CN103119030A - Matrix metalloproteinase inhibitors - Google Patents
Matrix metalloproteinase inhibitors Download PDFInfo
- Publication number
- CN103119030A CN103119030A CN2011800461515A CN201180046151A CN103119030A CN 103119030 A CN103119030 A CN 103119030A CN 2011800461515 A CN2011800461515 A CN 2011800461515A CN 201180046151 A CN201180046151 A CN 201180046151A CN 103119030 A CN103119030 A CN 103119030A
- Authority
- CN
- China
- Prior art keywords
- compound
- phenyl
- oxo
- phentriazine
- methyl
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/08—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 condensed with carbocyclic rings or 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- 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
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- 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
- A61P13/12—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
- 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
- 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
- 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
- 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
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
-
- 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
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Oncology (AREA)
- Transplantation (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Ophthalmology & Optometry (AREA)
- Pain & Pain Management (AREA)
- Vascular Medicine (AREA)
- Communicable Diseases (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Hospice & Palliative Care (AREA)
- Physical Education & Sports Medicine (AREA)
- Otolaryngology (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to certain hydroxy propionic acid derivatives and the processes for the synthesis of the same. This invention also relates to pharmacological compositions containing the compounds of the present invention, and methods of treating asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis, pulmonary inflammation, acute respiratory distress syndrome, perodontitis, multiple sclerosis, gingivitis, atherosclerosis, dry eye, neointimal proliferation, which leads to restenosis and ischemic heart failure, stroke, renal diseases, tumor metastasis, and other inflammatory disorders characterized by over-expression and over activation of a matrix metalloproteinase using the compounds.
Description
Technical field
The present invention relates to the synthetic method of some hydoxy-propionic acid derivative and these derivatives.the invention still further relates to the pharmaceutical composition that comprises the compounds of this invention and with the method for the following disease of these compounds for treating: asthma, rheumatoid arthritis, chronic obstructive pulmonary disease, rhinitis, osteoarthritis, psoriatic arthritis, psoriatic, pulmonary fibrosis, pneumonia, adult respiratory distress syndrome, periodontitis, multiple sclerosis, gingivitis, atherosclerosis, xerophthalmia, the intimal hyperplasia that causes restenosis and ischemic cardiac exhaustion, apoplexy, ephrosis, metastases, and feature is other inflammatory diseases of crossing expression and excess activation of matrix metalloproteinase.
Background technology
Metalloprotease (MMP) is neutral protease (enzyme) superfamily that is present in most of Mammalss.This superfamily is comprised of at least 26 members' the zinc enzyme that is produced by many cell types, and they have common structure and function feature.Based on the Consideration of structure and function, with proteolytic enzyme be categorized into different families and subfamily (people such as Vartak, J.Drug Targeting,
15, 1-20 page (2007); And Hopper, FEBS,
3541-6 page (1994)), such as collagenase (MMP-1 ,-8 and-13), gelatinase (MMP-2 and-9), metal elastic force enzyme (MMP-12), MT-MMP (MMP-14 ,-15 ,-16 ,-17 ,-24 and 25), matrix crack protein (MMP-7 and-26), matrix properdin (MMP-3 ,-10 and-11) and the enzyme that comes off (sheddase) such as TNF-saccharase (TACE and ACE).
Metalloproteinases is considered to play an important role in the physiological process that relates to reconstruct and lysis (such as the uterus reconstruct in airway disorders, fetal development, bone forming and menstrual period).One of main biological function of MMP is to utilize the ability of the various moietys of their hydrolysis tissues or matrix to come the decomposition of catalysis reticular tissue or extracellular matrix.Except the effect in degrade connective tissues, the activation that MMP also participates in other mmp enzyme former (pro) form causes the MMP activation thus.MMP also participates in the biosynthesizing of the TNF-α relevant with many pathological states.
The MMP-9 that belongs to gelatinase family plays an important role in chronic inflammatory disease (as chronic obstructive pulmonary disease, asthma and rheumatoid arthritis).Have been reported: in diseases such as asthma, interstitial pulmonary fibrosis (IPF), adult respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD), MMP-9 concentration raises.Owing to having proteoclastic ability, it is relevant with air flue and the reconstructed tissue of lung in chronic inflammation disease (such as Severe Asthma and chronic obstructive pulmonary disease) that MMP-9 is considered to.Due to the ability of the activity of the digestion with the moiety of regulating extracellular matrix and other proteolytic enzyme and cytokine, MMP-9 may also have important physiological role.MMP-9 secretes in neutrophilic granulocyte, scavenger cell and osteoclast, easily induce with cytokine and somatomedin, and MMP-9 participates in various physiological processes and pathologic process.
MMP-12 is also referred to as MMP12 or metal elastic force enzyme, expresses in the scavenger cell of activation, and has been found in smoker's pulmonary alveolar macrophage and the foam cell in atheromatous lesions secretion is arranged.The research of MMP-12 knock out mice has shown significant emophysematous formation, therefore supports its effect in chronic obstructive pulmonary disease.MMP-9 (Gelatinase B, 92kDa IV Collagenase Type) is a member of MMP family, and it is released with zymogen forms in vivo, then is activated via the protease cascade reaction.
MMP cross expression or overactivity or MMP and matrix metalloproteinase (TIMP) natural (namely, endogenous) imbalance between tissue depressant is considered to relevant with the pathogenesis of the disease that is decomposed into feature with reticular tissue or extracellular matrix.
Can be favourable to the inhibition of the activity of one or more MMP to the treatment of various diseases associated with inflammation, autoimmune disease and allergic disorder (such as the inflammation of the inflammation in joint, GI inflammation, skin, collagen remodeling, wound healing imbalance etc.).
The design of MMP inhibitor and treatment are used and to be shown, the effective inhibitor as the enzyme of MMP class requires this molecule to have and can be chelated to reactive site Zn
2+The functional group of ion (such as carboxylic acid, hydroxamic acid or sulfydryl) (people such as Whittaker, Chem.Rev., 99; 2735-76 page (1999)).
WO2004/014310 discloses the method for preparing the peripheral opioid antagonist compound that can be used for gastrointestinal motility disorders.WO02/060888 discloses the benzoic method of preparation chromanyl.WO94/20455 disclose can be used for preventing and treat the disease (such as asthma) that wherein has harmful inflammatory reaction or muscle spasm, as the styryl derivative of PDE-IV inhibitor.WO2004/110974 discloses the compound of the inhibitor that is described to matrix metalloproteinase and their physiologic function derivative.WO2004/113279 discloses the inhibitor of matrix metalloproteinase.WO2005/026120 discloses the compound of the inhibitor that is described to matrix metalloproteinase.U.S. Patent application the 2003/0139453rd discloses the difluoro butyric acid compound that can be used for treating the disease relevant to the zinc metalloprotein enzymic activity.WO2006/090235 has described the 5-phenyl-pentanoic acid derivatives that is described to matrix metallo-proteinase inhibitor that is used for the treatment of asthma and Other diseases.WO2008/023336 discloses beta-hydroxy and the amino-substituted carboxylic acid class that plays the matrix metallo-proteinase inhibitor effect.
Studied to identify for example several MMP hypotypes have been had optionally inhibitor.The MMP inhibitor that selectivity is high can avoid suppressing relevant to MMP but with to the machine-processed adiaphorous potential adverse effect of controlling disease incidence.
In addition, use the required amount of application of the higher MMP inhibitor for treating of selectivity lower, and can form different MMP difference distribution in vivo after administration.And then dosage reduces and also will increase the required amount of suppression of therapeutic activity and to observe safety range between the amount of suppression of toxicity.
Many medicines show as the form of asymmetric three-dimensional molecular (being chirality), therefore will have several steric isomer according to the quantity of the chiral centre that exists.Each independent isomer with chiral centre is importantly understood their pharmacology and toxicological action as the assessment of new chemical entities.Often there are pharmacodynamics, pharmacokinetics and/or toxicology difference between each enantiomer/diastereomer.Even natural physiology mediation person is achiral, but based on their target spot environment, their acceptor/enzyme can only can show skewed popularity to an optical purity enantiomer of agonist, antagonist or inhibitor.From the viewpoint of pharmacokinetics, chirality can exert an influence to absorption, distribution, metabolism and the removing of medicine.From these pharmacokinetic parameters aspect, pure single isomer of planting also may have superiority, and impels thus this quasi-molecule of exploitation as drug candidate.And known, chirality has remarkably influenced to physico-chemical property and the crystallinity of chiral molecules, thereby correspondingly pharmacokinetics and the exploitation of these molecules is had profound influence.Except above-mentioned, some management and regulation principle also guide the developer preferably to develop pure isomer as drug candidate, avoid unwanted isomer and the caused pharmacology of non-target molecule target interaction, pharmacokinetics and toxicological issues.
In this article, make the synthesis strategy of pure isomer and compare with analyzing disassemble technique, not only have advantage aspect cost and efficient, and can make more that the polyvoltine compound carries out pharmacy test.Therefore, as the compounds of this invention of homochiral isomer, compare with racemic compound, have the usefulness of improvement, the pharmacokinetics of improvement and/or the physico-chemical property of improvement.
The objective of the invention is to solve the problem that runs in this area.
