CN1642551B - 组蛋白脱乙酰基酶抑制剂 - Google Patents

组蛋白脱乙酰基酶抑制剂 Download PDF

Info

Publication number
CN1642551B
CN1642551B CN038058332A CN03805833A CN1642551B CN 1642551 B CN1642551 B CN 1642551B CN 038058332 A CN038058332 A CN 038058332A CN 03805833 A CN03805833 A CN 03805833A CN 1642551 B CN1642551 B CN 1642551B
Authority
CN
China
Prior art keywords
alkyl
amino
chemical compound
acid
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CN038058332A
Other languages
English (en)
Other versions
CN1642551A (zh
Inventor
K·范埃梅伦
M·G·C·费尔东克
S·F·A·范布兰德特
P·R·安日博
L·梅尔佩尔
A·B·戴亚特金
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceutica NV
Original Assignee
Janssen Pharmaceutica NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Janssen Pharmaceutica NV filed Critical Janssen Pharmaceutica NV
Publication of CN1642551A publication Critical patent/CN1642551A/zh
Application granted granted Critical
Publication of CN1642551B publication Critical patent/CN1642551B/zh
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/402—1-aryl substituted, e.g. piretanide
    • 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
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • 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
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/34—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving hydrolase
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Wood Science & Technology (AREA)
  • Neurology (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Pulmonology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Genetics & Genomics (AREA)
  • Analytical Chemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Physics & Mathematics (AREA)
  • Biophysics (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Ophthalmology & Optometry (AREA)

Abstract

本发明包括式(I)的新化合物，其中n、R1、R2、R3、R4、Q、X、Y、Z具有规定的含义，其具有抑制组蛋白脱乙酰基酶的酶活性；它们的制备方法、包含它们的组合物以及它们作为药物的用途。

