceptable salt
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French (fr)
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张和胜
曾广怀
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Tianjin Hemay Biotechnology Co Ltd
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Tianjin Hemay Biotechnology Co Ltd
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Priority to AU2017366515A priority Critical patent/AU2017366515B2/en
Priority to EP17873820.9A priority patent/EP3546449A4/en
Priority to JP2019528110A priority patent/JP7143295B2/ja
Priority to US16/464,228 priority patent/US20220372013A2/en
Priority to CA3049161A priority patent/CA3049161C/en
Publication of WO2018095378A1 publication Critical patent/WO2018095378A1/zh
Anticipated expiration legal-status Critical
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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
    • 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
    • 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 the field of organic chemistry and medicinal chemistry.
  • 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 (transdermal damage). Chronic inflammation can cause fibrosis in a subgroup of patients with Crohn's disease, with complications including stenosis and spasm, and is more likely to require repeated surgery. Crohn's disease is associated with an increased risk of gastrointestinal malignancies. Crohn's disease has been found to be related to cellular immunity mediated by TH1 (type 1 T helper cell, type 1 helper cell) and TH17 (type 17 T helper cell).
  • TH1 type 1 T helper cell
  • TH17 type 17 T helper cell
  • Gastrointestinal manifestations are mainly diarrhea, abdominal pain, and bloody stools; body manifestations are mainly weight loss, fever, loss of appetite, fatigue, anemia, etc., adolescent patients can see growth retardation; complications common fistula, abdominal abscess, intestinal stenosis and obstruction, Perianal lesions, large bleeding in the digestive tract, acute perforation are rare, and the disease may be cancerous in the long course.
  • Colonoscopy is generally characterized by segmental, asymmetrical mucosal inflammation, characterized by non-continuous lesions, longitudinal ulcers, and cobblestone-like appearance.
  • Histopathological changes of Crohn's disease biopsy specimens include: 1 focal inflammatory cells with focal discontinuous infiltration; 2 fissure ulcers; 3 aphthous ulcer; 4 crypt structural abnormalities, glandular hyperplasia , individual crypt abscess, mucus secretion reduction is not obvious, visible pyloric gland metaplasia or Paneth cell metaplasia; 5 non-caseous necrotizing granuloma; 6 lymphocytes and plasma cells-based chronic inflammatory cell infiltration, The intrinsic membrane bottom and submucosa are heavy, common lymphoid follicles are formed; 7 submucosal lymphatic vessels are dilated; 8 ganglion cell hyperplasia and/or pericardial inflammation.
  • Treatment of Crohn's disease in mild active period is mainly 5-aminosalicylic acid and budesonide. When treatment is ineffective, it is considered as moderate active Crohn's disease; moderate active Crohn's disease treatment
  • the drug's preferred hormone such as dexamethasone
  • TNF- ⁇ monoclonal antibody is used in patients with ineffective or intolerable hormone and immunotherapy.
  • Crohn's disease in severe active period is mainly caused by systemic hormones, TNF- ⁇ monoclonal antibody and surgical treatment.
  • Drugs that maintain treatment during remission include 5-aminosalicylic acid, thiopurine, and TNF- ⁇ monoclonal antibodies.
  • 5-aminosalicylic drugs such as sulfasalazine and mesalazine
  • 5-aminosalicylic drugs found that about 50% of patients found vomiting, loss of appetite and liver dysfunction and other digestive disorders, hemolytic anemia and folic acid deficiency anemia Blood system disorders.
  • it since it has a salicylic acid skeleton, there are cases where side effects occur in cases where allergic symptoms are exhibited for salicylic acid agents, such as diarrhea, abdominal pain, amylase increase, and renal dysfunction.
  • sulfasalazine since sulfasalazine has been found to have side effects of male infertility and urinary color, it also exerts mental stress on the patient.
  • Budesonide or azathioprine can also be used due to immunosuppression and short-term effects, but it can only be used for a short period of time. Discontinuation of biological agents can lead to recurrent episodes of disease and increase the refractory disease. Moreover, biological agents can also bring a large economic burden to patients. Monoclonal drugs (such as infliximab and adalimumab) may present with high blood pressure, chills, rashes, fever, headache, and eczema. Since infliximab is a chimeric antibody, it has the possibility of exhibiting antigenicity, sometimes causing acute oversensitivity.
  • TNF- ⁇ inhibitors such as lenalidomide, thalidomide have proven to be ineffective in the treatment of Crohn's disease. (See C.Yang et, Aliment Pharmacol Ther 2015; 41:1079-7093)
  • Crohn's disease is a chronic disease that requires a longer duration of medication.
  • the above data indicates that there is no long-term effective treatment for Crohn's disease, especially by oral administration. Therefore, there is a need to develop more targeted Crohn's disease therapies optimized for chronic use; or more effective drugs or safer drugs.
  • DNBS dinitrobenzenesulfonic acid
  • TNBS trinitrobenzenesulfonic acid
  • TNF- ⁇ inhibitors such as lenalidomide, thalidomide have proven to be ineffective in the treatment of Crohn's disease. (See C.Yang et, Aliment Pharmacol Ther 2015; 41:1079-7093.)
  • certain embodiments disclose a piperidine-2,6-dione derivative of formula (I), and pharmaceutically acceptable salts thereof:
  • R 1 represents one or more of H, halogen, -OH, -C 1-4 alkyl, -NH 2 , -NH C 1-4 alkyl, -N(C 1-4 alkyl) 2 or -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 of H, halogen, -C 1-4 alkyl, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -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 of H, halogen, -C 1-4 alkyl, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -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 11 represents a halogen or a -C 1-4 alkyl group.
  • piperidine-2,6-dione derivatives and pharmaceutically acceptable salts thereof selected from the group consisting of:
  • compositions comprising a piperidine-2,6-diketone derivative or a pharmaceutically acceptable salt thereof described in the present disclosure, and a pharmaceutically acceptable carrier, diluent or excipient.
  • certain embodiments disclose methods of treating Crohn's disease, comprising administering to a subject in need of the method a therapeutically effective amount of piperidine-2,6-di described in the present disclosure.
  • a ketone derivative or a pharmaceutically acceptable salt thereof or a therapeutically effective amount of the pharmaceutical composition described in the present disclosure are disclosed.
  • certain embodiments disclose piperidine-2,6-dione derivatives and pharmaceutically acceptable salts thereof for use in the treatment of Crohn's disease.
  • compositions for treating Crohn's disease comprising a piperidine-2,6-dione derivative or a pharmaceutically acceptable salt thereof described in the present disclosure, and A pharmaceutically acceptable carrier, diluent or excipient.
  • references to “an embodiment” or “another embodiment” or “an embodiment” or “some embodiments” throughout this specification are meant to include, in at least one embodiment, the Specific reference to elements, structures or features.
  • the appearance of the phrase “a” or “an embodiment” or “an embodiment” Furthermore, the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
  • a pharmaceutical composition comprising a "piperidine-2,6-dione derivative” includes a piperidine-2,6-dione derivative, or two or more piperidine-2, 6-dione derivatives.
  • Crohn's disease can be mild Crohn's disease, moderate Crohn's disease or severe Crohn's disease. Depending on the severity of disease activity, Crohn's disease can be divided into active Crohn's disease or Crohn's disease during remission.
  • the treatment goal of Crohn's disease is to induce active Crohn's disease into remission (ie, induce remission) and/or maintain disease during remission (ie, maintain remission).
  • CDAI Crohn's Disease Activity Index
  • total score the sum of the scores
  • CDAI ⁇ 150 is divided into remission period
  • CDAI ⁇ 150 is divided into active period
  • 150-220 is divided into mild
  • 221-450 points For moderate, >450 is divided into severe.
  • the patient's condition was scored according to the Best CDAI calculation described above, and the score was evaluated as clinical remission corresponding to the remission phase Crohn's disease of the present disclosure, and the mild activity corresponds to the mild Crohn's disease of the present disclosure, moderately The activity corresponds to the moderate Crohn's disease of the present disclosure, and the severe activity corresponds to the severe Crohn's disease of the present disclosure.
  • C 1 -C 4 alkyl describes an alkyl group having a total of 1 to 4 carbon atoms as defined below
  • C 3 -C 10 cycloalkyl is described as having a total of 3 to 10 carbon atoms as defined below.
  • Cycloalkyl The total number of carbons in the abbreviated symbols does not include carbon that may be present in the substituents of the group.
  • halogen means fluoro, chloro, bromo or iodo.
  • alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and a hydrogen atom, containing no unsaturated bonds, having from 1 to 12 carbon atoms, and which are attached to the remainder of the molecule by a single bond. Part. In certain embodiments, an alkyl group has from 1 to 8 carbon atoms. In certain embodiments, an alkyl group has from 1 to 6 carbon atoms. In certain embodiments, an alkyl group has from 1 to 4 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl ( Tert-butyl), 3-methylhexyl, 2-methylhexyl, and the like.
  • mammal refers to animals including, for example, dogs, cats, cows, sheep, horses, and humans. In certain embodiments, the mammal comprises a human.
  • patient refers to animals (eg, humans), companion animals (eg, dogs, cats or horses), and livestock (eg, cows, pigs, and sheep).
  • animals eg, humans
  • companion animals eg, dogs, cats or horses
  • livestock eg, cows, pigs, and sheep.
  • the patient is a mammal comprising males and females.
  • the patient is a human.
  • pharmaceutically acceptable refers to carriers, carriers, diluents, excipients and/or salts which must be compatible with the other ingredients of the formulation and which are not deleterious to the recipient.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweet that has been approved by the U.S. Food and Drug Administration for use in humans or animals. Flavoring agents, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers Various forms of vectors without side effects.
  • “Pharmaceutically acceptable salts” include “acceptable acid addition salts” and “acceptable base addition salts.”
  • “Acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free base, which are biologically or otherwise suitable and which are formed using inorganic or organic acids.
  • the inorganic acid is, for example but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.
  • the organic acid is, for example but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, and the like.
  • “Acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acid, which are biologically or otherwise suitable. These salts are prepared by adding an inorganic base 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, aluminum salts, and the like. In certain embodiments, the inorganic salts are 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, salts of cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, Trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, Caffeine, procaine, seabamin, choline, betaine, benzylamine, phenylethylenediamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, Anthraquinone, piperazine, piperidine, N-ethylpiperidine, polyamine resin, and the like.
  • the like such
  • solvent or solvent mixture means any and all solvents.
  • the solvent or solvent mixture is an organic solvent and water including, but not limited to, methanol, ethanol, 2-propanol, n-butanol, isobutanol, acetone, methyl ethyl ketone, ethyl acetate , 1,4-dioxane, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, N,N-dimethylformamide, cyclohexane, cyclopentane, n-hexane, positive Heptane, n-pentane, toluene, o-xylene, p-xylene, dimethyl sulfoxide (DMSO), pyridine, acetic acid, anisole, butyl acetate, cumene, ethyl formate
  • DMSO dimethyl
  • “Pharmaceutical composition” refers to a formulation of a compound described in the present disclosure and a medium which is generally accepted in the art for delivery of a biologically activating compound to a mammal such as a human.
  • Such media include all pharmaceutically acceptable carriers, diluents or excipients.
  • “Pharmaceutical composition” refers to a formulation of a compound described in the present disclosure and a medium which is generally accepted in the art for delivery of a biologically activating compound to a mammal such as a human.
  • Such media include all pharmaceutically acceptable carriers, diluents or excipients.
  • “Therapeutically effective amount” means a condition that ameliorates, attenuates or eliminates a particular disease or condition and a particular disease or condition, or avoids or delays a particular disease or condition or a particular disease or condition.
  • the amount of the compound described in the present disclosure which constitutes a “therapeutically effective amount” will vary depending on the compound, the state of the disease and its severity, and the age, body weight, etc. of the mammal to be treated, but the skilled person will The knowledge and the disclosure herein can be used to determine the amount of the compounds described in this disclosure.
  • treating encompasses a treatment-related disease or condition in a mammal, such as a human, having a related disease or condition, and includes:
  • disease and “disease state” may be used interchangeably or may be different, as a particular disease or condition may not have a known causative agent (and therefore cannot be explained by etiology) Therefore, it is not recognized as a disease, but is considered to be an undesired disease state or condition in which the clinician has identified more or less specific series of symptoms.
  • the compound described in the present disclosure or a pharmaceutically acceptable salt thereof may contain one or more asymmetric centers, and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms, and may be Absolute stereochemistry defines it as (R)- or (S)-, or (D)- or (L)- of an amino acid.
  • the present disclosure is intended 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 Resolution is carried out using conventional techniques, such as HPLC using a chiral column.
  • a compound described in this disclosure contains an olefinic double bond or other geometrically asymmetric center, unless otherwise stated, it is meant that the compound includes both E and Z geometric isomers. Again, it is meant to include all tautomeric forms.
  • Stepoisomer refers to a compound composed of the same atoms bonded by the same bond, but having different three-dimensional structures that are not interchangeable.
  • the present disclosure encompasses various stereoisomers and mixtures thereof.
  • substitution position of R 1 in the formula (I) may be one of the numbers 4, 5, 6, 7 or a combination of a plurality of positions; the substitution position of R 4 in the formula (II) may be the position 4, 5, 6, A position in 7 or a combination of positions; the substitution position of R 8 in formula (III) may be one of positions 4, 5, 6, 7 or a combination of positions.
  • certain embodiments disclose a piperidine-2,6-dione derivative of formula (I), and pharmaceutically acceptable salts thereof:
  • R 1 represents one or more of H, halogen, -OH, -C 1-4 alkyl, -NH 2 , -NH C 1-4 alkyl, -N(C 1-4 alkyl) 2 or -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 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 or -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 of -H, -F, -OH, -CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -NHCOCH 3 or -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 .
  • R 4 represents one or more of H, halogen, -OH, -C 1-4 alkyl, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 or -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 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 or -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 .
  • Certain embodiments disclose a piperidine-2,6-dione derivative of formula (II), and a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • R 8 represents one or more of H, halogen, -C 1-4 alkyl, -NH 2 , -NHC 1-4 alkyl, -N(C 1-4 alkyl) 2 , -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 11 represents a halogen or a -C 1-4 alkyl group.
  • R 8 represents one or more 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 or -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 a halogen or a -C 1-4 alkyl group.
  • 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 a halogen or a -C 1-4 alkyl group.
  • Certain embodiments disclose a piperidine-2,6-dione derivative of formula (III), and a pharmaceutically acceptable salt thereof, selected from the group consisting of:
  • piperidine-2,6-dione derivatives and pharmaceutically acceptable salts thereof selected from the group consisting of:
  • compositions comprising a piperidine-2,6-diketone derivative or a pharmaceutically acceptable salt thereof described in the present disclosure, and a pharmaceutically acceptable carrier, diluent or excipient.
  • certain embodiments disclose a method of treating Crohn's disease, comprising administering to a subject in need thereof a therapeutically effective amount of a piperidine-2,6-dione derivative described in the present disclosure Or a pharmaceutically acceptable salt thereof or a therapeutically effective amount of the pharmaceutical composition described in the present disclosure.
  • Certain embodiments disclose a method of treating Crohn's disease comprising administering to a subject in need of the method 1 mg to 10 g of the piperidine-2,6-dione derivative described in the present disclosure or a medicament thereof Accepted salt.
  • Certain embodiments disclose a method of treating Crohn's disease comprising administering to a subject in need of the method 10 mg to 3000 mg of the piperidine-2,6-dione derivative described in the present disclosure or a medicament thereof Accepted salt.
  • Certain embodiments disclose a method of treating Crohn's disease comprising administering to a subject in need of the method 100 mg to 1000 mg of the piperidine-2,6-dione derivative described in the present disclosure or a medicament thereof Accepted salt.
  • Certain embodiments disclose a method of treating Crohn's disease comprising administering to a subject in need of the method 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 described in the present disclosure or a pharmaceutically acceptable salt thereof.
  • Certain embodiments disclose methods of treating Crohn's disease, wherein Crohn's disease is mild Crohn's disease, moderate Crohn's disease, severe Crohn's disease, or remission period Crohn Disease.
  • Certain embodiments disclose methods of treating Crohn's disease, wherein the individual in need of the method is a mammal.
  • Certain embodiments disclose methods of treating Crohn's disease, wherein the individual in need of the method is a human.
  • Certain embodiments disclose a method of maintenance therapy for Crohn's disease comprising administering to a subject in need of such a method a therapeutically effective amount of a piperidine-2,6-dione derivative or a medicament thereof as described in the present disclosure An acceptable salt or a therapeutically effective amount of the pharmaceutical composition described in the present disclosure.
  • Certain embodiments disclose methods of treating Crohn's disease, wherein the piperidine-2,6-dione derivative or a pharmaceutically acceptable salt thereof described in the present disclosure is orally administered or contains the presently described A pharmaceutical composition of a piperidine-2,6-dione derivative or a pharmaceutically acceptable salt thereof.
  • Certain embodiments disclose a method of treating Crohn's disease, wherein the piperidine-2,6-dione derivative or a pharmaceutically acceptable salt thereof described in the present disclosure is orally administered in the form of a solid preparation or a liquid preparation or A pharmaceutical composition comprising the piperidine-2,6-dione derivative described in the present disclosure or a pharmaceutically acceptable salt thereof.
  • solid preparations that can be used in the methods of the present disclosure for treating Crohn's disease include, but are not limited to, tablets, capsules, and sugar pills.
  • Illustrative examples of tablets that can be used in the methods of the present disclosure for treating Crohn's disease include, but are not limited to, plain tablets, sugar coated tablets, and film coated tablets.
  • liquid formulations that can be used in the methods of the present disclosure for treating Crohn's disease include, but are not limited to, solutions and suspensions.
  • certain embodiments disclose piperidine-2,6-dione derivatives and pharmaceutically acceptable salts thereof for use in the treatment of Crohn's disease.
  • compositions for treating Crohn's disease comprising a piperidine-2,6-dione derivative or a pharmaceutically acceptable salt thereof described in the present disclosure, and A pharmaceutically acceptable carrier, diluent or excipient.
  • the piperidine-2,6-dione derivatives described in the present disclosure have a good therapeutic effect.
  • the piperidine-2,6-dione derivatives described in the present disclosure have better safety.
  • piperidine-2,6-dione derivatives described in the present disclosure are more tolerant.
  • compositions comprising a piperidine-2,6-dione derivative or a pharmaceutically acceptable salt thereof described in the present disclosure, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the route of administration of the piperidine-2,6-dione derivative described herein in the treatment of Crohn's disease to a mammal can be a parenteral route.
  • the route of administration of the piperidine-2,6-dione derivative described herein in the treatment of Crohn's disease to a mammal can be an oral route.
  • the route of administration of the piperidine-2,6-dione derivative described herein in the treatment of Crohn's disease to a mammal can be in the intrarectal route.
  • the piperidine-2,6-dione of the present disclosure may be obtained in any suitable form such as tablets, capsules, powders, oral solutions, suspensions, rectal gels, rectal foams, rectal enemas or rectal suppositories, and the like. derivative.