Summary of the invention
The hydoxy-propionic acid derivative of matrix metallo-proteinase inhibitor effect, the synthetic method of these derivatives and the pharmaceutical composition that contains the compounds of this invention have been the invention provides.The present invention relates to various diseases associated with inflammation, autoimmune disorder and allergic disorder and take matrix metalloproteinase cross to express and overactivity is used as the matrix metallo-proteinase inhibitor of effective therapeutical agent or preventive in other inflammatory diseases of feature.
The invention discloses a class new compound, be the MMP-9/12 double inhibitor and have desirable living features.Compound of the present invention has favourable usefulness and/or selectivity.
The pharmaceutical composition that contains this compound has also been united pharmaceutically acceptable carrier or thinner, and this pharmaceutical composition can be used for treatment or the prevention of struvite or autoimmune disorder.These pharmaceutical compositions can be by number of ways (for example comprise oral administration, topical, rectal administration, intranasal administration or by the parenteral approach) administration or Combined Preparation.Said composition is mode administration or the Combined Preparation of available slow release formulation also.
Except the given enantiomer that exemplifies, the present invention also provides racemic modification, diastereomer, pharmaceutically-acceptable salts, the pharmaceutically acceptable solvate with similar activity.The present invention also provides and comprises the pharmaceutical composition that this compound and washability comprise vehicle.
One or more the compounds of this invention for the treatment of significant quantity can be united use with one or more other therapeutical agents (for example other anti-inflammatory agent, beta-2-agonists, antihypertensive drug, immunosuppressor, anti-infection agent).
To be illustrated other purpose in subsidiary description, and describe other purpose based on this and will become obvious or understand other purpose by working of an invention.
Embodiment
On the one hand, the invention provides the compound with structure shown in structural formula I:
Structural formula I
Comprise their racemic modification, enantiomer and diastereomer or their pharmaceutically-acceptable salts, wherein,
U can be selected from Lian Jian ,-NH-,-C (=O)-,-(CH
2)
n-,-C (=S)-,-O-,-SO
2-or-S-, wherein n can be zero or 1 or 2 integer;
V can be selected from Lian Jian ,-NH-,-C (=O)-,-C (=S)-or-SO
2-;
W can be selected from Lian Jian ,-NH-,-C (=O)-,-(CH
2)
n-,-C (=S)-,-O-,-S-or-SO
2-;
R
1Can be selected from alkyl, thiazolinyl, alkynyl, cyano group, nitro, halogen, halo-C
1-C
6Alkyl, halo-C
1-C
6Alkoxyl group, azido-, sulfydryl, alkylthio ,-(CH
2)
n-OR
f,-C (=O)-R
f,-COOR
f,-NR
fR
q,-(CH
2)
n-C (=O) NR
fR
q,-(CH
2)
n-NHC (=O)-R
f,-(CH
2)
n-O-C (=O)-NR
fR
q, (CH
2)
nNHC (=O) NR
fR
q,-(CH
2)
n-O-C (=O)-R
f,-(CH
2)
n-NH-C (=O)-R
fPerhaps-(CH
2)
nS (=O)
m-NR
fR
q{ R wherein
fAnd R
qBe selected from separately hydrogen, alkyl, thiazolinyl, cycloalkyl aryl, heteroaryl, heterocyclic radical, alkylaryl, miscellaneous alkyl aryl and alkyl heterocyclic, n as previously mentioned and m be the integer of 0-2;
On the other hand, the invention provides the compound with structure shown in structural formula Ia:
Structural formula Ia
Comprise their racemic modification, enantiomer and diastereomer or their pharmaceutically-acceptable salts, wherein,
L
1Can be selected from Lian Jian ,-(CH
2)
n-,-NHCO (CH
2)
n-,-(CH
2)
nC (=O) NH-,-NHC (=O) NH-,-SO
2NH-,-NHSO
2-,-SO
2-,-NHC (=O) (O)-,-O-(CH
2)
n-,-(CH
2)
n-O-,-(CH
2)
nOC (=O) NH-,-C (=S) NH-,-NHC (=S)-or-NHC (=S) NH-, wherein n can be zero or 1 or 2 integer;
Can be selected from aryl, cycloalkyl, heteroaryl or heterocyclic radical, they separately can be further by one or more R that are independently selected from
1Substituting group replace.
R
1Can be selected from alkyl, thiazolinyl, alkynyl, cyano group, nitro, halogen, halo-C
1-C
6Alkyl, halo-C
1-C
6Alkoxyl group, azido-, sulfydryl, alkylthio ,-(CH
2)
n-OR
f,-C (=O)-R
f,-COOR
f,-NR
fR
q,-(CH
2)
n-C (=O) NR
fR
q,-(CH
2)
n-NHC (=O)-R
f,-(CH
2)
n-O-C (=O)-NR
fR
q, (CH
2)
nNHC (=O) NR
fR
q,-(CH
2)
n-O-C (=O)-R
f,-(CH
2)
n-NH-C (=O)-R
fPerhaps-(CH
2)
nS (=O)
m-NR
fR
q{ R wherein
fAnd R
qBe selected from separately hydrogen, alkyl, thiazolinyl, cycloalkyl aryl, heteroaryl, heterocyclic radical, alkylaryl, miscellaneous alkyl aryl, alkyl heterocyclic, n as previously mentioned and m be the integer of 0-2;
Another aspect the invention provides compound shown in structural formula Ib:
Structural formula Ib
Comprise their racemic modification, enantiomer and diastereomer or their pharmaceutically-acceptable salts, wherein,
R wherein
1As previously mentioned and v can be zero or 1-4 between integer;
Ra can be hydrogen or fluorine;
L
1With
As previously mentioned.
Another aspect the invention provides compound shown in structural formula Ic:
Structural formula Ic
Comprise their racemic modification, enantiomer and diastereomer or their pharmaceutically-acceptable salts, wherein,
L
1aTo be selected from S (O)
n, NHCO (CH
2)
nAnd NHCO (O);
Ra,
With
As previously mentioned.
The present invention also provides enantiomer, diastereomer, rotational isomer, N-oxide compound, polymorphic form, pharmaceutically-acceptable salts and the pharmaceutically acceptable solvate of these compounds, the prodrug with similar activity and meta-bolites; And provide comprise these compounds, their meta-bolites, enantiomer, diastereomer, conformer, N-oxide compound, polymorphic form, solvate or their pharmaceutically-acceptable salts comprises the pharmaceutical composition of vehicle together with pharmaceutically acceptable carrier and washability.
In one embodiment, the present invention relates to compound shown in structural formula (I), these compounds can include but not limited to following compounds, for example:
(2S)-2-[(S)-the 4-[(4-chloro-phenyl-) sulfinyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 1);
(2S)-2-[(S)-the 4-[(4-chloro-phenyl-) alkylsulfonyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 2);
(2S)-2-[(S)-4-[(3,4-difluorophenyl) sulfinyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 3);
(2S)-2-[(S)-4-[(2,3-dichlorophenyl) sulfinyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 4);
(2S)-2-[(S)-4-[(2,4-3,5-dimethylphenyl) sulfinyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 5);
(2S)-2-[(S)-the 4-[(4-fluorophenyl) alkylsulfonyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 6);
(2S)-2-[(S)-4-[(3,4-difluorophenyl) alkylsulfonyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 7);
2-[{4-[(2, the 3-dichlorophenyl) alkylsulfonyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 8);
(2S)-2-[(S)-4-[(2,4-3,5-dimethylphenyl) alkylsulfonyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 9);
(2S)-2-[(S)-(4-{[(4-ethylphenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 10);
(2S)-2-[(S)-(4-{[(4-chloro-phenyl-) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 11);
(2S)-2-[(S)-(4-{[(3,4-dichlorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 12);
(2S)-2-[(S)-hydroxyl (4-{[(4-p-methoxy-phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 13);
(2S)-2-[(S)-hydroxyl (4-{[(3-p-methoxy-phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 14);
(2S)-2-[(S)-hydroxyl (4-{[(4-aminomethyl phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 15);
(2S)-2-[(S)-(4-{[(4-fluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 16);
(2S)-2-{ (S)-hydroxyl [4-({ [4-methoxyl group-3-(trifluoromethyl) phenyl] carbonyl } amino) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 17);
(2S)-2-[(S)-hydroxyl (4-{[(5-methyl isophthalic acid, 2-oxazole-3-yl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 18);
(2S)-2-[(S)-(4-{[(3-chloro-4-fluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 19);
(2S)-2-[(S)-hydroxyl the 4-[(phenylcarbonyl group) and amino] phenyl } methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 20);
(2S)-2-[(S)-hydroxyl (4-{[(4-propyl group phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 21);
(2S)-2-[(S)-hydroxyl the 4-[(phenyloxycarbonyl) and amino] phenyl } methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 22);
(2S)-2-[(S)-hydroxyl the 4-[(phenyl acetyl) and amino] phenyl } methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 23);
(2S)-2-[(S)-(4-{[(2,4-dichlorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 24);
(2S)-2-[(S)-hydroxyl (4-{[(2-aminomethyl phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 25);
(2S)-2-[(S)-(4-{[(2-fluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 26);
(2S)-2-[(S)-(4-{[(3-chloro-phenyl-) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 27);
(2S)-2-[(S)-hydroxyl (4-{[(3-aminomethyl phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 28);
(2S)-2-[(S)-(4-{[(3-fluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 29);
(2S)-2-[(S)-(4-{[(2,6-Dimethoxyphenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 30);
(2S)-2-[(S)-the 4-[(cyclopentylcarbonyl) amino] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 31);