Description

组蛋白脱乙酰基酶抑制剂
本发明涉及具有抑制组蛋白脱乙酰基酶(HDAC)的酶活性化合物。本发明进一步涉及它们的制备方法、包含它们的组合物以及它们在体外和体内抑制HDAC和作为药物的用途，例如作为抑制增生状况的药物，如癌症和牛皮癣。
在所有真核细胞中，染色质中基因组DNA与组蛋白结合形成核小体。每个核小体由两组H2A、H2B、H3和H4组蛋白所形成的蛋白质八聚体组成。DNA缠绕在该蛋白核上，组蛋白的碱性氨基酸与DNA带负电的磷酸根基团相互作用。最常见的核心组蛋白翻译后修饰是保守的强碱性N末端赖氨酸残基的ε-氨基的可逆乙酰化。通过竞争性组蛋白乙酰转移酶和此处被称为“HDAC”的组蛋白脱乙酰基酶之间的动态平衡，建立组蛋白乙酰化的稳定状态。长期以来组蛋白的乙酰化和脱乙酰化被认为与转录调控有关。最近编码不同组蛋白乙酰转移酶和组蛋白脱乙酰基酶的基因克隆为组蛋白乙酰化和转录调控之间的关系提供了可能的解释。组蛋白的可逆乙酰化可导致染色质的重建，因而成为基因转录的调控机制。通常，组蛋白过乙酰化有利于基因的表达，而组蛋白脱乙酰化与转录阻抑相关联。组蛋白乙酰转移酶显示出转录辅激活因子的作用，而组蛋白脱乙酰基酶属于转录阻抑路径。
组蛋白乙酰化和脱乙酰化之间的动态平衡对于细胞的正常生长是必需的。组蛋白脱乙酰基酶的抑制导致细胞周期停滞、细胞分化、编程性细胞死亡和转化表型的逆转。因此HDAC抑制剂在治疗细胞增生性疾病或状况方面有很强的治疗潜力。(Marks等，Nature Review：Cancer 1：194-202，2001)。
对组蛋白脱乙酰基酶(HDAC)抑制剂的研究表明实际上这些酶在细胞增生和分化中有着重要的作用。抑制剂曲古抑菌素A(TSA)在G1和G2阶段都能导致细胞周期的阻滞，逆转不同细胞系的转化表型，并诱导Friend白血病细胞和其它细胞的分化。据报道TSA(和辛二酰苯胺异羟肟酸SAHA)在小鼠中可以抑制细胞的生长、诱导终末分化以及防止肿瘤的形成(Finnin等，Nature，401：188-193，1999)。
也有报道曲古抑菌素A在治疗纤维样变性方面有用，例如肝纤维化和肝硬化(Geerts等，欧洲专利申请EP 0 827 742，1998年3月11日公开)。
2001年5月31日公开的专利申请WO01/38322中与其它抑制剂一起公开了通式Cy-L1-Ar-Y1-C(O)-NH-Z组蛋白脱乙酰基酶抑制剂，提供了治疗细胞增生疾病和状态的组合物和方法。
2001年9月27目公开的专利申请WO01/70675公开了式Cy-X-Y1-W和Cy-S(O)2-NH-Y3-W组蛋白脱乙酰基酶抑制剂，并进一步提供了治疗细胞增生疾病和状态的组合物和方法。
所要解决的问题是提供具有高度酶活性的组蛋白脱乙酰基酶抑制剂，该抑制剂还要显示优越的性质例如细胞活性和提高的生物有效性，优选口服生物有效性，以及具有较少或者没有副作用。
本发明的新化合物解决了上述问题。这些化合物与现有技术的结构不同。
本发明化合物显示出极好的体外抑制组蛋白脱乙酰基酶的酶活性。本化合物在细胞活性方面具有优越的性质，并具有在G1和G2检测点(p21诱导能力)抑制细胞周期过程的特定性质。本发明化合物显示良好的代谢稳定性和较高的生物有效性，尤其是它们显示出口服生物有效性。
本发明涉及式(I)化合物
其N-氧化物形式、药学上可接受的加成盐及其立体化学异构体形式，其中
n为0、1、2或3，且当n为0时，为直接的键；
每个Q为氮或者
Figure G03805833219940520D000022
每个X为氮或者
每个Y为氮或者
Figure G03805833219940520D000024
每个Z为氮或者
Figure G03805833219940520D000025
R1为C(O)NR5R6、-N(H)C(O)R7、-C(O)-C1-6链烷二基(alkanediyl)SR7、-NR8C(O)N(OH)R7、-NR8C(O)C1-6链烷二基SR7、-NR8C(O)C＝N(OH)R7或者另一个Zn-螯合基团，其中R5和R6各自独立地选自氢、羟基、C1-6烷基、羟基C1-6烷基、氨基C1-6烷基或氨基芳基；
R7独立地选自氢、C1-6烷基、C1-6烷基羰基、芳基C1-6烷基、C1-6烷基吡嗪基、吡啶环酮(pyridinone)、吡咯烷环酮(pyrrolidinone)或甲基咪唑基；
R8独立地选自氢或C1-6烷基；
R2为氢、卤素、羟基、氨基、硝基、C1-6烷基、C1-6烷氧基、三氟甲基、二(C1-6烷基)氨基、羟基氨基或者萘磺酰基吡嗪基；
R3为氢、C1-6烷基、芳基C2-6烯二基(alkenediyl)、呋喃羰基、萘基羰基、-C(O)苯基R9、C1-6烷基氨基羰基、氨基磺酰基、芳基氨基磺酰基、氨基磺酰基氨基、二(C1-6烷基)氨基磺酰基氨基、芳基氨基磺酰基氨基、氨基磺酰基氨基C1-6烷基、二(C1-6烷基)氨基磺酰基氨基C1-6烷基、芳基氨基磺酰基氨基C1-6烷基、二(C1-6烷基)氨基C1-6烷基、C1-12烷基磺酰基、二(C1-6烷基)氨基磺酰基、三卤C1-6烷基磺酰基、二(芳基)C1-6烷基羰基、苯硫基C1-6烷基羰基、吡啶基羰基或者芳基C1-6烷基羰基，
其中各个R9独立地选自苯基；被一个、两个或者三个独立地选自卤素、氨基、C1-6烷基、C1-6烷氧基、羟基C1-4烷基、羟基C1-4烷氧基、氨基C1-4烷氧基、二(C1-4烷基)氨基C1-4烷氧基、二(C1-6烷基)氨基C1-6烷基、二(C1-6烷基)氨基C1-6烷基(C1-6烷基)氨基C1-6烷基、羟基C1-4烷基哌嗪基C1-4烷基、C1-4烷氧基哌啶基C1-4烷基、羟基C1-4烷氧基C1-4烷基哌嗪基、C1-4烷基哌嗪基C1-4烷基、二(羟基C1-4烷基)氨基C1-4烷基、吡咯烷基C1-4烷氧基、吗啉基C1-4烷氧基、或者吗啉基C1-4烷基的取代基取代的苯基；苯硫基；或者被二(C1-4烷基)氨基C1-4烷氧基、二(C1-6烷基)氨基C1-6烷基、二(C1-6烷基)氨基C1-6烷基(C1-6烷基)氨基C1-6烷基、吡咯烷基C1-4烷氧基、C1-4烷基哌啶基C1-4烷基、二(羟基C1-4烷基)氨基C1-4烷基或吗啉基C1-4烷氧基取代的苯硫基。
R4为氢、羟基、氨基、羟基C1-6烷基、C1-6烷基、C1-6烷氧基、芳基C1-6烷基、氨基羰基、羟基羰基、氨基C1-6烷基、氨基羰基C1-6烷基、羟基羰基C1-6烷基、羟基氨基羰基、C1-6烷氧基羰基、C1-6烷基氨基C1-6烷基或二(C1-6烷基)氨基C1-6烷基；
当R3和R4在同一个碳原子上时，R3和R4一起可以形成下式的二价基团
-C(O)-NH-CH2-NR10-            (a-1)
其中R10为氢或芳基；
当R3和R4在相邻的碳原子上时，R3和R4一起可以形成下式的二价基团
＝CH-CH＝CH-CH＝            (b-1)；
以上的芳基为苯基，或者被一个或者多个各自独立地选自卤素、C1-6烷基、C1-6烷氧基、三氟甲基、氰基或羟基羰基的取代基取代的苯基。
术语“组蛋白脱乙酰基酶抑制剂”或者“组蛋白脱乙酰基酶的抑制剂”是用于表示一种化合物，它能够与组蛋白脱乙酰基酶相互作用并抑制其活性，更具体地说抑制其酶活性。抑制组蛋白脱乙酰基酶的酶活性意味着降低组蛋白脱乙酰基酶从组蛋白上除去乙酰基的能力。优选地，这种抑制是特异性的，即组蛋白脱乙酰基酶抑制剂在一定浓度下能够降低组蛋白脱乙酰基酶从组蛋白上除去乙酰基的能力，该浓度低于该抑制剂产生一些其它不相关的生物效应所需的浓度。
如以上定义中和以下所使用，卤素是氟、氯、溴和碘的总称；C1-4烷基定义为具有1至4个碳原子的直链或者支链饱和烃基，如甲基、乙基、丙基、丁基、1-甲基乙基、2-甲基丙基等；C1-6烷基包括C1-4烷基和其具有5至6个碳原子的更高同系物，例如戊基、2-甲基-丁基，己基、2-甲基戊基等；C1-6链烷二基定义为具有1至6个碳原子的二价直链或支链饱和烃基，例如亚甲基、1，2-乙二基、1，3-丙二基、1，4-丁二基、1，5-戊二基、1，6-己二基及其支链异构体例如2-甲基戊二基、3-甲基戊二基、2，2-二甲基丁二基、2，3-二甲基丁二基等；三卤代C1-6烷基定义为含有三个相同或不同卤素取代基的C1-6烷基如三氟甲基；C2-6烯二基定义为具有一个双键并具有2至6个碳原子的二价直链或支链烃基，例如乙烯二基、2-丙烯二基、2-丁烯二基、2-戊烯二基、3-戊烯二基、3-甲基-2-丁烯二基等等；以及氨基芳基定义为被氨基取代的芳基。
术语“另一个Zn-螯合基团”指能够与可能位于酶结合位点的Zn-离子相互作用的基团。
药学上可接受的加成盐包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。上述药学上可接受的酸加成盐的含义包括式(I)化合物能够形成的具有治疗活性的无毒酸加成盐的形式。具有碱性的式(I)化合物可以通过用合适的酸处理所述碱性形式而转化成它们药学上可接受的酸加成盐。合适的酸包括，例如，无机酸例如氢卤酸，如盐酸或氢溴酸；硫酸；硝酸；磷酸等酸；有机酸，例如，乙酸、三氟乙酸、丙酸、羟基乙酸、乳酸、丙酮酸、草酸、丙二酸、琥珀酸(即丁二酸)、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、对甲基苯磺酸、环己烷氨基磺酸、水扬酸、对-氨基-水杨酸、扑酸(pamoic acid)等酸。
具有酸性的式(I)化合物可以通过用合适的有机或无机碱处理所述酸的形式而转化为它们的药学上可接受的碱加成盐。合适碱性盐形式包括，例如，铵盐、碱金属盐和碱土金属盐、如锂、钠、钾、镁、钙等盐，与有机碱的盐、如benzathine、N-甲基-D-葡糖胺、hydrabamine的盐，以及氨基酸例如精氨酸、赖氨酸等的盐。
术语“酸或碱加成盐”也包括式(I)化合物能够形成的水合物和溶剂加成形式。这些形式的实例有例如水合物、醇化物等。
此处所用术语“式(I)化合物的立体化学异构体形式”定义为由相同的原子以相同的键序列构成但具有不同的式(I)化合物可能具有的三维结构的所有可能的化合物，上述三维结构不能相互转换。除非另有说明或指示，化合物的化学名称包括所述化合物具有的所有可能的立体化学异构体形式的混合物。所述混合物可以含有所述化合物的基本分子结构的所有非对映体和/或对映体。所有以纯的形式或者相互掺和物形式的式(I)化合物的立体化学异构体形式都包括在本发明的范围之内。
式(I)化合物的N-氧化物形式的含义包括其中一个或多个氮原子被氧化成所谓的N-氧化物的式(I)化合物，特别是其中一个或多个哌啶-、哌嗪或哒嗪基-氮被N-氧化的N-氧化物。
一些式(I)化合物也可以以它们的互变异构体形式存在。这种形式虽然在上述式中没有明确表明，但也包括在本发明的范围之内。
在任何下文中所使用的术语“式(I)化合物”还包括药学上可接受的加成盐和所有立体异构体形式。
这里所用的术语“组蛋白脱乙酰基酶”和“HDAC”指从位于组蛋白N-端的赖氨酸残基的ε-氨基上除去乙酰基的酶家族的任何一个成员。除非在上下文中另有指示，术语“组蛋白”指来源于任何物种的任何组蛋白，包括H1、H2A、H2B、H3、H4和H5。人类HDAC蛋白质或基因产物包括但不局限于HDAC-1、HDAC-2、HDAC-3、HDAC-4、HDAC-5、HDAC-6、HDAC-7、HDAC-8、HDAC-9和HDAC-10。组蛋白脱乙酰基酶也可以来自于原生动物或真菌源。
第一组感兴趣的化合物包括施加一个或者多个以下限定的式(I)化合物：
a)n为0或1；
b)每个Q为
Figure G03805833219940520D000061
c)R1为-C(O)NH(OH)或-NHC(O)C1-6链烷二基SH；
d)R2为氢或硝基；
e)R3为C1-6烷基、芳基C2-6烯二基、呋喃羰基、萘基羰基、C1-6烷基氨基羰基、氨基磺酰基、二(C1-6烷基)氨基磺酰基氨基C1-6烷基、二(C1-6烷基)氨基C1-6烷基、C1-12烷基磺酰基、二(C1-6烷基)氨基磺酰基、三卤代C1-6烷基磺酰基、二(芳基)C1-6烷基羰基、苯硫基C1-6烷基羰基、吡啶基羰基或者芳基C1-6烷基羰基；
f)R4为氢；
g)当R3和R4在同一个碳原子上时，R3和R4一起可以形成式(a-1)的二价基团，其中R10为芳基；
当R3和R4在相邻的碳原子上时，R3和R4一起可以形成式(b-1)的二价基团。
第二组感兴趣的化合物包括施加一个或者多个以下限定的式(I)化合物：
a)n为1；
b)每个Q为
Figure G03805833219940520D000062
c)每个Z为氮；
d)R1为-C(O)NH(OH)；
e)R2为氢；
f)R3为萘基羰基、C1-12烷基磺酰基或者二(芳基)C1-6烷基羰基；
g)R4为氢；
第三组感兴趣的化合物包括式(I)化合物，其中R2为氢。
第四组感兴趣的化合物包括式(I)化合物，其中R1为-C(O)NH(OH)。
第五组感兴趣的化合物包括式(I)化合物，其中R2为氢且R1为-C(O)NH(OH)。
第六组感兴趣的化合物包括施加一个或者多个以下限定的式(I)化合物：
a)R1为C(O)NR5R6、-C(O)-C1-6链烷二基SR7、-NR8C(O)N(OH)R7、-NR8C(O)C1-6链烷二基SR7、-NR8C(O)C＝N(OH)R7或者另一个Zn-螯合基团，其中R5和R6各自独立地选自氢、羟基、羟基C1-6烷基或氨基C1-6烷基；
b)R2为氢、卤素、羟基、氨基、硝基、C1-6烷基、C1-6烷氧基、三氟甲基或二(C1-6烷基)氨基；
c)R3为氢、C1-6烷基、芳基C2-6烯二基、呋喃羰基、萘基羰基、-C(O)苯基R9、C1-6烷基氨基羰基、氨基磺酰基、芳基氨基磺酰基、氨基磺酰基氨基、二(C1-6烷基)氨基磺酰基氨基、二(C1-6烷基)氨基C1-6烷基、C1-12烷基磺酰基、二(C1-6烷基)氨基磺酰基或者吡啶基羰基，其中各个R9独立地选自苯基；被一个、两个或者三个独立地选自卤素、C1-6烷基、C1-6烷氧基的取代基取代的苯基；或苯硫基；
d)R4为氢、羟基、氨基、羟基C1-6烷基、C1-6烷基、C1-6烷氧基、芳基C1-6烷基、氨基羰基、氨基C1-6烷基、C1-6烷基氨基C1-6烷基或二(C1-6烷基)氨基C1-6烷基。
一组优选的化合物包括以下式(I)化合物，其中
R1为C(O)NR5R6、-C(O)-C1-6链烷二基SR7、-NR8C(O)N(OH)R7、-NR8C(O)C1-6链烷二基SR7、-NR8C(O)C＝N(OH)R7或者另一个Zn-螯合基团，其中R5和R6各自独立地选自氢、羟基、羟基C1-6烷基或氨基C1-6烷基；
R2为氢、卤素、羟基、氨基、硝基、C1-6烷基、C1-6烷氧基、三氟甲基或二(C1-6烷基)氨基；
R3为氢、C1-6烷基、芳基C2-6烯二基、呋喃羰基、萘基羰基、-C(O)苯基R9、C1-6烷基氨基羰基、氨基磺酰基、芳基氨基磺酰基、氨基磺酰基氨基、二(C1-6烷基)氨基磺酰基氨基、二(C1-6烷基)氨基C1-6烷基、C1-12烷基磺酰基、二(C1-6烷基)氨基磺酰基或者吡啶基羰基，其中各个R9独立地选自苯基；被一个、两个或者三个独立地选自卤素、C1-6烷基、C1-6烷氧基的取代基取代的苯基；苯硫基；和
R4为氢、羟基、氨基、羟基C1-6烷基、C1-6烷基、C1-6烷氧基、芳基C1-6烷基、氨基羰基、氨基C1-6烷基、C1-6烷基氨基C1-6烷基或二(C1-6烷基)氨基C1-6烷基。
进一步优选的一组化合物包括以下式(I)化合物，
其中n为0或1；每个Q为R1为-C(O)NH(OH)或-NHC(O)-C1-6链烷二基SH；R2为氢或硝基；R3为C1-6烷基、芳基C2-6烯二基、呋喃羰基、萘基羰基、C1-6烷基氨基羰基、氨基磺酰基、二(C1-6烷基)氨基磺酰基氨基C1-6烷基、二(C1-6烷基)氨基C1-6烷基、C1-12烷基磺酰基、二(C1-6烷基)氨基磺酰基、三卤代C1-6烷基磺酰基、二(芳基)C1-6烷基羰基、苯硫基C1-6烷基羰基、吡啶基羰基或者芳基C1-6烷基羰基；R4为氢；当R3和R4在同一个碳原子上时，R3和R4一起可以形成式(a-1)的二价基团，其中R10为芳基；或当R3和R4在相邻的碳原子上时，R3和R4一起可以形成式(b-1)的二价基团。
更优选的一组化合物包括以下式(I)化合物，
其中n为1；每个Q为
Figure G03805833219940520D000082
每个Z为氮；R1为-C(O)NH(OH)；R2为氢；R3为萘基羰基、C1-12烷基磺酰基或二(芳基)C1-6烷基羰基；R4为氢。
最优选的化合物为18号、5号和24号化合物。
Figure G03805833219940520D000083
式(I)化合物、它们的药学上可接受的盐及其N-氧化物和立体化学异构体形式可以通过常规的方式制备。
一般性的合成路线作为实例包括：
a)其中R1为-C(O)NH(OH)的式(I)异羟肟酸，该化合物被称作式(I-a)化合物，可以通过将式(II)中间体与合适的酸如三氟乙酸进行反应制得。所述反应在合适的溶剂中进行，例如甲醇。
b)式(II)中间体可以通过将式(III)中间体与式(IV)中间体在合适的试剂如N’-(乙基碳化亚氨(ethylcarbonimidoyl))-N，N-二甲基-1，3-丙二胺，单盐酸盐(EDC)和1-羟基-1H-苯并三唑(HOBT)的存在下进行反应制备。该反应可以在合适的溶剂例如DCM和THF的混合物中进行。
Figure G03805833219940520D000092
c)式(III)中间体可以通过将式(V)中间体与合适的碱例如NaOH在合适的溶剂例如乙醇的存在下进行反应制得。
式(I)化合物也可以采用固相合成技术有利地制得。通常，固相合成包括在合成中将中间体与聚合物载体进行反应。然后该聚合物-负载的中间体可以进行很多合成步骤。各步骤之后，都过滤树脂，并且用各种溶剂将其洗涤多次以除去杂质。在各步骤中，树脂可以被分开，以在下一步骤中与各种中间体进行反应，从而合成很大数量的化合物。进行该方法的最后步骤以后，将树脂通过一种试剂或者工序进行处理以从样品中除去树脂。固相化学中所用技术的更详细解释在例如“The Combinatorial Index”(B.Bunin，Acedemic Press)和Novabiochem’s 1999 Catalogue & Peptide SynthesisHandbook(Novabiochem AG，Switzerland)中已经描述，两者均结合于此作为参考。
式(I)化合物和一些中间体在它们的结构中可具有至少一个手性中心。该手性中心可以以R或者S构型存在。
用上述方法制备的式(I)化合物通常为对映异构体的外消旋混合物，其可以通过本领域已知的解析方法进行相互分离。式(I)外消旋化合物可以通过与合适的手性酸反应而被转化成相应的非对映体盐的形式。随后将所述非对映体盐的形式通过例如选择性地或者分步结晶进行分离，再将对映异构体用碱从中分离出来。另一种分离式(I)化合物对映异构体形式的方法包括采用手性固定相的液相色谱法。所述纯的立体化学异构体形式也可以由相应的合适原料的纯的立体化学异构体形式制得，只要反应能够立体有择地进行。优选地，如果需要特定的立体异构体，所述化合物将通过立体有择的制备方法合成。这些方法将有利地采用对映异构体纯原料。
式(I)化合物、其药学上可接受的酸加成盐及其立体异构体形式具有重要的药理学性质，因为它们具有对组蛋白脱乙酰基酶(HDAC)的抑制效果。
本发明提供一种通过给予有效量的本发明化合物抑制细胞包括变形细胞异常生长的方法。细胞异常生长是指与正常调节机制无关的生长(例如失去接触抑制)。其包括通过促使生长阻滞、终末分化、和/或癌细胞凋亡直接抑制肿瘤生长，以及通过抑制肿瘤形成新血管而间接抑制肿瘤生长。
本发明还提供向需要这种治疗的受治疗者如哺乳动物(特别是人)给予有效量的本发明化合物抑制肿瘤生长的方法。特别地，本发明提供一种通过给予有效量本发明化合物抑制肿瘤生长的方法。可以抑制的肿瘤的实例包括但不局限于肺癌(例如胰腺癌并包括非小细胞肺癌)、胰腺癌(例如胰腺癌如外分泌性胰腺癌)、结肠癌(结肠直肠癌，如结肠腺癌和结肠腺瘤)、前列腺癌包括晚期疾病、淋巴造血系统肿瘤(例如急性淋巴性白血病、B-细胞淋巴瘤、Burkitt′s淋巴瘤)、骨髓性白血病(例如急性骨髓性白血病(AML))、甲状腺滤泡癌、脊髓发育不良综合症(MDS)、间质细胞源性肿瘤(例如纤维肉瘤和横纹肌肉瘤)、黑色素瘤、畸胎癌、神经母细胞瘤、胶质瘤、皮肤良性肿瘤(例如角化棘皮瘤)、乳腺癌(例如晚期乳腺癌)、肾癌、卵巢癌、膀胱癌和表皮癌。
本发明化合物可以用于其它治疗目的，例如：
a)在对肿瘤进行放射以治疗癌症之前、期间和之后给予根据本发明的化合物以促进肿瘤的敏感性；
b)治疗关节病和骨状况例如类风湿性关节炎、骨关节炎、青少年关节炎、痛风、多关节炎、牛皮癣性关节炎、强直性脊柱炎和系统性红斑狼疮；
c)抑制平滑肌细胞增生包括血管增生失调、动脉粥样硬化和再狭窄(restenosis)等；
d)治疗炎症性疾病和皮肤疾病例如溃疡性结肠炎、克罗恩氏病、过敏性鼻炎、移植物对宿主反应疾病、结膜炎、哮喘、ARDS、贝切特氏病、移植排斥反应、uticaria、过敏性皮炎、斑形脱发(alopeciaareata)、硬皮病、疹病、湿疹、皮肤真菌病、痤疮、糖尿病、系统性红斑狼疮、川崎病、多发性硬化病、肺气肿、囊性纤维化和慢性支气管炎；
e)治疗子宫内膜异位症、子宫纤维瘤、功能性子宫出血和子宫内膜增生；
f)治疗眼睛血管化例如血管病损伤视网膜和脉络膜血管病；
g)治疗心脏功能障碍；
h)抑制免疫抑制疾病例如治疗HIV感染；
i)治疗肾功能障碍；
j)抑制内分泌紊乱；
k)抑制糖原异生功能障碍；
1)治疗神经系统疾病，例如帕金森病症或者导致认知紊乱的神经系统疾病例如阿尔茨海默氏病或与聚谷酰胺相关的神经性病症；
m)抑制神经肌肉病，例如淀粉样侧索硬化(amylotropic lateralsclerosis)；
n)治疗脊髓性肌萎缩；
o)治疗其它能够接受加强基因表达的状况；
p)增强基因治疗。
因此本发明公开了式(I)化合物用作药物以及用式(I)化合物制备治疗一种或多种上述状况的药物。
式(I)化合物、其药学上可接受的酸加成盐以及立体异构体形式具有重要的诊断性能，因为它们可用于检测或鉴别生物样品中的HDAC，包括检测和测定标记化合物和HDAC之间复合物的形成。
该检测或鉴别方法可以使用用标记试剂例如放射性同位素、酶、荧光物质、发光物质等标记的化合物。放射性同位素的实例包括125I、131I、3H和14C。酶通常通过与合适的底物结合而可被检测到，从而又催化可检测的反应。其实例包括例如β-半乳糖苷酶、β-葡糖苷酶、碱性磷酸变位酶、过氧化物酶和苹果酸脱氢酶，优选辣根过氧化物酶。发光物质包括例如鲁米诺、鲁米诺衍生物、虫荧光素、水母发光蛋白和荧虫素酶。