  • suitable form such as tablets, capsules, powders, oral solutions, suspensions, rectal gels, rectal foams, rectal enemas or rectal suppositories, and the like. derivative.
  • Illustrative examples of such tablets include, but are not limited to, plain tablets, sugar coated tablets, and film coated tablets.
  • Examples of pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present disclosure include, but are not limited to, any adjuvants, carriers, excipients, aids that have been approved by the U.S. Food and Drug Administration for use in humans or animals. Flowing agents, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, osmotic pressure agents, solvents or emulsifiers, etc.
  • Various forms of carriers that have no side effects on the composition of the pharmaceutical composition are well known in the pharmaceutical arts and are for example found in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990). The description is hereby incorporated by reference in its entirety.
  • the pharmaceutical composition of the present disclosure can be administered by any method that achieves its intended purpose.
  • administration can be by oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intra-articular, intraspinal, transtracheal, transocular, subcutaneous, intraperitoneal, transdermal or oral. get on.
  • the route of administration may be a parenteral route, an oral route, and an intrarectal route.
  • the dosage administered will depend on the age, health and weight of the recipient, and, if concurrent, depends on the type of concurrent treatment, the frequency of treatment, and the nature of the desired effect.
  • Suitable dosage forms include, but are not limited to, capsules, tablets, pellets, drages, semisolid preparations, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, lozenges. , gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, emulsions, which may be prepared according to methods known in the art.
  • Particularly suitable for oral administration are ordinary tablets (primary tablets), sugar-coated tablets, film-coated tablets, pills, capsules, powders, granules, syrups, juices or drops, suitable for rectal administration, suppositories, suitable Parenteral administration is a solution, an oil-based solution or an aqueous solution, in addition to a suspension, emulsion or implant, and suitable for topical use are ointments, creams or powders.
  • the product of the present disclosure may also be lyophilized, and the resulting lyophilizate is used, for example, to prepare an injection.
  • the formulations given may be sterilized and/or contain adjuvants such as wetting agents, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for varying osmotic pressure, buffer substances, Dyestuffs, flavoring agents and/or numerous additional active ingredients, such as one or more vitamins.
  • adjuvants such as wetting agents, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for varying osmotic pressure, buffer substances, Dyestuffs, flavoring agents and/or numerous additional active ingredients, such as one or more vitamins.
  • compositions of the present disclosure are prepared as tablets, solutions, granules, patches, for parenteral, transdermal, mucosal, nasal, buccal, sublingual or oral use. Ointment, capsule, aerosol or suppository.
  • Preservatives can be provided in the pharmaceutical compositions.
  • sodium benzoate, ascorbic acid, and an ester of p-hydroxybenzoic acid can be added as a preservative.
  • antioxidants and suspending agents can be used.
  • alcohols, esters, sulfated aliphatic alcohols, and the like can be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicate, magnesium aluminate , magnesium aluminate aluminate, synthetic aluminum silicate, calcium carbonate, calcium hydrogencarbonate, calcium hydrogen phosphate, calcium hydroxymethyl cellulose, etc. can be used as an excipient; magnesium stearate, talc, hardened oil, etc.
  • coconut oil olive oil, sesame oil, peanut oil, soybean can be used as a suspension or lubricant; vinegar cellulose as a derivative of sugars such as cellulose or sugar, or as a derivative of polyethylene
  • a methyl acetate-methacrylate copolymer of the substance can be used as a suspension; and a plasticizer such as a phthalate ester can be used as a suspension.
  • Suitable routes of administration may, for example, include oral administration, rectal administration, transmembrane administration, parenteral delivery, topical administration or enteral administration; parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary. Injection and intrathecal injection, direct intraventricular injection, intraperitoneal injection, intranasal injection or intraocular injection.
  • the compound can also be extended and/or timed at a predetermined rate in a sustained release or controlled release dosage form including depotinjections, osmotic pumps, pills, transdermal (including electromigration) patches, and the like. Pulse administration.
  • compositions of the present disclosure can be produced in a known manner, for example, by conventional methods of mixing, dissolving, granulating, making tablets, grinding, emulsifying, encapsulating, entrapping or tableting.
  • the pharmaceutical composition used can be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants, which facilitate the treatment of the active compound into A pharmaceutically acceptable formulation.
  • physiologically acceptable carriers comprising excipients and adjuvants, which facilitate the treatment of the active compound into A pharmaceutically acceptable formulation.
  • suitable formulations will depend on the route of administration chosen. Any of the well-known techniques, carriers, and excipients can be used as appropriate and understood in the art.
  • the injection can be prepared in the following conventional form: as a solution or suspension, a solid dosage form suitable as a solution or suspension prior to injection, or as an emulsion.
  • Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride and the like.
  • the injectable pharmaceutical compositions may contain minor amounts of non-toxic adjuvants such as wetting agents, pH buffering agents and the like.
  • Physiologically suitable buffers include, but are not limited to, Hank's solution, Ringer's solution, or physiological saline buffer.
  • Absorption enhancing formulations e.g., liposomes
  • the compounds can be readily formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art.
  • a carrier enables the compound of the present invention to be formulated into tablets, pills, troches, capsules, liquids, gels, syrups, ointments, suspensions, solutions, powders and the like.
  • the pharmaceutical preparations for oral administration are obtained by mixing the active compound with a solid excipient, arbitrarily grinding the resulting mixture and processing the mixture of granules, if necessary, by adding a suitable adjuvant to obtain a tablet or lozenge core.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, a Cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone (PVP).
  • a disintegrating agent such as crosslinked polyvinylpyrrolidone, agar or alginic acid or alginate such as sodium alginate may be added if necessary.
  • the coating core is suitably coated.
  • a concentrated sugar solution may optionally be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer A solution and a suitable organic solvent or solvent mixture.
  • a dye or pigment may be added to the tablet or lozenge coating.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions, and suitable Organic solvent or solvent mixture.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol.
  • the push-fit capsules can comprise the active ingredient in admixture with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate, and optionally a stabilizer.
  • the active ingredient can be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin or liquid polyethylene glycol.
  • a stabilizer may be added. All formulations for oral administration should achieve a dosage suitable for such administration.
  • compositions of the present disclosure may comprise from 0.1% to 95% of the piperidine-2,6-dione derivative described herein or a pharmaceutically acceptable salt thereof.
  • compositions of the present disclosure may comprise from 1% to 70% of the piperidine-2,6-dione derivative described herein or a pharmaceutically acceptable salt thereof.
  • composition or formulation to be administered will contain an amount of a piperidine-2,6-dione derivative described herein, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the treated Subject disease/condition.
  • the at least one compound described in the present disclosure or a pharmaceutical composition comprising at least one compound described in the present disclosure can be subjected to any suitable systemic and/or topical delivery of any of the compounds described in the present disclosure.
  • the method is administered to the patient.
  • Non-limiting examples of methods of administration include (a) administration by the oral route, including administration in the form of capsules, tablets, granules, sprays, syrups, or the like; (b) by non- Oral administration, for example, rectal, vaginal, intraurethral, intraocular, intranasal or intraaural, the administration includes an aqueous suspension, an oily preparation, or the like, or in the form of drops, sprays, suppositories, ointments, ointments, and the like.
  • compositions suitable for administration include those in which an effective amount of the active ingredient is included in such compositions.
  • the dose required for a therapeutically effective amount of the pharmaceutical composition described in this disclosure depends on the route of administration, the type of animal being treated, including the human, and the physical characteristics of the particular animal in question. The dosage can be adjusted to achieve the desired effect, but this will depend on factors such as body weight, diet, concurrent medical therapy, and other factors recognized by those skilled in the medical arts. More specifically, a therapeutically effective amount refers to an amount of a compound that is effective to prevent, alleviate or ameliorate the symptoms of the disease, or to prolong the life of the individual being treated. The actual ability of a person skilled in the art can well determine a therapeutically effective amount, particularly in accordance with the detailed disclosure provided by the present disclosure.
  • the dosage and specific mode of administration for in vivo administration will vary depending on the age, weight and type of mammal being treated, the particular compound employed, and the compound employed. Specific use. Those skilled in the art will be able to achieve the objective of determining an effective dosage level, i.e., the dosage level necessary to achieve the desired effect, using conventional pharmacological methods. Typically, human clinical application of the product begins at a lower dosage level as the dosage level increases until the desired effect is achieved. Alternatively, an established in vitro study can be used to establish an effective dosage and route of administration of the compositions identified by the methods using established pharmacological methods.
  • the application of potential products begins at a higher dose level, as the dose is reduced until the desired effect is no longer achieved or the undesirable side effects disappear.
  • the dosage range can be broader depending on the desired effect and therapeutic indication.
  • the dosage can be from about 10 [mu]g/kg body weight to 1000 mg/kg body weight, and in certain embodiments from about 100 [mu]g/kg body weight to 300 mg/kg body weight.
  • the dosage can be based on and calculated from the body surface area of the patient.
  • each physician can select the exact formulation, route of administration and dosage of the pharmaceutical compositions described in this disclosure based on the condition of the patient.
  • the dosage of the composition administered to the patient can range from about 0.5 mg/kg to 1000 mg/kg of patient body weight.
  • the dose may be administered once or two or more times during one or several days depending on the needs of the patient.
  • the human dosage of the compound is established by at least some of the conditions, the present disclosure will use those same dosages, or dosages ranging from about 0.1% to 500% of the determined human dose, in certain embodiments the dosage. The range of 25% to 250% of the determined human dose.
  • suitable human doses can be inferred from half effective doses or median values of infectious doses, or other suitable values from in vitro or in vivo studies, as in animals. Quantitative by the Institute for Toxicity Research and Performance.
  • the attending physician will know how and when to terminate, interrupt or adjust the administration. Conversely, if the clinical response is inadequate (excluding toxicity), the attending physician will also know to adjust the treatment to a higher level.
  • the size of the administered dose in the treatment of the condition of interest will vary with the severity of the condition being treated and the route of administration. The severity of the disease state can be assessed, for example, in part by standard prognostic evaluation methods.
  • the dosage and possible dosage frequency will also vary depending on the age, weight, and response of the individual patient. A protocol comparable to the above discussed protocol can be used in veterinary medicine.
  • the daily dosing regimen for an adult patient is, for example, an oral dose of from 0.1 mg to 2000 mg of each active ingredient, and in certain embodiments from 1 mg to 2000 mg of each active ingredient, for example from 5 mg to 1500 mg of each active ingredient.
  • the intravenous, subcutaneous or intramuscular dose of each active ingredient used is from 0.01 mg to 1000 mg, and in certain embodiments from 0.1 mg to 1000 mg, such as from 1 mg to 800 mg.
  • the dosage can be calculated as the free base.
  • the composition is administered from 1 to 4 times daily.
  • compositions described in this disclosure may be administered by continuous intravenous infusion, in certain embodiments at doses up to 2000 mg of each active ingredient per day.
  • doses up to 2000 mg of each active ingredient per day.
  • the compound is administered during continuous treatment, such as one week or weeks, or months or years.
  • the dose and dosing interval can be adjusted individually to provide a plasma level sufficient to maintain an adjustment effect or an active fraction of the lowest effective concentration (MEC).
  • MEC lowest effective concentration
  • the MEC of each compound is different, but the MEC can be evaluated from in vitro data.
  • the dosage required to achieve MEC will depend on the individual characteristics and route of administration. However, plasma concentration can be determined using HPLC (High Performance Liquid Chromatography) assay or bioassay.
  • the medication interval can also be determined using the MEC value. Treatments that maintain plasma levels above the MEC over a period of 10-90% of the time, in some embodiments, 30-90% of the time, and in some embodiments, 50-90% of the time should be used.
  • the regimen is administered to the composition.
  • the effective local concentration of the drug is independent of plasma concentration.
  • the amount of the composition to be administered depends on the individual to be treated, depending on the weight of the individual, the severity of the pain, the mode of administration, and the judgment of the prescribing physician.
  • the potency and toxicity of the compounds described in this disclosure can be assessed using known methods.
  • the toxicology of a particular compound or a subset of such compounds that share certain chemical moieties such as a mammalian cell line and, in certain embodiments, a human cell line
  • the toxicology of a particular compound or a subset of such compounds that share certain chemical moieties can be established by measuring the toxicity of the cell line in vitro.
  • the results of such studies are generally predictive of toxicity in animals such as mammals, or more specifically, toxicity in humans.
  • the toxicity of a particular compound in an animal model such as a mouse, rat, rabbit or monkey can be determined using known methods.
  • the efficacy of a particular compound can be determined using a number of accepted methods, such as in vitro methods, animal models, or human clinical trials.
  • the composition can be placed into a pack or dispenser device, which can contain one or more unit dosage forms containing the active ingredient.
  • the package may for example comprise a metal or plastic foil, such as a blister pack.
  • the pack or dispenser device can be provided with instructions for administration.
  • the packaging or dispensing device may also carry precautions associated with the container, the precautions being prescribed by a government agency that manages the manufacture, use or sale of the drug, the precaution reflecting that the drug form has been Approved for human or veterinary administration. Such considerations, for example, may be labels for prescription drugs approved by the State Food and Drug Administration or the US Food and Drug Administration, or approved product specifications.
  • Compositions comprising a compound of the invention may also be prepared in a suitable container, placed in a compatible pharmaceutical carrier, and labeled for treatment in a defined disease state.
  • LPS bacterial lipopolysaccharide
  • PBS phosphate buffer
  • Tween-20 Tween-20
  • PBST 0.05% Tween-20 in phosphate buffer solution
  • HRP horseradish peroxidase
  • TMB 3,3',5,5'-tetramethylbenzidine
  • DSS sodium dextran sulfate
  • 5-ASA 5-aminosalicylic acid
  • CMC-Na sodium carboxymethylcellulose
  • 1% CMC-Na an aqueous solution having a CMC-Na concentration of 1% (w/v);
  • DSS an aqueous solution having a DSS concentration of 1.6% (w/v);
  • DSS an aqueous solution having a DSS concentration of 0.9% (w/v);
  • Mg/kg mg/kg
  • Mg/kg/d mg/kg/day
  • Mean ⁇ SD mean ⁇ standard deviation
  • 30% ethanol an aqueous solution having an ethanol concentration of 30% (v/v);
  • OD value optical density value
  • Mm micron
  • Example 4 Using the synthesis method of Example 4, reacting 4-nitrophthalic anhydride with 1-(2-methoxyethyl)-3-amino-2,6-piperidinone acetate to obtain 5 -Nitro-2-(1-(2-methoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindoline-1,3-dione. 2.8 g of a white solid product (HPLC purity 99.62%) was obtained; yield 54.5. MS (m / e): 384.18 (M + Na + ).
  • Dimethyl 4-benzyloxy-3-nitrophthalate (30 g) and ethanol (300 ml) were added to the reaction flask to dissolve the pre-formed aqueous sodium hydroxide solution (24 g of sodium hydroxide). It was added to the reaction flask in 300 ml of water, heated to 70 ° C in an oil bath, and stirred for 7 hours, and the reaction was completed. The reaction system was cooled to room temperature, and concentrated under reduced pressure to a large portion of ethanol.
  • Tetrahydrofuran 100 ml was argon-protected, cooled to -78 ° C, and lithium hexamethyldisilazide (40 ml) was slowly added dropwise, and stirring was continued for 1 h.
  • N-fluorobisbenzenesulfonamide 11.67 g in 30 ml of tetrahydrofuran was added, and after stirring for 1 h, it was slowly warmed to room temperature and allowed to react overnight.
  • 3-Amino-3-methylpiperidine-2,6-dione hydrochloride was prepared by the method of PCT Int. Appl., 2006081251, 03Aug 2006.
  • N-((Benzyloxy)carbonyl)-glutamic anhydride was prepared by the method of Archives of Pharmacal Research, 31 (7), 834-837; 2008.
  • the crude product was obtained as a brown oily product, 1-(2-ethoxyethyl)-3-benzyloxylamino-2, from N-((benzyloxy)carbonyl)-glutamic acid. , 6-piperidinone 17.2 g.
  • Example 4 Using the synthesis method of Example 4, reacting 1-(2-ethoxyethyl)-3-amino-2,6-piperidinedione acetate with 3-nitrophthalic anhydride to obtain 4 -Nitro-2-(1-(2-ethoxyethyl)-2,6-dioxopiperidin-3-yl)-isoindoline-1,3-dione off-white solid product 1.326 g ( HPLC purity 95.24%); yield 39.4%. MS (m / e): 376.23 (M + H + ).
  • Example 4 Using the synthesis method of Example 4, the title compound was obtained from the reaction of 1-(2-ethoxyethyl)-3-amino-2,6-piperidinedione acetate and 3-fluorophthalic anhydride. The thick product was 1.566 g (HPLC purity 98.63%); the yield was 74.7%.
  • Example 4 Using the synthesis method of Example 4, the title compound was obtained by reacting 4-fluorophthalic anhydride with 1-(2-methoxyethyl)-3-amino-2,6-piperidinedione acetate. White solid product 2.905 g (HPLC purity 99.64%); yield 77.9%.
  • Example 4 Using the synthesis method of Example 4, the title compound was obtained by reacting 3-hydroxyphthalic anhydride with 1-(2-methoxyethyl)-3-amino-2,6-piperidinedione acetate. White solid product 2.833 g (HPLC purity 99.54%); yield 80.1%.
  • Example 4 Using the synthesis method of Example 4, the title was obtained by reacting 3-methylphthalic anhydride with 1-(2-methoxyethyl)-3-amino-2,6-piperidinedione acetate. Compound white solid product 2.234 g (HPLC purity 98.36%); yield 68.1%.
  • 3-Nitrophthalic anhydride (5g, 25.9mmol), L-glutamine (3.782g, 25.9mmol), 45ml acetonitrile in a 100ml three-necked bottle, protected by argon, magnetically stirred, refluxed at 90 ° C
  • the reaction was carried out for 14 hours, and the temperature was lowered.
  • N,N'-carbonyldiimidazole (12.591 g, 77.7 mmol) was added at room temperature, stirred at room temperature until no bubbles were released, and the reaction was further carried out in an oil bath at 84 ° C for 1 hour to stop heating.
  • reaction solution was added to 225 ml of 1 mol/L hydrochloric acid with vigorous stirring, stirred, and filtered.
  • the obtained cake was beaten with 25 ml of absolute ethanol, filtered, and the obtained solid was vacuum dried to obtain a yellow product 2-(2,6- 5-oxopiperidin-3-yl)-4-nitroisoindoline-1,3-dione 5.125 g, yield 65.3%.
  • the title compound can also be prepared by referring to the preparation method of Example 26 using 3-bromoethyl methyl ether instead of 3-bromopropyl methyl ether.
  • 1 H NMR (CDCl 3 , 600 MHz) ⁇ 7.38 (t, 1H), 7.11 (d, 1H), 6.85 (d, 1H), 5.30 (bs, 2H), 4.95 - 4.98 (m, 1H), 4.09 - 4.13 (m, 1H), 4.00-4.04 (m, 1H), 3.52-3.54 (m, 2H), 3.34 (s, 3H), 2.96-2.99 (m, 1H), 2.76-2.75 (m, 1H), 2.78 -2.80 (m, 1H), 2.08-2.11 (m, 1H).