(2S)-2-[(S)-hydroxyl (4-{[(2,4,5-, three fluoro-3-p-methoxy-phenyls) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 32);
(2S)-2-[(S)-hydroxyl (4-{[(2,3,4-trifluorophenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 33);
(2S)-2-{ (S)-hydroxyl [4-({ [2-(trifluoromethyl) phenyl] carbonyl } amino) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 34);
(2S)-2-[(S)-(4-{[(3,5-Dimethoxyphenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 35);
(2S)-2-[(S)-(4-{[(2,3-difluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 36);
(2S)-2-[(S)-(4-{[(3,5-dichlorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 37);
(2S)-2-[(S)-(4-{[(2,4-difluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 38);
(2S)-2-[(S)-(4-{[(2,6-difluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 39);
(2S)-2-[(S)-hydroxyl (4-{[(2-p-methoxy-phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 40);
(2S)-2-[(S)-the 4-[(cyclohexyl-carbonyl) amino] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 41);
(2S)-2-[(S)-(4-{[(4-ethoxyl phenenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 42);
(2S)-2-[(S)-(4-{[(3,4-difluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 43);
(2S)-2-{ (S)-hydroxyl [4-({ [4-(trifluoromethoxy) phenyl] carbonyl } amino) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 44);
(2S)-2-{ (S)-hydroxyl [4-({ [3-(trifluoromethyl) phenyl] carbonyl } amino) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 45);
(2S)-2-[(S)-[4-({ [2-fluoro-4-(trifluoromethyl) phenyl] carbonyl } amino) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 46);
(2S)-2-[(S)-(4-{[(3-chloro-2,6-difluoro phenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 47);
(2S)-2-{ (S)-hydroxyl [4-({ [4-(trifluoromethyl) phenyl] carbonyl } amino) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 48);
(2S)-2-[(S)-(4-{[(2,5-difluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 49);
(2S)-2-[(S)-(4-{[(2,3-two fluoro-4-aminomethyl phenyls) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 50);
(2S)-2-[(S)-[4-({ [4-fluoro-3-(trifluoromethyl) phenyl] carbonyl } amino) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 51);
(2S)-2-[(S)-the 4-[(cyclopropyl carbonyl) amino] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 52);
(2S)-2-[(S)-(4-{[(2-ethylphenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 53);
(2S)-2-[(S)-hydroxyl (4-{[(4-p-methoxy-phenyl) ethanoyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 54);
(2S)-2-[(S)-the 4-[(cyclobutyl carbonyl) amino] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 55);
(2S)-2-{ (S)-hydroxyl [4-(4-methoxyphenoxy) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 56);
(2S)-2-[(S)-[4-(3-chloro-4-fluorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 57);
(2S)-2-[(S)-[4-(4-chloro-3-methylphenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 58);
(2S)-2-[(S)-[4-(4-chloro-2-fluorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 59);
(2S)-2-[(S)-[4-(4-fluorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 60);
(2S)-2-[(S)-[4-(3,4-difluoro phenoxy group) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 61);
(2S)-2-[(S)-[4-(2-chlorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 62);
(2S)-2-[(S)-[4-(3-chlorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 63);
(2S)-2-[(S)-[4-(2,6-difluoro phenoxy group) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 64);
(2S)-2-[(S)-[4-(2,5-dichlorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 65);
(2S)-2-[(S)-[4-(2-chloro-4-fluorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 66);
(2S)-2-{ (S)-hydroxyl [4-(3-methoxyphenoxy) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 67);
(2S)-2-[(S)-[4-(2-chloro-4-methoxy phenoxy group) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 68);
(2S)-2-[(S)-[4-(2,4 difluorobenzene oxygen base) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 69);
(2S)-2-[(S)-[3-fluoro-4-(4-methylphenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 70);
(2S)-2-[(S)-[3-fluoro-4-(3-methylphenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 71);
(2S)-2-[(S)-[4-(3,4-dimethyl phenoxy)-3-fluorophenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 72);
(2S)-2-[(S)-[4-(3,4-dichlorophenoxy)-3-fluorophenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 73);
(2S)-2-[(S)-[4-(4-tertiary butyl phenoxy group)-3-fluorophenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 74);
(2S)-2-[(S)-[3-fluoro-4-(4-methoxyphenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 75);
Comprise their racemic modification, enantiomer and diastereomer or their pharmaceutically-acceptable salts.
On the other hand, the invention provides one or more pharmaceutical compositions of described compound and one or more pharmaceutically acceptable carriers, vehicle or thinner herein that comprise the treatment significant quantity.
On the other hand, the invention provides for compound shown in the structural formula I/Ia/Ib/Ic of medicine.
On the other hand, be provided for herein treating or prevent compound shown in the structural formula I/Ia/Ib/Ic of various struvite and allergic disorders, comprising the described treatment of needs or prevention mammiferous used described compound.
On the other hand, the invention provides compound shown in structural formula I/Ia/Ib/Ic, described various struvite and allergic disorders are asthma, rheumatoid arthritis, chronic obstructive pulmonary disease, rhinitis, osteoarthritis, psoriatic arthritis, psoriatic, pulmonary fibrosis, pneumonia, adult respiratory distress syndrome, periodontitis, multiple sclerosis, gingivitis, atherosclerosis, xerophthalmia, intimal hyperplasia, apoplexy, ephrosis or the metastases relevant with ischemic cardiac exhaustion to restenosis.
Another aspect the present invention relates to treat compound shown in the structural formula I/Ia/Ib/Ic of effective dose and one or more are used for the treatment of struvite and other therapeutic combination allergic disorder.The example of described other therapeutical agent includes but not limited to:
1) anti-inflammatory agent, experiment or commercially available, such as (i) non-steroidal anti-inflammatory agent: piroxicam, diclofenac, phenoxy propionic acid, fragrant that esters of gallic acid, pyrazoline ketone, salicylate class, phosphodiesterase inhibitor (comprising the PDE-4 inhibitor), p38MAP kinases/cathepsin inhibitors, CCR-3 antagonist, iNOS inhibitor, tryptase and elastase inhibitor, Beta 2 integrin antagonist, cell adhension inhibitors (particularly ICAM), adenosine 2a agonist, (ii) leukotriene LTC4/LTD4/LTE4/LTB4-inhibitor, 5-lipoxidase inhibitor, PAF-receptor antagonist, (iii) Cox-2 inhibitor, (iv) other MMP inhibitor, (v) interleukin--I inhibitor, (vi) reflunomide, such as Modrasone, amcinonide, Amelometasone, beclometasone, Betamethasone Valerate, budesonide, ciclesonide, clobetasol, cloticasone, Telocort, deflazacort, deprodone, dexbudesonide, diflorasone, difluprednate, fluticasone, flunisolide, halometasone, halogen pyrrone (haloperedone), hydrocortisone, methylprednisolone, Mometasone, prednicarbate, prednisolone, rimexolone, tixocortol, triamcinolone, ulobetasol, Rofleponide, GW215864, KSR592, ST-126, dexamethasone, and their pharmaceutically-acceptable salts, solvate.Preferred reflunomide for example comprises: flunisolide, beclometasone, triamcinolone, budesonide, fluticasone, Mometasone, ciclesonide, dexamethasone;
2) beta-2-agonists, experiment or commercially available, (i) suitable β 2-agonist for example comprises: one or more in salbutamol, salbutamol, bitolterol, pirbuterol, Levalbuterol, Tulobuterol, terbutaline, bambuterol, Racemic isoproterenol, Partusisten, Salmeterol, Ka Moteluo, Afromoterol, formoterol and their pharmaceutically-acceptable salts or solvate, and one or more β 2-agonists can selection from as known in the art or later discovery; (ii) β 2-agonist can comprise and is described in for example United States Patent (USP) the 3rd, 705,233,3,644,353,3,642,896,3,700,681,4,579,985,3,994,974,3,937,838,4,419,364,5,126,375,5,243,076,4, one or more compounds in 992,474 and 4,011,258;
3) antihypertensive drug, (i) ACE inhibitor, for example enalapril, lisinopril, valsartan, telmisartan, quinapril, (ii) angiotensin II receptor antagonists and agonist, for example losartan, Candesartan, Irb, valsartan, Eprosartan, (iii) beta-Blocking agent, and (iv) calcium channel blocker;
4) immunosuppressor, for example S-Neoral, azathioprine and methotrexate, antiphlogistic corticoid; And
5) anti-infection agent (for example, microbiotic, antiviral).
Definition
Term definition used herein is as follows:
Term " alkyl " refers to the complete saturated hydrocarbon chain of straight or branched, and except as otherwise noted, this hydrocarbon chain has 1 to 20 carbon atom, and washability ground is replaced by one or more halogen atoms.Being exemplified as of this term: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-hexyl, positive decyl, positive four decyls, trifluoromethyl, chloroethyl etc.
Except as otherwise noted, term " thiazolinyl " refers to comprise side chain or the unbranched unsaturated alkyl of at least one two key, and this thiazolinyl has cis or trans geometric configuration, and preferably has 2 to 20 carbon atoms.The example of thiazolinyl comprises: vinyl, 2-propenyl, pseudoallyl.