生物样品可定义为身体组织或体液。体液的实例有脑脊髓液、血、血浆、血清、尿、痰液、唾液等。
鉴于它们有用的药理学性质，受试化合物可以配制成各种用于给药目的的药物剂型。
为了制备本发明的药物组合物，用有效量的具体化合物以碱或酸加成盐的形式作为活性成分，与药学上可接受的载体结合形成紧密的混合物，该载体可以采取各种各样的形式，取决于给药所需的剂型。合乎需要的是这些药物组合物采用适合的，优选口服、直肠、经皮、或者非肠道注射给药的单位剂型。例如，在制备口服剂型组合物时，可以使用任何常用的药物介质，例如对于口服液体制剂如混悬液、糖浆剂、酏剂和溶液可以用水、二元醇、油类、醇类等；或者对于散剂、药丸、胶囊剂和片剂可以用固体载体例如淀粉、糖、白陶土、润滑剂、粘合剂、崩解剂等。
由于易于给药，片剂和胶囊剂代表最有利的口服剂量单位剂型，在这种情况下显然采用固体药物载体。对于非肠道组合物，载体通常包括无菌水作为至少大部分，虽然也可以包括其它成分，例如用于助溶。例如可以制备其中载体包括生理盐水溶液、葡萄糖溶液或生理盐水与葡萄糖溶液混合物的注射用溶液。也可以制备注射用混悬液，在这种情况下使用合适的液体载体、悬浮剂等。在适合用于经皮给药的组合物中，载体任选包括渗透促进剂和/或合适的润湿剂，任选以较小的比例与任何天然的合适添加剂结合，该添加剂不会对皮肤产生明显的有害效果。所述添加剂可以使促进皮肤给药和/或有助于制备所需组合物。这些组合物可以以各种方式给药，例如透皮帖剂、spot-on或软膏剂。
将上述药物组合物配制成剂量单位剂型对于方便给药和统一剂量非常有利。本说明书和权利要求书中所用的剂量单位剂型是指合适作为单位剂量的物理分散单元，每个单位含有通过计算能够产生预期治疗效果的预定量活性成分和所需的药物载体。这种剂量单位剂型的实例有片剂(包括刻痕片剂和糖衣片剂)、胶囊剂、药丸、粉末袋、糯米纸囊剂、注射用溶液或混悬液、茶匙量制剂、汤匙量制剂等，及其分开的复合体。
本领域技术人员很容易通过下文中提供的测定结果确定有效量。通常认为治疗有效量为0.05mg/kg体重至100mg/kg体重，特别是0.05mg/kg体重至10mg/kg体重。将所需要的剂量以2个、3个、4个或更多亚-剂量在全天中以适当间隔给药比较合适。所述小剂量可以被配制成单位剂量剂型，例如每单位剂量剂型含有5至500mg，特别是10mg至500mg活性成分。
作为本发明的另一方面，考虑了将HDAC-抑制剂与另一种抗癌药剂结合，特别是用作药物，更具体地说用于治疗癌或相关疾病。
对于治疗上述状况，本发明化合物可以有利地与一种或多种其它药物制剂，更具体地，与其它抗癌药剂结合。抗癌药剂的实例有：
-铂配位化合物，例如顺铂、卡铂、oxalyplatin；
-紫杉烷类化合物，例如紫杉醇或多西他赛；
-拓扑异构酶I抑制剂，例如喜树碱化合物如依立替康或托泊替康；
-拓扑异构酶II抑制剂，例如抗肿瘤鬼臼毒素衍生物如依托泊苷或替尼泊苷；
-抗肿瘤长春花生物碱，如长春花碱、长春新碱或长春瑞宾；
-抗肿瘤核苷衍生物，例如5-氟尿嘧啶、吉西他滨或卡培他滨；
-烷化剂，例如氮芥或亚硝基脲如环磷酰胺、苯丁酸氮芥、卡莫司汀或洛莫司汀；
-抗肿瘤蒽环霉素衍生物，例如柔红霉素、多柔比星、伊达比星、或米托蒽醌；
-HER2抗体，例如曲妥单抗；
-雌激素受体拮抗剂或选择性雌激素受体调节剂，例如他莫西芬、托瑞米芬、屈洛昔芬、faslodex或雷洛昔芬；
-芳香酶抑制剂，例如依西美坦、阿纳托唑、来曲唑和伏氯唑；
-分化诱导试剂，例如类视黄醇、维生素D和视黄酸代谢阻滞剂(RAMBA)，例如异维生素A酸(accutane)；
-DNA甲基转移酶抑制剂，例如氮杂胞苷；
-激酶抑制剂，例如flavoperidol、甲磺酸伊马替尼或gefitinib；
-法呢基转移酶(farnesyltransferase)抑制剂；或
-其它HDAC抑制剂。
此处所用术语“铂配位化合物”指任何抑制肿瘤细胞生长的铂配位化合物，其提供离子形式的铂。
术语“紫杉烷类化合物”指具有紫杉烷环系的一类化合物，与某些物种的紫杉(红豆杉属)提取物有关，或来源于该提取物。
术语“拓扑异构酶抑制剂”用于指能够改变真核细胞中DNA拓扑结构的酶。它们对重要的细胞功能和细胞增生是很关键的。在真核细胞中有两种类型的拓扑异构酶，即I型和II型。拓扑异构酶I是分子量约为100,000的单体酶。该酶结合于DNA并引起瞬时单链分离，使双螺旋展开(或容许其展开)，随后在从DNA链上脱离之前将裂缝重新封闭。拓扑异构酶II具有类似的作用机理，包括诱导DNA链分离或形成自由基。
术语“喜树碱类化合物”用于指与母体喜树碱化合物有关或者源于该母体喜树碱的化合物，它是来源于生长于中国的树Camptothecinacuminata和生长于印度的树Nothapodytes foetida的一种水不溶性生物碱。
术语“鬼臼毒素化合物”用于指与母体鬼臼毒素有关或源于该母体鬼臼毒素的化合物，它是从曼德拉草(mandrake)植物中提取得到的。
术语“抗肿瘤长春花生物碱”用于指与长春花属植物(长春花)提取物有关或者来源于该提取物的化合物。
术语“烷化剂”包括各类化学物质，它们具有在生理条件下能够向生物重要大分子如DNA提供烷基的共同特征。对于大部分更重要的药物例如氮芥和亚硝基脲，在配位化合物进行降解反应后，在体内产生活性烷基化残基，其中一些反应是酶催反应。烷化剂最重要的药理作用是扰乱与细胞增生特别是DNA合成和细胞分裂有关的基础机制。烷化剂妨碍快速增生组织中DNA的功能和完整性是它们的治疗用途和它们的许多毒性的基础。
术语“抗肿瘤蒽环霉素衍生物”包括从真菌Strep.peuticus var.caesius获得的抗生素以及它们的衍生物，特征在于具有四环素环状结构，该结构带有通过配糖键相连的特殊糖六碳氨糖。
初期的乳腺癌中人表皮生长因子受体2蛋白(HER 2)的扩增已显示与对某些患者较差的预断有关。曲妥单抗是高度纯化重组DNA-来源的人单克隆IgG1 κ抗体，它能高亲和力并且高选择性地结合于胞外HER2受体区域。
许多乳腺癌具有雌激素受体，且这些肿瘤的生长可以被雌激素刺激。术语“雌激素受体拮抗剂”和“选择性雌激素受体调节剂”用于指结合于雌激素受体(ER)的雌甾二醇的竞争性抑制剂。当结合到ER时，选择性雌激素受体调节剂诱导受体的三维形状发生改变，抑制其结合于DNA上的雌激素应答单元(ERE)。
对于绝经后的妇女，循环雌激素的主要来自于肾上腺和卵巢雄激素(雄烯二酮和睾甾酮)通过周围组织的芳香酶转化成雌激素(雌激素酮和雌甾二醇)。通过芳香酶抑制或灭活除去雌激素对于绝经后的激素-依赖性乳腺癌患者是一种有效和选择性的治疗。
此处所用术语“抗雌激素药剂”不仅包括雌激素受体拮抗剂和选择性雌激素受体调节剂，而且还包括上述芳香酶抑制剂。
术语“分化诱导试剂”包括以各种方式抑制细胞增生和诱导分化的化合物。已知维生素D和类视黄醇对调节各种正常和恶性细胞的生长和分化具有重要的作用。视黄酸代谢阻滞剂(RAMBA′s)通过抑制细胞色素P450-介导的视黄酸异化作用来提高内源视黄酸水平。
DNA甲基化改变是人肿瘤形成中最常见的异常。选择基因启动子的高度甲基化通常与相关基因的失活相关联。术语“DNA甲基转移酶抑制剂”用于指通过药理上抑制DNA甲基转移酶和使肿瘤抑制基因表达再激活而起作用的化合物。
术语“激酶抑制剂”包括与细胞周期过程和程序细胞死亡(凋亡)相关的强激酶抑制剂。
术语“法呢基转移酶抑制剂”用于指被设计用于防止Ras和其它细胞内蛋白质法呢基化的化合物。已有显示它们能够影响恶性细胞增生和存活。
术语“其它HDAC抑制剂”包括但不局限于：
-短链脂肪酸，例如丁酸、4-苯基丁酸或丙戊酸(valproic acid)；
-异羟肟酸，例如辛二酰苯胺异羟肟酸(SAHA)、二芳基异羟肟酸A-161906、双环-芳基-N-羟基-羧酰胺、pyroxamide、CG-1521、PXD-101、磺酰胺异羟肟酸、LAQ-824、曲古抑菌素A(TSA)、oxamflatin、scriptaid、m-羧基肉桂酸二异羟肟酸、或trapoxin-异羟肟酸类似物；
-环四肽，例如trapoxin、apidicin或缩酚肽(depsipeptide)；
-苯甲酰胺类，例如MS-275、或C1-994，或者
-depudecin。
对于治疗癌症，本发明化合物可以如上所述向患者给药，并结合放射治疗。放射指电离辐射，特别是γ辐射，尤其是现在常用的线性加速器或者放射核放出的辐射。肿瘤的放射核照射可以位于肿瘤外或肿瘤内。
本发明还涉及抗癌药剂与本发明HDAC抑制剂的复方药。
本发明还涉及根据本发明的复方药用于医疗例如抑制肿瘤细胞的生长。
本发明还涉及根据本发明的复方药用于抑制肿瘤细胞的生长。
本发明还涉及一种抑制受治疗者肿瘤细胞生长的方法，包括给受治疗者服用有效量的本发明的复方药。
本发明进一步提供一种通过给予有效量的本发明复方药抑制细胞包括变形细胞异常生长的方法。
另一种药物和HDAC抑制剂可以同时给药(例如以分开的或者单位组合物的形式)或者以任意顺序先后给药。对于后者，两个化合物在一定期间内以一定的剂量和方式进行给药，以确保足以实现有益或协同效果。可以理解，优选的给药方法和顺序以及复方药各组分的各自剂量和服用方式取决于所给予的具体的另一种药物和HDAC抑制剂、它们的给予途径、受治疗的具体肿瘤和受治疗的具体宿主。给予的最佳方法和顺序以及剂量和服药方式可以由本领域的技术人员通过常规的方法参考此处所提供的信息很快地进行确定。
在一个疗程中，铂配位化合物的给药剂量较好地为1至500mg每平方米(mg/m2)体表面积，例如50至400mg/m2，具体地对于顺氯氨铂剂量为约75mg/m2，以及对于卡波铂约为约300mg/m2。
在一个疗程中，紫杉烷类化合物的给药剂量较好地为50至400mg每平方米(mg/m2)体表面积，例如75至250mg/m2，具体地对于紫杉醇剂量约为175至250mg/m2，以及对于多西他赛约为75至150mg/m2。
在一个疗程中，喜树碱类化合物的给药剂量较好地为0.1至400mg每平方米(mg/m2)体表面积，例如1至300mg/m2，具体地对于依立替康剂量约为100至350mg/m2，以及对于托泊替康约为1至2mg/m2。
在一个疗程中，抗肿瘤鬼臼毒素衍生物的给药剂量较好地为30至300mg每平方米(mg/m2)体表面积，例如50至250mg/m2，具体地对于依托泊苷剂量约为35至100mg/m2，以及对于替尼泊甙约为50至250mg/m2。
在一个疗程中，抗肿瘤长春花生物碱的给药剂量较好地为2至30mg每平方米(mg/m2)体表面积，具体地对于长春碱剂量约为3至12mg/m2，对于长春新碱剂量约为1至2mg/m2，以及对于长春瑞宾剂量约为10至30mg/m2。
在一个疗程中，抗肿瘤核苷衍生物的给药剂量较好地为200至2500mg每平方米(mg/m2)体表面积，例如700至1500mg/m2，具体地对于5-FU剂量约为200至500mg/m2，对于吉西他滨剂量约为800至1200mg/m2，以及对于卡倍他滨约为1000至250mg/m2。
在一个疗程中，烷化剂例如氮芥或亚硝基脲的给药剂量较好地为100至500mg每平方米(mg/m2)体表面积，例如120至200mg/m2，具体地对于环磷酰胺剂量约为100至500mg/m2，对于苯丁酸氮芥剂量约为0.1至0.2mg/kg，对于卡莫司汀剂量约为150至200mg/m2，以及对于洛莫司汀剂量约为100至150mg/m2。
在一个疗程中，蒽环霉素类衍生物的给药剂量较好地为10至75mg每平方米(mg/m2)体表面积，例如15至60mg/m2，具体地对于多柔比星剂量约为40至75mg/m2，对于柔红霉素剂量约为25至45mg/m2，以及对于伊达比星(idarubicin)剂量约为10至15mg/m2。
在一个疗程中，曲妥单抗的给药剂量较好地为1至5mg每平方米(mg/m2)体表面积，特别是2至4mg/m2。
抗雌激素药的给药剂量较好的约为1至100mg每日，取决于具体的药物和所治疗的病症。他莫西芬较好的口服剂量为5至50mg，优选10至20mg，每天两次，持续足够的治疗时间，以达到和维持治疗效果。托瑞米芬较好的口服给药剂量为约60mg，每天一次，持续足够的治疗时间，以达到和维持治疗效果。阿纳托唑较好的口服给药剂量为约1mg，每天一次。屈洛昔芬较好的口服给药剂量为约20至100mg，每天一次。雷洛昔芬较好的口服给药剂量为约60mg，每天一次。依西美坦较好的口服给药剂量为约25mg，每天一次。
每个疗程可以给予这些剂量例如一次、两次或更多次，其可以每隔7、14、21或者28天进行重复给药。
鉴于它们有价值的药理性质，根据本发明的复方药，即另一种药物和HDAC抑制剂可以被配制成各种给药目的的剂型。这些组分可以被单独配制成各自的药物组合物，或者配制成含有两者组分的单一药物组合物。
因此本发明也涉及含有另一种药物和HDAC抑制剂以及一种或多种药物载体的药物组合物。
本发明还涉及一种根据本发明的以包括一种抗癌药剂和本发明HDAC抑制剂以及一种或多种药物载体的药物组合物形式的复方药。
本发明进一步涉及根据本发明的复方药在制备用于抑制肿瘤细胞生长的药物组合物的用途。
本发明进一步涉及含有本发明HDAC抑制剂作为第一活性成分以及一种抗癌药剂作为第二活性成分的药品，作为一种复方制剂以同时的、分开的或者先后使用的方式用于治疗癌症患者。
实验部分
以示范为目的提供以下实施例。
“BSA”指牛血清白蛋白，“DCM”指二氯甲烷，“DIEA”指二异丙基乙胺，“DMF”指二甲基甲酰胺，“DMSO”指二甲基亚砜，“EtOAc”指乙酸乙酯，“Fmoc”指芴基甲氧基羰基，“Hepes”指4-(-2-羟乙基)-1-哌嗪-乙磺酸，“HOBT”指1-羟基-1H-苯并三唑，“MeOH”指甲醇，“PyBop”指苯并三唑-1-基-氧代-三-吡咯烷-鏻六氟磷酸盐，“PyBrOP”指溴代-三-吡咯烷-鏻-六氟磷酸盐，“TEA”指三乙胺，“TFA”指三氟乙酸，“THF”指四氢呋喃，“ExtrelutTM”是Merck KgaA，Darmstadt，Germany的产品，是含有硅藻土的短柱子。
A.中间体的制备
实施例A1
a)中间体1的制备
Figure G03805833219940520D000191
中间体1
将1-(苯基甲基)-哌嗪(0.068mol)的乙腈p.a.(135ml)溶液逐渐地加入到碳酸钾(0.18mol)和2-(甲磺酰)-5-嘧啶羧酸乙酯(0.082mol)的乙腈p.a.(135ml)溶液中，将反应混合物室温搅拌45分钟。然后，将该反应混合物保持过夜。加入DCM(400ml)。再加入水(300ml)，并分出有机层，干燥(MgSO4)，过滤并蒸发溶剂。将残留物(28g)通过硅胶柱层析(洗脱液：DCM/MeOH 95/5)进行纯化。收集纯品组分并蒸发溶剂。残留物用乙腈进行结晶，过滤并真空干燥，得15.1g中间体1。
b)中间体2的制备
中间体2
将中间体1(0.03mol)与EtOH(250ml)的混合物以Pd/C10％(2g)作为催化剂于50℃下进行氢化。吸收H2(1当量)后，过滤除去催化剂，滤液蒸发。将残留物通过硅胶柱层析(洗脱液：DCM/(MeOH/NH3)90/10)进行纯化。收集产物部分并蒸发溶剂，得6.8g(＞96％)中间体2。
c)中间体3的制备
中间体3
在N2流下，将二甲基-氨基磺酰氯(0.0015mol)的DCM(1ml)溶液于5℃加入到溶于DCM(1ml)的中间体2(0.0012mol)与TEA(0.0017mol)的混合物中。将该混合物在室温下搅拌18小时。加入10％的碳酸钾。将混合物用DCM萃取。分出有机层，干燥(MgSO4)，过滤并蒸干溶剂。残留物(0.69g)用乙醚提取。过滤沉淀并干燥，得0.64g(73％)中间体3，熔点193℃。
实施例A2
中间体4的制备
Figure G03805833219940520D000202
中间体4
在氮气流下，将2-(甲磺酰基)-5-嘧啶羧酸乙酯(0.0434mol)的乙腈(100ml)溶液于10℃滴加到4-哌啶甲胺(0.0868mol)和碳酸钾(0.0434mol)的乙腈(200ml)溶液中。将混合物在室温搅拌2小时，倒出到冰水中，并用DCM萃取。分出有机层，干燥(MgSO4)，过滤并蒸发溶剂。将残留物(14.18g)通过硅胶(20-45μm)柱层析(洗脱液：DCM/MeOH/NH4OH 90/10/1至80/20/2)进行纯化。收集纯的部分并蒸发溶剂，得3.7g(32％)中间体4。
实施例A3
a)中间体5的制备
中间体5
将溶于DCM(5ml)的中间体2(0.0002mol)、α-苯基苯乙酰氯(0.0003mol)和吗啉甲基-PS-清除剂(供应商Novabiochem目录编号01-64-0171：吗啉甲基聚苯乙烯HL(200-400目)，2％二乙烯基苯)(0.150g)的混合物室温搅拌20小时，然后加入三(2-氨基乙基)胺PS-清除剂(供应商Novabiochem目录编号01-64-0170：三-(2-氨基甲基)-胺聚苯乙烯HL(200-400目)，1％二乙烯基苯)(0.150g)，并将该反应混合物再搅拌4小时。过滤除去清除剂，用DCM洗涤，蒸发溶剂，得中间体5。
b)中间体6的制备
Figure G03805833219940520D000212
中间体6
将溶于氢氧化钠1N(1.5ml)的中间体5(0.0003mol)、THF(4ml)和MeOH(1ml)的混合物室温搅拌3天，然后将反应混合物用HCl(1.5ml，1N)中和。将混合物通过ExtrelutTM NT(供应商：Merck)过滤，并在氮气流下进行干燥，得中间体6。
c)中间体7的制备
Figure G03805833219940520D000213
中间体7
将溶于DCM/DMF(5ml)的中间体6(0.0003mol)、HOBT-6-羧酰胺甲基-PS-清除剂(0.200g；Novabiochem目录编号01-64 0425)和N，N-二甲基-4-吡啶胺(0.00015mol)的混合物室温搅拌15分钟，然后加入N，N′-四甲基二(hanetetraylbis)-2-丙胺(0.070ml)，将反应混合物振摇4小时。将树脂用DCM洗涤3次，DMF洗涤3次，再用DCM洗涤3次和用DMF洗涤3次，最后用DCM洗涤6次。加入O-(四氢-2H-吡喃-2-基)-羟胺(0.00026mol)的DCM(5ml)溶液，将反应混合物振摇20小时，然后加入PS连接的异氰酸甲酯(供应商Novabiochem目录编号01-64-0289：异硫氰酸甲酯聚苯乙烯HL(200-400目)，2％二乙烯基苯)(0.150g)，并将混合物振摇4小时。过滤除去清除剂，用DCM洗涤2次，采用滤液，得中间体7。
B.最终化合物的制备
实施例B1
将N-Fmoc-羟胺-2-氯三苯甲基树脂(Novabiochem，目录编号01-64-0165)用50％的哌啶DMF溶液去保护(室温，24小时)。将树脂用DCM和DMF洗涤几次，并在DMF中进行膨胀。一次性加入2当量的酸1、PyBrOP和4当量的DIEA。将混合物振荡24小时，抽去液体，将树脂用DCM和DMF洗涤几次。树脂在含有2当量胺的DMF中进行膨胀，室温下振荡24小时，抽去液体，将树脂用DCM和DMF洗涤几次。将树脂于含有4当量TEA的DMF中进行膨胀，一次性加入芳基磺酰氯(2当量)。将反应物搅拌过夜，抽去液体，将树脂用DCM和DMF洗涤。用5％的TFA的DCM溶液分离出最终产物，采用高效液相色谱和质谱进行分析，在预先称重的试管中蒸发。
1.基于树脂的负荷
作为示例目的的反应路线如下。
Figure G03805833219940520D000231
实施例B2
将N-Fmoc-羟胺-2-氯三苯甲基-树脂(Novabiochem，目录编号01-64-0165)用50％的哌啶DMF溶液去保护(室温，24小时)1。将树脂用DCM和DMF洗涤2几次，并在DMF中进行膨胀。一次性加入2当量的酸3，PyBrOP4和4当量的DIEA。将混合物振荡24小时，抽去液体，将树脂用DCM和DMF洗涤几次。将树脂在含有2当量胺的DMF中进行膨胀，室温下振荡24小时，抽去液体，将树脂用DCM和DMF洗涤。用5％的TFA的DCM溶液分离出最终产物，采用高效液相色谱和质谱进行分析，并在预先称重的试管中进行蒸发。
1.在一个实施例中(化合物1)使用了羧酸甲硫醇4-甲氧基三苯甲基-树脂(Novabiochem 01-64-0238)。
2.在一种情况下(化合物I)，在不同的洗涤步骤中也使用甲醇。
3.基于树脂的负荷
4.在一种情况下(化合物1)，用PyBOP代替PyBrOP。
实施例B3
将N-Fmoc-羟胺-2-氯三苯甲基-树脂(Novabiochem，01-64-0165)用50％的哌啶DMF溶液去保护(室温，24小时)1。将树脂用DCM和DMF洗涤2几次，并在DMF中进行膨胀。一次性加入2当量的酸3，PyBrOP4和4当量的DIEA。将混合物振荡24小时，抽去液体，将树脂用DCM和DMF洗涤几次。将树脂在含有2当量胺的DMF中进行膨胀，室温下振荡24小时，抽去液体，将树脂用DCM和DMF洗涤。将3当量的酸，DIC以及DIEA与树脂在室温下振荡过夜。将树脂抽干液体，并用DCM和DMF洗涤。用5％的TFA的DCM溶液分离出最终产物，采用高效液相色谱和质谱进行分析，并在预先称重的试管中进行蒸发。
实施例B4
a)中间体8钠盐的制备
Figure G03805833219940520D000241
中间体8钠盐
将乙醇(6ml)中的中间体3(0.0016mol)和氢氧化钠(0.0033mol)混合物进行搅拌并回流2小时，然后冷却至室温。将沉淀过滤，用乙醇洗涤，干燥，得到0.59g(＞100％)中间体8钠盐。
b)中间体9的制备
Figure G03805833219940520D000242
中间体9
在氮气流下，将N’-(乙基碳化亚氨)-N，N’-二甲基-1，3-丙二胺、单盐酸盐(0.0021mol)逐步加入到DCM/DMF(10ml)中的中间体8钠盐(0.0016mol)、O-(四氢-2H-吡喃-2-基)-羟胺(0.0021mol)和1-羟基-1H-苯并三唑(0.0021mol)的混合物中，将混合物室温搅拌一个周末。加入10％的碳酸钾溶液。将混合物用DCM进行苹取。分离有机层，干燥(硫酸镁)，过滤，蒸干溶剂。残留物(0.94克)用kromasil柱层析进行纯化(洗脱液：DCM/甲醇/氢氧化铵97/3/0.1；15-40微米)。收集纯馏分，蒸发溶剂，残余物(0.45克，65％)用二乙醚提取。将沉淀过滤并干燥，得0.422g(61％)中间体9，熔点为183℃。