  • mice Wistar rats, male, weighing 100-120 g.
  • mice 90 male Wistar rats were fasted for 40 hours, 5% glucose injection was given by subcutaneous injection during fasting, and 60 normal and moderately sized rats were selected from fasted rats. Animals were weighed by weight. They were randomly divided into 6 groups: normal control group, model control group, sulfasalazine group (300 mg/kg), and Example 27, respectively, with 5, 15 and 30 mg/kg dose groups, 10 in each group.
  • the corresponding drug or the corresponding volume of 1% CMC-Na was administered 4 hours after induction from DNBS, once a day, body weight was recorded and fecal traits were scored, and treated on the 6th day of the experiment. Animals take colon tissue to observe each indicator knot fruit.
  • Example 27 Sulfasalazine: Preparation method: suspension with 1% CMC-Na, ready to use.
  • the animals were observed to observe the results of each index. After the animals were sacrificed, the colon was taken, the degree of colon adhesion was observed, and the length of the colon was measured. After the colon contents were removed, the ulcer area was calculated and the weight of the colon tissue was weighed. The colon tissue was divided into two in the longitudinal direction, and half of the colon tissue was fixed in a 10% formalin solution for later use. After the other half of the colon tissue was frozen in liquid nitrogen, the transfer was stored at -80 ° C for use in the detection of MPO.
  • the ulcer area calculation method the length of the ulcer point (cm) ⁇ the width of the ulcer point (cm).
  • the frozen tissue was ground to a powder, and the amount was weighed.
  • the mixture was weighed according to 25 mg/ml plus 50 mM potassium phosphate buffer (containing 0.5% cetyltrimethylammonium bromide), and homogenized by an electric homogenizer.
  • a 1 ml suspension was centrifuged to remove the supernatant. 7 ⁇ l supernatant was added to take a 96 well plate, together with 200 ⁇ l o-dianisidine mixture (containing 0.167mg / ml o-dianisidine and 0.0006% H 2 O 2 Potassium phosphate buffer), placed in a microplate reader 450nm Detection 0, 30, 60,
  • Data statistical analysis method The data variance homogeneity test was performed using Spss13.0. If the data variance is homogeneous (P>0.05), the one-way ANOVA LSD test is performed; if the data variance analysis is significant (P ⁇ 0.05), then Dunnett's multiple comparison (parameter method) or Kruskal-Wallis nonparametric test. If the Kruskal-Wallis nonparametric test results are significant (P ⁇ 0.05), the Mann-Whitney U test is further used for pairwise comparison.
  • Example 27 can reduce the degree of colon ulcer at a dose of 30 mg/kg, and reduce the ulcer area by about 80%.
  • the MPO activity of colon tissue was significantly decreased (P ⁇ 0.05), and its therapeutic effect was better than that of the positive drug sulfasalazine-300 mg/kg.
  • mice 110 male Wistar rats were fasted for 40 hours, 5% glucose injection (10 ml/kg) was given by subcutaneous injection during fasting, and 48 normal and moderate weight were selected from fasted rats. Rats were randomly divided into 5 groups according to body weight: normal control group, model control group, sulfasalazine group (300 mg/kg), dexamethasone group (0.1 mg/kg), and Example 26 group (30 mg). /kg), Example 27 (30 mg/kg), 8 per group.
  • Animals were anesthetized with isoflurane and specially filled with a special gastric applicator (Note: a 2 mm diameter rat grate nested on a 1 mm diameter mouse gavage), gently inserted by the anus In the intestinal cavity at 8 cm, the model control group, the Example 26 group, and the Example 27 group were respectively injected with 50 mg/ml DNBS in 30% ethanol solution 0.5 ml, and the normal control group was injected with 30% ethanol 0.5 ml, and the animals were enema after enema removal. The applicator was inverted for 15 minutes under anesthesia.
  • the corresponding drug or the corresponding volume of 1% CMC-Na was administered intragastrically 4 hours after induction from DNBS, and once a day, the animals were treated on the 6th day of the experiment to observe the results of each index.
  • the degree of colon adhesion was scored, the length of the colon and the area of the ulcer were measured, the weight of the colon was weighed, and the ratio of colon weight to length was calculated.
  • Example 26 Example 27, sulfasalazine and dexamethasone: Preparation method: suspension with 1% CMC-Na, ready to use.
  • the Mann-Whitney U test performs a pairwise comparison.
  • the results of this experiment showed that the growth rate of the animals induced by DNBS ethanol solution was lower than that of the normal control group.
  • the weight growth rate of the sulfasalazine group, the Example 26 group and the Example 27 group began from the fourth day of the experiment. Higher than the model control animals, the weight gain of the dexamethasone group was slower, which indirectly suggested that each drug could improve the colonic injury of the animals.
  • Colonic index results showed that the colonic ulcer area and colon weight of the model control group were significantly higher than the normal control group (P ⁇ 0.05), and the colon was significantly shortened. Compared with the model control group, there was a significant decrease in the area of colon ulcer in each drug-administered group (P ⁇ 0.05).
  • Example 26 and Example 27 have a better therapeutic effect on the improved model.
  • mice 102 male Wistar rats were fasted for 40 hours, subcutaneously given 5% glucose saline during fasting, and 72 normal and moderately weighted rats were selected from fasting rats. Animals were randomly divided into 9 groups (see Table 9 for a detailed table).
  • the rats were fasted for 40 hours and then anesthetized with ether.
  • the rats were gently inserted into the intestine cavity at 8 cm from the anus.
  • the model control group and each experimental group were injected with 0.5 mg of 50 mg/ml DNBS in 30% ethanol solution.
  • the normal control group was injected with the corresponding volume of 30% ethanol, and the enema of each animal
  • the post-anesthesia state was inverted for 15 min.
  • the day 0 of the experiment the corresponding drug or the corresponding volume of 1% CMC-Na was administered 4 hours after the induction of DNBS, and the body weight was recorded once a day.
  • the animals were treated on the 7th day of the experiment and the colon was adhered to the colon. The degree was scored, the length of the colon and the area of the ulcer were measured, the weight of the colon was weighed, and the ratio of the weight to the colon was calculated.
  • One-WayAnova one-way ANOVA was performed on the length of the colon and the length of the colon per unit length using SPSS22. Statistical analysis was performed between the groups. The adhesion score and the ulcer area were analyzed by non-parametric Mann-Whitney U test. Statistical analysis was performed between.
  • the formula for calculating the weight growth inhibition rate per unit length (model group colon long weight-to-length ratio - administration group colon long weight-to-length ratio) / (model group colon long weight-to-length ratio - blank group colon long weight-to-length ratio).
  • mice 102 male Wistar rats were fasted for 72 hours, and 5% glucose saline was given twice by subcutaneous injection during fasting. 88 rats with normal and moderate body weight were selected from fasting rats. Animals were randomly divided into 11 groups (see Table 13 for a detailed table).
  • the rats were fasted for 72 hours and then anesthetized with ether.
  • the rats were gently inserted into the intestine cavity at 8 cm from the anus.
  • the model control group and each experimental group were injected with 0.5 mg of 50 mg/ml DNBS in 30% ethanol.
  • the control group was injected with the corresponding volume of 30% ethanol, and the animals were anesthetized and inverted for 15 min after enema.
  • On the day of the model preparation the day 0 of the experiment, 4 hours after the induction of DNBS, the corresponding drug or the corresponding volume of 1% CMC-Na was administered, once a day, daily. Animal weights were recorded and animals were treated on day 7 of the experiment, the degree of colon adhesion was scored, colon length and ulcer area were measured, colon weight was weighed and colon weight to length ratio was calculated.
  • Each experimental drug was suspended in 1% CMC-Na and configured as a 3 mg/ml homogeneous suspension at a dose of 10 ml/kg. I.g.: gavage; qd ⁇ 7: once a day for 7 days.
  • One-WayAnova one-way ANOVA was performed on the length of the colon and the length of the colon per unit length using SPSS22. Statistical analysis was performed between the groups. The adhesion score and the ulcer area were analyzed by non-parametric Mann-Whitney U test. Statistical analysis was performed between.
  • the formula for calculating the weight growth inhibition rate per unit length (model group colon long weight-to-length ratio - administration group colon long weight-to-length ratio) / (model group colon long weight-to-length ratio - blank group colon long weight-to-length ratio).
  • mice were fasted one day before the experiment. On the day of the experiment, 6 mice (ICR mice, weighing 19-21 g, and 3 females) were selected for each experimental group. First, select one male and one animal for oral gavage at 1000mg/kg for 5-10 minutes. If there is no obvious side effects, the remaining 4 animals will be orally administered according to this dose for 10-15 minutes. The boxes were kept in balanced 7 days, and the state was observed daily and the body weight was recorded. The animal grouping plan and initial dose of the drug are shown in the following table:
  • observation index 0-15 minutes after administration
  • Nervous system response tremor, convulsion, abnormal movement disorder, etc.
  • Autonomic nerve eyeball protruding salivation, tearing urination (hematuria), diarrhea, vertical hair breathing, etc.
  • Animal status lethargy, hyperactivity, excitatory hair loss, diarrhea, abnormal behavior, etc.
  • mice The animals in each group showed slight fluctuations in body weight. At 1000 mg/kg, each compound had no adverse effect on the body weight changes of mice.

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Abstract

公开了哌啶-2,6-二酮衍生物、其药物组合物及在治疗克罗恩氏病中的用途。

Description

哌啶-2,6-二酮衍生物以及克罗恩氏病的治疗
相关申请
本公开要求2016年11月24日向中华人民共和国国家知识产权局提交的申请号为201611041317.5、发明名称为“哌啶-2,6-二酮衍生物在治疗炎症性肠病中的应用”的发明专利申请的全部权益，并通过引用的方式将上述发明专利申请的全部内容并入本公开。
领域
本公开涉及有机化学与药物化学领域。
背景
克罗恩氏病(Crohn’s disease,克罗恩氏病)是一种胃肠道(GI)的慢性炎症性自身免疫疾病。克罗恩氏病可以影响从口腔到肛门之间消化道的任何部位。显微镜下，克罗恩氏病影响整个肠壁(透壁的损伤)。慢性炎症在克罗恩氏病患者亚组中可导致纤维化，具有并发症，包括狭窄和瘘，并更可能需要反复手术。克罗恩氏病与提高的胃肠道恶性肿瘤风险相关。克罗恩氏病经研究发现，克罗恩氏病与TH1(type 1 T helper cell，1型辅助细胞)、TH17(type 17 T helper cell，17型辅助细胞)介导的细胞免疫有关。
克罗恩氏病临床表现呈多样化，包括消化道表现、全身表现、肠外表现以及并发症。消化道表现主要为腹泻、腹痛，可有血便；全身表现主要为体重减轻、发热、食欲不振、疲劳、贫血等，青少年患者可见生长发育迟缓；并发症常见瘘管、腹腔脓肿、肠狭窄和梗阻、肛周病变，消化道大出血、急性穿孔较少见，病程长者可发生癌变。结肠镜检一般表现为节段性、非对称性的各种黏膜炎症，其中具有特征的表现为非连续性病变、纵行溃疡和鹅卵石样外观。克罗恩氏病黏膜活检标本的组织病理学改变主要有：①固有膜炎性细胞呈局灶性不连续浸润；②裂隙状溃疡；③阿弗他溃疡；④隐窝结构异常，腺体增生，个别隐窝脓肿，黏液分泌减少不明显，可见幽门腺化生或潘氏细胞化生；⑤非干酪样坏死性肉芽肿；⑥以淋巴细胞和浆细胞为主的慢性炎性细胞浸润，以固有膜底部和粘膜下层为重，常见淋巴滤泡形成；⑦粘膜下淋巴管扩张；⑧神经节细胞增生和(或)神经节周围炎。
轻度活动期克罗恩氏病治疗以5-氨基水杨酸类和布地奈德为主，治疗无效则视为中度活动期克罗恩氏病；中度活动期克罗恩氏病治疗药物首选激素(如地塞米松)，无效或依赖后考虑与硫巯嘌呤类或甲氨蝶呤合用；TNF-α单抗用于上述激素和免疫治疗无效或不能耐受者。重度活动期克罗恩氏病以全身激素、TNF-α单抗和手术治疗为主。缓解期维持治疗的药物包括5-氨基水杨酸类、硫巯嘌呤类和TNF-α单抗。
5-氨基水杨酸类药物(如柳氮磺吡啶和美沙拉嗪)使用过程发现，50％左右的患者发现呕吐、食欲不振和肝功能障碍等消化器官障碍，溶血性贫血和叶酸缺乏性贫血等血液系统障碍。另外，因为具有水杨酸骨架，所以，在对水杨酸类药剂显示过敏症状的病例中有出现副作用的可能性，如腹泻、腹痛、淀粉酶上升和肾功能障碍等。另外，因为发现柳氮磺吡啶有男性不育和尿带色的副作用，所以，对患者也造成精神上大的压力。由于免疫抑制和短期见效的特性，布地奈德或硫唑嘌呤也可以使用，但是只能短期使用，停用生物制剂会导致疾病的反复发作，增加疾病的难治性。而且生物制剂也会给患者带来较大的经济负担。单抗类药物(如英夫利昔单抗和阿达木单抗)则可能出现高血压、畏寒、发疹、发热、头痛、湿疹等。由于英夫利西是嵌合型抗体，有显示抗原性的可能性，有时引起急性超过敏反应。
小分子TNF-α抑制剂例如来那度胺、沙利度胺，经证实并不能用于有效的治疗克罗恩氏病。(详见C.Yang et,Aliment Pharmacol Ther 2015；41:1079-7093)
而且，克罗恩氏病是一种慢性疾病，需要较长的药物持续时间。以上数据表明还没有可长期有效的治疗克罗恩氏病的药物，尤其是通过口服给药的药物。因此，存在发展针对慢性用途优化的靶向性更强的克罗恩氏病疗法的需求；或者有效性更好的药物或安全性更好的药物。
概述
二硝基苯磺酸(DNBS)或三硝基苯磺酸(TNBS)诱导的炎症性模型被广泛用于克罗恩氏病产生机理的研究及克罗恩氏病治疗药物的开发评估。具体可见参考文献：TNBS诱导的大鼠炎症性肠病模型的建立，J.Med.Res.,July 2008,Vol 37No.7。本文通过引用的方式将上述参考文献的全部内容并入本文。
小分子TNF-α抑制剂例如来那度胺、沙利度胺，经证实并不能有效的治疗克罗恩氏病。(详见C.Yang et,Aliment Pharmacol Ther 2015；41:1079-7093.)