Term " cycloalkyl " refers to have 3 to 20 ring carbon atoms and forms 1 to 3 ring and washability contains the non-aromatic cyclic group of one or more ethylene linkages.Multi-loop system can be volution, condensed ring or bridged ring.The example of cycloalkyl comprises: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, cyclopentenyl, cyclohexenyl, adamantyl, two ring [2.2.1] heptyl, two ring [2.2.2] octanes, three ring [3.3.1.1] decane etc.
Term " aryl " refers to have 6 to 14 carbon atoms and the aroma system that is connected 3 rings (these rings can condense or directly connect).The representative example of this aryl includes but not limited to: phenyl, xenyl, naphthyl, phenanthrene, anthryl, Azulene base, indanyl.It is not the ring of complete aromaticity that aryl also can comprise one or more, and the example of this aroma system is: indane, indenes, 2,3-Dihydrobenzofuranes, 1,2,3,4-naphthane.
Term " heteroaryl " refers to have 5 to 14 carbon atoms and is connected 3 rings (these rings can condense or directly connect) and contains 1 to 8 heteroatomic aroma system that is selected from N, O and S.The example of heteroaryl is: pyridyl, quinolyl, oxazolyl, imidazolyl, pyrryl, thiophenyl, 1,2, the 3-triazolyl, 1,2,4-triazolyl, tetrazyl, thiazolyl, oxadiazolyl, benzimidazolyl-, thiadiazolyl group, pyridazinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furyl, benzofuryl, indyl, benzothiazolyl, benzoxazolyl etc.
Term " heterocyclic radical " refers to non-aromatic have 3 to 12 annular atomses and maximum 8 heteroatomic monocycle or multi-loop systems (can be condensed ring, volution or bridged ring) that are selected from N, O and S.The example of heterocyclic ring system comprises: piperidines, morpholine, piperazine, isoquinoline 99.9, oxazolidine, tetrahydrofuran (THF), dihydrofuran, dihydropyridine, dihydro-isoxazole, Dihydrobenzofuranes, azabicyclohexane, indoline, tetrahydroquinoline, tetramethyleneimine, azatropylidene, azetidine, ethylenimine, tetrahydropyridine, benzothiazine, benzoxazine, isoindoline, azabicyclo [3.1.0] hexyl, phenoxazine, tetrahydropyrans, Isosorbide-5-Nitrae-dioxane etc.
Term " cycloalkylalkyl ", " arylalkyl ", " heteroarylalkyl ", " heterocyclic radical alkyl " refer to respectively be connected to via alkyl cycloalkyl, aryl, heteroaryl or the heterocyclic radical of molecule rest part.
Term " amino " refers to-NH
2
Term " alkoxyl group " expression O-alkyl, wherein alkyl as previously mentioned.
Term " halogen " or " halo " refer to fluorine, chlorine, bromine or iodine.
Term " halo-C
1-C
6Alkyl " refer to the C that one or more hydrogen are replaced by halogen
1-C
6Alkyl.
Term " halo-C
1-C
6Alkoxyl group " refer to that the halogen atom bond is to C
1-C
6Alkoxyl group.The example of this group comprises: trifluoromethoxy, trichlorine methoxyl group, difluoro-methoxy, fluorine methoxyl group, 2,2,2-trifluoro ethoxy, 2-bromine oxethyl etc.
Term " hydroxyl " refers to OH.
Term " sulfydryl " refers to-SH.
Term " alkylthio " refers to the sulfydryl that hydrogen is replaced by alkyl, such as methylthio group, ethylmercapto group, rosickyite base, tertiary butyl sulfenyl, cyclopropyl sulfenyl etc.
Term " cyano group " refers to C ≡ N.
Term " azido-" refers to N=N=N.
Term " leavings group " refers under synthesis condition performance or potentially shows as unstable and performance or the potential group that easily separates from synthetic product that shows as under prescribed condition.The example of leavings group includes but not limited to: the groups such as halogen (for example, F, Cl, Br, I), trifluoromethanesulfonic acid base, toluenesulphonic acids base, methylsulfonic acid base, alkoxyl group, thio alkoxy or hydroxyl.
Term " protecting group " thereby refer to prevents that in certain position of molecule, chemical reaction occuring makes its impregnable group during this molecule is by chemically modified.Except as otherwise noted, protecting group can be used for following group, such as hydroxyl, amino or carboxyl." protecting group in organic synthesis " (" Protective Groups in Organic Synthesis ") (second edition) at T.W.Greene and P.G.M.Wuts; John Wiley and Sons; New York has described the example of protecting group in N.Y.As long as to the conditional stability of follow-up reaction and can remove this protective material in the situation that do not destroy this molecule rest part, the kind of carboxyl-protecting group, amino protecting group or hydroxyl protecting group is inessential through the group of protective material derivatize.
The compound of describing herein can contain one or more unsymmetrical carbons, so they can be the forms of diastereomer.These compounds can be also the forms of conformer/rotational isomer.The present invention includes all this isomeric forms.Each stereomeric carbon can have R configuration or S configuration.Have specific three-dimensional chemical configuration although the specific compound that exemplifies in the application may be depicted as, can infer the opposite stereochemical compound of each chiral centre or their mixture.
The present invention includes " pharmaceutically-acceptable salts " of described compound, this term comprises the salt of hydroxy-acid group, can provide corresponding base addition salt by making compound and suitable alkali reaction.The example of this alkali is: alkali metal hydroxide comprises potassium hydroxide, sodium hydroxide and lithium hydroxide; Alkaline earth metal hydroxides is such as magnesium hydroxide and calcium hydroxide.In addition, also comprise the salt of organic bases, described organic bases such as Methionin, arginine, guanidine, thanomin, choline etc.; The salt of mineral alkali, described mineral alkali is ammonium or substituted ammonium salt for example.In due course, the compounds of this invention also can form acid salt by processing described compound with pharmaceutically acceptable organic acid and mineral acid (for example haloid acid (all example hydrochloric acids, Hydrogen bromide, hydroiodic acid HI)); The corresponding salt of other mineral acid, such as vitriol, nitrate, phosphoric acid salt etc.; And alkylsulfonate and single arylsulphonate, such as ethane sulfonate, tosylate and benzene sulfonate; And the corresponding salt of other organic acid, such as acetate, tartrate, maleate, succinate, Citrate trianion etc.Different aspect some physical properties (for example solvability), but these salt are equivalent to described compound for purpose of the present invention from its salt form herein.
Term " pharmaceutically acceptable solvate " refers to the solvate of water (that is, hydrate) or pharmaceutically acceptable solvent, such as with solvate of ethanol etc.This solvate is also included within the application scope of disclosure.In addition, some crystal habit of described compound can be the form with polymorphic form herein, also in the application scope of disclosure.
Term " polymorphic form " comprises all crystal habits and the metamict of compound of the present invention, all within the scope of the invention.
Term " pharmaceutically acceptable carrier " comprises solid, semisolid and liquid filling agent, thinner, encapsulating material and the pharmaceutical adjunct of nontoxic inertia, does not limit type.
Term " pharmaceutically acceptable " expression can be used for especially people of animal by the approval of the administration of federal government or state government or according to American Pharmacopeia or other generally acknowledged ancient books and records record.
the compounds of this invention is favourable to the treatment of inflammation and autoimmune disease, and the example of described inflammation and autoimmune disease can include but not limited to: respiratory tract disease, such as asthma (comprising the asthma reaction that allergen is induced), cystic fibrosis, bronchitis (comprising chronic bronchitis), chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS), chronic pneumonia, rhinitis and upper respiratory tract inflammatory disease (URID), ventilator-induced lung injury, silicosis, sarcoidosis of lung, idiopathic pulmonary fibrosis, broncho-pulmonary dysplasia, sacroiliitis (rheumatoid arthritis for example, osteoarthritis, infective arthritis, psoriatic arthritis, traumatic arthritis, rubella arthritis, conjunctivo-urethro-synovial syndrome, urarthritis and joint prosthesis lost efficacy, gout, acute synovitis, spondylitis) and non-arthritis disease (protrusion of thoracic intervertebral disk/break/sagging prolapse of lumbar intervertebral disc for example, the synovia capsulitis, tendinitis, tenosynovitis, fibromyalgia syndrome and strained ligament and nervous other the relevant inflammatory conditions of regional muscle skeleton), GI inflammatory diseases (ulcerative colitis for example, diverticulitis, Crohn's disease, inflammatory bowel, irritable bowel syndrome and gastritis), multiple sclerosis, systemic lupus erythematous, scleroderma, the autoimmunity exocrine gland is sick, the autoimmunity encephalomyelitis, diabetes, tumor-blood-vessel growth and transfer, cancer (comprises breast, colon, rectum, lung, kidney, ovary, stomach, the uterus, pancreas, liver, the oral cavity, larynx and prostatic malignant tumour, melanoma, acute and chronic leukemia), periodontopathy, nerve degenerative diseases, senile dementia, Parkinson's disease, epilepsy, muscle deterioration, inguinal hernia, retinal degeneration, diabetic retinopathy, macular degeneration, inguinal hernia, eye inflammation, bone absorpting disease, osteoporosis, osteopetrosis, graft-vs-host reaction, allograft rejection, septicemia, endotoxemia, toxic shock syndrome, tuberculosis, coventional type interstitial pneumonia and Cryptogenic organizing pneumonitis, bacterial meningitis, the systematicness emaciation, the emaciation of infection or malignant tumour secondary, the emaciation of acquired immune deficiency syndrome (AIDS) (AIDS) secondary, malaria, leprosy, leishmaniasis, Lyme disease, glomerulonephritis, glomerular sclerosis, renal fibrosis, hepatic fibrosis, pancreatitis, hepatitis, endometriosis, pain (for example pain relevant to inflammation and/or wound), the diseases associated with inflammation of skin (for example dermatitis), tetter, skin ulcer, psoriatic, eczema, systemic vasculitis, vascular dementia, thrombosis, atherosclerosis, restenosis, reperfusion injury, calcify plaque, myocarditis, aneurysma, apoplexy, pulmonary hypertension, left ventricular remodeling and heart failure.It will be appreciated by those skilled in the art that treatment mentioned herein extend comprise prevention and make a definite diagnosis after treatment.