c)化合物2的制备
化合物2
将0.5毫升的三氟乙酸加入至中间体9(0.0009mol)的甲醇溶液(10毫升)。室温下搅拌混合物18小时。过滤沉淀物，用DCM洗涤，干燥。得到0.176克(59％)的化合物2，熔点大于260℃。
实施例B5
中间体10的制备
Figure G03805833219940520D000252
中间体10
将中间体2(0.0019mol)与磺酰胺(0.0021mol)在1，2-二甲氧基-乙烷(5ml)中的混合物搅拌并回流4天。加入水。过滤混合物，干燥，得0.51g(83％)中间体10，熔点为192℃。
如实施例[B4]所述类似地对中间体10进行处理，得0.034g(13％)化合物3，熔点为212℃。
Figure G03805833219940520D000253
化合物3
实施例B6
中间体11的制备
中间体11
在氮气流下，将二甲基-氨基磺酰氯(0.007mol)的DCM(5ml)溶液于10℃下加入到中间体4(0.0057mol)和TEA(0.0085mol)的DCM(5ml)溶液中。将混合物搅拌过夜，然后倒入到冰水中并用DCM进行萃取。分离有机相，用硫酸镁进行干燥，过滤，并蒸发溶剂。将残留物用CH3CN/乙醚进行结晶，滤出沉淀，干燥，得0.492g(24％)中间体11，熔点为142。
如实施例[B4]所述类似地对中间体11进行处理，得0.7g(85％)化合物4，熔点为182℃。
Figure G03805833219940520D000261
化合物4
实施例B7
化合物5的制备
Figure G03805833219940520D000262
化合物5
将中间体7(0.0003mol)与乙酸、三氟乙酸(5毫升，甲醇中为5％)的混合物室温搅拌20小时，然后将混合物吹干，得到化合物5。
实施例B8
中间体12的制备
Figure G03805833219940520D000263
中间体12
将乙腈(20ml)中的中间体2(0.0025mol)，2-萘甲酰氯(0.003mol)和碳酸钾(0.005mol)的混合物搅拌并回流过夜，然后冷却至室温，倒出至冰水中，用DCM萃取。分离有机相，用硫酸镁进行干燥，过滤，并蒸发溶剂。残留物从乙醚中结晶，过滤出沉淀并干燥，得0.97g(100％)中间体12，熔点为140℃。如实施例[B4]所述类似地对中间体12进行处理，得0.338g(86％)化合物6，熔点为130℃。
Figure G03805833219940520D000271
化合物6
表F-1列出了根据上述实施例其中之一制备的化合物。在表格中使用了以下缩写。Co.No.代表化合物号码，Ex.[Bn°]代表与Bn°实施例所述相同的方法，C2HF3O2代表三氟乙酸盐，一些化合物通过熔点进行表征(mp.)，其它化合物以质谱数据[MH+](ms.)进行表征。
Figure G03805833219940520D000272
C.药理学实施例
通过组蛋白脱乙酰基酶体外抑制实验(见实施例C.1)测定式(I)化合物对组蛋白脱乙酰酶活性的抑制作用。
通过细胞毒性或存活率比色分析测定，确定A2780肿瘤细胞上式(I)化合物细胞活性(Mosmann Tim，Journal of ImmunologicalMethods 65：55-63，1983)(见实施例C.2)。
通过含水介质中的动态溶解性实验测定了逐步稀释时化合物溶于含水溶液的能力(见实施例C.3)。
用单一含水缓冲溶剂连续三次稀释化合物的DMSO母液。每次稀释后通过浊度计测定稀释后的浊度。
药物的通透性反映了其从一种介质转移到或穿过另外一种介质的能力。尤其是指药物穿过肠膜到血流和/或从血流到靶位的能力。通透性可以通过形成滤膜固定的人工膜性磷脂双层进行测定(实施例C.4)。在滤膜固定的人工膜性磷脂双层实验中，一个96孔微量滴定板与一个96孔过滤板形成一个“三明治”结构，使每个复合孔都被分隔为两个室，供体溶液处于底部，受体溶液处于顶部，其被一个125微米的微量过滤盘(滤孔为0.45微米)所分隔，并包被以2％(wt/v)二油酰基磷脂酰胆碱(dioleoylphosphatidyl-choline)的十二烷溶液。所处条件为，当该系统与含水缓冲溶液接触时将在过滤通道内部形成多片状双分子层。化合物穿过该人工膜性系统的通透性以厘米/秒进行测定。本实验目的是为了考察在两个不同的pH值(4.0和7.4)的条件下，药物穿过平行人工膜的能力。化合物通过紫外-光谱测定法在250-500nm的最佳波长下进行检测。
药物代谢是指油溶性生物异源的或生物体内生的物质通过酶催反应，转变为极性，水溶性的可排泄的代谢物的过程。药物代谢的主要器官是肝脏。代谢产物通常比母体药物活性低或者没有活性。然而，一些代谢物活性增强或者出现毒性效果。因此药物代谢可能包括“解毒”和“中毒”的过程。决定机体对药物和化学制剂的应付能力的一个主要酶系统是细胞色素P450单加氧酶，它是NADPH依赖性酶。化合物的代谢稳定性可以通过使用人体亚细胞组织进行体外实验而测定(见实施例C.5)。在这里，化合物的代谢稳定性通过化合物与微粒体共温育15分钟后代谢的药物的百分数进行评价。化合物的量通过LC-MS分析进行测定。
肿瘤抑制因子P53在应答DNA受损时可以转录激活多种基因包括WAF1/CIP1基因。在正常细胞中而非转染细胞中的包括细胞周期蛋白、细胞周期蛋白依赖性激酶(CDK)和增殖细胞核抗原(PCNA)的复合物中发现了WAF1基因的21Kda产物，该产物表现为通用的CDK活性抑制剂。p21WAF1结合并抑制CDK的其中一个结果是阻断CDK-依赖性磷酸化以及随后Rb蛋白的失活，这在细胞周期过程中是至关重要的。因此由于细胞接触HDAC抑制剂而诱导产生p21WAF1是一个有效的特异性指示剂，显示细胞周期过程在G1和G2监测点被阻滞。
化合物诱导产生p21 WAF1的能力可以通过p21 WAF1酶联免疫吸附测定(癌基因的WAF1 ELISA)进行测量。p21 WAF1实验是采用小鼠单克隆抗体以及兔多克隆抗体的“三明治”酶免疫测定。将人WAF1蛋白的特异抗体-兔多克隆抗体固定在试剂盒提供的塑料孔表面上。任何待检测样品中的p21 WAF1将结合在俘获抗体上。生物素化的检测剂单克隆抗体也可以识别人p21 WAF1蛋白，并能够与已经结合在俘获抗体上的任何p21 WAF1蛋白结合。随后，检测剂抗体与辣根过氧化物酶结合的链霉抗生物素(streptavidin)进行结合。这个辣根过氧化物酶催化产色底物四甲联苯胺由无色溶液向蓝色溶液转变(或者加入终止剂后转变为黄色溶液)，颜色的强度与样品中与板结合的p21WAF1蛋白的量成正比。带色反应产物可以通过分光光度计进行定量。通过已知浓度p21 WAF1蛋白(冻干的)制备标准曲线，获得定量数据(见实施例C.6)。
实施例C1：组蛋白脱乙酰酶抑制的体外测定方法
将60微克/毫升的HeLa细胞核提取物(Biomol提供)与2×10-8M的放射性标记的肽底物一起温育。作为测定HDAC活性的底物，使用的是合成的肽即组蛋白H4的14-21氨基酸序列。底物在具有6-氨基己酸间隔区的氨基端进行生物素化，羧基端通过酰胺基团进行保护，并且特异性的在16位赖氨酸进行[3H]乙酰化。将底物(生物素-(6-氨基己酸)-甘氨酸-丙氨酸-([3H]-乙酰基-赖氨酸-精氨酸-组氨酸-精氨酸-赖氨酸-缬氨酸-氨基))加入至含有25mM Hepes，1M蔗糖，0.1mg/ml BSA和0.01％TritonX-100的pH值为7.4的缓冲溶液中。30分钟后，加入盐酸和醋酸以终止脱乙酰化反应(两者的终浓度分别为0.035mM和3.8mM)。终止反应后，通过乙酸乙酯萃取游离态的3H醋酸盐。混合并离心后，等分量的上层(有机相)放射性通过β计数器测定。
每次实验需要平行设定对照组(含有HeLa细胞核提取物和DMSO，而不含化合物)，空白组(只含有DMSO而不含有HeLa细胞核提取物或化合物)以及样品组(含有溶解在DMSO的化合物以及HeLa细胞核提取物)。在第一个实验中，首先测试10-5M浓度时的化合物。当在此浓度化合物显示出活性时，制备在10-5-10-12M浓度范围内测试化合物的浓度-反应曲线。在每个测试中，对照组和样品组数值需要减去空白组数值。对照组代表100％的底物脱乙酰化。对于每个样品，其放射性用对照组平均值的百分数表示。在合适的情况下，通过对分级数据的概率值分析计算IC50(代谢物的减少量达到对照组50％所需的药物浓度)。此后检测化合物的活性用pIC50(IC50值的负对数值)表示。所有检测的化合物在10-5M浓度时具有酶活性，21个化合物的pIC50≥5(见表格F2)
实施例C.2：化合物对A2780细胞的抗增生活性的测定
将所有检测的化合物溶解在DMSO中，然后用培养基进一步稀释。在细胞增生实验中DMSO的终浓度不得超过0.1％(v/v)。对照组含有A2780细胞以及DMSO但是无化合物，空白组含有DMSO但是无细胞。MTT溶解在磷酸缓冲液中，浓度为5mg/ml。配制甘氨酸缓冲液，其由0.1M甘氨酸和0.1M氯化钠组成，并用1N的氢氧化钠溶液调节pH值至10.5(所有的试剂均购自Merck)。
人卵巢癌细胞A2780(Dr.T.C.Hamilton[Fox Chase CancerCentre，Pennsylvania，USA]赠)的培养基为RPMI 1640培养基并补充以2mM的L-谷氨酸，50ug/ml艮他霉素以及10％的胎牛血清。细胞按常规方法在37℃含有5％ CO2湿润空气中保持单层生长。每星期将细胞进行一次传代，使用胰蛋白酶/EDTA溶液，分裂比例为1∶40。所有的培养基以及补充物均购自Life Technologies。通过Gen-探针衣原体组织培养试剂盒(BioMérieux提供)测定，细胞没有被衣原体污染。
将细胞接种在NUNCTM 96孔培养板上(Life Technologies提供)，过夜使细胞贴附在板上。用于铺板的密度为1500细胞/孔，每孔培养基总体积为200微升。细胞贴附在板上后，换培养基，加入药物和/或溶剂至终体积为200微升。温育4天后，培养基用200微升新鲜培养基更换，以MTT法测定细胞密度以及存活率。向每孔加入25微升的MTT溶液，将细胞在37℃进一步温育2小时。小心吸去培养基，加入25微升的甘氨酸的缓冲液后再加入100微升的DMSO，溶解蓝色的MTT-甲
Figure G03805833219940520D000321
产物。将微测试板在微板振荡器上振荡10分钟，用Emax96孔板分光光度计(Sopachem提供)在540纳米波长下测定吸光度。在实验中，每种实验条件下的结果均为三个重复孔的平均值。作为最初的筛选，化合物在10-6M的单个固定浓度下进行测定，对于有活性的化合物重复进行实验以得到完整的浓度-反应曲线。对于每一个实验，必须平行设定对照组(不含有药物)和空白组(不含有细胞或药物)。对照组和样品组数值需要减去空白组数值。对于每一个样品，细胞生长的平均值(吸光度单位)可以表示为对照组细胞生长平均值的百分数。在合适的情况下，通过对分级数据的概率值分析(Finey，D.J.，ProbitAnalyses，2ndEd.Chapter 10，Graded Responses，CambridgeUniversity Press，Cambridge 1962)计算IC50(细胞生长减少量达到对照组50％所需的药物浓度)。以下检测化合物的活性用pIC50(IC50值的负对数值)表示。大部分检测的化合物在10-6M浓度时具有细胞活性，9个化合物的pIC50≥5(见表格F-2)
实施例C.3：水性培养基中的动态溶解性
在第一步稀释过程中，将10μl活性化合物溶解于DMSO的浓缩母液(5mM)加入到100μl pH值为7.4的磷酸盐柠檬酸盐缓冲液中，混合均匀。在第二步稀释过程中，进一步将第一步稀释液的等分量(20μl)分散到100μl pH值为7.4的磷酸盐柠檬酸盐缓冲液中，并混合均匀。最后，在第三步稀释过程中，取20μl第二步样品，进一步稀释到100μl pH值为7.4的磷酸盐柠檬酸盐缓冲液中，混合均匀。所有的稀释步骤均在96孔板上进行操作。最后一步稀释结束后，立即用浊度计测定三个连续稀释步骤的浊度。每个化合物同时稀释三份，以消除偶然误差。通过浊度测定结果，进行评分并归入三类。具有高溶解性的化合物为3分，此类化合物在一次稀释时为澄清溶液。具有中等溶解性的化合物为2分，此类化合物在第一次稀释时浑浊，第二次稀释后澄清。具有低溶解性的化合物为1分，此类化合物第一次和第二次稀释后均浑浊。对9个化合物的溶解度进行了测定，其中7个为3分，2个为1分(见表F-2)
实施例C.4：平行人工膜通透性分析
将母液样品(10μl浓度为5mM的母液溶解于100％的DMSO中的等分量)稀释至含有2毫升pH值为4或者7.4的含水缓冲系统(PSR4系统溶液浓度(pION))的深孔板或者预混合板中。
在样品溶液加入到参比板之前，首先将150微升的缓冲液加入到孔中，测定空白的紫外吸收。然后弃去缓冲液，将该板作为参比板使用。所有的测定均在抗紫外板中进行(Costar或Greiner提供)。
在参比板的空白测定后，将150μl稀释样品加入到参比板，200μl稀释液加入到供体板1。受体过滤板1(Millipore提供，型号：MAIP N45)包被以4μl人工膜形成性溶液(含0.1％的2，6-二-叔丁基-4-甲基苯酚的1，2-二油酰基-sn-甘油-3-磷酸胆碱的十二烷溶液)，置于供体板的上方形成“三明治”结构。将缓冲液(200μl)分散到上方受体孔中，用盖子盖住三明治结构，在暗处室温储存18小时。
向孔中加入150μl缓冲液，然后进行受体过滤板2的空白紫外测定。受体滤过板2的空白测定后，弃去缓冲液，将150μl受体溶液从受体过滤板1转移到受体板2中，然后从“三明治”结构中除去受体过滤板1。在对供体板2进行空白测定后(如上)，将150μl供体溶液从供体板1中转移到供体板2中。对供体板2，受体板2以及参比板进行紫外光谱扫描(使用SpectraMAX 190)。通过PSR4p命令软件(command software)处理所有的光谱数据并计算化合物的通透性。所有的化合物均重复测定三次。在每个实验中使用卡马西平、灰黄霉素、无环鸟苷、阿替洛尔、速尿和氯噻嗪作为标准，给化合物评分并分为三类：低通透性(平均效应＜0.5×10-6cm/s，分数为1分)，中等通透性(1×10-6cm/s＞平均效应≥0.5×10-6cm/s，分数为2分)或者高通透性(平均效应≥0.5×10-6cm/s，分数为3分)。两个化合物在测量的一个pH值下分数为1分。
实施例C.5：代谢稳定性实验
根据Gorrod等的方法(Xenobiotica 5：453-462，1975)，将组织机械匀浆后离心分离，制备亚细胞组织。以冰冷的0.1M的Tris-HCl缓冲液(pH值为7.4)冲洗肝脏组织以洗去过多的血。将组织吸干，称重，并用手术剪将组织粗略剪碎。然后加入三倍体积的冰冷的0.1M的磷酸盐(Tris-HCl)缓冲液(pH值为7.4)，用配备有Teflon杵的Potter-S(Braun，意大利)或者Sorvall Omni-Mix匀浆器进行匀浆，共7次，每次10秒钟。在两种情形中，在整个匀浆过程中，试管均需要置于冰中。
使用Sorvall离心机或者Beckman超速离心机于4℃离心组织匀浆，离心力为9000xg，离心时间为20分钟。收集上清液，置于-80℃进行保存，命名为“S9”。
使用Beckman超速离心机于4℃对“S9”进行进一步离心，离心力为100000xg，离心时间为60分钟。小心吸取上清液，等分后命名为“细胞溶胶”。将沉淀重新悬浮在pH值为7.4的0.1M磷酸盐缓冲液中，终体积为每0.5克原组织重量1毫升缓冲液，并命名为“微粒体”。
将所有的亚细胞成分分别等分后，立即至于液氮中冷冻，并在使用前于-80℃保藏。
对于待测样品，温育混合物包括：0.1M的PBS，5uM的化合物，1mg/ml的微粒体以及NADPH生成系统(0.8mM 6萄糖-6-磷酸，0.8mM的氯化镁以及0.8单位的萄糖-6-磷酸脱氢酶)。对照样品包含同样的材料，但是用热灭活的微粒体(95℃加热10分钟)代替上述微粒体。对照样品中化合物的回收率始终为100％。
将混合物在37℃预温育5分钟。在0分钟时加入0.8mM的NADP，开始反应(t＝0)，将样品温育15分钟(t＝15)。加入2倍体积的DMSO以终止反应。然后将样品以900×g离心10分钟，将上清液在室温下保存不超过24小时后进行分析。所有的温育均平行进行两次。对上清液进行LC-MS分析。在Xterra MS C18柱上洗脱样品(50×4.6mm，粒径为5μm，Waters，美国)。本实验中使用了Alliance2790HPLC系统(Waters，美国提供)，用缓冲液A、溶液B、C以2.4ml/min的流速进行洗脱。缓冲液A：25mM醋酸铵的水/乙腈(95/5)溶液(pH5.2)，溶液B为乙腈，溶液C为甲醇。梯度设定：将有机相浓度从0％-50％溶液B和50％溶液C(5分钟)，线性增加到100％溶液B(1分钟)，并使有机相浓度继续保持恒定1.5分钟。样品总注射体积为25微升。
装备Quattro(Micromass，Manchester，英国提供)三重四极质谱仪，以及ESI源作为检测器。离子源以及去溶剂化温度分别设定为120和350℃，氮气作为雾化剂以及干燥气体，以正扫描模式获得数据(单离子反应)，锥形电压设定为10伏，滞留时间为1秒钟。
代谢稳定性可以表达为与活性微粒体共温育15分钟后化合物代谢的百分数(E(act))(％代谢＝100％-(15min时E(act)的总离子流(TIC)/0min时E(act)的TIC)×100)。代谢低于20％的化合物定义为高代谢稳定。代谢在20-70％之间的化合物定义为中等代谢稳定，代谢高于70％的化合物定义为低代谢稳定。进行所用代谢稳定性筛选实验时，必须同时包括3个参比化合物。维拉帕米用作低代谢稳定性的化合物(代谢百分数为73％)，西沙比利用作中等代谢稳定性的化合物(代谢百分数为45％)，丙醇用作中等至高代谢稳定性的化合物(代谢百分数为25％)。这些参比化合物可以验证代谢稳定性实验。
对实验中一个化合物进行了测试，其代谢百分数低于20％。
实施例C.6：p21诱导能力
以下实验方案适用于测定人A2780卵巢癌细胞中P21蛋白的表达水平。在96微孔板上接种A2780细胞(细胞浓度为20000个细胞/180μl)，培养基为RPMI1640培养基并补充以2mM的L-谷氨酸、50ug/ml艮他霉素以及10％的胎牛血清。在细胞消化的24小时前，加入化合物使终浓度为10-5，10-6，10-7以及10-8M。将所有检测的化合物溶解在DMSO中，并用培养基进行进一步稀释。加入化合物24小时后，从细胞移去上清液，用200μl的冰冷PBS洗涤细胞，吸去孔内液体，加入30μl消化缓冲液(含有50mM Tris-HCl(pH 7.6)，150mM氯化钠，1％Nonidet P40以及10％的甘油)。将培养板于-70℃温育过夜。
将合适数目的微量滴定孔从箔袋中移去，置于空的孔固定器中。制备洗涤缓冲液(20倍洗板浓度：100毫升20倍浓度浓缩的PBS溶液和表面活性剂，含有2％的氯乙酰胺)的工作液(1倍浓度)。将冻干p21WAF标准液溶解在蒸馏水中，并进一步以样品稀释液进行稀释(试剂盒中提供)。样品通过用样品稀释液稀释(1∶4)而进行配制。将样品(100μl)和p21WAF标准品(100μl)注入适当的孔中，在室温下温育2小时。以1倍的清洗缓冲液将孔洗涤3次，向每孔中加入100μl的检测抗体试剂(生物素化的p21WAF1单克隆抗体溶液)。在室温下培养1小时，以1倍的洗涤缓冲液将孔洗涤3次。将400倍浓度的结合物(过氧化物酶-链霉抗生物素结合物：400倍浓度的浓溶液)稀释，并向每孔中加入100微升1倍浓度的溶液，室温下温育30分钟，以1倍浓度的洗涤缓冲液将孔洗涤3次，再用蒸馏水洗涤1次。将底物溶液(产色底物)(100μl)加入孔中，将孔室温下避光培养30分钟，按照以前底物溶液加入的顺序向每个孔中加入终止液。使用分光光度板阅读器测定每孔的吸光度，工作波长为双波长：450/595纳米。
对于每个实验，必须平行设定对照组(不含有药物)以及空白组(不含有细胞或药物)。对照组和样品组数值需要减去空白组数值。对于每个样品，化合物对p21WAF1的诱导作用强度(吸光度单位)可以表示为对照组p21WAF1数值的百分数。诱导的百分数高于130％为显著诱导。对三个化合物进行了本实验测定，其中有两个化合物显示出显著诱导作用。
表F-2：表F2列出了化合物在实施例C.1、C.2和C.3中的测定结果。
  化合物号   酶活性pIC50   细胞活性pIC50   溶解度分数
8 ＞5
  7   ＞5
  9   ＞5
  10   ＞5
11 ＞5
  12   ＞5
  1   ＜5   ＜5   1
  18   6.173   6.166   1
  5   7.096   6.181
  23   6.932   5.796
  24   7.073   6.084
  25   6.29   ＜5
  26   6.984   5.378
  27   6.433   ＜5
  6   7.104   5.828   3
  19   5.536   ＜5   3
  20   5.451   ＜5
21 5.679 ＜5 3
  22   5.599   5.297   3
  2   6.615   5.534   3
  3   6.881   ＜5   3
  4   7.27   5.528   3
D.组合物实施例：包膜片剂
片剂核心制备
将100g式(I)化合物，570g乳糖以及200g淀粉的混合物充分混合，然后用5g十二烷基硫酸钠和10g聚乙烯-吡咯烷酮的水(200ml)溶液进行湿润。将湿润的粉末混合物过筛，干燥，再过筛。然后加入100g微晶纤维素和15g氢化植物油。将整个混合物混合均匀，压片，得到10000片，每片含有10mg式(I)化合物。
包膜
向10g甲基纤维素的变性乙醇(75ml)溶液中加入5g乙基纤维素的二氯甲烷(150ml)溶液。然后加入75ml二氯甲烷和2.5毫升1，2，3-丙三醇。熔解10克聚乙二醇，将其溶解在75ml二氯甲烷中。将后者加入到前者溶液中，然后加入2.5g十八烷酸镁，5g聚乙烯-吡咯烷酮和30ml毫升浓的颜料悬浮液，将上述混合物混匀，将片剂核心在包膜设备中用所得混合物进行包膜。