一方面，某些实施方案公开了式(I)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐：
Figure PCTCN2017112669-appb-000001
其中，
R1表示一个或多个H、卤素、-OH、-C1-4烷基、-NH2、-NH C1-4烷基、-N(C1-4烷基)2或-NHCOC1-4烷基；
R2表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；以及
R3表示-H或-C1-4烷基。
另一方面，某些实施方案公开了式(II)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐：
Figure PCTCN2017112669-appb-000002
其中，
R4表示一个或多个H、卤素、-C1-4烷基、-NH2、-NHC1-4烷基、-N(C1-4烷基)2、-NHCOC1-4烷基；
R5表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；
R6表示-S-、-SO-、-SO2-、-NH-或-N(C1-4烷基)-；以及
R7表示-H或-C1-4烷基。
又一方面，某些实施方案公开了式(III)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐：
Figure PCTCN2017112669-appb-000003
其中，
R8表示一个或多个H、卤素、-C1-4烷基、-NH2、-NHC1-4烷基、-N(C1-4烷基)2、-NHCOC1-4烷基；
R9表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；
R10表示-O-、-S-、-SO-、-SO2-、-NH-或-N(C1-4烷基)-；
R11表示-H或-C1-4烷基；以及
R11表示卤素、-C1-4烷基。
上述式(I)、式(II)和式(III)所示的化合物均属于本公开中所述的哌啶-2,6-二酮衍生物。
再一方面，某些实施方案公开了哌啶-2,6-二酮衍生物及其药物可接受的盐，其选自：
4-乙酰基氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-甲基氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-二甲氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氟-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4,5,6,7-四氟-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-羟基乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
5-氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-5-羟基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-5-氟-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-7-羟基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-甲基硫乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-甲基亚磺酰乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-甲基磺酰基乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-甲氧乙基)-3-氟-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-甲氧乙基)-3-甲基-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-乙酰氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氟-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
5-氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-乙氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氟基-2-(1-(2-乙氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
5-氟-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-甲氧丁基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-羟基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-甲基-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二及其药物可接受的盐；
4-氨基-5-甲氧基-2-(1-(2-甲氧基乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；以及
4-氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐。
另一方面，某些实施方案公开了药物组合物，其包含本公开中所述的哌啶-2,6-二酮衍生或其药物可接受的盐，以及药物可接受的载体、稀释剂或赋形剂。
又一方面，某些实施方案公开了治疗克罗恩氏病的方法，其包括对需要所述方法的个体给予治疗有效量的本公开中所述的哌啶-2,6-二 酮衍生物或其药物可接受的盐或治疗有效量的本公开中所述的药物组合物。
再一方面，某些实施方案公开了用于治疗克罗恩氏病的哌啶-2,6-二酮衍生物及其药物可接受的盐。
另一方面，某些实施方案公开了用于治疗克罗恩氏病的药物组合物，其包含本公开中所述的哌啶-2,6-二酮衍生或其药物可接受的盐，以及药物可接受的载体、稀释剂或赋形剂。
详述
在以下的说明中，包括某些具体的细节以对各个公开的实施方案提供全面的理解。然而，相关领域的技术人员会认识到，不采用一个或多个这些具体的细节，而采用其他方法、部件、材料等的情况下可实现实施方案。
除非本公开中另外要求，在整个说明书和其后的权利要求书中，词语“包括”和“包含”应解释为开放式的、含括式的意义，即“包括但不限于”。
在整个本说明书中提及的“一实施方案”或“另一实施方案”或“实施方案”或“某些实施方案”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此，在整个说明书中不同位置出现的短语“一实施方案”或“实施方案”或“另一实施方案”不必全部指同一实施方案。此外，具体要素、结构或特征可以任何适当的方式在一个或多个实施方案中结合。
应当理解，在本公开的说明书和所附的权利要求书中用到的单数形式的冠词“一”(对应于英文“a”、“an”和“the”)包括复数的对象，除非文中另外明确地规定。因此，例如提到的包含“哌啶-2,6-二酮衍生物”的药物组合物包括一种哌啶-2,6-二酮衍生物，或两种或多种哌啶-2,6-二酮衍生物。
定义
因此，除非另有相反的说明，否则说明书及所附权利要求中所用的下列术语具有以下的意思：
术语“克罗恩氏病”是一种病因不十分清楚的慢性非特异性肠道免疫炎性疾病。更具体的定义可见参考文献：炎症性肠病诊断与治疗的共识意见(2012年·广州)，《胃肠病学》，2012年第17卷第12期，第763页-第781页。本文通过引用的方式将其全部内容并入本文。。
根据疾病活动严重程度，克罗恩氏病可以是轻度克罗恩氏病、中度克罗恩氏病或重度克罗恩氏病。依据疾病活动性的严重程度，克罗恩氏病可以分为活动期克罗恩氏病或缓解期克罗恩氏病。
克罗恩氏病的治疗目标是诱导活动期的克罗恩氏病进入缓解期 (也就是诱导缓解)和/或维持疾病在缓解期(也就是维持缓解)。
在临床研究中，蒙特利尔CD表型法是一种克罗恩氏病分类方法，具体如下：
表1.克罗恩氏病的蒙特利尔分型
Figure PCTCN2017112669-appb-000004
注：a随着时间推移B1可发展为B2或B3；bL4可与L1、L2、L3同时存在；cp为肛周病变，可与B1、B2、B3同时存在。
在临床上，也可用克罗恩氏病活动指数(CDAI)评估疾病活动性的严重程度及进行疗效评价。可以参考Best CDAI计算法。具体如下：
表2.Best CDAI计算法
Figure PCTCN2017112669-appb-000005
注：a血细胞比容正常值按国人标准；总分＝各项分值之和，CDAI<150分为缓解期，CDAI≥150分为活动期，150-220分为轻度，221-450分为中度，>450分为重度。
按照上述Best CDAI计算法对患者病情进行评分，经评分评价为临床缓解的对应于本公开的缓解期克罗恩氏病，轻度活动对应于本公开的轻度克罗恩氏病，中度活动对应于本公开的中度克罗恩氏病，重度活动对应于本公开的重度克罗恩氏病。
本公开中命名的某些化学基团前面所置的简写符号表示在所指示的化学基团存在的碳原子总数。例如，C1-C4烷基描述如下文所定义的具有总共1至4个碳原子的烷基，而C3-C10环烷基描述如下文所定义的具有总共3至10个碳原子的环烷基。简写符号中的碳总数不包含可能存在于所述基团的取代基中的碳。
术语“卤素”是指氟、氯、溴或碘。
术语“烷基”是指直链或支链的烃链基团，仅由碳与氢原子组成，不含有不饱和键，具有1至12个碳原子，且其通过单键连接至分子的其余部份。在某些实施方案中，烷基具有1至8个碳原子。在某些实施方案中，烷基具有1至6个碳原子。在某些实施方案中，烷基具有1至4个碳原子。烷基的示例性实例包括但不限于甲基、乙基、正丙基、1-甲基乙基(异丙基)、正丁基、正戊基、1,1-二甲基乙基(叔丁基)、3-甲基己基、2-甲基己基等。
术语“哺乳动物”是指包括例如狗、猫、牛、羊、马和人类等的动物。在某些实施方案中，哺乳动物包括人类。
术语“患者”是指动物(例如，人)、伴侣动物(例如，狗、猫或马)和家畜(例如，牛、猪和羊)。在某些实施方案中，患者是包括雄性和雌性的哺乳动物。在某些实施方案中，患者为人类。
本公开所用术语“可药用”或“药物可接受”是指必须与制剂的其它成分相容并且不会对其接受者有害的载体、载剂、稀释剂、赋形剂和/或盐。
“任选的”或“任选地”意为随后描述的事件或状况可以发生也可以不发生，且说明书包括该事件或状况发生的情况及未发生的情况。
“药物可接受的载体、稀释剂或赋形剂”包括但不限于已经被美国食品与药品管理局认可的而可用于人类或动物的任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、香味增强剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗压剂、溶剂或乳化剂等对组成药物组合物无副作用的各种形式的载体。
“药物可接受的盐”包括“可以接受的酸加合盐”和“可以接受的碱加合盐”。
“可以接受的酸加合盐”指保持游离碱的生物学有效性和性质的那些盐，所述酸加合盐是在生物学或其它方面合适的并且是使用无机酸或有机酸来形成的，所述无机酸例如但不限于盐酸、氢溴酸、硫酸、硝酸、磷酸等，所述有机酸例如但不限于乙酸、2,2-二氯乙酸、己二酸、褐藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯羧酸、4-乙酰胺基苯羧酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环己烷基氨基磺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟基乙烷磺酸、甲酸、富马酸、粘酸、龙胆酸、葡庚糖酸、 葡糖酸、葡糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、乙醇酸、马尿酸、异丁酸、乳酸、乳糖醛酸、月桂酸、马来酸、苹果酸、丙二酸、扁桃酸、甲烷磺酸、黏酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、焦谷氨酸、丙酮酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸、十一碳烯酸等。
“可以接受的碱加合盐”指保持游离酸的生物学有效性和性质的那些盐，所述碱加合盐是在生物学或其它方面合适的。向游离酸中加入无机碱或有机碱来制备这些盐。由无机碱衍生的盐包括但不限于钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。在某些实施方案中，无机盐为铵、钠、钾、钙及镁盐。由有机碱衍生的盐包括但不限于伯、仲和叔胺的盐、包括天然存在的取代的胺在内的取代的胺、环胺和碱性离子交换树脂的盐，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明、胆碱、甜菜碱、苄胺、苯乙二胺、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨基丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。在某些实施方案中，有机碱是异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。
术语“溶剂或溶剂混合物”是指任何和所有溶剂。在某些实施方案中，溶剂或溶剂混合物为有机溶剂和水，其包括但不限于甲醇、乙醇、2-丙醇、正丁醇、异丁醇、丙酮、甲基乙基酮、乙酸乙酯、1,4-二噁烷、乙醚、甲基叔丁基醚、四氢呋喃、乙腈、二氯甲烷、氯仿、N,N-二甲基甲酰胺、环己烷、环戊烷、正己烷、正庚烷、正戊烷、甲苯、邻二甲苯、对二甲苯、二甲基亚砜(DMSO)、吡啶、乙酸、苯甲醚、乙酸丁酯、异丙基苯、甲酸乙酯、甲酸、乙酸异丁酯、乙酸异丙酯、乙酸甲酯、3-甲基-1-丁醇、甲基异丁基酮、2-甲基-1-丙醇、1-戊醇、乙酸丙酯、乙二醇和1-甲基-2-吡咯烷酮，以及任何和所有两种或更多种这类溶剂的混合物。在某些实施方案中，溶剂或溶剂混合物为单一溶剂和二元混合物。在某些实施方案中，溶剂或溶剂混合物为水和有机溶剂的单一溶剂以及水和有机溶剂的二元混合物。
“药物组合物”指本公开中所述的化合物与通常被本领域所接受的将生物活化化合物输送至诸如人类等哺乳动物的介质所形成的制剂。这样的介质包括所有药物可接受的载体、稀释剂或赋形剂。
“药物组合物”指本公开中所述的化合物与通常被本领域所接受的将生物活化化合物输送至诸如人类等哺乳动物的介质所形成的制剂。这样的介质包括所有药物可接受的载体、稀释剂或赋形剂。
“治疗有效量”指改善、减弱或消除特定疾病或病况和特定疾病或病况的症状、或者避免或延迟特定疾病或病况或者特定疾病或病况 的症状的发病的化合物或化合物组合的量。根据化合物、疾病状态及其严重性、以及待治疗哺乳动物的年龄、体重等，构成“治疗有效量”的本公开中所述的化合物的量将会不同，但是本领域的技术人员根据其自身的知识以及本公开可以依惯例确定本公开中所述的化合物的量。
本公开所用的“进行治疗”或“治疗”涵盖患有相关疾病或病症的哺乳动物例如人类中治疗相关的疾病或疾病状态，并且包括：
(i)预防疾病或疾病状态在哺乳动物中发生，尤其是当该哺乳动物易感于所述疾病状态，但尚未被诊断出患有这种疾病状态时；
(ii)抑制疾病或疾病状态，即阻止其发生；或者
(iii)缓解疾病或疾病状态，即使疾病或疾病状态消退或不进展。
正如本公开所用的那样，术语“疾病”和“疾病状态”可以相互交换使用，或者可以是不同的，因为特殊的疾病或疾病状态可能并没有已知的致病因子(因此不能用病因学解释)，因此其不被公认为是疾病，而是被认为是不期望的疾病状态或病症，其中临床医生已经鉴定出或多或少的特定系列的症状。
本公开中所述的化合物或其药物可接受的盐可以含一个或多个不对称中心，并且因此可以产生对映异构体、非对映异构体、以及其它立体异构形式，可以根据绝对立体化学将其定义为(R)-或(S)-，或氨基酸的(D)-或(L)-。本公开旨在包括所有这些可能的异构体，以及其外消旋形式和光学纯的形式。可使用手性合成子(chiral synthon)或手性试剂制备旋光的(+)和(-)、(R)-和(S)-、或(D)-和(L)-异构体，或使用常规技术进行拆分，如使用手性柱的HPLC。当本公开中所述的化合物含有烯双键或其它几何不对称中心时，除非另有说明，否则意味着化合物包括E和Z几何异构体。同样，还意味着包括所有的互变异构形式。
“立体异构体”指由相同的键键合的相同的原子组成的，但具有不可互换的不同三维结构的化合物。本公开涵盖各种立体异构体及其混合物。
本公开中所述的化合物取代基编号如下：
Figure PCTCN2017112669-appb-000006
Figure PCTCN2017112669-appb-000007
式(I)中R1的取代位置可以是编号4、5、6、7中的一个位置或者多个位置的组合；式(II)中R4的取代位置可以是位置4、5、6、7中的一个位置或者多个位置的组合；式(III)中R8的取代位置可以是位置4、5、6、7中的一个位置或者多个位置的组合。
参考以下附图、描述和权利要求，本公开的这些特点、方面和优点以及其他特点、方面和优点将变得更易于理解。
具体实施方案
一方面，某些实施方案公开了式(I)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐：
Figure PCTCN2017112669-appb-000008
其中，
R1表示一个或多个H、卤素、-OH、-C1-4烷基、-NH2、-NH C1-4烷基、-N(C1-4烷基)2或-NHCOC1-4烷基；
R2表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；以及
R3表示-H或-C1-4烷基。
某些实施方案公开了式(I)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐，
Figure PCTCN2017112669-appb-000009
其中：
R1表示一个或多个-H、-F、-Cl、-Br、-OH、-CH3、-CH2CH3、-CH2CH2CH3、-NHCH3、-NH2、-NHCH2CH3、-N(CH3)2、-N(CH2CH3)2、-NHCOCH3或-NHCOCH2CH3；
R2表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；以及
R3表示-H、-CH3或-CH2CH3。
某些实施方案公开了式(I)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐，
Figure PCTCN2017112669-appb-000010
其中：
R1表示一个或多个-H、-F、-OH、-CH3、-NHCH3、-N(CH3)2、-NHCOCH3或-NH2；
R2表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；以及
R3表示-H、-CH3或-CH2CH3。
某些实施方案公开了式(I)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐，其选自：
4-乙酰基氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-甲基氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-二甲氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉 -1,3-二酮及其药物可接受的盐；
4-氟-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4,5,6,7-四氟-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-羟基乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
5-氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-5-羟基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-5-氟-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-7-羟基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-乙酰氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氟-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
5-氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-乙氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氟基-2-(1-(2-乙氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
5-氟-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-甲氧丁基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-羟基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-甲基-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二及其药物可接受的盐；
4-氨基-5-甲氧基-2-(1-(2-甲氧基乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；以及
4-氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐。
另一方面，某些实施方案公开了式(II)所示的哌啶-2,6-二酮衍生及其药物可接受的盐：
Figure PCTCN2017112669-appb-000011
其中，
R4表示一个或多个H、卤素、-OH、-C1-4烷基、-NH2、-NHC1-4烷基、-N(C1-4烷基)2或-NHCOC1-4烷基；
R5表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；
R6表示-S-、-SO-、-SO2-、-NH-或-N(C1-4烷基)-；以及
R7表示-H或-C1-4烷基。
某些实施方案公开了式(II)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐，
Figure PCTCN2017112669-appb-000012
R4表示一个或多个-H、-F、-Cl、-Br、-OH、-CH3、-NHCH3、-NHCH2CH3、-NH2、-N(CH3)2、-N(CH2CH3)2、-NHCOCH3或-NHCOCH2CH3；
R5表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；
R6表示-S-、-SO-、-SO2-、-NH-或-N(CH3)-；以及
R7表示-H、-CH3或-CH2CH3。
某些实施方案公开了式(II)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐，
Figure PCTCN2017112669-appb-000013
其中，
R4表示-NH2或-NHCOCH3；
R5表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；
R6表示-S-、-SO-、-SO2-、-NH-或-N(CH3)-；以及
R7表示-H、-CH3或-CH2CH3。
某些实施方案公开了式(II)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐，其选自：