The preparation of compound disclosed herein can be adopted the known technology in organic synthesis field for example or technology that those skilled in the art of the invention were familiar with.In addition, the compounds of this invention can be synthetic by methods described herein.Yet the method for synthetic compound of the present invention is not limited to these.In addition, the order of described each synthesis step can change herein, to generate required compound.
Can prepare compound of the present invention according to the arbitrary scheme in following scheme.
Can prepare compound VI I, VIII and IX by following scheme I.
Accordingly, Compound I I (wherein
As previously mentioned, X is O or S, R
kH, halogen, alkyl, alkoxyl group, cyano group, halo-C
1-C
6Alkyl or halo-C
1-C
6Alkoxyl group, and z is 0-4) can obtain compound IV with the compound III reaction, compound IV then with compound V (wherein
As previously mentioned, L and W are respectively that O or S and Rx are alkyl, aryl or aralkyl) reaction and obtain compound VI.
Path A (when X is S): then compound VI further gets compound VI II through oxidation through being hydrolyzed to get compound VI I.
Path B (when X is O): compound VI is through being hydrolyzed to get Compound I X.
Can be under alkali (for example salt of wormwood, cesium carbonate, sodium acetate or potassium acetate) exists, in solvent (for example dimethyl formamide, acetonitrile, toluene, tetrahydrofuran (THF), acetone, dioxane or their mixture), make Compound I I and compound III reacting generating compound IV.
by at alkali (Tetramethyl Ethylene Diamine for example, diisopropylethylamine, Tributylamine, N-ethylpiperidine, 1,4-two nitrine dicyclo [2.2.2] octanes, 1,8-two nitrine dicyclo [5.4.0] 11 carbon-7-alkene, 4-methyl-diaminopropane or (-) Tocosamine) exist under, in solvent (for example methylene dichloride or diethyl ether), by with titanium tetrachloride, trifluoromethanesulfonic acid dibutyl boron ester, dialkyl group boron chloride or trifluoromethanesulfonic acid tin (II) generate enolate, make compound IV and compound V that asymmetric aldol addition (Aldol addition) occur and obtain compound VI.
Under existing at solvent (for example tetrahydrofuran (THF), water or their mixture), make compound VI (path A is when X is S) hydrolysis with hydrogen peroxide and lithium hydroxide, get compound VI I.
Can be in solvent (for example chloroform, methylene dichloride, methyl alcohol, water, tetrachloromethane or their mixture), with compound VI I oxidation, get compound VI II with oxygenant (for example metachloroperbenzoic acid, potassium hydrogen persulfate or hydrogen peroxide).
Be hydrolyzed to get the method for compound VI I according to compound VI, with compound VI (path B is when X is O) hydrolysis, get Compound I X.
Can prepare compounds X II by following scheme II.
Scheme II
Can make compounds X and the addition of compound V aldol get compounds X I according to the method that compound IV and the addition of compound V aldol get compound VI.
Can with one or more reductive agents (for example palladium-carbon/hydrogen, Raney's nickel/hydrogen, platinum/hydrogen or their mixture), compounds X I be reduced in solvent (for example tetrahydrofuran (THF), methyl alcohol, ethanol, propyl alcohol, Virahol or their mixture), get compounds X II.
Can prepare compound shown in structural formula XV and XVIII by following scheme III.
Accordingly, can carry out compounds X II by two kinds of paths and (work as G
1When being amino) reaction.
Path C: compounds X II and compounds X III (R wherein
kWith z as previously mentioned) linked reaction occurs, get compounds X IV, then through being hydrolyzed to get compounds X V.
Path D: (wherein X is leavings group (for example halogen), R for compounds X II and compounds X VI
jBe-(CH
2)
0-1-CO-,-C (O) O-,-SO
2-, R
kAs previously mentioned) linked reaction occurs and get compounds X VII, then through being hydrolyzed to get compounds X VIII.
Can carry out the linked reaction of compounds X II and compounds X III with suitable alkali (such as salt of wormwood, sodium carbonate, triethylamine, diisopropylethylamine etc.) under solvent (as acetonitrile, dimethyl formamide, toluene, tetrahydrofuran (THF), acetone or dioxane etc.) exists, get compounds X IV (path C).
Can be hydrolyzed to get the another compounds X IV hydrolysis of the method for compound VI I according to compound VI, get compounds X V.
Can be in solvent (for example methylene dichloride, tetrahydrofuran (THF), dimethyl formamide, dioxane, acetonitrile or acetone) with alkali (for example triethylamine (TEA), N-methyl-morpholine (NMM), N, N-Dimethylamino pyridine (DMAP) or N, N-diisopropylethylamine (DIPEA)) carry out the linked reaction of compounds X II and compounds X VI, get compounds X VII (path D).
Can be hydrolyzed to get the method for compound VI I according to compound VI, another compounds X VII hydrolysis and obtain compounds X VIII.
Can come compound shown in composite structure formula XXI by following scheme IV.
Scheme IV
Accordingly, can make compounds X II (work as G
1When being COOH) get compounds X X with compounds X IX coupling, then through being hydrolyzed to get compounds X XI.
Can be at coupling agent 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide (EDCI) or N in organic solvent (for example methylene dichloride, ethylene dichloride, chloroform and tetracol phenixin), N'-dicyclohexylcarbodiimide (DCC) and or under the deactivated catalyst HOBT of the property selected and organic bases (Dimethylamino pyridine, N-methylmorpholine or diisopropylethylamine) exist, carry out the linked reaction of compounds X II and compounds X IX, get compounds X X.Perhaps, also can be by converting corresponding acyl chlorides (using thionyl chloride, oxalyl chloride etc.) or acid anhydrides (pivaloyl chloride etc.) to and activating XII with corresponding aniline coupling.
Can be hydrolyzed to such an extent that the method for compound VI I is hydrolyzed to compounds X X according to compound VI, get compounds X XI.
Although use specific reagent (such as alkali, acid, solvent, condensing agent, hydrolytic reagent, catalyzer etc. in such scheme; be described as mentioned above), but be understood that and also can use other reagent well known by persons skilled in the art (such as other acid, alkali, solvent, condensing agent, reductive agent, deprotection agent, hydrolytic reagent, catalyzer etc.).Similarly, can be according to actual needs, need not undo experimentation, those skilled in the art and just can adjust temperature of reaction and duration of the reaction.
Table 1 has been listed the compound that synthesizes according to synthetic method shown in scheme I-IV.
Herein described compound can by in oral, local, rectum, nose or the parenteral approach give animal to be used for the treatment of purpose.Pharmaceutical composition disclosed herein comprises pharmaceutically described compound herein and one or more pharmaceutically acceptable carriers, vehicle or the thinner of significant quantity.
The solid preparation that is used for oral administration comprises: capsule, tablet, pill, pulvis, granule, lozenge, lozenge, cachet.With regard to solid preparation, active compound can be mixed with following auxiliary material: the pharmaceutically acceptable vehicle of one or more inertia or carrier (for example Trisodium Citrate, secondary calcium phosphate) and/or weighting agent or extender (for example, starch based, lactose, sucrose, glucose, N.F,USP MANNITOL, silicic acid or their mixture); Tackiness agent, for example carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic or their mixture; Disintegrating agent, for example agar, calcium carbonate, yam starch, Lalgine, some silicate, sodium carbonate or their mixture; Absorption enhancer, for example quaternary ammonium compound; Wetting agent, for example hexadecanol, mono stearate glyceryl ester or their mixture; Sorbent material, for example kaolin; Lubricant, for example talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate or their mixture.
Also can comprise buffer reagent in capsule, tablet or pill.
Can prepare tablet, capsule, pill or granule by using one or more layers dressing or shell (for example enteric-coating material or other coating material well known by persons skilled in the art), in order to regulate the release of activeconstituents.
The liquid form preparation that is used for oral administration comprises: pharmaceutically acceptable emulsion, solution, suspension agent, syrup or elixir.In this liquid form preparation, active compound and water or one or more nontoxic solvents, solubilizing agent or emulsifying agent (for example water, ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide), oils (for example fatty acid ester of Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil, glycerine, sorbitol anhydride or their mixture) can be mixed.Oral compositions can also comprise one or more auxiliarys (for example wetting agent, emulsifying agent, suspending agent, sweeting agent, correctives, perfume compound or their mixture).