Claims (10)

1.一种式(I)化合物，
Figure FFW00000037650100011
其药学上可接受的加成盐及其立体化学异构体形式，其中
n为0或1，且当n为0时，为直接的键；
每个Q为氮或者
Figure FFW00000037650100012
每个X为氮或者
每个Y为氮或者
每个Z为氮或者
Figure FFW00000037650100015
R1为-C(O)NH(OH)或-NHC(O)C1-6链烷二基SH；
R2为氢、卤素、羟基、氨基、硝基、C1-6烷基、C1-6烷氧基、三氟甲基、二(C1-6烷基)氨基或者羟基氨基；
R3为C1-6烷基、苯基C2-6烯二基、呋喃羰基、C1-6烷基氨基羰基、氨基磺酰基、二(C1-6烷基)氨基磺酰基氨基C1-6烷基、二(C1-6烷基)氨基C1-6烷基、C1-12烷基磺酰基、二(C1-6烷基)氨基磺酰基或三卤C1-6烷基磺酰基；
R4为氢、羟基、氨基、羟基C1-6烷基、C1-6烷基或C1-6烷氧基；
当R3和R4在同一个碳原子上时，R3和R4一起可以形成下式的二价基团
-C(O)-NH-CH2-NR10-    (a-1)
其中R10为苯基；
当R3和R4在相邻的碳原子上时，R3和R4一起可以形成下式的二价基团
＝CH-CH＝CH-CH＝    (b-1).
2.权利要求1所述的化合物，其中
R2为氢、卤素、羟基、氨基、硝基、C1-6烷基、C1-6烷氧基、三氟甲基或二(C1-6烷基)氨基。
3.权利要求1所述的化合物，其中每个Q为R2为氢或硝基；R4为氢。
4.权利要求1或3所述的化合物，其中n为1；每个Q为
Figure FFW00000037650100021
每个Z为氮；R1为-C(O)NH(OH)；R2为氢；R3为C1-12烷基磺酰基；和R4为氢。
5.权利要求1、3或4所述化合物，该化合物选自18号、5号和24号化合物：
Figure FFW00000037650100022
6.一种药物组合物，其包括药学上可接受的载体和作为活性成分的治疗有效量的权利要求1至5任何一项所述的化合物。
7.一种制备权利要求6的药物组合物的方法，其中将该药学上可接受的载体与权利要求1至5任何一项所述的化合物进行均质混合。
8.权利要求1至5任意一项所述的化合物，该化合物用作药物。
9.一种制备权利要求1所述化合物的方法，其特征在于将式(II)中间体与三氟乙酸进行反应，得到式(I-a)异羟肟酸，其中R1为-C(O)NH(OH)，
10.权利要求1所定义的化合物用于制备用于检测或鉴定生物样品中组蛋白脱乙酰基酶的试剂的用途，所述检测或鉴定包括检测或测定权利要求1所定义的标记化合物与组蛋白脱乙酰基酶之间的络合物的形成。
CN038058332A 2002-03-13 2003-03-11 组蛋白脱乙酰基酶抑制剂 Expired - Lifetime CN1642551B (zh)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US36379902P 2002-03-13 2002-03-13
US60/363,799 2002-03-13
PCT/EP2003/002515 WO2003075929A1 (en) 2002-03-13 2003-03-11 Inhibitors of histone deacetylase

Publications (2)

Publication Number Publication Date
CN1642551A CN1642551A (zh) 2005-07-20
CN1642551B true CN1642551B (zh) 2011-09-14

Family

ID=27805289

Family Applications (2)

Application Number Title Priority Date Filing Date
CN038058332A Expired - Lifetime CN1642551B (zh) 2002-03-13 2003-03-11 组蛋白脱乙酰基酶抑制剂
CNB038056755A Expired - Fee Related CN100519527C (zh) 2002-03-13 2003-03-11 组织蛋白去乙酰酶抑制剂

Family Applications After (1)

Application Number Title Priority Date Filing Date
CNB038056755A Expired - Fee Related CN100519527C (zh) 2002-03-13 2003-03-11 组织蛋白去乙酰酶抑制剂

Country Status (26)

Country Link
US (16) US7541369B2 (zh)
EP (4) EP1485370B1 (zh)
JP (4) JP4644428B2 (zh)
KR (2) KR20040090985A (zh)
CN (2) CN1642551B (zh)
AR (1) AR039566A1 (zh)
AT (4) ATE425152T1 (zh)
AU (4) AU2003218736B2 (zh)
BR (2) BR0307624A (zh)
CA (4) CA2475764C (zh)
DE (3) DE60326436D1 (zh)
DK (1) DK1485353T3 (zh)
EA (2) EA007272B1 (zh)
ES (4) ES2371632T3 (zh)
HK (1) HK1078473A1 (zh)
HR (2) HRP20040799A2 (zh)
IL (7) IL164003A0 (zh)
MX (2) MXPA04008806A (zh)
NO (2) NO20044113L (zh)
NZ (2) NZ534832A (zh)
OA (2) OA12790A (zh)
PL (2) PL212089B1 (zh)
TW (1) TW200400822A (zh)
UA (4) UA78032C2 (zh)
WO (4) WO2003076400A1 (zh)
ZA (6) ZA200407233B (zh)