4-氨基-2-(1-(2-甲基硫乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮或其药物可接受的盐；
4-氨基-2-(1-(2-甲基亚磺酰乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮或其药物可接受的盐；以及
4-氨基-2-(1-(2-甲基磺酰基乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮或其药物可接受的盐。
又一方面，某些实施方案公开了式(III)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐：
Figure PCTCN2017112669-appb-000014
其中，
R8表示一个或多个H、卤素、-C1-4烷基、-NH2、-NHC1-4烷基、-N(C1-4烷基)2、-NHCOC1-4烷基；
R9表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；
R10表示-O-、-S-、-SO-、-SO2-、-NH-或-N(C1-4烷基)-；
R11表示-H或-C1-4烷基；以及
R11表示卤素、-C1-4烷基。
某些实施方案公开了式(III)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐，
Figure PCTCN2017112669-appb-000015
其中，
R8表示一个或多个-H、-F、-Cl、-Br、-OH、-CH3、-NHCH3、-NHCH2CH3、-NH2、-N(CH3)2、-N(CH2CH3)2、-NHCOCH3或-NHCOCH2CH3；
R9表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；
R10表示-O-、-S-、-SO-、-SO2-、-NH-或-N(CH3)-；
R11表示-H、-CH3或-CH2CH3；以及
R12表示卤素或-C1-4烷基。
某些实施方案公开了式(III)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐，
Figure PCTCN2017112669-appb-000016
其中，
R8表示-NH2或-NHCOCH3；
R9表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；
R10表示-O-、-S-、-SO-、-SO2-、-NH-或-N(CH3)-；
R11表示-H、-CH3或-CH2CH3；以及
R12表示卤素或-C1-4烷基。
某些实施方案公开了式(III)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐，其选自：
4-氨基-2-(1-(2-甲氧乙基)-3-氟-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；以及
4-氨基-2-(1-(2-甲氧乙基)-3-甲基-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐。
上述式(I)、式(II)和式(III)所示的化合物均属于本公开中所述的哌啶-2,6-二酮衍生物。
某些实施方案公开了哌啶-2,6-二酮衍生物及其药物可接受的盐，其选自：
4-乙酰基氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-甲基氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-二甲氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氟-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4,5,6,7-四氟-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-羟基乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
5-氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-5-羟基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-5-氟-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-7-羟基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-甲基硫乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-甲基亚磺酰乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-甲基磺酰基乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-甲氧乙基)-3-氟-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-甲氧乙基)-3-甲基-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-乙酰氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氟-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮 及其药物可接受的盐；
5-氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-乙氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氟基-2-(1-(2-乙氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
5-氟-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-甲氧丁基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-羟基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
4-甲基-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二及其药物可接受的盐；
4-氨基-5-甲氧基-2-(1-(2-甲氧基乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮及其药物可接受的盐；
4-氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；以及
4-氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐。
又一方面，某些实施方案公开了药物组合物，其包含本公开中所述的哌啶-2,6-二酮衍生或其药物可接受的盐，以及药物可接受的载体、稀释剂或赋形剂。
再一方面，某些实施方案公开了治疗克罗恩氏病的方法，其包括对需要所述方法的个体给予治疗有效量的本公开中所述的哌啶-2,6-二酮衍生物或其药物可接受的盐或治疗有效量的本公开中所述的药物组合物。
某些实施方案公开了治疗克罗恩氏病的方法，其包括对需要所述方法的个体给予1mg-10g的本公开中所述的哌啶-2,6-二酮衍生物或其药物可接受的盐。
某些实施方案公开了治疗克罗恩氏病的方法，其包括对需要所述方法的个体给予10mg-3000mg的本公开中所述的哌啶-2,6-二酮衍生物或其药物可接受的盐。
某些实施方案公开了治疗克罗恩氏病的方法，其包括对需要所述方法的个体给予100mg-1000mg的本公开中所述的哌啶-2,6-二酮衍生物或其药物可接受的盐。
某些实施方案公开了治疗克罗恩氏病的方法，其包括对需要所述方法的个体给予100mg、150mg、200mg、250mg、300mg、350mg、 400mg、450mg、500mg、550mg、600mg、650mg、700mg、750mg、800mg、850mg、900mg或1000mg的本公开中所述的哌啶-2,6-二酮衍生物或其药物可接受的盐。
某些实施方案公开了治疗克罗恩氏病的方法，其中克罗恩氏病为轻度克罗恩氏病、中度克罗恩氏病、重度克罗恩氏病或缓解期克罗恩氏病。
某些实施方案公开了治疗克罗恩氏病的方法，其中需要所述方法的个体为哺乳动物。
某些实施方案公开了治疗克罗恩氏病的方法，其中需要所述方法的个体为人类。
某些实施方案公开了克罗恩氏病维持治疗的方法，其包括对需要所述方法的个体给予治疗有效量的本公开中所述的哌啶-2,6-二酮衍生物或其药物可接受的盐或治疗有效量的本公开中所述的药物组合物。
某些实施方案公开了治疗克罗恩氏病的方法，其中口服给予本公开中所述的哌啶-2,6-二酮衍生物或其药物可接受的盐或含有本公开中所述的哌啶-2,6-二酮衍生物或其药物可接受的盐的药物组合物。
某些实施方案公开了治疗克罗恩氏病的方法，其中以固体制剂或液体制剂形式口服给予本公开中所述的哌啶-2,6-二酮衍生物或其药物可接受的盐或含有本公开中所述的哌啶-2,6-二酮衍生物或其药物可接受的盐的药物组合物。
能够用于本公开的治疗克罗恩氏病的方法的固体制剂的示例性实例包括但不限于片剂、胶囊剂和糖丸。
能够用于本公开的治疗克罗恩氏病的方法的片剂的示例性实例包括但不限于素片、糖衣片和薄膜衣片。
能够用于本公开的治疗克罗恩氏病的方法的液体制剂的示例性实例包括但不限于溶液剂和混悬剂。
另一方面，某些实施方案公开了用于治疗克罗恩氏病的哌啶-2,6-二酮衍生物及其药物可接受的盐。
又一方面，某些实施方案公开了用于治疗克罗恩氏病的药物组合物，其包含本公开中所述的哌啶-2,6-二酮衍生或其药物可接受的盐，以及药物可接受的载体、稀释剂或赋形剂。
本公开中所述的哌啶-2,6-二酮衍生物具有良好的治疗作用。
本公开中所述的哌啶-2,6-二酮衍生物具有更好的安全性。
本公开中所述的哌啶-2,6-二酮衍生物具有更好的耐受性。
药物组合物
某些实施方案公开了药物组合物，其包含本公开中所述的哌啶-2,6-二酮衍生或其药物可接受的盐，以及药物可接受的载体、稀释剂或赋形剂。
在某些实施方案中，本公开中所述的哌啶-2,6-二酮衍生物用于治疗克罗恩氏病给予哺乳动物时的给药途径可以为非肠胃外途径。
在某些实施方案中，本公开中所述的哌啶-2,6-二酮衍生物用于治疗克罗恩氏病给予哺乳动物时的给药途径可以为口服途径。
在某些实施方案中，本公开中所述的哌啶-2,6-二酮衍生物用于治疗克罗恩氏病给予哺乳动物时的给药途径可以为直肠内途径。
可以以任何合适的形式如片剂、胶囊剂、粉剂、口服溶液、悬浮液、直肠凝胶、直肠泡沫、直肠灌肠剂或直肠栓剂等获得本公开所述的哌啶-2,6-二酮衍生物。所述的片剂的示例性实例包括但不限于素片、糖衣片和薄膜衣片。
能够用于本公开的药物组合物中的药物可接受的载体的实例包括但不限于已经被美国食品与药品管理局认可的而可用于人类或动物的任何佐剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、香味增强剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗透压剂、溶剂或乳化剂等对组成药物组合物无副作用的各种形式的载体。用于治疗用途的可接受载体或稀释剂在药物领域是公知的，并且例如在Remington’s Pharmaceutical Sciences(雷明顿制药学),18th Ed.,Mack Publishing Co.,Easton,PA(1990))中有描述，本文将其全部内容引入作为参考。
本公开中的药物组合物可以通过任何实现其预期目的的方法被施用。例如，施用可以通过口服、胃肠外、局部、肠内、静脉内、肌内、吸入、鼻、关节内、脊柱内、经气管、经眼、皮下、腹膜内、经皮或口含等途径进行。给药途径可以为非肠胃外途径、口服途径以及直肠内途径。所施用的剂量将取决于接受者的年龄、健康状况和体重，如果有并行治疗，还取决于并行治疗的种类、治疗的频率，以及所需效果的性质。
合适的剂型包括但不限于胶囊剂、片剂、小丸、糖锭剂(dragee)、半固体制剂、散剂、颗粒剂、栓剂、软膏剂、乳膏剂、洗剂、吸入剂、注射剂、泥罨剂、凝胶剂、带剂(tape)、滴眼剂、溶液剂、糖浆剂、气雾剂、混悬剂、乳剂，其可以根据本领域已知的方法制备。
特别适合口服施用的是普通片剂(素片)、糖衣片、薄膜衣片、丸剂、胶囊剂、散剂、颗粒剂、糖浆剂、汁液(juice)或滴剂，适合直肠施用的是栓剂，适合胃肠外施用的是溶液剂，也可以是基于油的溶液或水溶液，此外还有混悬剂、乳剂或植入剂，适合局部使用的是软膏剂、乳膏剂或散剂。本公开中的产品也可以被冻干，生成的冻干物用于例如制备注射剂。所给出的制剂可以被灭菌和/或包含辅助剂(assistant)，如润湿剂、防腐剂、稳定剂和/或润湿剂、乳化剂、用于改变渗透压的盐、缓冲物质、染料、矫味剂和/或众多另外的活性成分，例如一种或多种维生素。
在某些实施方案中，本公开中的药物组合物被制备成胃肠外、经皮、粘膜、鼻、口颊、舌下或经口使用的片剂、溶液剂、颗粒剂、贴剂、膏剂、胶囊剂、气雾剂或栓剂。
在药物组合物中可以提供防腐剂、稳定剂、染料、甜味剂、芳香剂、香料等。例如，可加入作为防腐剂的苯甲酸钠、抗坏血酸以及对羟基苯甲酸的酯。另外，可以使用抗氧化剂和混悬剂。
在不同的实施方案中，醇、酯、硫酸化脂族醇等可用作表面活性剂；蔗糖、葡萄糖、乳糖、淀粉、结晶纤维素、甘露醇、轻质无水硅酸盐、铝酸镁、铝酸甲基硅酸镁、合成硅酸铝、碳酸钙、碳酸氢钙、磷酸氢钙、羟甲基纤维素钙等可用作赋形剂；硬脂酸镁、滑石、硬化油等可用作光滑剂；椰子油、橄榄油、麻油、花生油、大豆可用作混悬剂或润滑剂；作为诸如纤维素或糖等糖类的衍生物的醋酞纤维素、或作为聚乙烯的衍生物的乙酸甲酯-异丁烯酸酯共聚物可用作混悬剂；以及诸如酞酸酯等的增塑剂可用作混悬剂。
合适的给药途径可以例如包括口服给药、直肠给药、透膜给药、肠胃外输送、局部给药或肠内给药；肠胃外输送包括肌内注射、皮下注射、静脉注射、髓内注射以及鞘内注射、直接心室内注射、腹膜内注射、鼻内注射或眼内注射。化合物也能够在包括储库型注射(depotinjections)、渗透泵、丸剂、透皮(包括电迁移)贴片等在内的缓释或控释的剂型中以预先确定的速率进行延长和/或定时、脉冲给药。
本公开中的药物组合物可按已知的方法进行生产，例如，通过常规的混合、溶解、粒化、制造锭剂、研磨、乳化、包囊、截留或压片等操作方法进行生产。
因此根据本公开，所使用的药物组合物可使用一种或多种包含赋形剂和辅助剂的生理可接受的载体以常规方法配制，该赋形剂和辅助剂有利于将活性化合物处理成为药学可用的制剂。合适的制剂取决于所选的给药途径。可以如本领域中适合的并理解的那样使用任何公知的技术、载体和赋形剂。
能够将注射剂制备成下列常规形式：作为溶液或混悬液，在注射前适合制成溶液或混悬液的固体剂型，或作为乳剂。合适的赋形剂是，例如水、盐水、葡萄糖、甘露醇、乳糖、卵磷脂、白蛋白、谷氨酸钠、盐酸半胱氨酸等。另外，如果需要，注射剂药物组合物可以含有少量无毒的辅助物，例如湿润剂、pH缓冲剂等。生理适合的缓冲剂包括但不限于Hank溶液、Ringer溶液或生理盐水缓冲液。如果需要，可使用吸收增强制剂(例如脂质体)。
对于口服给药，通过组合所述活性化合物与本领域公知的药物可接受的载体，能够容易地组方所述化合物。为了使待治疗患者口服摄取，这样的载体能使本发明化合物被配制为片剂、丸剂、锭剂、胶囊、液体、凝胶、糖浆、膏剂、混悬液、溶液、粉剂等。能够通过下述方 法获得用于口服的药物制剂：将活性化合物与固体赋形剂混合，任意研磨所得混合物并且将加工颗粒混合物，如果需要，在加入合适的辅助剂后进行加工以获得片剂或锭剂核。合适的赋形剂特别是诸如糖等的填充剂，包括乳糖、蔗糖、甘露醇或山梨醇；纤维素制剂，例如玉米淀粉、小麦淀粉、米淀粉、马铃薯淀粉、明胶、西黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯酮(PVP)。如果需要可加入崩解剂，例如交联的聚乙烯吡咯烷酮、琼脂或海藻酸或诸如海藻酸钠的海藻酸盐。对锭剂核进行合适的包被。出于该目的，可使用浓缩的糖溶液，该糖溶液可任选地包含阿拉伯胶、滑石、聚乙烯吡咯烷酮、卡波普凝胶(carbopol gel)、聚乙二醇和/或二氧化钛、紫胶漆溶液以及合适的有机溶剂或溶剂混合物。为了识别或表征活性化合物剂量的不同组合，可向片剂或锭剂包衣中加入染料或色素。出于该目的，可使用浓缩的糖溶液，该糖溶液可任选地包含阿拉伯胶、滑石、聚乙烯吡咯烷酮、卡波普凝胶、聚乙二醇和/或二氧化钛、紫胶漆溶液、以及合适的有机溶剂或溶剂混合物。
能够用于口服的药物制剂包括明胶制成的推入配合胶囊，以及诸如甘油或山梨醇的明胶和增塑剂制成的软的、密封的胶囊。推入配合胶囊能够包含与诸如乳糖的填充剂、诸如淀粉的粘合剂和/或诸如滑石或硬脂酸镁的润滑剂以及任选的稳定剂混合的活性成分。在软胶囊中，活性成分可溶解或悬浮在合适的液体中，例如脂肪油、液状石蜡或液状聚乙二醇。另外，可加入稳定剂。所有口服给药的制剂应该达到适于这种给药的剂量。
在某些实施方案中，本公开中的药物组合物可以包含0.1％-95％的本公开中所述的哌啶-2,6-二酮衍生物或其药物可接受的盐。
在某些实施方案中，本公开中的药物组合物可以包含1％-70％的本公开中所述的哌啶-2,6-二酮衍生物或其药物可接受的盐。
在任何情况下，待施用的组合物或制剂将含有一定量的本公开中所述的哌啶-2,6-二酮衍生物或其药物可接受的盐，其量可有效治疗受治疗的受试对象疾病/病况。
给药方法
可将本公开中所述的至少一种化合物或包含至少一种本公开中所述的化合物的药物组合物以任何适宜系统的和/或局部的输送本公开中所述的化合物的任何方法进行的方法对患者进行给药。给药方法的非限制性实例包括(a)通过口服途径给药，该给药包括以胶囊、片剂、颗粒剂、喷雾剂、糖浆剂或其它这类形式进行给药；(b)通过非口服途径给药，例如直肠、阴道、尿道内、眼内、鼻内或耳内，所述给药包括以水性悬浮液、油性制剂等或以滴剂、喷雾剂、栓剂、药膏、软膏等方式进行给药；(c)经皮下注射、腹膜内注射、静脉内注射、肌内注 射、皮内注射、眶内注射、囊内注射、脊柱内注射、胸骨内注射等进行给药，包括输液泵输送；(d)诸如直接在肾脏区域或心脏区域中进行注射的局部(locally)给药，例如通过储库型植入；以及(e)局部(topically)给药；如本领域中技术人员所认为的适当的给药方式是本公开中所述的化合物与活组织接触。
最适合途径取决于被治疗疾病状态的性质与严重性。本领域技术人员也熟悉确定给药方法(口腔、静脉内、吸入、皮下、直肠等)、剂型、适当医药赋形剂及与将化合物传递至有需要的对象有关的其它事项。
适于给药的药物组合物包括其中含有有效量的活性成分以达到其预期效果的组合物。本公开中所述的药物组合物的治疗有效量所需的剂量取决于给药途径、包括人在内的被治疗动物的类型以及所考虑的特定动物的身体特征。可以调整剂量以达到期望的效果，但是这将取决于下列因素：体重、饮食、同时的药物治疗以及其它医学领域的技术人员公认的其它因素。更具体地，治疗有效量指有效阻止、减轻或改善疾病症状，或延长接受治疗个体寿命的化合物的量。本领域技术人员的实际能力可很好地确定治疗有效量，特别是按照本公开所提供的详细公开。
正如本领域技术人员所显而易见的，用于体内给药的剂量和具体的给药方式的变化将取决于年龄、体重和所治疗的哺乳动物的种类、所使用的具体化合物以及所使用的这些化合物的具体用途。本领域技术人员使用常规的药理学方法可达到确定有效剂量水平的目的，即达到确定预期效果所必需的剂量水平的目的。通常，以较低剂量水平开始进行产物的人体临床应用，随着剂量水平的增加直至达到所期望的效果。或者，采用已确立的药理学方法，能够使用可接受的体外研究来建立本方法鉴定的组合物的有效剂量和给药途径。
在非人动物研究中，潜在产物的应用以较高剂量水平开始，随着剂量的减少直至不再实现所期望的效果或者不良副作用消失。取决于预期效果和治疗适应症，剂量范围可较宽泛。通常，剂量可为约10μg/kg体重至1000mg/kg体重，在某些实施方案中为约100μg/kg体重至300mg/kg体重。或者，正如本领域技术人员所理解的，剂量可基于患者的体表面积并且按照其计算。
各医师能够根据患者的状况来选择本公开中所述的药物组合物的确切制剂、给药途径和剂量。通常，向患者给药的组合物的剂量范围可以为约0.5mg/kg至1000mg/kg患者体重。根据患者需要，剂量可在一天或数天期间单独一次给予或两次或多次给予。在化合物的人用剂量因至少某些条件已确立的情况下，本公开将使用那些相同的剂量，或剂量范围为约0.1％至500％的确定的人用剂量，在某些实施方案中剂量范围为25％至250％已确定的人用剂量。在没有确定的人用剂量 的情况下，如新发现的药物化合物的情况，适宜的人用剂量能够从半数有效量或感染剂量中位数数值，或来自体外或体内研究的其它合适的值进行推断，正如在动物中的毒性研究和效能研究所定量化的。
应当指出，由于毒性和器官功能障碍，主治医师将知道如何且何时终止、中断或调整给药。相反，如果临床反应不充分(排除毒性)，则主治医生也将知道将治疗调整至较高水平。在所关注病症的治疗中给药剂量的大小将随着待治疗疾病状态的严重性和给药途径的变化而变化。例如部分通过标准的预后评价方法可评价所述疾病状态的严重性。此外，所述剂量和可能的剂量频率也将根据个体患者的年龄、体重、以及反应的变化而变化。与上述讨论方案相当的方案可用于兽医学中。
虽然可基于逐一的药物分析(drug-by-drug)可决定确切的剂量，但是在大多数情况下，能够就药剂进行某些概括。成人患者的日给药方案为，例如口服剂量为0.1mg至2000mg各活性成分，在某些实施方案中为1mg至2000mg各活性成分，例如5mg至1500mg各活性成分。在其它实施方案中，所使用的各活性成分的静脉内、皮下或肌内剂量为0.01mg至1000mg，在某些实施方案中为0.1mg至1000mg，例如1mg至800mg。在给予药物可接受盐的情况下，可按照游离碱来计算剂量。在某些实施方案中，每日1至4次将所述组合物进行给药。或者，本公开中所述的组合物可通过连续的静脉输注进行给药，在某些实施方案中以每日高达2000mg的各活性成分的剂量进行给药。正如本领域技术人员所理解的，在某些情形中，为了有效且迅速地治疗迅速发展的疾病或感染，以超过或远远超过上述剂量范围的量给予本公开中所述的化合物是必要的。在某些实施方案中，将所述化合物在连续治疗期间进行给药，例如一周或数周、或数月或数年。
可以个别地调整剂量和用药间隔以提供足以维持调整效果或最低有效浓度(MEC)的活性部分的血浆水平。每种化合物的MEC不同，但是能够从体外数据评估MEC。达到MEC的所需剂量取决于个体特征和给药途径。然而，能够使用HPLC(高效液相色谱)测定或生物测定来确定血浆浓度。
使用MEC值还能够测定用药间隔。应使用在10-90％的时间内、在某些实施方案中在30-90％的时间内、以及在某些实施方案中在50-90％的时间内将血浆水平维持在MEC以上的治疗方案对组合物进行给药。
在局部给药或选择性吸收的情况下，药物的有效局部浓度与血浆浓度无关。
当然，被给药的组合物的量取决于待治疗的个体，取决于所述个体的体重、痛苦的严重性、给药方式以及开处方医师的判断。
使用已知的方法能够对本公开中所述的化合物的效能和毒性进行评估。例如，通过在体外测定细胞系的毒性可建立特定化合物或共享某些化学部分的该化合物子集的毒理学，所述细胞系例如哺乳动物细胞系并且在某些实施方案中为人的细胞系。这类研究的结果通常可预测诸如哺乳动物等的动物体内的毒性，或更具体地，可预测人体内的毒性。或者，使用已知方法可测定特定化合物在诸如小鼠、大鼠、家兔或猴等动物模型中的毒性。使用若干公认的方法，例如体外方法、动物模型或人体临床试验，可确定特定化合物的效能。几乎对每类疾病状态都存在着公认的体外模型，该疾病状态包括但不限于癌症、心血管疾病和多种免疫机能障碍。类似地，可接受的动物模型可用于确定治疗这些疾病状态的化学药物的效能。当选择模型测定效能时，技术人员能够在本领域现有技术的指导下选择合适的模型、剂量和给药途径以及治疗方案。当然，人体临床试验还能够用于测定化合物在人体内的效能。
如果需要，可将所述组合物置于包装或分配装置中，该包装或分配装置可以包含一种或多种含有活性成分的单位剂型。所述包装可以例如包括金属或塑料箔，例如泡罩包装。所述包装或分配装置可带有给药说明书。所述包装或分配装置还可以带有与所述容器相关的注意事项，该注意事项是由管理药物生产、使用或销售的政府机构规定的，该注意事项反映了所述药物形式已经由该机构批准用于人类或兽类给药。这类注意事项，例如，可以是由国家食品药品监督管理总局或美国食品和药物管理局批准的用于处方药的标签，或者是批准的产品说明书。还可以在合适的容器中制备、放置在相容的药物载体中组方的包含本发明化合物在内的组合物，并对其标记以用于指定的疾病状态的治疗。