Can especially allocate injection (injection of for example sterilizing) and water suspending agent with one or more suitable dispersion agents or wetting agent and suspending agent according to method known to those skilled in the art.Adoptable acceptable vehicle and solvent comprise the mixture of one or more or they in water, Ringer's solution, isotonic sodium chloride.
The suppository that is used for the rectal administration of the compounds of this invention, can by with medicine and suitable non-irritating excipient (such as theobroma oil and polyoxyethylene glycol, at normal temperatures for solid but under body temperature for liquid so in rectum thawing and discharge medicine) prepare.
Being used for the topical of the compounds of this invention or the formulation of percutaneous dosing comprises: ointment, paste, emulsifiable paste, lotion, gelifying agent, pulvis, solution, sprays, inhalation or patch.Can be with active compound and one or more pharmaceutically acceptable carriers under aseptic condition, and mix with various sanitass or buffer reagent to washability as required.Eye drops, ear drop, eye ointment, pulvis and solution are also contained in scope of the present invention.
Pharmaceutical preparation can adopt the form of unit dosage.In unit dosage, pharmaceutical preparation can be subdivided into the unitary dose of the activeconstituents that contains appropriate amount.Unit dosage can be to contain packaged preparation, ointment, capsule, pouch, tablet, gelifying agent, emulsifiable paste or the arbitrary combination of separative capsule or pulvis and this packing formulation of quantity in vial or ampoule.
Experimental procedure
Use various desiccant dryness all kinds of SOLVENTS (such as dimethyl formamide, benzene, tetrahydrofuran (THF) etc.) according to the step described in document.
Synthesizing of initiator:
3-[4-((4S)-4-benzyl-2-oxo-1,3-thiazoles alkane-3-yl)-4-oxo butyl]-3H-benzo [d] [1,2,3] triazine-4-ketone synthetic
Described in WO2008/023336 54-55 page, synthetic this title compound.
The building-up process of scheme I (path A)
Example I: (2S)-2-[(S)-the 4-[(4-chloro-phenyl-) alkylsulfonyl] phenyl } (hydroxyl) methyl]-4-(4-oxo
-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 2) synthetic
Step 1:4-[(4-chloro-phenyl-) sulfanyl] phenyl aldehyde synthetic
To 4-chlorothio-phenol (1.0g, 0.0069mol) dimethyl formamide (5ml) solution in add salt of wormwood (2.8g, 0.0207mol) and 4-fluorobenzaldehyde (0.904g, 0.0072mol), reaction mixture is heated to about 100 ℃ and kept about 4 hours.After reaction is completed, add water and use ethyl acetate extraction.Organic layer is concentrated, carry out purifying with chromatography column, use 7% ethyl acetate/hexane as eluent, obtain title compound (output: 0.6g).
Molecular weight=248
LCMS-M+1(248.97)
Step 2:3-{ (3S)-4-[(4S)-4-benzyl-2-oxo-1,3-thiazolidine-3-yl]-3-[(S)-the 4-[(4-chloro-phenyl-) sulfanyl] phenyl } (hydroxyl) methyl]-4-oxo butyl }-1, synthesizing of 2,3-phentriazine-4 (3H)-ketone
In argon gas atmosphere, to the 3-{4-[(4S that is cooled to about 0 ℃)-4-benzyl-2-oxo-1,3-thiazolidine-3-yl]-4-oxo butyl }-1,2,3-phentriazine-4 (3H)-ketone (0.2g, 0.00049mol) methylene dichloride (5ml) solution in add lentamente titanium tetrachloride (0.12g, 0.00063mol).After about 30 minutes, add Tetramethyl Ethylene Diamine (0.068g, 0.00058mol) under about 0 ℃.At this temperature, reaction mixture was stirred about 45 minutes, and then added very lentamente the 4-[(4-chloro-phenyl-) sulfanyl] methylene dichloride (5ml) solution of phenyl aldehyde (0.206g, 0.00083mol).This reaction mixture is stirred again about 5 hours under room temperature.When completing, first add the chlorination ammonium solution and add again dilute hydrochloric acid cancellation reaction, then extract with methylene dichloride and water, carry out purifying with chromatography column, use 8% ethyl acetate/hexane as eluent, and obtain title compound (output: 0.150g).
Molecular weight=657
LCMS-M+1(658.02)
Step 3:(2S)-2-[(S) (hydroxyl) methyl-{ 4-[(4-chloro-phenyl-) sulfinyl] phenyl }]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 1) synthetic
In argon gas atmosphere under 0 ℃ to 3-{ (3S)-4-[(4S)-4-benzyl-2-oxo-1,3-thiazolidine-3-yl]-3-[(S)-the 4-[(4-chloro-phenyl-) sulfanyl] phenyl } (hydroxyl) methyl]-4-oxo butyl }-1,2,3-phentriazine-4 (3H)-ketone (0.1g, 0.0001mol) tetrahydrofuran (THF) (5ml) solution in add superoxol (0.0102g, 0.0003mol), then add lithium hydroxide (0.006g, 0.00015mol).Under room temperature, reaction mixture was stirred about 2 hours.Come the cancellation reaction with the sodium pyrosulfate acidified reaction mixture, with ethyl acetate and water extraction.The organic layer that so obtains is concentrated, and (TLC) carries out purifying with the preparation of lamina chromatography, uses 10% ethanol/methylene as eluent, obtains title compound (output: 0.090g).
MS=497.95
LCMS-M-1(496.04)
NMR(DMSO-d
6,400MHz)δ8.04-8.06(2H,d,J=8.0Hz),7.92-7.93(1H,d,J=4.0Hz),7.81-7.83(1H,d,J=8.0Hz),7.67-7.69(2H,d,J=8.0Hz),7.57-7.59(4H,d,J=8Hz),7.42-7.44(2H,d,J=8Hz),4.84(1H,m),4.38-4.29(2H,m),2.54-2.57(1H,m),2.07(1H,m),1.89(1H,m)。
Prepare following compounds according to above-mentioned synthesis path:
(2S)-2-[(S)-4-[(3,4-difluorophenyl) sulfinyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 3);
Molecular weight: 499.48
(2S)-2-[(S)-4-[(2,3-dichlorophenyl) sulfinyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 4);
Molecular weight: 532.39
(2S)-2-[(S)-4-[(2,4-3,5-dimethylphenyl) sulfinyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 5);
Molecular weight: 491.55
Step 4:(2S)-2-[(S) (hydroxyl) methyl-{ 4-[(4-chloro-phenyl-) alkylsulfonyl] phenyl }]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 2) synthetic
Under about 0 ℃ to (2S)-2-[(S)-{ 4-[(4-chloro-phenyl-) sulfinyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1; 2; 3-phentriazine-3 (4H)-yl) butyric acid (0.09g; 0.00018mol) chloroform (5ml) solution in add metachloroperbenzoic acid (0.124g; 0.00072mol), under room temperature, reaction mixture was stirred about 1 hour.When completing, with sodium metabisulfite solution cancellation reaction, then use dichloromethane extraction.With the organic layer dried over sodium sulfate, concentrated, (TLC) carries out purifying with the preparation of lamina chromatography, uses 10% ethanol/methylene as eluent, obtains title compound (output: 0.04g).
MS=513.95
LCMS-M-1(512.00)
NMR(DMSOd
6,400MHz)δ:8.16(2H,m),8.08(1H,m),7.93-7.95(4H,d,J=8.0Hz),7.82-7.84(1H,d,J=8.0Hz),7.68-7.70(2H,d,J=8Hz),7.53-7.55(2H,d,J=8Hz),4.90(1H,m),4.30-4.40(2H,m),2.50(1H,m),1.90-2.10(2H,m)。
Prepare following compounds according to above-mentioned synthesis path:
(2S)-2-[(S)-the 4-[(4-fluorophenyl) alkylsulfonyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 6)
Molecular weight: 497.49
(2S)-2-[(S)-4-[(3,4-difluorophenyl) alkylsulfonyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 7)
Molecular weight: 515.48
2-[{4-[(2, the 3-dichlorophenyl) alkylsulfonyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 8)
Molecular weight: 548.39
(2S)-2-[(S)-4-[(2,4-3,5-dimethylphenyl) alkylsulfonyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 9)
Molecular weight: 507.55
The building-up process of scheme I (path B)
Example II: (2S)-2-{ (S)-hydroxyl [4-(4-methoxyphenoxy) phenyl] methyl }-4-(4-oxo-1,2,3-
Synthesizing of phentriazine-3 (4H)-yl) butyric acid (compound 56)
Synthesizing of step 1:4-(4-methoxyphenoxy) phenyl aldehyde
To 4-methoxyphenol (1.0g, 0.0080mol) dimethyl formamide (5ml) solution in add salt of wormwood (3.3g, 0.024mol) and 4-fluorobenzaldehyde (1.1g, 0.0088mol), reaction mixture is heated to about 100 ℃ and kept about 4 hours.When reaction is completed, add wherein water, use ethyl acetate extraction.Organic layer is concentrated, carry out purifying with chromatography column, use 7% ethyl acetate/hexane as eluent, obtain title compound (output: 0.9g).