Families Citing this family (187)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6951862B2 (en) 1998-06-30 2005-10-04 Neuromed Technologies, Inc. Calcium channel blockers comprising two benzhydril moieties
US7186726B2 (en) 1998-06-30 2007-03-06 Neuromed Pharmaceuticals Ltd. Preferentially substituted calcium channel blockers
AU2002327627B2 (en) 2001-09-14 2006-09-14 Methylgene Inc. Inhibitors of histone deacetylase
US7868204B2 (en) 2001-09-14 2011-01-11 Methylgene Inc. Inhibitors of histone deacetylase
US6897220B2 (en) 2001-09-14 2005-05-24 Methylgene, Inc. Inhibitors of histone deacetylase
US7390813B1 (en) 2001-12-21 2008-06-24 Xenon Pharmaceuticals Inc. Pyridylpiperazines and aminonicotinamides and their use as therapeutic agents
EP1485348B1 (en) 2002-03-13 2008-06-11 Janssen Pharmaceutica N.V. Carbonylamino-derivatives as novel inhibitors of histone deacetylase
CN100445276C (zh) * 2002-03-13 2008-12-24 詹森药业有限公司 用作组蛋白去乙酰酶抑制剂的磺酰基衍生物
US7767679B2 (en) 2002-03-13 2010-08-03 Janssen Pharmaceutica N.V. Sulfonylamino-derivatives as novel inhibitors of histone deacetylase
WO2003076438A1 (en) * 2002-03-13 2003-09-18 Janssen Pharmaceutica N.V. Piperazinyl-, piperidinyl- and morpholinyl-derivatives as novel inhibitors of histone deacetylase
EA007272B1 (ru) * 2002-03-13 2006-08-25 Янссен Фармацевтика Н. В. Новые ингибиторы гистондеацетилазы
TWI319387B (en) 2002-04-05 2010-01-11 Astrazeneca Ab Benzamide derivatives
EP1547617B1 (en) * 2002-08-20 2010-04-28 Astellas Pharma Inc. Arthrodial cartilage extracellular matrix degradation inhibitor
WO2004024710A1 (en) * 2002-09-13 2004-03-25 Glaxo Group Limited Urea compounds active as vanilloid receptor antagonists for the treatment of pain
US20040127571A1 (en) * 2002-09-19 2004-07-01 University Of South Florida Method of Treating Leukemia with a Combination of Suberoylanilide Hydromaxic Acid and Imatinib Mesylate
WO2004052292A2 (en) * 2002-12-06 2004-06-24 University Of South Florida Histone deacetylase inhibitor enhancement of trail-induced apoptosis
PL1622569T3 (pl) 2003-04-24 2016-06-30 Incyte Holdings Corp Pochodne aza spiro alkanów jako inhibitory metaloproteaz
WO2005011654A2 (en) 2003-07-29 2005-02-10 Xenon Pharmaceuticals Inc. Pyridyl derivatives and their use as therapeutic agents
AU2004261267B9 (en) 2003-07-30 2009-04-09 Xenon Pharmaceuticals Inc. Pyridyl derivatives and their use as therapeutic agents
BRPI0412348A (pt) 2003-07-30 2006-09-05 Xenon Pharmaceuticals Inc derivados de piperazina e seu uso como agentes terapêuticos
JP4831577B2 (ja) 2003-07-30 2011-12-07 ゼノン・ファーマシューティカルズ・インコーポレイテッド ピリダジン誘導体および治療剤としての用途
ES2568769T3 (es) 2003-07-30 2016-05-04 Xenon Pharmaceuticals Inc. Derivados de piperazina y su uso como agentes terapéuticos
US7754711B2 (en) 2003-07-30 2010-07-13 Xenon Pharmaceuticals Inc. Pyridazine derivatives and their use as therapeutic agents
WO2005030705A1 (en) 2003-09-24 2005-04-07 Methylgene, Inc. Inhibitors of histone deacetylase
US7253204B2 (en) 2004-03-26 2007-08-07 Methylgene Inc. Inhibitors of histone deacetylase
JP2007532492A (ja) * 2004-04-09 2007-11-15 ニューロメッド ファーマシューティカルズ リミテッド カルシウムチャネルブロッカーとしてのジアリールアミン誘導体
WO2005110413A2 (en) 2004-05-19 2005-11-24 Solvay Pharmaceuticals Gmbh Medicaments containing n-sulfamoyl-n'-arylpiperazines for the prophylaxis or treatment of obesity and related conditions
GB0412072D0 (en) * 2004-05-28 2004-06-30 Syngenta Participations Ag Chemical compounds
CA2566525A1 (en) 2004-06-14 2005-12-22 F. Hoffmann-La Roche Ag Thiophene derivatives, their manufacture and use as pharmaceutical agents
CA2566515A1 (en) 2004-06-14 2005-12-22 F. Hoffmann-La Roche Ag Thiophene hydroxamic acid derivatives and their use as hdac inhibitors
EP1781639B1 (en) * 2004-07-28 2012-01-25 Janssen Pharmaceutica NV Substituted indolyl alkyl amino derivatives as novel inhibitors of histone deacetylase
ME01058B (me) * 2004-07-28 2012-10-20 Janssen Pharmaceutica Nv Supstituisani derivati propenil piperazina kao novi inhibitori histonske deacetilaze
EP1776358B1 (en) * 2004-07-28 2009-05-27 Janssen Pharmaceutica N.V. Substituted propenyl piperazine derivatives as novel inhibitors of histone deacetylase
MX2007001634A (es) * 2004-08-11 2007-04-23 Kyorin Seiyaku Kk Nuevo derivado de acido amino benzoico ciclico.
TW200626155A (en) 2004-09-20 2006-08-01 Xenon Pharmaceuticals Inc Heterocyclic derivatives and their use as therapeutic agents
AR051095A1 (es) 2004-09-20 2006-12-20 Xenon Pharmaceuticals Inc Derivados heterociclicos y su uso comoinhibidores de la estearoil-coa desaturasa
AU2005329423A1 (en) 2004-09-20 2006-09-28 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors
CN101083982A (zh) 2004-09-20 2007-12-05 泽农医药公司 用于治疗硬脂酰CoA去饱和酶介导的疾病的杂环衍生物
WO2006034279A1 (en) 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as therapeutic agents
BRPI0515478A (pt) 2004-09-20 2008-07-22 Xenon Pharmaceuticals Inc derivados heterocìclicos e seu uso como mediadores de estearoil-coa-desaturase
CN101084207A (zh) 2004-09-20 2007-12-05 泽农医药公司 杂环衍生物及其作为硬脂酰CoA去饱和酶抑制剂的用途
TW200626154A (en) 2004-09-20 2006-08-01 Xenon Pharmaceuticals Inc Heterocyclic derivatives and their use as therapeutic agents
GB0421908D0 (en) 2004-10-01 2004-11-03 Angeletti P Ist Richerche Bio New uses
US7855205B2 (en) * 2004-10-29 2010-12-21 Janssen Pharmaceutica Nv Pyrimidinyl substituted fused-pyrrolyl compounds useful in treating kinase disorders
WO2006082834A1 (ja) * 2005-02-02 2006-08-10 Kowa Co., Ltd. ケラチノサイト増殖に起因する疾患の予防・治療剤
EP2502649A1 (en) 2005-02-03 2012-09-26 TopoTarget UK Limited Combination therapy using HDAC inhibitors and erlotinib for treating cancer
CA2596015A1 (en) 2005-02-14 2006-08-24 Sampath K. Anandan Fused heterocyclic compounds useful as inhibitors of histone deacetylase
CA2598456A1 (en) * 2005-02-16 2006-08-24 Schering Corporation Heterocyclic substituted piperazines with cxcr3 antagonist activity
CN101203509B (zh) * 2005-02-16 2013-05-08 默沙东公司 具有cxcr3拮抗剂活性的胺-连接的吡啶基和苯基取代的哌嗪-哌啶
AU2006223086A1 (en) * 2005-03-11 2006-09-21 The Regents Of The University Of Colorado Histone deacetylase inhibitors sensitize cancer cells to epidermal growth factor inhibitors
CN101163471A (zh) 2005-04-20 2008-04-16 默克公司 含有氨基甲酸酯、脲、酰胺和磺酰胺取代的苯并噻吩异羟肟酸衍生物
WO2006115845A1 (en) 2005-04-20 2006-11-02 Merck & Co., Inc. Benzothiophene derivatives
JP2008536925A (ja) 2005-04-20 2008-09-11 メルク エンド カムパニー インコーポレーテッド ベンゾチオフェンヒドロキサム酸誘導体
GB0509225D0 (en) 2005-05-05 2005-06-15 Chroma Therapeutics Ltd Inhibitors of enzymatic activity
GB0509223D0 (en) 2005-05-05 2005-06-15 Chroma Therapeutics Ltd Enzyme inhibitors
KR101329437B1 (ko) 2005-05-13 2013-11-14 토포타겟 유케이 리미티드 Ｈｄａｃ 억제제의 약학 제형
WO2006122926A1 (en) 2005-05-18 2006-11-23 Janssen Pharmaceutica N.V. Substituted aminopropenyl piperidine or morpholine derivatives as novel inhibitors of histone deacetylase
GB0510204D0 (en) * 2005-05-19 2005-06-22 Chroma Therapeutics Ltd Enzyme inhibitors
BRPI0611187A2 (pt) 2005-06-03 2010-08-24 Xenon Pharmaceuticals Inc derivados aminotiazàis como inibidores da estearoil-coa desaturase humana
CA2610196A1 (en) * 2005-06-09 2006-12-14 Merck Frosst Canada Ltd. Azacyclohexane derivatives as inhibitors of stearoyl-coenzyme a delta-9 desaturase
ATE533759T1 (de) * 2005-06-23 2011-12-15 Janssen Pharmaceutica Nv Imidazolinon- und hydantoinderivate als neue inhibitoren von histondeacetylase
CA2612420A1 (en) 2005-06-24 2007-01-04 Merck & Co., Inc. Modified malonate derivatives
CN101263121A (zh) * 2005-07-14 2008-09-10 塔克达圣地亚哥公司 组蛋白脱乙酰基酶抑制剂
WO2007009236A1 (en) * 2005-07-20 2007-01-25 Merck Frosst Canada Ltd. Heteroaromatic compounds as inhibitors of stearoyl-coenzyme a delta-9 desaturase
JP2009506069A (ja) 2005-08-26 2009-02-12 ブレインセルス，インコーポレイティド ムスカリン性受容体調節による神経発生
EP2258359A3 (en) 2005-08-26 2011-04-06 Braincells, Inc. Neurogenesis by muscarinic receptor modulation with sabcomelin
US20070088043A1 (en) * 2005-10-18 2007-04-19 Orchid Research Laboratories Limited. Novel HDAC inhibitors
AU2006304787A1 (en) 2005-10-21 2007-04-26 Braincells, Inc. Modulation of neurogenesis by PDE inhibition
AU2006307918B2 (en) 2005-10-27 2012-06-21 Janssen Pharmaceutica N.V. Squaric acid derivatives as inhibitors of histone deacetylase
CA2625210A1 (en) 2005-10-31 2007-05-10 Braincells, Inc. Gaba receptor mediated modulation of neurogenesis
KR100696139B1 (ko) * 2005-11-01 2007-03-20 한국화학연구원 히스톤 디아세틸라제 저해활성을 갖는 알킬카바모일나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체 및그의 제조방법
JP5377968B2 (ja) 2005-11-10 2013-12-25 トポターゲット ユーケー リミテッド 癌治療のために単独で用いるまたは化学療法薬と併用するヒストンデアセチラーゼ（ｈｄａｃ）阻害剤
AR057579A1 (es) 2005-11-23 2007-12-05 Merck & Co Inc Compuestos espirociclicos como inhibidores de histona de acetilasa (hdac)
CA2635015C (en) * 2006-01-19 2014-06-03 Janssen Pharmaceutica N.V. Substituted indolyl-alkyl-amino-derivatives as inhibitors of histone deacetylase
US7888360B2 (en) 2006-01-19 2011-02-15 Janssen Pharmaceutica N.V. Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase
CN101370790B (zh) 2006-01-19 2015-10-21 詹森药业有限公司 作为组蛋白去乙酰化酶抑制剂的吡啶和嘧啶衍生物
EP1979327A1 (en) 2006-01-19 2008-10-15 Janssen Pharmaceutica, N.V. Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase
PT1981874E (pt) 2006-01-19 2009-09-02 Janssen Pharmactuica N V Derivados de aminofenil como novos inibidores de histonadesacetilase
ES2376121T3 (es) 2006-01-19 2012-03-09 Janssen Pharmaceutica, N.V. Derivados de heterociclilalquilo como nuevos inhibidores de histona deacetilasa.
US20070202186A1 (en) 2006-02-22 2007-08-30 Iscience Interventional Corporation Apparatus and formulations for suprachoroidal drug delivery
AU2007221207A1 (en) 2006-02-28 2007-09-07 Merck Sharp & Dohme Corp. Inhibitors of histone deacetylase
US20100216734A1 (en) 2006-03-08 2010-08-26 Braincells, Inc. Modulation of neurogenesis by nootropic agents
GB0605573D0 (en) * 2006-03-21 2006-04-26 Angeletti P Ist Richerche Bio Therapeutic Compounds
US8598168B2 (en) 2006-04-07 2013-12-03 Methylgene Inc. Inhibitors of histone deacetylase
AU2007243519A1 (en) 2006-04-26 2007-11-08 Merck Sharp & Dohme Corp. Disubstituted aniline compounds
US7678808B2 (en) 2006-05-09 2010-03-16 Braincells, Inc. 5 HT receptor mediated neurogenesis
AU2007249399A1 (en) 2006-05-09 2007-11-22 Braincells, Inc. Neurogenesis by modulating angiotensin
US8119652B2 (en) 2006-05-18 2012-02-21 Merck Sharp & Dohme Corp. Aryl-fused spirocyclic compounds
EP2049124A4 (en) 2006-07-20 2010-02-10 Merck & Co Inc PHOSPHOR DERIVATIVES AS HISTONDEACETYLASE HEMMER
EP2068872A1 (en) 2006-09-08 2009-06-17 Braincells, Inc. Combinations containing a 4-acylaminopyridine derivative
US20100184806A1 (en) 2006-09-19 2010-07-22 Braincells, Inc. Modulation of neurogenesis by ppar agents
GB0619753D0 (en) 2006-10-06 2006-11-15 Chroma Therapeutics Ltd Enzyme inhibitors
KR101181194B1 (ko) 2006-10-18 2012-09-18 화이자 프로덕츠 인코포레이티드 바이아릴 에터 우레아 화합물
BRPI0622100A2 (pt) 2006-10-30 2011-12-27 Chroma Therapeutics Ltd hidroxamatos como inibidores de desacetilase de histona
US20080242648A1 (en) * 2006-11-10 2008-10-02 Syndax Pharmaceuticals, Inc., A California Corporation COMBINATION OF ERa+ LIGANDS AND HISTONE DEACETYLASE INHIBITORS FOR THE TREATMENT OF CANCER
US8030344B2 (en) 2007-03-13 2011-10-04 Methylgene Inc. Inhibitors of histone deacetylase
DK2142529T3 (da) 2007-04-27 2014-02-10 Purdue Pharma Lp Trpv1-antagonister og anvendelser deraf
US7737175B2 (en) 2007-06-01 2010-06-15 Duke University Methods and compositions for regulating HDAC4 activity
US8110550B2 (en) 2007-06-06 2012-02-07 University Of Maryland, Baltimore HDAC inhibitors and hormone targeted drugs for the treatment of cancer
JP5464709B2 (ja) 2007-06-08 2014-04-09 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ ピペリジン／ピペラジン誘導体
AU2008258487B2 (en) * 2007-06-08 2012-11-15 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
JO2972B1 (en) 2007-06-08 2016-03-15 جانسين فارماسوتيكا ان. في Piperidine / piperazine derivatives
CA2687912C (en) 2007-06-08 2015-11-03 Janssen Pharmaceutica N.V. Piperidine/piperazine derivatives
EP2170339B1 (en) 2007-06-27 2014-10-15 Merck Sharp & Dohme Corp. Pyridyl and pyrimidinyl derivatives as histone deacetylase inhibitors
CA2690191C (en) 2007-06-27 2015-07-28 Merck Sharp & Dohme Corp. 4-carboxybenzylamino derivatives as histone deacetylase inhibitors
WO2009015237A1 (en) * 2007-07-23 2009-01-29 Syndax Pharmaceuticals, Inc. Novel compounds and methods of using them
WO2009015203A1 (en) * 2007-07-23 2009-01-29 Syndax Pharmaceuticals, Inc. Novel compounds and methods of using them
CA2697551C (en) 2007-09-20 2013-03-12 Irm Llc Piperidine derivatives as modulators of gpr119 activity
CN101868446A (zh) 2007-09-25 2010-10-20 托波塔吉特英国有限公司 某些异羟肟酸化合物的合成方法
WO2009058895A1 (en) * 2007-10-30 2009-05-07 Syndax Pharmaceuticals, Inc. Administration of an inhibitor of hdac and an mtor inhibitor
US20090131367A1 (en) * 2007-11-19 2009-05-21 The Regents Of The University Of Colorado Combinations of HDAC Inhibitors and Proteasome Inhibitors
EP2274301B1 (en) 2008-03-27 2012-09-26 Janssen Pharmaceutica, N.V. Aza-bicyclohexyl substituted indolyl alkyl amino derivatives as novel inhibitors of histone deacetylase
US20110182888A1 (en) * 2008-04-08 2011-07-28 Peter Ordentlich Administration of an Inhibitor of HDAC, an Inhibitor of HER-2, and a Selective Estrogen Receptor Modulator
AU2009253892B2 (en) 2008-06-05 2015-07-30 Janssen Pharmaceutica Nv Drug combinations comprising a DGAT inhibitor and a PPAR-agonist
CN102118969B (zh) * 2008-06-12 2017-03-08 詹森药业有限公司 组胺h4受体的二氨基吡啶、二氨基嘧啶和二氨基哒嗪调节剂
BRPI0921496A2 (pt) 2008-11-04 2016-01-19 Chemocentryx Inc composto, composição farmacêutica, e, métodos para tratar doença ou distúrbio, para inibir ligação de quimiocinas a um receptor, para formar imagem de um dito tumor, orgão ou tecido, e para detectar níveis elevados de cxcr7 em uma amostra
US8853202B2 (en) 2008-11-04 2014-10-07 Chemocentryx, Inc. Modulators of CXCR7
TWI558710B (zh) 2009-01-08 2016-11-21 古利斯股份有限公司 具有鋅連接部位的磷酸肌醇３－激酶抑制劑
MX2011007864A (es) 2009-01-28 2011-09-30 Karus Therapeutics Ltd Isosteros para realzar la transcripcion y su uso en terapia.
WO2010099217A1 (en) 2009-02-25 2010-09-02 Braincells, Inc. Modulation of neurogenesis using d-cycloserine combinations
GB0903480D0 (en) 2009-02-27 2009-04-08 Chroma Therapeutics Ltd Enzyme Inhibitors
AU2010234526B2 (en) 2009-04-06 2016-07-21 Agios Pharmaceuticals, Inc. Pyruvate kinase M2 modulators, therapeutic compositions and related methods of use
TWI598337B (zh) 2009-06-29 2017-09-11 阿吉歐斯製藥公司 治療化合物及組成物
US8609672B2 (en) 2010-08-27 2013-12-17 University Of The Pacific Piperazinylpyrimidine analogues as protein kinase inhibitors
EP3520749A1 (en) 2010-10-15 2019-08-07 Clearside Biomedical, Inc. Device for ocular access
PT2640709T (pt) * 2010-11-16 2016-07-13 Acetylon Pharmaceuticals Inc Compostos de pirimidina hidroxiamida como inibidores de proteína desacetilase e métodos de utilização dos mesmos
WO2012071369A2 (en) 2010-11-24 2012-05-31 The Trustees Of Columbia University In The City Of New York A non-retinoid rbp4 antagonist for treatment of age-related macular degeneration and stargardt disease
CA2821975A1 (en) 2010-12-17 2012-06-21 Shunqi Yan N-(4-(azetidine-1-carbonyl)phenyl)-(hetero-) arylsulfonamide derivatives as pyruvate kinase m2 pkm2 modulators
ES2569712T3 (es) 2010-12-21 2016-05-12 Agios Pharmaceuticals, Inc. Activadores de PKM2 bicíclicos
TWI549947B (zh) 2010-12-29 2016-09-21 阿吉歐斯製藥公司 治療化合物及組成物
US8404738B2 (en) * 2011-01-21 2013-03-26 Hoffmann-La Roche Inc. 4-amino-N-hydroxy-benzamides for the treatment of cancer
AU2012226586B2 (en) 2011-03-09 2017-04-13 Cereno Scientific Ab Compounds and methods for improving impaired endogenous fibrinolysis using histone deacetylase inhibitors
HUE028910T2 (en) 2011-04-01 2017-01-30 Curis Inc Phosphonoinoside-3-kinase inhibitor with zinc-binding radical
KR101873543B1 (ko) 2011-05-03 2018-07-02 아지오스 파마슈티컬스 아이엔씨. 치료에 사용하기 위한 피루베이트 키나아제 활성제
CN102807526B (zh) * 2011-06-21 2015-12-02 寿光富康制药有限公司 组蛋白去乙酰化酶抑制剂ZYJ-D08a及其差向异构体的制备方法与应用
CA2837178C (en) 2011-06-22 2016-09-20 Purdue Pharma L.P. Trpv1 antagonists including dihydroxy substituent and uses thereof
FR2976943B1 (fr) * 2011-06-23 2013-07-12 Metabolys Derives de piperazine, leurs procedes de preparation et leurs utilisations dans le traitement de l'insulinoresistance
WO2013142817A2 (en) 2012-03-23 2013-09-26 Dennis Brown Compositions and methods to improve the therapeutic benefit of indirubin and analogs thereof, including meisoindigo
US9333202B2 (en) 2012-05-01 2016-05-10 The Trustees Of Columbia University In The City Of New York Non-retinoid antagonists for treatment of age-related macular degeneration and stargardt disease
US20150141470A1 (en) 2012-05-08 2015-05-21 The Broad Institute, Inc. Diagnostic and treatment methods in patients having or at risk of developing resistance to cancer therapy
JP6329958B2 (ja) 2012-11-07 2018-05-23 カルス セラピューティクス リミテッド 新規ヒストンデアセチラーゼインヒビターおよび治療におけるその使用
CN105189484B (zh) 2012-11-29 2018-05-04 凯莫森特里克斯股份有限公司 Cxcr7拮抗剂
WO2014124219A1 (en) 2013-02-08 2014-08-14 General Mills, Inc. Reduced sodium food product
DK2968304T3 (en) 2013-03-14 2019-01-28 Univ Columbia 4-PHENYLPIPERIDINES, THEIR PREPARATION AND USE.
US9944644B2 (en) 2013-03-14 2018-04-17 The Trustees Of Columbia University In The City Of New York Octahydropyrrolopyrroles their preparation and use
US9637450B2 (en) 2013-03-14 2017-05-02 The Trustees Of Columbia University In The City Of New York Octahydrocyclopentapyrroles, their preparation and use
US9938291B2 (en) 2013-03-14 2018-04-10 The Trustess Of Columbia University In The City Of New York N-alkyl-2-phenoxyethanamines, their preparation and use
CN105246529B (zh) 2013-05-03 2019-06-14 科尼尔赛德生物医学公司 用于眼部注射的设备和方法
KR20160007577A (ko) 2013-05-10 2016-01-20 카루스 떼라퓨틱스 리미티드 신규한 히스톤 디아세틸라제 억제제들
WO2014197317A1 (en) 2013-06-03 2014-12-11 Clearside Biomedical, Inc. Apparatus and methods for drug delivery using multiple reservoirs
EP3027607B1 (en) 2013-07-29 2020-08-26 Sunshine Lake Pharma Co., Ltd. Substituted heteroaryl compounds and methods of use thereof
EP3054952B1 (en) 2013-10-08 2022-10-26 Acetylon Pharmaceuticals, Inc. Combinations of histone deacetylase 6 inhibitors and the her2 inhibitor lapatinib for use in the treatment of breast cancer
US9278963B2 (en) * 2013-10-10 2016-03-08 Acetylon Pharmaceuticals, Inc. Pyrimidine hydroxy amide compounds as histone deacetylase inhibitors
EP3060217B1 (en) 2013-10-24 2022-06-08 Mayo Foundation for Medical Education and Research Treatment of polycystic diseases with an hdac6 inhibitor
CA2932411A1 (en) 2013-12-03 2015-06-11 Acetylon Pharmaceuticals, Inc. Combinations of histone deacetylase inhibitors and immunomodulatory drugs
CN104725359B (zh) 2013-12-20 2017-05-03 广东东阳光药业有限公司 取代的哌嗪化合物及其使用方法和用途
US9464073B2 (en) 2014-02-26 2016-10-11 Acetylon Pharmaceuticals, Inc. Pyrimidine hydroxy amide compounds as HDAC6 selective inhibitors
MX2016011833A (es) 2014-03-12 2017-03-29 Chong Kun Dang Pharmaceutical Corp Nuevos compuestos como inhibidores de histona desacetilasa 6 y composiciones farmaceuticas que los comprenden.
DK3137168T3 (da) 2014-04-30 2022-03-21 Univ Columbia Substituerede 4-phenylpiperidiner, deres fremstilling og anvendelse
EP3166603B1 (en) 2014-07-07 2020-02-12 Acetylon Pharmaceuticals, Inc. Treatment of leukemia with histone deacetylase inhibitors
US10722147B2 (en) 2014-08-13 2020-07-28 Nightbalance B.V. Activation by temperature sensor
GB201419264D0 (en) 2014-10-29 2014-12-10 Karus Therapeutics Ltd Compounds
GB201419228D0 (en) 2014-10-29 2014-12-10 Karus Therapeutics Ltd Compounds
UY36391A (es) * 2014-11-05 2016-06-01 Flexus Biosciences Inc Compuestos moduladores de la enzima indolamina 2,3-dioxigenasa (ido1), sus métodos de síntesis y composiciones farmacèuticas que las contienen
CA2969790A1 (en) 2014-12-05 2016-06-09 University of Modena and Reggio Emilia Combinations of histone deacetylase inhibitors and bendamustine
KR20170095964A (ko) * 2014-12-12 2017-08-23 에이스틸론 파마수티컬스 인코포레이티드 Hdac1/2 억제제로서 피페리딘 유도체
MA41291A (fr) 2014-12-30 2017-11-07 Forma Therapeutics Inc Dérivés de la pyrrolotriazinone et de l'imidazotriazinone en tant qu'inhibiteurs de la protéase spécifique de l'ubiquitine n° 7 (usp7) pour le traitement d'un cancer
TWI698436B (zh) 2014-12-30 2020-07-11 美商佛瑪治療公司 作為泛素特異性蛋白酶７抑制劑之吡咯并及吡唑并嘧啶
US9932351B2 (en) 2015-02-05 2018-04-03 Forma Therapeutics, Inc. Thienopyrimidinones as ubiquitin-specific protease 7 inhibitors
JP2018504430A (ja) 2015-02-05 2018-02-15 フォーマ セラピューティクス，インコーポレイテッド ユビキチン特異的プロテアーゼ７阻害物質としてのキナゾリノン及びアザキナゾリノン
US9938300B2 (en) 2015-02-05 2018-04-10 Forma Therapeutics, Inc. Isothiazolopyrimidinones, pyrazolopyrimidinones, and pyrrolopyrimidinones as ubiquitin-specific protease 7 inhibitors
US10272084B2 (en) 2015-06-01 2019-04-30 Regenacy Pharmaceuticals, Llc Histone deacetylase 6 selective inhibitors for the treatment of cisplatin-induced peripheral neuropathy
MD3307271T2 (ro) 2015-06-11 2024-01-31 Agios Pharmaceuticals Inc Metode de utilizare a activatorilor de piruvat kinază
EP3398598B1 (en) * 2015-12-31 2022-04-06 Hitgen Inc. Sulfonamide derivative and preparation method and use thereof
JP2019515909A (ja) 2016-04-19 2019-06-13 アセチロン ファーマシューティカルズ インコーポレイテッドＡｃｅｔｙｌｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． 慢性リンパ性白血病の治療を目的とするｈｄａｃ阻害剤単独またはｂｔｋ阻害剤との配合物
WO2017192565A1 (en) 2016-05-02 2017-11-09 Clearside Biomedical, Inc. Systems and methods for ocular drug delivery
CN110177527B (zh) 2016-08-12 2022-02-01 科尼尔赛德生物医学公司 用于调节药剂递送用针的插入深度的装置和方法
WO2018204515A1 (en) 2017-05-02 2018-11-08 Georgia Tech Research Corporation Targeted drug delivery methods using a microneedle
JP7402792B2 (ja) 2017-09-26 2023-12-21 デイナ ファーバー キャンサー インスティチュート，インコーポレイテッド 多発性骨髄腫を治療するための新規なｕｓｐ７阻害剤
EP3774815A1 (en) 2018-03-30 2021-02-17 Biotheryx Inc. Thienopyrimidinone compounds
EP3849554A4 (en) 2018-09-11 2022-06-01 Curis, Inc. POLYTHERAPY WITH A PHOSPHOINONOSITIDE 3-KINASE INHIBITOR HAVING A ZINC-BINDING METAL
AU2019368263A1 (en) * 2018-10-22 2021-04-29 Dana-Farber Cancer Institute, Inc. USP7 inhibition
MX2021006915A (es) 2018-12-12 2021-08-24 Chemocentryx Inc Inhibidores de cxcr7 para el tratamiento de cancer.
EP4387609A2 (en) 2021-08-18 2024-06-26 ChemoCentryx, Inc. Aryl sulfonyl (hydroxy) piperidines as ccr6 inhibitors
EP4387965A2 (en) 2021-08-18 2024-06-26 ChemoCentryx, Inc. Aryl sulfonyl compounds as ccr6 inhibitors
WO2023222115A1 (zh) * 2022-05-20 2023-11-23 四川汇宇制药股份有限公司 一种羟基酰胺类衍生物及其应用
CN117263936B (zh) * 2023-11-21 2024-02-23 中国中医科学院医学实验中心 一种咪唑并[1, 2-a]吡啶衍生物及其制备方法和在中枢神经系统渗透性HDAC6抑制药物中的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001038322A1 (en) * 1999-11-23 2001-05-31 Methylgene, Inc. Inhibitors of histone deacetylase