实施例
在本公开中，使用了以下缩写：
在本公开中，使用了以下缩写：
LPS：细菌脂多糖；
PBS：磷酸盐缓冲液；
Tween-20：吐温-20；
PBST：0.05％吐温-20的磷酸盐缓冲液溶液；
HRP：辣根过氧化物酶；
TMB：3,3’,5,5’-四甲基联苯胺；
DSS：葡聚糖硫酸钠；
5-ASA：5-氨基水杨酸；
CMC-Na：羧甲基纤维素钠；
1％CMC-Na：CMC-Na浓度为1％(重量/体积)的水溶液；
1.6％DSS：DSS浓度为1.6％(重量/体积)的水溶液；
0.9％DSS：DSS浓度为0.9％(重量/体积)的水溶液；
mg/kg：毫克/公斤；
mg/kg/d：毫克/公斤/天；
ml/kg：毫升/公斤；
cm：厘米；
Mean±SD：平均值±标准差；
30％乙醇：乙醇浓度为30％(体积/体积)的水溶液；
cm2：平方厘米；
U/mg：单位/毫克；
g：克；
mmol：毫摩尔；
mol/L：摩尔/升；
i.g：灌胃；
ml：毫升；
μl：微升；
nm：纳米；
s：秒；
OD值：光密度值；
μm：微米；
Qd、QD、Q.D或qd：每天1次；
实验中可能使用的设备或仪器：
Figure PCTCN2017112669-appb-000017
Figure PCTCN2017112669-appb-000018
中国专利ZL200510013292.3中公开了4-氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备方法。本文通过引用的方式将其全部内容并入本文。
实施例1
4-乙酰基氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
按照中国专利ZL200510013292.3中公开的制备方法制备4-氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮。
将4-氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮(3.0克)溶于二氯甲烷(DCM)(30毫升)，加入三乙胺(TEA)(2.75克，3.77毫升)和4-二甲氨基吡啶(DMAP)(0.126克)，以氩气置换空气。将反应体系降温至0摄氏度，搅拌下加入乙酰氯(4.59克，4.16毫升)，缓慢升至室温，至反应完全。向反应液中加入水(60毫升)淬灭反应，以二氯甲烷萃取一次；有机相以饱和氯化钠水溶液洗涤一次，有机相以无水硫酸镁干燥、过滤、减压浓缩得到粗产品。粗产品用硅胶柱层析纯化得到产品1.8克固体；用二氯甲烷溶解固体，滴加乙醚，析出产品，所得产品再用二氯甲烷溶解，加乙醚析出产品，减压干燥得到实施例1白色固体产品1.3克(HPLC纯度98.06％)；收率38.3％。核磁共振氢谱1HNMR(氘代氯仿(CDCl3),400MHz)δ9.411(bs,1H),8.823-8.802(d,1H),7.730-7.690(dd,1H),7.557-7.537(dd,1H),4.995-4.950(m,1H),4.146-4.001(m,2H),3.555-3.521(m,2H),3.345(s,3H),3.048-2.956(m,1H),2.848-2.719(m,2H),2.267(s,3H),2.186-2.086(m,1H)。MS(m/e):374.21(M+H+)。
实施例2
4-甲基氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二 酮的制备
将4-氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮(4.0克)、二碳酸二叔丁酯(10.528克)和4-二甲氨基吡啶(0.147克)加入反应瓶中，加入四氢呋喃(40毫升)，室温搅拌反应过夜。将反应液减压浓缩得到粗产品。粗产品用硅胶柱层析纯化得到白色固体产品4-二叔丁氧羰基氨基-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1，3-二酮3.3克；收率74.1％。MS(m/e):554.40(M+Na+)。
将4-二叔丁氧羰基氨基-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮(2.05克)溶于二氯甲烷(600毫升)，加入四氢呋喃(3毫升)，室温搅拌反应至反应完全。向反应液中加入饱和碳酸钠水溶液淬灭反应；分液，有机相以无水硫酸镁干燥、过滤，滤液减压浓缩得到4-叔丁氧羰基氨基-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮1.66克(HPLC纯度98.62％)；收率100％。MS(m/e):454.29(M+Na+)。
将4-叔丁氧羰基氨基-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮(3.0克)、碘甲烷(2.96克)和碳酸钾(2.88克)加入反应瓶中，加入N，N-二甲基甲酰胺(30毫升)，室温搅拌反应过夜。将反应液以二氯甲烷(100毫升)稀释，用水洗涤有机相；水相以二氯甲烷萃取。合并有机相，以饱和氯化钠水溶液洗涤有机相，有机相以无水硫酸镁干燥、过滤、滤液减压浓缩得到粗产品。粗产品用硅胶柱层析纯化得到4-叔丁氧羰基甲基氨基-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮黄色油状物2.91克(HPLC纯度96.43％)；收率94.0％。MS(m/e):468.31(M+Na+)。
将4-叔丁氧羰基甲基氨基-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮(2.9克)溶于二氯甲烷(30毫升)，加入四氢呋喃(6毫升)，室温搅拌反应2小时。将反应液减压浓缩得到粗产品，粗产品以甲基叔丁基醚(35毫升)溶解固体，搅拌过夜，析出黄色固体产品，过滤，收集固体减压干燥得到黄色固体产品1.83克(HPLC纯度98.62％)；收率81.6％。1HNMR(CDCl3,400MHz)δ7.538-7.499(dd,1H),7.112-7.094(d,1H),6.887-6.866(d,1H),4.949-4.904(m,1H),4.122-3.999(m,2H),3.543-3.510(m,2H),3.341(s,3H),2.989-2.950(m,1H),2.981(s,3H),2.820-2.700(m,2H),2.115-2.060(m,1H)。MS(m/e):346.24(M+H+)。
实施例3
4-二甲氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
将4-氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮(3.0克)、碘甲烷(14.2克)和碳酸钾(6.25克)加入耐压反应管中， 加入N,N-二甲基甲酰胺(20毫升)，密封，置于油浴中加热至80摄氏度，搅拌反应80小时。将反应液以二氯甲烷(200毫升)稀释，过滤，滤液减压浓缩得到黑色油状粗产品。粗产品用硅胶柱层析纯化得到棕色固体3.2克；棕色固体以乙酸乙酯(20毫升)搅拌打浆过夜，过滤，收集固体减压干燥得到黄色粉末状固体产品1.67克(HPLC纯度97.22％)；收率51.4％。1HNMR(CDCl3,400MHz)δ7.543-7.504(dd,1H),7.308-7.287(d,1H),7.121-7.100(d,1H),5.004-4.959(m,1H),4.115-3.999(m,2H),3.537-3.507(m,2H),3.337(s,3H),3.108(s,6H),2.982-2.944(m,1H),2.803-2.751(m,2H),2.094-2.079(m,1H)。MS(m/e):360.27(M+H+)。
实施例4
4-氟-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
将1-(2-甲氧乙基)-3-苄氧酰胺基-2,6-哌啶二酮醋酸盐(35克)、钯碳(3.5克，钯含量10％)和乙酸(13毫升)加入反应瓶中，以氢气球置换空气三次，室温下搅拌反应72小时。将反应液过滤，收集滤液直接用于下步反应。
将上述滤液(含1-(2-甲氧乙基)-3-氨基-2,6-哌啶二酮醋酸盐理论量2.0克)、3-氟酞酐(1.35克)、乙酸钠(0.67克)和乙酸(43毫升)加入反应瓶中，置于油浴中加热至140摄氏度，搅拌反应5小时。将反应液减压浓缩，得到黑色粗产品。粗产品用硅胶柱层析纯化，得到白色固体产品1.56克(HPLC纯度99.88％)；收率57.4％。1HNMR(CDCl3,400MHz)δ7.796-7.746(m,1H),7.717-7.700(d,1H),7.447-7.403(m,1H),5.028-4.982(m,1H),4.127-3.998(m,2H),3.541-3.510(m,2H),3.340(s,3H),3.019-2.951(m,1H),2.895-2.739(m,2H),2.171-2.085(m,1H)。MS(m/e):357.19(M+Na+)。
实施例5
4,5,6,7-四氟-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
用实施例4中的合成方法，由2,3,4,5-四氟邻苯二甲酸酐和1-(2-甲氧乙基)-3-氨基-2,6-哌啶二酮醋酸盐反应制得标题化合物。得到白色固体产品2.93克(HPLC纯度97.58％)；收率78.6％。1HNMR(CDCl3,400MHz)δ4.999-4.953(m,1H),4.118-3.984(m,2H),3.530-3.500(m,2H),3.333(s,3H),3.029-2.991(m,1H),2.803-2.764(m,2H),2.136-2.117(m,1H)。MS(m/e):389.22(M+H+)。
实施例6
4-氨基-2-(1-(2-羟基乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的 制备
将3-氨基-N-(2,6-二氧-3-哌啶基)苯邻二甲酰亚胺(3.5克)、2-溴乙醇(4.8克)、碳酸钾(1.77克)和N,N-二甲基甲酰胺(35毫升)加入反应瓶中，置于油浴中加热至40摄氏度，搅拌反应80小时。将反应体系降至室温，加入水(80毫升)淬灭反应，加入乙酸乙酯，搅拌，有固体析出；将此混合物减压抽滤，滤饼舍弃，收集滤液；将滤液分液，水相以乙酸乙酯反萃4次，合并有机相，以饱和氯化钠水溶液洗涤；有机相以无水硫酸镁干燥、过滤、减压浓缩得到粗产品。粗产品用硅胶柱层析纯化得到黄色固体产品2.0克(HPLC纯度95.53％)；收率49.2％。1HNMR(CDCl3,400MHz)δ7.457-7.419(t,1H),7.176-7.158(d,1H),6.886-6.865(d,1H),4.990-4.945(m,1H),4.135-4.065(m,2H),3.813-3.785(m,2H),3.006-2.966(m,1H),2.829-2.714(m,2H),2.153-2.114(m,1H)。MS(m/e):340.18(M+Na+)。
实施例7
5-氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
用实施例4中的合成方法，由4-硝基邻苯二甲酸酐和1-(2-甲氧乙基)-3-氨基-2,6-哌啶二酮醋酸盐反应制得5-硝基-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮。得到白色固体产品2.8克(HPLC纯度99.62％)；收率54.5。MS(m/e):384.18(M+Na+)。
将5-硝基-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮(2.6克)、钯碳(0.26克)和四氢呋喃(30毫升)加入反应瓶中，以氢气球置换空气三次，室温下搅拌反应20小时，反应完全。将反应液过滤，收集滤液，以水泵减压浓缩得到粗产品。粗产品以乙酸乙酯打浆纯化，得到黄色固体产品1.56克(HPLC纯度95.74％)；收率65.4％。1HNMR(CDCl3,400MHz)δ7.607-7.587(d,1H),7.012-7.007(d,1H),6.846-6.820(dd,1H),4.970-4.925(m,1H),4.135-3.982(m,2H),3.540-3.509(m,2H),3.340(s,3H),3.024-2.903(m,1H),2.829-2.710(m,2H),2.117-2.062(m,1H)。MS(m/e):354.22(M+Na+)。
实施例8
4-氨基-5-羟基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
将4-羟基邻苯二甲酸二甲酯(125克)和浓硫酸(600毫升)加入反应瓶中，搅拌下降温至0摄氏度；向体系中缓慢滴加发烟硝酸(39.44克)，控制体系温度小于5摄氏度，约1小时滴加完毕。撤掉冰浴，升至室温，搅拌反应22小时，反应完全。将反应液缓慢倒入冰水中淬灭反应，加乙酸乙酯萃取水相5次；合并有机相，以无水硫酸镁干燥、过滤，收集滤液，依次以水泵、油泵减压浓缩得到4-羟基-3-硝基邻苯二甲酸 二甲酯169克(HPLC纯度36.54％)，直接用于下步反应。MS(m/e):254.07(M-H)-。
将4-羟基-3-硝基邻苯二甲酸二甲酯(164克)、溴化苄(135.9克)、碳酸钾(400克)和丙酮(1730毫升)加入反应瓶中，置于油浴中加热至70摄氏度，搅拌反应23小时，反应完全。将反应体系降至室温，减压抽滤，滤饼以二氯甲烷淋洗，收集滤液；将滤液减压浓缩，向浓缩物中加入二氯甲烷(2000毫升)和饱和氯化钠水溶液(1000毫升)萃取分液，有机相以无水硫酸镁干燥、过滤、减压浓缩得到黄色固体粗品。粗品以乙酸乙酯重结晶纯化，得到4-苄氧基-3-硝基邻苯二甲酸二甲酯白色固体产品40克(HPLC纯度96.96％)；收率18.1％。MS(m/e):346.14(M+H+)。
将4-苄氧基-3-硝基邻苯二甲酸二甲酯(30克)和乙醇(300毫升)加入反应瓶中，将预配制好的氢氧化钠水溶液(24克氢氧化钠溶于300毫升水中)加入反应瓶中，置于油浴中加热至70摄氏度，搅拌反应7小时，反应完全。将反应体系降至室温，减压浓缩，至缩出大部分乙醇；室温下，向浓缩物中加入4N盐酸水溶液酸化，至pH＝2，有大量白色固体析出；将此混合物减压抽滤，收集滤饼，以油泵减压干燥，得到4-苄氧基-3-硝基邻苯二甲酸白色固体产品27.5克(HPLC纯度99.55％)；收率100％。MS(m/e):316.15(M-H)-。
将4-苄氧基-3-硝基邻苯二甲酸(19.1克)和乙酸酐(120毫升)加入反应瓶中，置于油浴中加热至140摄氏度，搅拌反应6小时。将反应体系降至室温，反应液减压浓缩得到粗品，粗品以甲基叔丁基醚和正己烷打浆纯化得到4-苄氧基-3-硝基邻苯二甲酸酐棕色固体产品16.8克；收率93.3％。
用实施例4中的合成方法，由4-苄氧基-3-硝基邻苯二甲酸酐和2-甲氧乙基)-3-氨基-2,6-哌啶二酮醋酸盐反应制得4-硝基-5-苄氧基-2-(1-(2-甲氧基乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮白色固体产品22.3克(HPLC纯度99.69％)；收率85.0％。MS(m/e):468.22(M+H+)。
用实施例7中的合成方法，由4-硝基-5-苄氧基-2-(1-(2-甲氧基乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮反应制得标题化合物。得到黄色固体产品18.4克(HPLC纯度99.03％)；收率86.8％。1HNMR(二甲基亚砜(DMSO),400MHz)δ10.820(s,1H),6.974-6.955(d,1H),6.915-6.896(d,1H),5.936-5.935(bs,2H),5.099-5.053(q,1H),3.917-3.730(m,2H),3.363-3.331(t,2H),3.217(s,3H),3.002-2.911(m,1H),2.762-2.702(m,1H),2.560-2.450(m,1H),2.027-1.963(m,1H)。MS(m/e):348.17(M+H+)。
实施例9
4-氨基-5-氟-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
将4-氟邻苯二甲酸(1.0克)和浓硫酸(5毫升)加入反应瓶中，搅拌下降温至0摄氏度；向体系中缓慢滴加浓硝酸(1.05克，65％含量)，滴加完毕后，转入油浴，升至80摄氏度，搅拌反应7小时，HPLC显示反应完全。将反应液缓慢倒入冰水(20克)中淬灭反应，加乙酸乙酯萃取水相；合并有机相，以饱和氯化钠水溶液洗涤，有机相以无水硫酸镁干燥、过滤，收集滤液，依次以水泵、油泵减压浓缩得到粗产品黄色固体1.3克，直接用于下步反应。
取氯化亚砜5毫升加入反应瓶中，置于油浴中加热至90摄氏度，搅拌反应11小时。将反应体系降至室温，反应液以水泵减压浓缩得到粗品黄色油状物0.56克；直接用于下步反应。
用实施例4中的合成方法，将上述所得4-氟-3-硝基邻苯二甲酸酐和1-(2-甲氧乙基)-3-氨基-2,6-哌啶二酮醋酸盐反应制得到黑色固体5-氟-4-硝基-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮0.3克(HPLC纯度90.63％)。MS(m/e):380.21(M+H+)。
用实施例7中的合成方法，由5-氟-4-硝基-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮反应制得标题化合物。得到黄色固体产品0.137克(HPLC纯度97.59％)；收率57.2％。1HNMR(CDCl3,400MHz)δ7.256-7.208(dd,1H),7.158-7.129(dd,1H),5.269(bs,2H),4.959-4.914(m,1H),4.140-3.988(m,2H),3.544-3.512(m,2H),3.341(s,3H),3.000-2.961(m,1H),2.795-2.745(m,2H),2.121-2.081(m,1H)。MS(m/e):350.2(M+H+)。
实施例10
4-氨基-7-羟基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
4-叔丁氧羰基氨基-7-羟基邻苯二甲酸二甲酯参照Journal of Organic Chemistry,62(12),4088-4096；1997方法制备。
将3-叔丁氧羰基氨基-6-羟基邻苯二甲酸二甲酯(3.0克)、1-(2-甲氧乙基)-3-氨基-2,6-哌啶二酮醋酸盐(4.5克)和吡啶(60毫升)加入反应瓶中，置于油浴中加热至100摄氏度，搅拌反应40小时。将反应液降至室温，减压浓缩得到粗产品。粗产品用硅胶柱层析纯化，得到4-叔丁基氧羰基氨基-7-羟基-2-(1-(2-甲氧基乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮黄色固体产品2.35克(HPLC纯度95.96％)；收率48.8％。MS(m/e):470.28(M+Na+)。
将4-叔丁基氧羰基氨基-7-羟基-2-(1-(2-甲氧基乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮(2.25克)溶于二氯甲烷(20毫升)，加入四氢呋喃(4毫升)，室温搅拌反应6小时，反应完全。将反应液减压浓缩 得到粗产品，粗产品以甲基叔丁基醚打浆纯化，得到棕色固体产品1.413克(HPLC纯度95.35％)；收率77.4％。1HNMR(CDCl3,400MHz)δ7.020-6.998(d,1H),6.858-6.835(d,1H),4.934-4.889(m,1H),4.145-3.995(m,2H),3.555-3.521(m,2H),3.346(s,3H),3.031-2.926(m,1H),2.827-2.742(m,2H),2.140-2.059(m,1H)。MS(m/e):348.22(M+H+)。
实施例11
4-氨基-2-(1-(2-甲基硫乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
将3-氨基-N-(2,6-二氧-3-哌啶基)苯邻二甲酰亚胺(2.5克)、2-氯乙基甲基硫醚(2.55克)、碳酸钾(3.8克)、碘化钠(0.28克)和N,N-二甲基甲酰胺(35毫升)加入反应瓶中，置于油浴中加热至50摄氏度，搅拌反应20小时，反应完全。将反应体系降至室温，加入二氯甲烷和水萃取分液，水相以二氯甲烷反萃2次，合并有机相，以无水硫酸镁干燥、过滤，减压浓缩得到粗产品。粗产品用硅胶柱层析纯化得到黄色固体产品2.111克(HPLC纯度96.68％)；收率55.3％。1HNMR(CDCl3,400MHz)δ7.457-7.418(dd,1H),7.180-7.161(dd,1H),6.885-6.863(dd,1H),4.966-4.921(m,1H),4.110-3.973(m,2H),2.994-2.926(m,1H),2.820-2.753(m,2H),2.683-2.646(t,2H),2.144(s,3H),2.125-2.079(m,1H)。MS(m/e):348.19(M+H+)。
实施例12
4-氨基-2-(1-(2-甲基亚磺酰乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
将4-氨基-2-(1-(2-甲基硫基乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮4.85克、间氯过氧苯甲酸(3.13克)和二氯甲烷(170毫升)加入反应瓶中，室温搅拌反应18小时。向反应体系中加入饱和碳酸氢钠水溶液(100毫升)，萃取分液，水相以二氯甲烷(150毫升×3)反萃，合并有机相，以无水硫酸镁干燥、过滤，减压浓缩得到粗产品。粗产品用硅胶柱层析纯化，得到黄色固体4-氨基-2-(1-(2-甲基亚磺酰基乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮0.846克(HPLC纯度95.09％)；收率16.7％。1HNMR(CDCl3,400MHz)δ7.462-7.423(dd,1H),7.172-7.155(d,1H),6.895-6.874(d,1H),4.974-4.931(m,1H),4.371-4.192(m,2H),3.073-2.909(m,3H),2.827-2.696(m,2H),2.650-2.647(d,3H),2.144-2.104(m,1H)。MS(m/e):364.22(M+H+)。
实施例13
4-氨基-2-(1-(2-甲基磺酰基乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
参照实施例12中的合成方法，由4-氨基-2-(1-(2-甲硫基乙基)-2,6- 二氧代哌啶-3-基)-异吲哚啉-1,3-二酮反应制得黄色固体产品1.78克(HPLC纯度99.47％)；收率33.6％。1HNMR(CDCl3,400MHz)δ7.470-7.431(dd,1H),7.184-7.167(d,1H),6.896-6.876(d,1H),4.988-4.943(m,1H),4.400-4.231(m,2H),3.311-3.277(t,2H),2.999(s,3H),3.012-2.932(m,1H),2.834-2.697(m,2H),2.153-2.110(m,1H)。MS(m/e):380.23(M+H+)。
实施例14
4-氨基-2-(1-(2-甲氧乙基)-3-氟-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
4-氨基-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮参照PCT Int.Appl.,2006105697,12Oct 2006方法制备。