Step 2:3-[(3S)-4-[(4S)-4-benzyl-2-oxo-1,3-thiazolidine-3-yl]-3-{ (S)-hydroxyl [4-(4-methoxyphenoxy) phenyl] methyl }-4-oxo butyl]-1, synthesizing of 2,3-phentriazine-4 (3H)-ketone
In argon gas atmosphere under 0 ℃ to 3-[4-((4S)-4-benzyl-2-oxo-1,3-thiazolidine-3-yl)-4-oxo butyl]-3H-benzo [d] [1,2,3] triazine-4-ketone (5.5g, 0.013mol) methylene dichloride (50ml) solution in add lentamente titanium tetrachloride (3.19g, 0.0169mol).Reaction mixture was stirred about 30 minutes, then add lentamente Tetramethyl Ethylene Diamine (3.77g, 0.0325mol) under 0 ℃, reaction mixture is continued to stir about 45 minutes at this temperature.Then, add lentamente methylene dichloride (20ml) solution of 4-(4-methoxyphenoxy) phenyl aldehyde (5.2g, 0.022mol), stirred about 5 hours.When completing, first add the chlorination ammonium solution and add again dilute hydrochloric acid cancellation reaction, extract with methylene dichloride and water, carry out purifying with chromatography column, use 8% ethyl acetate/hexane as eluent, obtain title compound (output: 2.6g).
Step 3:(2S)-2-{ (S)-hydroxyl [4-(4-methoxyphenoxy) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 56) synthetic
In argon gas atmosphere under about 0 ℃ to 3-[(3S)-4-[(4S)-4-benzyl-2-oxo-1,3-thiazolidine-3-yl]-3-{ (S)-hydroxyl [4-(4-methoxyphenoxy) phenyl] methyl }-4-oxo butyl]-1,2,3-phentriazine-4 (3H)-ketone (2.5g, 0.0040mol) tetrahydrofuran (THF) (30ml) solution in add superoxol (0.408g, 0.012mol), then add lithium hydroxide (0.256g, 0.0061mol), this reaction mixture was stirred about 2 hours.The cancellation reaction, extract with ethyl acetate and water with the sodium pyrosulfate acidified reaction mixture.Concentrated organic layer carries out purifying with chromatography column, uses 8% ethanol/methylene as eluent, obtains title compound (output: 0.9g).
MS=461.46
LCMS-M-1(460.08)
NMR(DMSO-d
6,400MHz)δ:8.19-8.21(1H,d,J=8.0Hz),8.15-8.17(1H,d,J=8.0Hz),8.04-8.08(1H,d,J=16.0Hz),7.89-7.92(1H,d,J=12.0Hz),7.18-7.20(2H,d,J=8Hz),6.93(4H,d),6.72-6.74(2H,d,J=8Hz),4.77-4.78(1H,m,J=4Hz),4.30-4.40(2H,m),3.73(3H,s),2.59(1H,m),2.03-2.07(2H,m)。
Prepare following compounds according to above-mentioned synthesis path:
(2S)-2-[(S)-[4-(3-chloro-4-fluorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 57)
Molecular weight: 482.28
(2S)-2-[(S)-[4-(4-chloro-3-methylphenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 58)
Molecular weight: 478.25
(2S)-2-[(S)-[4-(4-chloro-2-fluorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 59)
Molecular weight: 482.28
(2S)-2-[(S)-[4-(4-fluorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 60)
Molecular weight: 448.29
(2S)-2-[(S)-[4-(3,4-difluoro phenoxy group) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 61)
Molecular weight: 466.31
(2S)-2-[(S)-[4-(2-chlorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 62)
Molecular weight: 464.26
(2S)-2-[(S)-[4-(3-chlorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 63)
Molecular weight: 464.26
(2S)-2-[(S)-[4-(2,6-difluoro phenoxy group) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 64)
Molecular weight: 466.31
(2S)-2-[(S)-[4-(2,5-dichlorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 65)
Molecular weight: 498.25 and 500.16
(2S)-2-[(S)-[4-(2-chloro-4-fluorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 66)
Molecular weight: 482.28
(2S)-2-{ (S)-hydroxyl [4-(3-methoxyphenoxy) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 67)
Molecular weight: 460.30
(2S)-2-[(S)-[4-(2-chloro-4-methoxy phenoxy group) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 68)
Molecular weight: 494.29
(2S)-2-[(S)-[4-(2,4 difluorobenzene oxygen base) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 69)
Molecular weight: 466.31
(2S)-2-[(S)-[3-fluoro-4-(4-methylphenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 70)
Molecular weight: 462.36
(2S)-2-[(S)-[3-fluoro-4-(3-methylphenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 71)
Molecular weight: 462.34
(2S)-2-[(S)-[4-(3,4-dimethyl phenoxy)-3-fluorophenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 72)
Molecular weight: 476.46
(2S)-2-[(S)-[4-(3,4-dichlorophenoxy)-3-fluorophenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 73)
Molecular weight: 516.33 and 518.29
(2S)-2-[(S)-[4-(4-tertiary butyl phenoxy group)-3-fluorophenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 74)
Molecular weight: 504.44
(2S)-2-[(S)-[3-fluoro-4-(4-methoxyphenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 75)
Molecular weight: 478.38
The building-up process of scheme II
EXAMPLE III: 3-[(3S, 4S)-4-(4-aminophenyl)-3-{[(4S)-4-benzyl-2-oxo-1,3-thiazoles alkane-3-
Base] carbonyl }-the 4-hydroxybutyl]-1,2,3-phentriazine-4 (3H)-ketone synthetic
Step 1:3-{ (3S)-4-[(4S)-4-benzyl-2-oxo-1,3-thiazoles alkane-3-yl]-3-[(S)-hydroxyl (4-nitrophenyl) methyl]-4-oxo butyl }-1,2,3-phentriazine-4 (3H)-ketone synthetic
Under about 0 ℃ to 3-{4-[(4S)-4-benzyl-2-oxo-1,3-thiazolidine-3-yl]-4-oxo butyl }-1,2,3-phentriazine-4 (3H)-ketone (20g, 0.049mol) methylene dichloride (350ml) solution in add titanium tetrachloride (58.8ml, 0.311mol), under room temperature (approximately 25 ℃), reaction mixture was stirred about 20 minutes.Add wherein Tetramethyl Ethylene Diamine (18.5ml, 0.122mol) under 0 ℃, reaction mixture was stirred about 20 minutes.Add methylene dichloride (50ml) solution of 4-nitrobenzaldehyde (12.6g, 0.083mol) at this temperature, stirred about 2 hours in room temperature (approximately 25 ℃) is lower.When completing, add the saturated solution of ammonium chloride in the reaction mixture, then add dilute hydrochloric acid.Organic layer is extracted with methylene dichloride, concentrated, carry out purifying with silicagel column (60-120 order), use 25% ethyl acetate: hexane obtains target product (output: 18.2g) as eluent.
MS=560.15(M+1)
Step 2:3-[(3S, 4S)-4-(4-aminophenyl)-3-{[(4S)-4-benzyl-2-oxo-1,3-thiazoles alkane-3-yl] carbonyl }-the 4-hydroxybutyl]-1,2,3-phentriazine-4 (3H)-ketone synthetic
Under room temperature (approximately 25 ℃) to 3-{ (3S)-4-[(4S)-4-benzyl-2-oxo-1,3-thiazolidine-3-yl]-3-[(S)-hydroxyl (4-nitrophenyl) methyl]-4-oxo butyl }-1,2,3-phentriazine-4 (3H)-ketone (18g, 0.032mol) tetrahydrofuran (THF) (100ml) and methyl alcohol (100ml) solution in add 10%Pd/C (6.0g), the H of about 1 hour is provided with the pressure of 50psi with the Parr device
2Gas.With diatomite, reaction mixture is filtered, with 10% ethanol/methylene wash residue.Filtrate is concentrated, carry out purifying with silica gel (60-120 order) post, use 60% ethyl acetate: hexane obtains target product (output: 14.57g) as eluent.
MS=512.02(M-18)
The building-up process of scheme III
EXAMPLE IV: (2S)-2-[(S)-[4-({ [2-fluoro-4-(trifluoromethyl) phenyl] carbonyl } amino) phenyl] (hydroxyl)
Methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 46) synthetic
Step 1:N-{4-[(1S, 2S)-2-{[(4S)-4-benzyl-2-oxo-1,3-thiazolidine-3-yl] carbonyl }-1-hydroxyl-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyl] phenyl }-2-fluoro-4-(trifluoromethyl) benzamide synthetic
Under about 0 ℃ to 3-[(3S, 4S)-4-(4-aminophenyl)-3-{[(4S)-4-benzyl-2-oxo-1,3-thiazolidine-3-yl] carbonyl }-the 4-hydroxybutyl]-1,2,3-phentriazine-4 (3H)-ketone (0.3g, 0.00057mol) methylene dichloride (40ml) solution in add triethylamine (0.24ml, 0.0017mol).Add 2-fluoro-4-trifluoromethyl benzoyl chloride (0.19g, 0.00086mol) in reaction mixture in nitrogen atmosphere, under room temperature, reaction mixture was stirred about 2 hours.When completing, add water, organic layer is extracted and concentrates, obtain crude product (output: 153mg).