Family Cites Families (129)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB901749A (en) * 1957-12-06 1962-07-25 Ciba Ltd New 2-substituted pyrimidines
US2927924A (en) * 1958-04-03 1960-03-08 Lilly Co Eli Novel phenethyl-substituted piperazines
US3331845A (en) * 1963-04-04 1967-07-18 American Cyanamid Co 1-substituted-4-substituted amino alkylene piperazines
BE637271A (zh) * 1963-04-04 1900-01-01
US3459731A (en) 1966-12-16 1969-08-05 Corn Products Co Cyclodextrin polyethers and their production
US4049811A (en) 1968-07-23 1977-09-20 Boehringer Mannheim G.M.B.H. Compositions using cycloalkano-quinolone derivatives and their method of use
US3966743A (en) 1968-07-23 1976-06-29 Boehringer Mannheim G.M.B.H. Ortho fused cycloalkano-4-quinolone-3-carboxylic acid derivatives
GB1345872A (en) 1970-09-03 1974-02-06 Wyeth John & Brother Ltd Amino-and acylamino-pyridine and hydropyridine derivatives
JPS5755714B2 (zh) * 1972-03-18 1982-11-25
US4186199A (en) * 1978-11-02 1980-01-29 American Hoechst Corporation Indolo-,1,2-dihydroindolo-, and 1,2,6,7-tetrahydroindolo [1,7-ab][1,5] benzodiazepines
DE2939292A1 (de) 1979-09-28 1981-04-09 Boehringer Mannheim Gmbh, 6800 Mannheim N-phenoxyalkylpiperidin-derivate, verfahrenn zu deren herstellung sowie diese verbindungen enthaltende arzneimittel
PH17194A (en) 1980-03-06 1984-06-19 Otsuka Pharma Co Ltd Novel carbostyril derivatives,and pharmaceutical composition containing the same
CA1183847A (en) 1981-10-01 1985-03-12 Georges Van Daele N-(3-hydroxy-4-piperidinyl)benzamide derivatives
JPS6143173A (ja) * 1984-08-06 1986-03-01 Mitsui Petrochem Ind Ltd 新規ピリミジン誘導体およびその製法
JPS6187672A (ja) * 1984-10-08 1986-05-06 Mitsui Petrochem Ind Ltd 新規ピリミジン誘導体
EP0188095A1 (en) 1984-12-13 1986-07-23 East Rock Technology Inc. Process for the manufacture of a toroidal ballast choke and machine for use in such process
CA1307786C (en) * 1984-12-14 1992-09-22 Keiichi Yokoyama Quinazoline derivatives and antihypertensive preparations containing same as effective components
JPS61140568A (ja) * 1984-12-14 1986-06-27 Mitsui Petrochem Ind Ltd キナゾリン誘導体及びそれを有効成分とする血圧降下剤
US4840947A (en) * 1986-10-14 1989-06-20 Hoechst-Roussel Pharmaceuticals, Inc. Antiinflammatory and analgesic piperidin-4-yl-tetracyclic benzodiazepines and use thereas
JP2744663B2 (ja) * 1988-12-29 1998-04-28 三井化学株式会社 ピリミジン類及びその薬学的に許容される塩類
HU206337B (en) 1988-12-29 1992-10-28 Mitsui Petrochemical Ind Process for producing pyrimidine derivatives and pharmaceutical compositions
DK0382185T3 (da) * 1989-02-10 1994-07-04 Otsuka Pharma Co Ltd Carbostyrilderivater
JP2664238B2 (ja) 1989-03-01 1997-10-15 日清製粉株式会社 ニコチン酸またはそのエステル誘導体
US5342846A (en) 1990-12-05 1994-08-30 Synphar Laboratories, Inc. 7-substituted-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid compounds and 7-(substituted triazolyl pyrrolidin-1-yl) 4-oxoquinoline-3-carboxylic acid derivatives useful as antibacterial agents
EP0524146A1 (de) * 1991-07-19 1993-01-20 Ciba-Geigy Ag Aminosubstituierte Piperazinderivate
TW213903B (zh) * 1991-08-16 1993-10-01 Boehringer Ingelheim Kg
DE4228792A1 (de) 1992-08-29 1994-03-03 Hoechst Ag Pyridylaminopiperidine, Verfahren zu ihrer Herstellung, sie enthaltende Mittel und deren Verwendung als Fungizide
US5338738A (en) 1993-04-19 1994-08-16 Bristol-Myers Squibb Company Cerebral function enhancers: acyclic amide derivatives of pyrimidinylpiperidines
US5459151A (en) 1993-04-30 1995-10-17 American Home Products Corporation N-acyl substituted phenyl piperidines as bronchodilators and antiinflammatory agents
FR2722788B1 (fr) * 1994-07-20 1996-10-04 Pf Medicament Nouvelles piperazides derivees d'aryl piperazine, leurs procedes de preparation, leur utilisation a titre de medicament et les compositions pharmaceutiques les comprenant
US6083903A (en) 1994-10-28 2000-07-04 Leukosite, Inc. Boronic ester and acid compounds, synthesis and uses
ES2104509B1 (es) 1995-06-13 1998-07-01 Ferrer Int Nuevos compuestos derivados de 2-(3,4-disustituido-1-piperazinil)-5-fluoropirimidina.
JPH0959236A (ja) * 1995-08-23 1997-03-04 Dai Ichi Seiyaku Co Ltd ベンズアミド化合物
EP0862463A1 (en) 1995-11-23 1998-09-09 Janssen Pharmaceutica N.V. Solid mixtures of cyclodextrins prepared via melt-extrusion
ZA9610745B (en) 1995-12-22 1997-06-24 Warner Lambert Co 4-Subsituted piperidine analogs and their use as subtype selective nmda receptor antagonists
US5952349A (en) * 1996-07-10 1999-09-14 Schering Corporation Muscarinic antagonists for treating memory loss
US5866702A (en) 1996-08-02 1999-02-02 Cv Therapeutics, Incorporation Purine inhibitors of cyclin dependent kinase 2
EP0827742A1 (en) 1996-09-04 1998-03-11 Vrije Universiteit Brussel Use of histone deacetylase inhibitors for treating fribosis or cirrhosis
SE9604786D0 (sv) * 1996-12-20 1996-12-20 Astra Pharma Inc New compounds
FR2761960B1 (fr) 1997-04-09 1999-05-28 Pechiney Emballage Flexible Eu Film a base de polyolefine pour former un emballage par pliage
AUPO721997A0 (en) * 1997-06-06 1997-07-03 Queensland Institute Of Medical Research, The Anticancer compounds
EP0891930A1 (de) 1997-07-17 1999-01-20 Alusuisse Technology & Management AG Verpackungsfolie
DE19743435A1 (de) 1997-10-01 1999-04-08 Merck Patent Gmbh Benzamidinderivate
US6750228B1 (en) * 1997-11-14 2004-06-15 Pharmacia Corporation Aromatic sulfone hydroxamic acid metalloprotease inhibitor
KR100699514B1 (ko) 1998-03-27 2007-03-26 얀센 파마슈티카 엔.브이. Ｈｉｖ를 억제하는 피리미딘 유도체
US6384080B1 (en) * 1998-04-20 2002-05-07 Fujisawa Pharmaceutical Co., Ltd. Anthranilic acid derivatives as inhibitors of the cGMP-phosphodiesterase
JPH11335375A (ja) * 1998-05-20 1999-12-07 Mitsui Chem Inc ヒストン脱アセチル化酵素阻害作用を有するベンズアミド誘導体
JP2002522421A (ja) * 1998-08-04 2002-07-23 アストラゼネカ アクチボラグ サイトカイン産生の阻害剤として有用なアミド誘導体
GB9823873D0 (en) * 1998-10-30 1998-12-30 Pharmacia & Upjohn Spa 2-ureido-thiazole derivatives,process for their preparation,and their use as antitumour agents
KR100658489B1 (ko) 1998-11-10 2006-12-18 얀센 파마슈티카 엔.브이. Ｈｉｖ 복제를 억제하는 피리미딘
BR9916211A (pt) 1998-12-14 2001-09-11 American Home Prod Derivados de 3,4-diamino-3-ciclobuteno-1,2-diona que inibem adesão de leucócito mediada por vla-4
US6635657B1 (en) * 1998-12-23 2003-10-21 Eli Lilly And Company Aromatic amides
CZ27399A3 (cs) 1999-01-26 2000-08-16 Ústav Experimentální Botaniky Av Čr Substituované dusíkaté heterocyklické deriváty, způsob jejich přípravy, tyto deriváty pro použití jako léčiva, farmaceutická kompozice a kombinovaný farmaceutický přípravek tyto deriváty obsahující a použití těchto derivátů pro výrobu léčiv
CN100354271C (zh) * 1999-03-03 2007-12-12 三进制药株式会社 哌嗪衍生物及其制备方法
DE60009777T2 (de) 1999-04-01 2004-08-19 Pfizer Products Inc., Groton Verbindung für Behandlung und Vorsorge bei Diabetes
EP1185512A2 (en) 1999-05-24 2002-03-13 Cor Therapeutics, Inc. INHIBITORS OF FACTOR Xa
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
AU5108000A (en) * 1999-06-10 2001-01-02 Yamanouchi Pharmaceutical Co., Ltd. Novel nitrogen-contaiing heterocyclic derivatives or salts thereof
GB9918035D0 (en) 1999-07-30 1999-09-29 Novartis Ag Organic compounds
CA2383781A1 (en) * 1999-09-01 2001-03-08 Aventis Pharma Deutschland Gmbh Sulfonyl carboxamide derivatives, method for their production and their use as medicaments
ATE322494T1 (de) 2000-01-07 2006-04-15 Universitaire Instelling Antwe Purin derivate, ihre herstellung und verwendung
US6608052B2 (en) 2000-02-16 2003-08-19 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
CA2404002A1 (en) * 2000-03-24 2001-09-27 Methylgene, Inc. Inhibitors of histone deacetylase
DE10023484A1 (de) * 2000-05-09 2001-11-22 Schering Ag Anthranylamide und deren Verwendung als Arzneimittel
WO2002000651A2 (en) 2000-06-27 2002-01-03 Bristol-Myers Squibb Pharma Company Factor xa inhibitors
WO2002018335A1 (fr) 2000-08-28 2002-03-07 Yamanouchi Pharmaceutical Co., Ltd. Derives d'amine cyclique
ES2167276B1 (es) * 2000-10-20 2003-04-01 Esteve Labor Dr Nuevos derivados de cianoaril (o cianoheteroaril)-carbonil-piperazinil-pirimidinas, su preparacion y su aplicacion como medicamentos.
JO2409B1 (en) 2000-11-21 2007-06-17 شركة جانسين فارماسوتيكا ان. في Second-phenyl carboxy amides are useful as lipid-lowering agents
BR0209128A (pt) * 2001-04-18 2005-11-01 Euro Celtique Sa Compostos, composições farmacêuticas, métodos para o tratamento de dores, métodos para a modulação de uma resposta farmacológica e usos de compostos
SE0101769D0 (sv) * 2001-05-18 2001-05-18 Astrazeneca Ab Novel compounds
SE0101771D0 (sv) * 2001-05-18 2001-05-18 Astrazeneca Ab Novel compounds
US6784173B2 (en) * 2001-06-15 2004-08-31 Hoffmann-La Roche Inc. Aromatic dicarboxylic acid derivatives
DE10130374A1 (de) 2001-06-23 2003-01-02 Boehringer Ingelheim Pharma Substituierte N-Acyl-anilinderivate, deren Herstellung und deren Verwendung als Arzneimittel
JO3429B1 (ar) 2001-08-13 2019-10-20 Janssen Pharmaceutica Nv مشتقات برميدينات مثبطة فيروس الايدز
US6897220B2 (en) 2001-09-14 2005-05-24 Methylgene, Inc. Inhibitors of histone deacetylase
US7129034B2 (en) 2001-10-25 2006-10-31 Cedars-Sinai Medical Center Differentiation of whole bone marrow
GB0127929D0 (en) 2001-11-21 2002-01-16 Celltech R&D Ltd Chemical compounds
GB0229931D0 (en) 2002-12-21 2003-01-29 Astrazeneca Ab Therapeutic agents
ES2416304T3 (es) * 2002-01-18 2013-07-31 Astellas Pharma Inc. Derivado de 2-acilaminotiazol o sal del mismo
US20060058553A1 (en) 2002-02-07 2006-03-16 Axys Pharmaceuticals, Inc. Novel bicyclic hydroxamates as inhibitors of histone deacetylase
AU2003202115A1 (en) * 2002-02-12 2003-09-04 Pfizer Inc. Non-peptide compounds affecting the action of gonadotropin-releasing hormone (gnrh)
EA007272B1 (ru) 2002-03-13 2006-08-25 Янссен Фармацевтика Н. В. Новые ингибиторы гистондеацетилазы
EP1485378B1 (en) 2002-03-13 2008-06-18 Janssen Pharmaceutica N.V. Piperazinyl-, piperidinyl- and morpholinyl-derivatives as novel inhibitors of histone deacetylase
CN100445276C (zh) 2002-03-13 2008-12-24 詹森药业有限公司 用作组蛋白去乙酰酶抑制剂的磺酰基衍生物
WO2003076438A1 (en) 2002-03-13 2003-09-18 Janssen Pharmaceutica N.V. Piperazinyl-, piperidinyl- and morpholinyl-derivatives as novel inhibitors of histone deacetylase
EP1485348B1 (en) 2002-03-13 2008-06-11 Janssen Pharmaceutica N.V. Carbonylamino-derivatives as novel inhibitors of histone deacetylase
US7767679B2 (en) 2002-03-13 2010-08-03 Janssen Pharmaceutica N.V. Sulfonylamino-derivatives as novel inhibitors of histone deacetylase
US6897307B2 (en) 2002-03-28 2005-05-24 Novartis Ag Process for preparing 2,6-diaminopurine derivatives
ATE399012T1 (de) 2002-04-03 2008-07-15 Topotarget Uk Ltd Carbaminsäurederivate enthaltend eine piperazin verknüpfung als hdac-inhibitoren
TWI319387B (en) 2002-04-05 2010-01-11 Astrazeneca Ab Benzamide derivatives
GB0209715D0 (en) 2002-04-27 2002-06-05 Astrazeneca Ab Chemical compounds
DE10233412A1 (de) 2002-07-23 2004-02-12 4Sc Ag Neue Verbindungen als Histondeacetylase-Inhibitoren
BR0313371A (pt) 2002-08-02 2005-07-05 Argenta Discovery Ltd Composto, uso de um composto e método de tratamento de doença
ITMI20030025A1 (it) 2003-01-10 2004-07-11 Italfarmaco Spa Derivati dell'acido idrossammico ad attivita' antinfiammatoria.
TW200418806A (en) 2003-01-13 2004-10-01 Fujisawa Pharmaceutical Co HDAC inhibitor
US7465719B2 (en) 2003-01-17 2008-12-16 Topotarget Uk Limited Carbamic acid compounds comprising an ester or ketone linkage as HDAC inhibitors
TW200424174A (en) 2003-02-06 2004-11-16 Hoffmann La Roche New TP diamide
AU2003900608A0 (en) 2003-02-11 2003-02-27 Fujisawa Pharmaceutical Co., Ltd. Hdac inhibitor
US7244751B2 (en) 2003-02-14 2007-07-17 Shenzhen Chipscreen Biosciences Ltd. Histone deacetylase inhibitors of novel benzamide derivatives with potent differentiation and anti-proliferation activity
KR20050122210A (ko) 2003-03-17 2005-12-28 다케다 샌디에고, 인코포레이티드 히스톤 탈아세틸화 효소 억제제
TW200424187A (en) 2003-04-04 2004-11-16 Hoffmann La Roche New oxime derivatives and their use as pharmaceutically active agents
AU2004230889B2 (en) 2003-04-07 2008-03-13 Pharmacyclics Llc Hydroxamates as therapeutic agents
KR20060119705A (ko) 2003-07-30 2006-11-24 교와 핫꼬 고교 가부시끼가이샤 인다졸 유도체
TWI351963B (en) 2003-09-17 2011-11-11 Yeastern Biotech Co Ltd Fungal immunomodulatory protein (fip) prepared by
EP1673349B1 (en) 2003-09-22 2010-06-30 S*Bio Pte Ltd Benzimidazole derivatives: preparation and pharmaceutical applications
WO2005028447A1 (en) 2003-09-22 2005-03-31 S*Bio Pte Ltd Benzimidazole derivates: preparation and pharmaceutical applications
WO2005030705A1 (en) 2003-09-24 2005-04-07 Methylgene, Inc. Inhibitors of histone deacetylase
WO2005040161A1 (en) 2003-10-27 2005-05-06 S*Bio Pte Ltd Biaryl linked hydroxamates: preparation and pharmaceutical applications
TW200530166A (en) 2003-10-27 2005-09-16 S Bio Pte Ltd Acylurea connected and sulfonylurea connected hydroxamates
GB0402496D0 (en) 2004-02-04 2004-03-10 Argenta Discovery Ltd Novel compounds
US20050197336A1 (en) 2004-03-08 2005-09-08 Miikana Therapeutics Corporation Inhibitors of histone deacetylase
CA2559733C (en) 2004-03-26 2014-05-13 Methylgene Inc. Inhibitors of histone deacetylase
EP1781639B1 (en) 2004-07-28 2012-01-25 Janssen Pharmaceutica NV Substituted indolyl alkyl amino derivatives as novel inhibitors of histone deacetylase
ME01058B (me) 2004-07-28 2012-10-20 Janssen Pharmaceutica Nv Supstituisani derivati propenil piperazina kao novi inhibitori histonske deacetilaze
EP1776358B1 (en) 2004-07-28 2009-05-27 Janssen Pharmaceutica N.V. Substituted propenyl piperazine derivatives as novel inhibitors of histone deacetylase
WO2006122926A1 (en) 2005-05-18 2006-11-23 Janssen Pharmaceutica N.V. Substituted aminopropenyl piperidine or morpholine derivatives as novel inhibitors of histone deacetylase
ATE533759T1 (de) 2005-06-23 2011-12-15 Janssen Pharmaceutica Nv Imidazolinon- und hydantoinderivate als neue inhibitoren von histondeacetylase
UA92608C2 (en) 2005-06-30 2010-11-25 Янссен Фармацевтика Н.В. Cyclic anilino - pyridinotriazines as gsk-3 inhibitors
WO2007016532A2 (en) 2005-08-02 2007-02-08 Novartis Ag Mutations and polymorphisms of hdac4
AU2006307918B2 (en) 2005-10-27 2012-06-21 Janssen Pharmaceutica N.V. Squaric acid derivatives as inhibitors of histone deacetylase
US7888360B2 (en) 2006-01-19 2011-02-15 Janssen Pharmaceutica N.V. Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase
ES2376121T3 (es) 2006-01-19 2012-03-09 Janssen Pharmaceutica, N.V. Derivados de heterociclilalquilo como nuevos inhibidores de histona deacetilasa.
PT1981874E (pt) 2006-01-19 2009-09-02 Janssen Pharmactuica N V Derivados de aminofenil como novos inibidores de histonadesacetilase
CN101370790B (zh) 2006-01-19 2015-10-21 詹森药业有限公司 作为组蛋白去乙酰化酶抑制剂的吡啶和嘧啶衍生物
EP1979327A1 (en) 2006-01-19 2008-10-15 Janssen Pharmaceutica, N.V. Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase
CA2635015C (en) 2006-01-19 2014-06-03 Janssen Pharmaceutica N.V. Substituted indolyl-alkyl-amino-derivatives as inhibitors of histone deacetylase
US20090270419A1 (en) 2006-09-15 2009-10-29 Janine Arts Combinations of class-i specific histone deacetylase inhibitors with proteasome inhibitors
US20100270419A1 (en) 2007-12-14 2010-10-28 Raphael Yoeli Redundancies and flows in vehicles
GB0901749D0 (en) 2009-02-03 2009-03-11 Oxford Nanopore Tech Ltd Adaptor method