将4-氨基-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮(5g)溶于四氢呋喃(100ml)中，氩气保护，降温至-78℃，缓慢滴加六甲基二硅基氨基锂(40ml)，完毕，继续搅拌1h。加入N-氟代双苯磺酰胺(11.67g溶于30ml四氢呋喃中)，完毕，搅拌1h后，缓慢升至室温，反应过夜。反应混合物加入150ml饱和氯化铵水溶液，150ml乙酸乙酯，分液，水相用100ml乙酸乙酯萃取，合并有机相，200ml饱和食盐水洗涤，有机相无水硫酸钠干燥，过滤，浓缩，残余物柱层析(乙酸乙酯/石油醚＝1/3)，得黄色固体968mg(HPLC纯度97.20％)，收率18.4％。1HNMR(CDCl3,400MHz)δ7.461-7.499(dd,1H),7.171-7.153(d,1H),6.931-6.899(d,1H),4.193-4.024(m,2H),3.670-3.640(t,2H),3.606-3.5558(m,1H),3.020(s,3H),2.371-2.960(m,1H),2.656-2.555(m,1H),2.433-2.342(m,1H)。MS(m/e):372.22(M+Na+)。
实施例15
4-氨基-2-(1-(2-甲氧乙基)-3-甲基-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
3-氨基-3-甲基哌啶-2,6-二酮盐酸盐参照PCT Int.Appl.,2006081251,03Aug 2006方法制备。
用实施例4中的合成方法，由3-氨基-3-甲基哌啶-2,6-二酮盐酸盐和3-硝基邻苯二甲酸酐反应得到白色固体2-(3-甲基-2,6-二氧代哌啶-3-基)-4-硝基异吲哚啉-1,3-二酮2.7克(HPLC纯度66.03％)；收率69.1％。MS(m/e):318.12(M+H+)。
用实施例11中的合成方法，由2-(3-甲基-2,6-二氧代哌啶-3-基)-4-硝基异吲哚啉-1,3-二酮反应制得黄色固体4-硝基-2-(1-(2-甲氧基乙基)3-甲基-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮0.736克(HPLC纯度96.45％)；收率28.3％。MS(m/e):376.26(M+H+)。
用实施例7中的合成方法，由4-硝基-2-(1-(2-甲氧基乙基)3-甲基 -2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮反应制得标题化合物。得到黄色固体产品0.572克(HPLC纯度94.51％)；收率84.1％。1HNMR(CDCl3,400MHz)δ7.430-7.391(t,1H),7.104-7.086(d,1H),6.854-6.833(d,1H),4.112-4.074(m,2H),3.615-3.580(m,2H),3.373(s,3H),2.844-2.793(m,1H),2.734-2.690(m,2H),2.046-1.993(m,1H),1.969(s,3H)。MS(m/e):368.22(M+Na+)。
实施例16
4-乙酰氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
N-((苄氧基)羰基)-谷氨酸酐参照Archives of Pharmacal Research,31(7),834-837；2008方法制备。
将N-((苄氧基)羰基)-谷氨酸酐(19克)、3-甲氧基丙胺(6.4克)、三乙胺(7.3克)、4-二甲氨基吡啶(0.88克)和四氢呋喃(270毫升)加入反应瓶中，室温下搅拌反应40小时，反应完全。所得反应液即为产物的四氢呋喃溶液，直接用于下步反应。
称取N,N’-羰基二咪唑(23.4克)，分批加入上述反应液溶液中，室温下搅拌反应72小时，反应完全。反应液减压浓缩，向浓缩物中加入二氯甲烷(500毫升)溶解，依次以1N盐酸水溶液(250毫升)、饱和碳酸氢钠水溶液(250毫升)和饱和氯化钠水溶液(250毫升)洗涤，有机相以无水硫酸镁干燥、过滤，减压浓缩得到棕色油状产品1-(2-甲氧丙基)-3-苄氧酰胺基-2,6-哌啶二酮23.7克；直接用于下步反应。MS(m/e):357.24(M+Na+)。
用实施例4中的合成方法，由1-(2-甲氧丙基)-3-苄氧酰胺基-2,6-哌啶二酮反应制得标题化合物，得到白色固体产品0.434克(HPLC纯度97.71％)；收率12.5％。1HNMR(CDCl3,400MHz)δ9.411(bs,1H),8.822-8.801(d,1H),7.729-7.689(dd,1H),7.555-7.535(dd,1H),4.943-4.987(m,1H),3.993-3.879(m,2H),3.428-3.397(t,2H),3.304(s,3H),3.005-2.936(m,1H),2.825-2.705(m,2H),2.266(s,3H),2.146-2.092(m,1H),1.880-1.802(m,2H)。MS(m/e):410.31(M+Na+)。
实施例17
4-氟-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
用实施例4中的合成方法，由1-(2-甲氧丙基)-3-氨基-2,6-哌啶二酮醋酸盐和3-氟酞酐反应制得标题化合物。得到淡黄色粘稠状产品0.631克(HPLC纯度97.42％)；收率31.1％。1HNMR(CDCl3,400MHz)δ7.792-7.743(m,1H),7.715-7.697(d,1H),7.444-7.400(m,1H),4.978-4.932(m,1H),3.988-3.871(m,2H),3.421-3.390(t,2H),3.300(s,3H),3.000-2.938(m,1H),2.851-2.691(m,2H),2.142-2.091(m,1H), 1.872-1.797(m,2H)。MS(m/e):349.22(M+H+)。
实施例18
5-氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
用实施例4中的合成方法，由5-硝基邻苯二甲酸酐和1-(2-甲氧丙基)-3-氨基-2,6-哌啶二酮醋酸盐反应制得5-硝基-2-(1-(2-甲氧丙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮。得到浅黄色油状产品1.118克(HPLC纯度98.44％)；收率20％。MS(m/e):376.25(M+H+)。
用实施例7中的合成方法，由5-硝基-2-(1-(2-甲氧丙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮反应制得浅黄色固体产品0.697克(HPLC纯度97.79％)；收率67.7％。1HNMR(CDCl3,400MHz)δ7.624-7.603(d,1H),7.031-7.027(d,1H),6.861-6.835(dd,1H),4.925-4.879(m,1H),3.977-3.863(m,2H),3.421-3.390(t,2H),3.301(s,3H),2.969-2.922(m,1H),2.820-2.676(m,2H),2.108-2.056(m,1H),1.869-1.794(m,2H)。MS(m/e):346.24(M+H+)。
实施例19
4-氨基-2-(1-(2-乙氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
用实施例16中的合成方法，由N-((苄氧基)羰基)-谷氨酸酐反应制得棕色油状产物粗品1-(2-乙氧乙基)-3-苄氧酰胺基-2,6-哌啶二酮17.2克。
用实施例4中的合成方法，由1-(2-乙氧乙基)-3-氨基-2,6-哌啶二酮醋酸盐和3-硝基邻苯二甲酸酐反应制得4-硝基-2-(1-(2-乙氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮灰白色固体产品1.326克(HPLC纯度95.24％)；收率39.4％。MS(m/e):376.23(M+H+)。
用实施例7中的合成方法，由4-硝基-2-(1-(2-乙氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮反应制得黄色固体4-氨基-2-(1-(2-乙氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮0.631克(HPLC纯度94.95％)；收率51.7％。1HNMR(CDCl3,400MHz)δ7.450-7.411(dd,1H),7.174-7.156(d,1H),6.881-6.860(d,1H),4.963-4.918(m,1H),4.119-3.994(m,2H),3.575-3.480(m,4H),3.023-2.921(m,1H),2.839-2.714(m,2H),2.140-2.035(m,1H),1.180-1.145(t,3H)。MS(m/e):346.24(M+H+)。
实施例20
4-氟基-2-(1-(2-乙氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
用实施例4中的合成方法，由1-(2-乙氧乙基)-3-氨基-2,6-哌啶二酮醋酸盐和3-氟酞酐反应制得标题化合物淡黄色粘稠状产品1.566克(HPLC纯度98.63％)；收率74.7％。1HNMR(CDCl3,400MHz)δ7.792-7.743(m,1H),7.715-7.698(d,1H),7.444-7.400(m,1H),5.019-4.974(m,1H),4.147-3.984(m,2H),3.570-3.475(m,4H),3.045-2.941(m,1H),2.862-2.733(m,2H),2.167-2.087(m,1H),1.178-1.143(t,3H)。MS(m/e):349.23(M+H+)。
实施例21
5-氟-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮的制备
用实施例4中的合成方法，由4-氟邻苯二甲酸酐和1-(2-甲氧乙基)-3-氨基-2,6-哌啶二酮醋酸盐反应制得标题化合物白色固体产品2.905克(HPLC纯度99.64％)；收率77.9％。1HNMR(CDCl3,400MHz)δ7.912-7.880(dd,1H),7.572-7.549(dd,1H),7.457-7.408(dt,1H),5.023-4.978(m,1H),4.144-3.988(m,2H),3.544-3.512(m,2H),3.342(s,3H),3.056-2.933(m,1H),2.859-2.738(m,2H),2.175-2.080(m,1H)。MS(m/e):357.20(M+Na+)。
实施例22
4-氨基-2-(1-(2-甲氧丁基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
用实施例11中的合成方法，由3-氨基-N-(2,6-二氧代-3-哌啶基)邻苯二甲酰亚胺和1-溴-4-甲氧基丁烷反应制得标题化合物黄色固体产品2.625克(HPLC纯度99.02％)；收率79.9％。1HNMR(CDCl3,400MHz)δ7.455-7.416(dd,1H),7.178-7.160(dd,1H),6.884-6.863(dd,1H),4.927-4.882(m,1H),3.858-3.816(m,2H),3.402-3.371(t,2H),3.317(s,3H),3.007-2.916(m,1H),2.819-2.685(m,2H),2.117-2.067(m,1H),1.651-1.571(m,4H)。MS(m/e):360.28(M+H+)。
实施例23
4-羟基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
用实施例4中的合成方法，由3-羟基邻苯二甲酸酐和1-(2-甲氧乙基)-3-氨基-2,6-哌啶二酮醋酸盐反应制得标题化合物白色固体产品2.833克(HPLC纯度99.54％)；收率80.1％。1HNMR(CDCl3,400MHz)δ7.649-7.609(dd,1H),7.539(bs,1H),7.430-7.412(d,1H),7.214-7.193(d,1H),4.980-4.934(m,1H),4.146-3.991(m,2H),3.549-3.516(m,2H),3.342(s,3H),3.048-2.941(m,1H),2.843-2.724(m,2H),2.165-2.083(m,1H)。MS(m/e):333.19(M+H+)。
实施例24
4-甲基-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮的制备
用实施例4中的合成方法，由3-甲基邻苯二甲酸酐和1-(2-甲氧乙基)-3-氨基-2,6-哌啶二酮醋酸盐反应制得标题化合物白色固体产品2.348克(HPLC纯度98.36％)；收率68.1％。1HNMR(CDCl3,400MHz)δ7.716-7.697(d,1H),7.623-7.586(t,1H),7.508-7.489(d,1H),5.017-4.972(m,1H),4.143-3.996(m,2H),3.547-3.516(t,2H),3.344(s,3H),3.006-2.944(m,1H),2.855-2.732(m,2H),2.698(s,3H),2.153-2.084(m,1H)。MS(m/e):353.23(M+Na+)。
实施例25
4-氨基-5-甲氧基-2-(1-(2-甲氧基乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮的制备
将4-氨基-5-羟基-2-(1-(2-甲氧基乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮)(2.5克)、碘甲烷(1.02克)、碳酸钾(1.99克)和N,N-二甲基甲酰胺(25毫升)加入反应瓶中，室温搅拌反应16小时，反应完全。室温下，将反应液加入水中，搅拌，过滤，收集滤饼即为粗品。粗品以叔丁基甲基醚/乙酸乙酯打浆纯化得到黄色固体产品1.94克(HPLC纯度96.08％)；收率74.6％。1HNMR(CDCl3,400MHz)δ7.180-7.160(d,1H),6.891-6.871(d,1H),5.388(bs,2H),4.954-4.909(m,1H),4.136-3.987(m,2H),3.943(s,3H),3.541-3.511(t,2H),3.340(s,3H),2.983-2.944(m,1H),2.793-2.744(m,2H),2.130-2.035(m,1H)。MS(m/e):362.22(M+H+)。
实施例26
4-氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮或其药物可接受的盐
将3-硝基邻苯二甲酸酐(5g,25.9mmol)，L-谷氨酰胺(3.782g,25.9mmol)，45ml乙腈置于100ml三口瓶中，氩气保护，磁力搅拌，于90℃回流反应，14小时，完毕，降温，室温下加入N,N’-羰基二咪唑(12.591g,77.7mmol)，室温下搅拌至无气泡放出，重新置于84℃油浴中反应1小时，停止加热，冷却至室温，剧烈搅拌下将反应液加入到225ml 1mol/L盐酸中，搅拌，过滤，所得滤饼用25ml无水乙醇打浆，过滤，所得固体真空干燥得黄色产品2-(2,6-二氧代哌啶-3-基)-4-硝基异吲哚啉-1,3-二酮5.125g，收率65.3％。
取2-(2,6-二氧代哌啶-3-基)-4-硝基异吲哚啉-1,3-二酮(3g,9.9mmol)，45ml N,N-二甲基甲酰胺置于100ml单口瓶中，一次性加入氢化钠(60％含量,0.872g,21.8mmol)，室温下搅拌15分钟，将3-溴丙基甲基醚(1.8g,12mmol)溶于4ml N,N-二甲基甲酰胺中缓慢滴入，完 毕，继续反应2.5小时，将反应液倾入400ml饱和氯化铵水溶液中，乙酸乙酯萃取(200ml/次,共3次)，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩，残余物用柱层析分离得4-硝基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮(1.211g)，收率32.3％。
取4-硝基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮(1.875g,5mmol)，钯碳(10％,0.4g)，10ml甲醇，10ml四氢呋喃置于100ml单口瓶中，置换体系气体为氢气，常压室温下搅拌过夜，原料反应完毕，将反应液通过硅藻土过滤，滤液浓缩，残余物硅胶柱柱层析，得4-氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮(1.135g)，HPLC纯度96.51％，收率：65.8％。MS(m/e):346(M+H+)。
实施例27
4-氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备
中国专利ZL200510013292.3中公开了4-氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮的制备方法。本文通过引用的方式将其全部内容并入本文。
也可以参照实施例26的制备方法使用3-溴乙基甲基醚替换3-溴丙基甲基醚制备标题化合物。1HNMR(CDCl3,600MHz)δ7.38(t,1H),7.11(d,1H),6.85(d,1H),5.30(bs,2H),4.95-4.98(m,1H),4.09-4.13(m,1H),4.00-4.04(m,1H),3.52-3.54(m,2H),3.34(s,3H),2.96-2.99(m,1H),2.76-2.75(m,1H),2.78-2.80(m,1H),2.08-2.11(m,1H)。MS(m/e):332(M+H+)。
生物学实施例1
哌啶-2,6-二酮衍生物对DNBS诱导大鼠炎症性肠炎模型治疗作用实验
实验动物：Wistar大鼠，雄性，体重100-120g。
实验方法：90只雄性Wistar大鼠禁食40小时，禁食期间皮下注射给予一次5％葡萄糖注射液，从禁食大鼠中选出60只状态正常和体重适中的大鼠，按体重将动物随机分为6组：正常对照组、模型对照组、柳氮磺吡啶组(300mg/kg)、实施例27分别设5、15和30mg/kg剂量组，每组各10只。动物用乙醚麻醉，用特制灌胃器(注：由直径为2毫米的大鼠灌胃器嵌套在直径为1毫米的小鼠灌胃器上特制而成)，由肛门轻缓插入8厘米处的肠腔内，模型对照组、柳氮磺吡啶组、实施例27各剂量组分别注入50mg/ml DNBS的30％乙醇溶液0.5ml，正常对照组注入30％乙醇溶液0.5ml，取出灌胃器后动物在麻醉状态倒置15分钟。模型制备当天为实验第1天，从DNBS诱导4小时后开始给予相应药物或相应体积的1％CMC-Na，每天给药1次，记录体重并对粪便性状进行评分，于实验第6天处理动物取结肠组织观察各指标结 果。
实施例27、柳氮磺吡啶：配制方法：以1％CMC-Na混悬，现用现配。
表3.分组表
Figure PCTCN2017112669-appb-000019
注：i.g：灌胃；qd×6：每天给药一次，共给药6次。
实验第6天处理动物观察各指标结果。动物处死后取结肠，观察结肠粘连程度，并测量结肠长度；清除结肠内容物后计算溃疡面积、称量结肠组织重量。结肠组织纵向一分为二，将其中一半结肠组织固定在10％的福尔马林溶液中，以待后用。另一半结肠组织投入液氮速冻后，转移置于-80℃保存备用，用于检测MPO。
表4.大鼠结肠粘连程度评分标准：
Figure PCTCN2017112669-appb-000020
参考文献：Videla S,Vilaseca J,Medina C,et al.Selective inhibition of phosphodiesterase-4 ameliorates chronic colitis and prevents intestinal fibrosis[J].Journal of Pharmacology and Experimental Therapeutics,2006, 316(2):940-945。
溃疡面积计算方法：溃疡点长度(cm)×溃疡点宽度(cm)。
取冻存的组织液氮中研磨成粉末，取适量称重，按25mg/ml加50mM磷酸钾缓冲液(含有0.5％十六烷基三甲基溴化铵)中，电动匀浆器匀浆，取1ml混悬液离心取上清液。取7μl上清液加至96孔板中，再加200μl邻联茴香胺混合液(含0.167mg/ml邻联茴香胺和0.0006％H2O2磷酸钾缓冲液)，置于酶标仪450nm处检测0、30、60、
90s OD值。
数据统计学分析方法：运用Spss13.0进行数据方差齐性检验，如果数据方差齐性(P>0.05)，则进行单因素方差分析LSD检验；若数据方差分析显著(P≤0.05)，则进行Dunnett’s多重比较(参数法)或选用Kruskal-Wallis非参数检验，如果Kruskal-Wallis非参数检验结果显著(P≤0.05)，则进一步采用Mann-Whitney U检验进行两两比较。
实验结果
表5.各实验组动物结肠指标结果(Mean±SD)
Figure PCTCN2017112669-appb-000021
注：*：与正常对照组相比，P<0.01。#：与模型对照组相比，P<0.05。
表6.各实验组动物结肠指标结果(Mean±SD)
Figure PCTCN2017112669-appb-000022
注：*：与正常对照组相比，P<0.05。#：与模型对照组相比，P<0.05。
结肠组织相关指标结果显示，与正常对照组相比，模型对照组动物结肠显著缩短，结肠组织异常增生而结肠重量增加。同时，结肠组织MPO活性显著升高，结肠内有较大面积的溃疡损伤；阳性药柳氮磺吡啶300mg/kg剂量下，可相应减少结肠异常增生而降低结肠重量，对结肠溃疡也有一定的改善作用，减少溃疡面积约60％；实施例27在5mg/kg、15mg/kg和30mg/kg能减轻结肠粘连程度、降低结肠组织重量和溃疡程度以及结肠组织MPO活性等，均呈现一定的剂量效应，具有较好的治疗作用，并且不会引起动物体重降低。其中，实施例27在30mg/kg剂量下可降低结肠溃疡程度，减少溃疡面积约80％，同时，
结肠组织MPO活性显著降低(P<0.05)，其治疗作用优于阳性药柳氮磺吡啶-300mg/kg。
生物学实施例2
哌啶-2,6-二酮衍生物对DNBS诱导大鼠炎症性肠炎模型治疗作用实验
实验分组与造模：110只雄性Wistar大鼠禁食40小时，禁食期间皮下注射给予一次5％葡萄糖注射液(10ml/kg)，从禁食大鼠中选出48只状态正常和体重适中的大鼠，按体重将动物随机分为5组：正常对照组、模型对照组、柳氮磺吡啶组(300mg/kg)、地塞米松组(0.1mg/kg)、实施例26组(30mg/kg)，实施例27组(30mg/kg)，每组8只。动物用异氟烷麻醉，用特制灌胃器(注：由直径为2毫米的大鼠灌胃器嵌套在直径为1毫米的小鼠灌胃器上特制而成)，由肛门轻缓插入8厘米处的肠腔内，模型对照组、实施例26组、实施例27组分别注入50mg/ml DNBS的30％乙醇溶液0.5ml，正常对照组注入30％乙醇0.5ml，各动物灌肠后取出灌胃器，在麻醉状态倒置15分钟。模型制备当天为实验第1天，从DNBS诱导4小时后开始灌胃给予相应药物或相应体积的1％CMC-Na，每天给药1次，于实验第6天处理动物观察各指标结果。对结肠黏连程度进行评分、测量结肠长度以及溃疡面积、称取结肠重量并计算结肠重量长度比。
实施例26、实施例27、柳氮磺吡啶和地塞米松：配制方法：以1％CMC-Na混悬，现用现配。
表7.分组表
Figure PCTCN2017112669-appb-000023
注：qd×6：每天给药一次，共给药6次。
数据统计学分析方法：运用Spss进行Levene’s Test进行数据均一性检验，如果数据均一(P>0.05)，则进行单因素方差分析检验；如果方差分析显著(P≤0.05)，则进行Dunnett’s多重比较(参数法)。如果Levene’s Test的结果显著(P≤0.05)，则进行Kruskal-Wallis非参数检验，
如果Kruskal-Wallis非参数检验结果显著(P≤0.05)，则进一步采用
Mann-Whitney U检验进行两两比较。
实验结果：
表8.实验组动物结肠指标结果(Mean±SD)
Figure PCTCN2017112669-appb-000024
注：*：与正常对照组相比，P<0.05。**：与正常对照组相比，P<0.01。#：与模型对照组相比，P<0.05。##：与模型对照组相比，P<0.01。