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001038322A1 (en) * 1999-11-23 2001-05-31 Methylgene, Inc. Inhibitors of histone deacetylase

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Foks, Henryk等.Studies on pyrazine derivatives. Part X..CAN:89:59875 & Pol. J. Pharmacol. Pharm., 30(1), 105-11, 1978.1999,CA摘要.
Foks, Henryk等.Studies on pyrazine derivatives. Part X..CAN:89:59875 &amp *
J. Med. Chem., 33(7), 2028-32, 1990.1997,CA摘要. *
Pol. J. Pharmacol. Pharm., 30(1), 105-11, 1978.1999,CA摘要. *
Walsh, David A.等.Synthesis and antiallergy activity ofN-[2-(dimethylamino)ethyl]-4-aryl-1-piperazinecarboxamidederivatives..CAN:113:17483 & J. Med. Chem., 33(7), 2028-32, 1990.1997,CA摘要.
Walsh, David A.等.Synthesis and antiallergy activity ofN-[2-(dimethylamino)ethyl]-4-aryl-1-piperazinecarboxamidederivatives..CAN:113:17483 &amp *

Also Published As

Publication number Publication date
US7541369B2 (en) 2009-06-02
US9150560B2 (en) 2015-10-06
US20130245034A1 (en) 2013-09-19
US7615553B2 (en) 2009-11-10
MXPA04008806A (es) 2004-11-26
WO2003076400A1 (en) 2003-09-18
US20090170836A1 (en) 2009-07-02
CA2476296C (en) 2011-02-22
HRP20040803A2 (en) 2005-02-28
US20150353549A1 (en) 2015-12-10
EA200401199A1 (ru) 2005-02-24
EA007272B1 (ru) 2006-08-25
IL164007A (en) 2011-03-31
CN1639125A (zh) 2005-07-13
DE60326549D1 (en) 2009-04-23
US8268833B2 (en) 2012-09-18
US20100048588A1 (en) 2010-02-25
EP1485370A1 (en) 2004-12-15
ZA200407232B (en) 2005-10-06
JP4472353B2 (ja) 2010-06-02
CN1642551A (zh) 2005-07-20
ZA200407234B (en) 2005-10-06
WO2003076421A1 (en) 2003-09-18
EP1485099A1 (en) 2004-12-15
JP4836405B2 (ja) 2011-12-14
ATE425152T1 (de) 2009-03-15
DE60326436D1 (en) 2009-04-16
ES2322252T3 (es) 2009-06-18
OA12791A (en) 2006-07-10
ATE521592T1 (de) 2011-09-15
MXPA04008797A (es) 2004-11-26
AU2003212337A1 (en) 2003-09-22
US7816363B2 (en) 2010-10-19
HK1078473A1 (en) 2006-03-17
NZ534834A (en) 2005-07-29
DE60333260D1 (en) 2010-08-19
AU2003212337B2 (en) 2009-06-11
PL212089B1 (pl) 2012-08-31
UA78033C2 (en) 2007-02-15
OA12790A (en) 2006-07-10
WO2003076430A1 (en) 2003-09-18
CA2475764C (en) 2011-05-31
AU2003218737A1 (en) 2003-09-22
EP1485364A1 (en) 2004-12-15
US20050222414A1 (en) 2005-10-06
PL370992A1 (en) 2005-06-13
KR20040090985A (ko) 2004-10-27
US8524711B2 (en) 2013-09-03
IL164004A0 (en) 2005-12-18
US8916554B2 (en) 2014-12-23
JP4725944B2 (ja) 2011-07-13
US20120252790A1 (en) 2012-10-04
JP4644428B2 (ja) 2011-03-02
TW200400822A (en) 2004-01-16
IL164003A0 (en) 2005-12-18
WO2003075929A1 (en) 2003-09-18
US9556161B2 (en) 2017-01-31
AU2003218736A1 (en) 2003-09-22
US7501417B2 (en) 2009-03-10
UA78031C2 (en) 2007-02-15
PL370991A1 (en) 2005-06-13
CA2476296A1 (en) 2003-09-18
CA2476583C (en) 2011-07-05
CA2476583A1 (en) 2003-09-18
US20050107384A1 (en) 2005-05-19
US20050119250A1 (en) 2005-06-02
UA78032C2 (en) 2007-02-15
US20140171439A1 (en) 2014-06-19
ES2322950T3 (es) 2009-07-02
EP1485099B1 (en) 2010-07-07
ATE424395T1 (de) 2009-03-15
JP2005525381A (ja) 2005-08-25
EP1485353A1 (en) 2004-12-15
US20050096468A1 (en) 2005-05-05
US20130303506A1 (en) 2013-11-14
US20150065478A1 (en) 2015-03-05
ZA200407235B (en) 2005-10-04
ZA200407236B (en) 2005-10-06
JP2005526067A (ja) 2005-09-02
US8114999B2 (en) 2012-02-14
ES2347544T3 (es) 2010-11-02
IL164007A0 (en) 2005-12-18
JP2005523907A (ja) 2005-08-11
PL213783B1 (pl) 2013-05-31
NZ534832A (en) 2005-09-30
AU2003218737B2 (en) 2008-04-10
AU2003212335A1 (en) 2003-09-22
ZA200407233B (en) 2005-10-06
BR0307624A (pt) 2005-01-11
IL164006A0 (en) 2005-12-18
EP1485364B1 (en) 2009-03-11
EP1485353B1 (en) 2011-08-24
ZA200407237B (en) 2005-09-28
CA2476065A1 (en) 2003-09-18
US20120108603A1 (en) 2012-05-03
NO20044113L (no) 2004-09-28
CN100519527C (zh) 2009-07-29
US8343988B2 (en) 2013-01-01
JP2005525379A (ja) 2005-08-25
AU2003218736B2 (en) 2009-01-08
US8697717B2 (en) 2014-04-15
US20090170881A1 (en) 2009-07-02
NO20044194L (no) 2004-10-01
HRP20040799A2 (en) 2005-04-30
AR039566A1 (es) 2005-02-23
AU2003212335B8 (en) 2009-04-23
BR0308081A (pt) 2004-12-21
CA2476065C (en) 2012-07-24
DK1485353T3 (da) 2011-11-28
IL164005A0 (en) 2005-12-18
IL164006A (en) 2010-11-30
ATE473005T1 (de) 2010-07-15
EA200401201A1 (ru) 2005-02-24
EP1485370B1 (en) 2009-03-04
US8455498B2 (en) 2013-06-04
UA77263C2 (en) 2006-11-15
ES2371632T3 (es) 2012-01-05
US9533979B2 (en) 2017-01-03
US20090227558A1 (en) 2009-09-10
US20100010004A1 (en) 2010-01-14
CA2475764A1 (en) 2003-09-18
KR20040090979A (ko) 2004-10-27
AU2003212335B2 (en) 2008-11-27
EA008245B1 (ru) 2007-04-27

Similar Documents

Publication Publication Date Title
CN1642551B (zh) 组蛋白脱乙酰基酶抑制剂
CN101450934B (zh) 用作组蛋白去乙酰酶抑制剂的磺酰基衍生物
CN100503599C (zh) 作为组蛋白脱乙酰酶的新颖抑制剂的羰基氨基衍生物
CN100396679C (zh) 用作组蛋白脱乙酰化酶抑制剂的哌嗪基、哌啶基和吗啉基衍生物
CN101374828B (zh) 作为组蛋白脱乙酰酶抑制剂的杂环烷基衍生物
CN101370803B (zh) 作为组蛋白脱乙酰酶抑制剂的取代的吲哚基-烷基-氨基衍生物
CN101370791B (zh) 作为组蛋白脱乙酰基酶抑制剂的吡啶和嘧啶衍生物
JP5055268B2 (ja) ヒストンデアセチラーゼの新規な阻害剤としての置換されたアミノプロペニルピペリジンまたはモルホリン誘導体
EP1943232B1 (en) Squaric acid derivatives as inhibitors of histone deacetylase

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1078473

Country of ref document: HK

C14 Grant of patent or utility model
GR01 Patent grant
REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1078473

Country of ref document: HK

CX01 Expiry of patent term

Granted publication date: 20110914

CX01 Expiry of patent term