本次实验结果显示，动物经DNBS乙醇溶液诱导后，诱导动物体重增长速度低于正常对照组，从实验第4天开始柳氮磺吡啶组、实施例26组、实施例27组动物体重增长速度高于模型对照组动物，地塞米松组体重增长较慢，间接提示各药物对动物结肠损伤有改善作用。
粪便性状结果显示，各DNBS诱导组动物诱导后均有腹泻症状出现，至实验第5天，各给药组动物腹泻和稀便症状较模型对照组略有改善。
结肠指标结果显示，模型对照组动物结肠溃疡面积、结肠重量显著高于正常对照组(P<0.05)，同时结肠明显缩短。与模型对照组相比，各给药组结肠溃疡面积均具有显著的减少(P<0.05)。
综合上述结果显示，实施例26、实施例27对改善模型具有较好的治疗作用。
生物学实施例3
哌啶-2,6-二酮衍生物对DNBS诱导大鼠炎症性肠炎模型治疗作用实验
实验分组与造模：选取102只雄性Wistar大鼠禁食40小时，禁食期间皮下注射给予一次5％葡萄糖盐水，从禁食大鼠中选取72只状态正常和体重适中的大鼠，按体重将动物随机分为9组(详见表9分组表)。
将大鼠禁食40小时后乙醚麻醉，用特制灌胃器，由肛门轻缓插入8cm处的肠腔内，模型对照组、各实验组组注入50mg/ml DNBS的30％乙醇溶液0.5ml，正常对照组注入相应体积的30％乙醇，各动物灌肠 后麻醉状态倒置15min。模型制备当天为实验第0天，DNBS诱导4h后开始给予相应药物或相应体积的1％CMC-Na，每天给药1次，每日记录动物体重，于实验第7天处理动物，对结肠黏连程度进行评分、测量结肠长度以及溃疡面积、称取结肠重量并计算结肠重量长度比。
表9.分组表
Figure PCTCN2017112669-appb-000025
注：实施例各化合物均使用1％CMC-Na混悬，配置成3mg/ml均一的混悬液，给药体积为10ml/kg。qd×7：每天给药一次，共给药7次。ig：灌胃。
应用SPSS22对大鼠结肠长度、结肠单位长度下重量进行One-WayAnova单因素方差分析，对各组间进行统计学分析；对黏连评分以及溃疡面积使用非参数Mann-Whitney U检验，对各组间进行统计学分析。
表10.大鼠结肠粘连程度评分标准
Figure PCTCN2017112669-appb-000026
实验结果
表11.各组受试大鼠7天内体重变化表(g,Mean±SD)
Figure PCTCN2017112669-appb-000027
Figure PCTCN2017112669-appb-000028
表12.各实验组动物结肠相关数据
Figure PCTCN2017112669-appb-000029
注：***:与空白对照组相比P<0.001。#:与模型对照组相比P<0.05。##:与模型对照组相比0.001≤P＜0.01。
单位长度重量增长抑制率计算公式：(模型组结肠长重量长度比-给药组结肠长重量长度比)/(模型组结肠长重量长度比-空白组结肠长重量长度比)。
各实验组动物经治疗，均可有效缓解结肠病理变化(黏连、增生、溃疡)。
生物学实施例4
哌啶-2,6-二酮衍生物对DNBS诱导大鼠炎症性肠炎模型治疗作用实验
实验分组与造模：选取102只雄性Wistar大鼠禁食72小时，禁食期间皮下注射给予2次5％葡萄糖盐水，从禁食大鼠中选取88只状态正常和体重适中的大鼠，按体重将动物随机分为11组(详见表13分组表)。
将大鼠禁食72小时后乙醚麻醉，用特制灌胃器，由肛门轻缓插入8cm处的肠腔内，模型对照组、各实验组注入50mg/ml DNBS的30％乙醇溶液0.5ml，正常对照组注入相应体积的30％乙醇，各动物灌肠后麻醉状态倒置15min。模型制备当天为实验第0天，DNBS诱导4h后开始给予相应药物或相应体积的1％CMC-Na，每天给药1次，每日 记录动物体重，于实验第7天处理动物，对结肠黏连程度进行评分、测量结肠长度以及溃疡面积、称取结肠重量并计算结肠重量长度比。
表13.分组表
Figure PCTCN2017112669-appb-000030
注：各实验药物均使用1％CMC-Na混悬，配置成3mg/ml均一的混悬液，给药体积为10ml/kg。i.g.：灌胃；qd×7：每天给药1次，共给药7天。
表14.大鼠结肠粘连程度评分标准
Figure PCTCN2017112669-appb-000031
应用SPSS22对大鼠结肠长度、结肠单位长度下重量进行One-WayAnova单因素方差分析，对各组间进行统计学分析；对黏连评分以及溃疡面积使用非参数Mann-Whitney U检验，对各组间进行统计学分析。
实验结果
表15.各组受试大鼠7天内体重变化表(g,Mean±SD)
Figure PCTCN2017112669-appb-000032
表16.各实验组动物结肠相关数据
Figure PCTCN2017112669-appb-000033
注：***:与空白对照组相比P<0.001。**:与空白对照组相比0.001≤P<0.01。#:与模型对照组相比P<0.05，##:与模型对照组相比0.001≤p<0.01。
单位长度重量增长抑制率计算公式：(模型组结肠长重量长度比-给药组结肠长重量长度比)/(模型组结肠长重量长度比-空白组结肠长重量长度比)。
各实验组动物经治疗，均可有效缓解结肠病理变化(黏连、增生、溃疡)。
生物学实施例5
哌啶2,6-二酮衍生物小鼠单次口服急性毒性实验
实验步骤
实验前一天对小鼠进行禁食处理，实验当天每个实验组分别选取6只小鼠(ICR小鼠，体重范围19-21g，雌性各三只)。首先选取雌雄各一只动物进行1000mg/kg口服灌胃，观察5-10分钟，如无明显毒副作用，将剩余4只动物依此剂量进行口服灌胃，观察10-15分钟，如无死亡装盒，平衡饲养7天，每日观察状态并记录体重。动物分组计划及药物初始剂量如下表所示：
表17.动物分组信息表
Figure PCTCN2017112669-appb-000034
给药后0-15分钟观察指标
行动：不安定多动发生
神经系统反应：震颤痉挛惊厥运动失调姿态异常等
自主神经：眼球突出流涎流泪排尿(血尿)腹泻竖毛呼吸等七日内观察指标
体重
动物状态：嗜睡多动兴奋脱毛腹泻行为异常死亡等
实验结果
表18.受试动物7天内毒性反应概述表
注：表18中组别未标注剂量的均为1000mg/kg；“n＝1”表示本组中的受试动物例数为1只，未标注“n＝1”的组中的受试动物例数为3只。观察指标未说明的为未发现异常。
Figure PCTCN2017112669-appb-000035
Figure PCTCN2017112669-appb-000036
表19.受试雄性小鼠每日体重变化表(g,Mean±SD)
Figure PCTCN2017112669-appb-000037
表20.受试雌性小鼠每日体重变化表(g,Mean±SD)
Figure PCTCN2017112669-appb-000038
Figure PCTCN2017112669-appb-000039
各组别动物体重轻微波动上升态势，在1000mg/kg剂量下各化合物对小鼠体重变化均无不良影响。
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应该理解，前文涉及本公开的示例性实施方式，并且可以在不背离权利要求中所述的本公开的实质和范围的情况下进行修改。

Claims (24)

  1. 式(I)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐：
    Figure PCTCN2017112669-appb-100001
    其中，
    R1表示一个或多个H、卤素、-OH、-C1-4烷基、-NH2、-NHC1-4烷基、-N(C1-4烷基)2或-NHCOC1-4烷基；
    R2表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；以及
    R3表示-H或-C1-4烷基。
  2. 如权利要求1所述的式(I)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐：
    Figure PCTCN2017112669-appb-100002
    其中，
    R1表示一个或多个-H、-F、-Cl、-Br、-OH、-CH3、-CH2CH3、-CH2CH2CH3、-NHCH3、-NH2、-NH CH2CH3、-N(CH3)2、-N(CH2CH3)2、-NHCOCH3或-NHCOCH2CH3；
    R2表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；以及
    R3表示-H、-CH3或-CH2CH3。
  3. 如权利要求1所述的式(I)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐：
    Figure PCTCN2017112669-appb-100003
    其中，
    R1表示一个或多个-H、-F、-OH、-CH3、-NHCH3、-N(CH3)2、-NHCOCH3或-NH2；
    R2表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；以及
    R3表示-H、-CH3或-CH2CH3。
  4. 如权利要求1所述的式(I)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐：
    Figure PCTCN2017112669-appb-100004
    其选自：
    4-乙酰基氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-甲基氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-二甲氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氟-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4,5,6,7-四氟-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-2-(1-(2-羟基乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    5-氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-5-羟基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉 -1,3-二酮及其药物可接受的盐；
    4-氨基-5-氟-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-7-羟基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-乙酰氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氟-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    5-氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-2-(1-(2-乙氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氟基-2-(1-(2-乙氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    5-氟-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-2-(1-(2-甲氧丁基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-羟基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-甲基-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二及其药物可接受的盐；
    4-氨基-5-甲氧基-2-(1-(2-甲氧基乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；以及
    4-氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐。
  5. 式(II)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐：
    Figure PCTCN2017112669-appb-100005
    Figure PCTCN2017112669-appb-100006
    其中，
    R4表示一个或多个H、卤素、-OH、-C1-4烷基、-NH2、-NHC1-4烷基、-N(C1-4烷基)2或-NHCOC1-4烷基；
    R5表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；
    R6表示-S-、-SO-、-SO2-、-NH-或-N(C1-4烷基)-；以及
    R7表示-H或-C1-4烷基。
  6. 如权利要求5所述的式(II)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐：
    Figure PCTCN2017112669-appb-100007
    其中，
    R4表示一个或多个-H、-F、-Cl、-Br、-OH、-CH3、-NHCH3、-NHCH2CH3、-NH2、-N(CH3)2、-N(CH2CH3)2、-NHCOCH3或-NHCOCH2CH3；
    R5表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；
    R6表示-S-、-SO-、-SO2-、-NH-或-N(CH3)-；以及
    R7表示-H、-CH3或-CH2CH3。
  7. 如权利要求5所述的式(II)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐：
    Figure PCTCN2017112669-appb-100008
    其中，
    R4表示-NH2或-NHCOCH3；
    R5表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；
    R6表示-S-、-SO-、-SO2-、-NH-或-N(CH3)-；以及
    R7表示-H、-CH3或-CH2CH3。
  8. 如权利要求5所述的式(II)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐：
    Figure PCTCN2017112669-appb-100009
    其选自：
    4-氨基-2-(1-(2-甲基硫乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-2-(1-(2-甲基亚磺酰乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；以及
    4-氨基-2-(1-(2-甲基磺酰基乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐。
  9. 式(III)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐：
    Figure PCTCN2017112669-appb-100010
    其中，
    R8表示一个或多个H、卤素、-C1-4烷基、-NH2、-NHC1-4烷基、-N(C1-4烷基)2或-NHCOC1-4烷基；
    R9表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；
    R10表示-O-、-S-、-SO-、-SO2-、-NH-或-N(C1-4烷基)-；
    R11表示-H或-C1-4烷基；以及
    R12表示卤素或-C1-4烷基。
  10. 如权利要求9所述的式(III)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐，
    Figure PCTCN2017112669-appb-100011
    R8表示一个或多个-H、-F、-Cl、-Br、-OH、-CH3、-NHCH3、-NHCH2CH3、-NH2、-N(CH3)2、-N(CH2CH3)2、-NHCOCH3或-NHCOCH2CH3；
    R9表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；
    R10表示-O-、-S-、-SO-、-SH-或-N(CH3)-；
    R11表示-H、-CH3或-CH2CH3；以及
    R12表示卤素或-C1-4烷基。
  11. 某如权利要求9所述的式(III)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐，
    Figure PCTCN2017112669-appb-100012
    其中，
    R8表示-NH2或-NHCOCH3；
    R9表示-CH2CH2-、-CH2CH2CH2-或-CH2CH2CH2CH2-；
    R10表示-O-、-S-、-SO-、-SO2-、-NH-或-N(CH3)-；
    R11表示-H、-CH3或-CH2CH3；以及
    R12表示卤素或-C1-4烷基。
  12. 如权利要求9所述的式(III)所示的哌啶-2,6-二酮衍生物及其药物可接受的盐，其选自：
    4-氨基-2-(1-(2-甲氧乙基)-3-氟-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；以及
    4-氨基-2-(1-(2-甲氧乙基)-3-甲基-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐。
  13. 哌啶-2,6-二酮衍生物及其药物可接受的盐，其选自：
    4-乙酰基氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-甲基氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-二甲氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氟-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4,5,6,7-四氟-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-2-(1-(2-羟基乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    5-氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-2-(1-(2-甲氧乙基)-3-氟-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-2-(1-(2-甲氧乙基)-3-甲基-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-乙酰氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-5-氟-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-7-羟基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-2-(1-(2-甲基硫乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-2-(1-(2-甲基亚磺酰乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-2-(1-(2-甲基磺酰基乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-2-(1-(2-二甲氨基乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉 -1,3-二酮及其药物可接受的盐；
    4-氨基-2-(1-(2-甲氧乙基)-3-氟-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-2-(1-(2-甲氧乙基)-3-甲基-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-乙酰氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氟-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    5-氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-2-(1-(2-乙氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氟基-2-(1-(2-乙氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    5-氟-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-2-(1-(2-甲氧丁基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-羟基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-甲基-2-(1-(2-甲氧乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-5-甲氧基-2-(1-(2-甲氧基乙基)-2,6-二氧代哌啶-3-基)-异吲哚啉-1,3-二酮及其药物可接受的盐；
    4-氨基-2-(1-(2-甲氧乙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐；以及
    4-氨基-2-(1-(2-甲氧丙基)-2,6-二氧杂哌啶-3-基)异吲哚啉-1,3-二酮及其药物可接受的盐。
  14. 药物组合物，其包含权利要求1至13中任一权利要求所述的哌啶-2,6-二酮衍生物或其药物可接受的盐，以及药物可接受的载体、稀释剂或赋形剂。
  15. 治疗克罗恩氏病的方法，其包括对需要所述方法的个体给予治疗有效量的权利要求1至13中任一权利要求所述的哌啶-2,6-二酮衍生物或其药物可接受的盐或治疗有效量的权利要求14所述的药物组合物。
  16. 如权利要求15所述的方法，其中所述克罗恩氏病为轻度克罗恩氏病、中度克罗恩氏病、重度克罗恩氏病或缓解期克罗恩氏病。
  17. 如权利要求15或16所述的方法，其中所述个体为人类。
  18. 如权利要求15至17中任一权利要求所述的方法，其中口服给予所述哌啶-2,6-二酮衍生物或其药物可接受的盐或含有所述哌啶-2,6-二酮衍生物或其药物可接受的盐的药物组合物。
  19. 如权利要求18所述的方法，其中以固体制剂或液体制剂形式口服给予所述哌啶-2,6-二酮衍生物或其药物可接受的盐或含有所述哌啶-2,6-二酮衍生物或其药物可接受的盐的药物组合物。
  20. 如权利要求19所述的方法，其中所述固体制剂为片剂、胶囊剂或糖丸。
  21. 如权利要求20所述的方法，其中所述片剂为素片、糖衣片或薄膜衣片。
  22. 如权利要求19所述的方法，其中所述液体制剂为溶液剂或混悬剂。
  23. 用于治疗克罗恩氏病的权利要求1至13中任一权利要求所述的哌啶-2,6-二酮衍生物及其药物可接受的盐。
  24. 用于治疗克罗恩氏病的药物组合物，其包含权利要求1至13中任一权利要求所述的哌啶-2,6-二酮衍生物或其药物可接受的盐，以及药物可接受的载体、稀释剂或赋形剂。
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