Step 2:(2S)-2-[(S) (hydroxyl) methyl-[4-({ [2-fluoro-4-(trifluoromethyl) phenyl] carbonyl } amino) phenyl]]-4-(4-oxo-1, synthesizing of 2,3-phentriazine-3 (4H)-yl) butyric acid (compound 46)
To N-{4-[(1S, 2S)-2-{[(4S)-4-benzyl-2-oxo-1,3-thiazolidine-3-yl] carbonyl }-1-hydroxyl-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyl] phenyl }-2-fluoro-4-(trifluoromethyl) benzamide (0.153g, 0.000213mol) tetrahydrofuran (THF) (20ml) solution in add hydrogen peroxide (0.022g, 0.00064mol), lithium hydroxide (0.0134g, 0.000032mol) and water (2.0ml), under room temperature, reaction mixture was stirred about 1 hour.Use the ethyl acetate extraction organic layer, use anhydrous sodium sulfate drying, concentrated, obtain crude product.TLC carries out purifying with preparation property, uses 10% methyl alcohol: methylene dichloride obtains title product (output: 61.0mg) as eluent.
MS：545.16(M+1)
NMR(DMSO-d
6,400MHz)δ:10.56(1H,s),8.22-8.17(2H,m),8.07(1H,t,J=7.44Hz),7.92-7.87(3H,m),7.73(1H,d,J=8.04Hz),7.56(2H,d,J=8.4Hz),7.25(2H,d,J=8.4Hz),4.82(1H,d,J=6.04Hz),4.40-4.32(2H,m),2.75-2.60(1H,m),2.30-2.0(2H,m)
EXAMPLE V: (2S)-2-[(S)-(4-{[(4-ethylphenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-
Oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 10) synthetic
Step 1:3-{ (3S)-4-[(4S)-4-benzyl-2-oxo-1,3-thiazoles alkane-3-yl]-3-[(S)-hydroxyl (4-nitrophenyl) methyl]-4-oxo butyl }-1,2,3-phentriazine-4 (3H)-ketone synthetic
Under 0 ℃ to 3-{4-[(4S)-4-benzyl-2-oxo-1,3-thiazolidine-3-yl]-4-oxo butyl }-1,2,3-phentriazine-4 (3H)-ketone (1g, 0.0025mol) methylene dichloride (20ml) solution in drip titanium tetrachloride (2.94ml, 0.0029mol), under room temperature (approximately 25 ℃), reaction mixture was stirred about 40 minutes.Add wherein Tetramethyl Ethylene Diamine (0.712g, 0.0061mol) under about 0 ℃, reaction mixture was stirred 30 minutes again.At this temperature, methylene dichloride (50ml) solution of 4-nitrobenzaldehyde (0.64g, 0.0042mol) is added in reaction mixture, stirred about 2 hours in room temperature (approximately 25 ℃) is lower.When completing, add the ammonium chloride saturated solution, add methylene dichloride and water in reaction mixture.Carry out purifying with silica gel (60-120 order), use 30% ethyl acetate: hexane obtains title product (output: 0.62g) as eluent.
MS：559.91(M+1)
Step 2:3-[(3S, 4S)-4-(4-aminophenyl)-3-{[(4S)-4-benzyl-2-oxo-1,3-thiazoles alkane-3-yl] carbonyl }-the 4-hydroxybutyl]-1,2,3-phentriazine-4 (3H)-ketone synthetic
Under room temperature (approximately 25 ℃) to 3-{ (3S)-4-[(4S)-4-benzyl-2-oxo-1,3-thiazolidine-3-yl]-3-[(S)-hydroxyl (4-nitrophenyl) methyl]-4-oxo butyl }-1,2,3-phentriazine-4 (3H)-ketone (0.61g, 0.0011mol) the solution of tetrahydrofuran (THF) (20ml) in add 10%Pd/C (0.5g), the H2 gas of about 2 hours is provided with sacculus.With diatomite, reaction mixture is filtered, use 10% methyl alcohol: the methylene dichloride wash residue.Filtrate is concentrated, obtain target compound (output: 0.6g).
MS：511.94(M-18)
Step 3:N-{4-[(1S, 2S)-2-{[(4S)-4-benzyl-2-oxo-1,3-thiazoles alkane-3-yl] carbonyl }-1-hydroxyl-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyl] phenyl }-4-ethyl benzamide synthetic
Under about 0 ℃ to 3-[(3S, 4S)-4-(4-aminophenyl)-3-{[(4S)-4-benzyl-2-oxo-1,3-thiazolidine-3-yl] carbonyl }-the 4-hydroxybutyl]-1,2,3-phentriazine-4 (3H)-ketone (0.6g, 0.0011mol) methylene dichloride (20ml) solution in add triethylamine (0.47ml, 0.0034mol).Then, add 4-ethylamino benzonitrile acyl chlorides (0.29g, 0.0017mol), under 0 ℃, reaction mixture was stirred about 30 minutes.Add methylene dichloride and water in reactant, obtain crude product (output: 680mg).
MS：662.04(M+1)
Step 4:(2S)-2-[(S) carbonyl-(4-{[(4-ethylphenyl)] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 10) synthetic
Under 0 ℃ to N-{4-[(1S, 2S)-2-{[(4S)-4-benzyl-2-oxo-1,3-thiazolidine-3-yl] carbonyl }-1-hydroxyl-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyl] phenyl }-4-ethyl benzamide (0.35g, 0.00053mol) tetrahydrofuran (THF) (10ml) solution in add hydrogen peroxide (0.3ml, 2.65 moles), reaction mixture was stirred about 15 minutes.Then, add lithium hydroxide (0.033g, 0.00079mol) and water (5ml) under room temperature, again stirred about 2 hours.When completing, add the shrend reaction of going out, use ethyl acetate extraction.With the organic layer anhydrous sodium sulfate drying, concentrated, carry out purifying with the preparation of lamina chromatography, use 10% methyl alcohol: methylene dichloride obtains title product (output: 84.0mg) as eluent.
MS：485.17(M-1)
NMR(DMSO-d
6,400MHz)δ:10.06(1H,s),8.20-8.15(2H,m),8.06-8.02(1H,m),7.89-7.85(3H,m),7.61(2H,d,J=8.4Hz),7.35(2H,d,J=8.4Hz),7.21(2H,d,J=8.4Hz),4.80-4.78(1H,m),4.40-4.32(2H,m),2.70-2.65(3H,m),2.20-2.00(2H,m)。
Prepare following compounds according to above-mentioned synthesis path:
(2S)-2-[(S)-(4-{[(4-chloro-phenyl-) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 11)
Molecular weight: 492.91
(2S)-2-[(S)-(4-{[(3,4-dichlorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 12)
Molecular weight: 528.84
(2S)-2-[(S)-hydroxyl (4-{[(4-p-methoxy-phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 13)
Molecular weight: 489.97
(2S)-2-[(S)-hydroxyl (4-{[(3-p-methoxy-phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 14)
Molecular weight: 489.97
(2S)-2-[(S)-hydroxyl (4-{[(4-aminomethyl phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 15)
Molecular weight: 473.01
(2S)-2-[(S)-(4-{[(4-fluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 16)
Molecular weight: 477.96
(2S)-2-{ (S)-hydroxyl [4-({ [4-methoxyl group-3-(trifluoromethyl) phenyl] carbonyl } amino) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 17)
Molecular weight: 557.94
(2S)-2-[(S)-hydroxyl (4-{[(5-methyl isophthalic acid, 2-oxazole-3-yl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 18)
Molecular weight: 464.96
(2S)-2-[(S)-(4-{[(3-chloro-4-fluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 19)
Molecular weight: 510.80
(2S)-2-[(S)-hydroxyl the 4-[(phenylcarbonyl group) and amino] phenyl } methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 20)
Molecular weight: 459.95
(2S)-2-[(S)-hydroxyl (4-{[(4-propyl group phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 21)
Molecular weight: 501.92
(2S)-2-[(S)-hydroxyl the 4-[(phenyloxycarbonyl) and amino] phenyl } methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 22)
Molecular weight: 475.92
(2S)-2-[(S)-hydroxyl the 4-[(phenyl acetyl) and amino] phenyl } methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 23)
Molecular weight: 473.94
(2S)-2-[(S)-(4-{[(2,4-dichlorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 24)
Molecular weight: 526.84
(2S)-2-[(S)-hydroxyl (4-{[(2-aminomethyl phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 25)
Molecular weight: 472.92
(2S)-2-[(S)-(4-{[(2-fluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 26)
Molecular weight: 476.88
(2S)-2-[(S)-(4-{[(3-chloro-phenyl-) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 27)
Molecular weight: 492.85
(2S)-2-[(S)-hydroxyl (4-{[(3-aminomethyl phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 28)
Molecular weight: 472.92
(2S)-2-[(S)-(4-{[(3-fluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 29)
Molecular weight: 476.88
(2S)-2-[(S)-(4-{[(2,6-Dimethoxyphenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 30)
Molecular weight: 518.92
(2S)-2-[(S)-the 4-[(cyclopentylcarbonyl) amino] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 31)
Molecular weight: 450.94
(2S)-2-[(S)-hydroxyl (4-{[(2,4,5-, three fluoro-3-p-methoxy-phenyls) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 32)
Molecular weight: 543.09
(2S)-2-[(S)-hydroxyl (4-{[(2,3,4-trifluorophenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 33)
Molecular weight: 513.06
(2S)-2-{ (S)-hydroxyl [4-({ [2-(trifluoromethyl) phenyl] carbonyl } amino) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 34)
Molecular weight: 527.11
(2S)-2-[(S)-(4-{[(3,5-Dimethoxyphenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 35)
Molecular weight: 519.13
(2S)-2-[(S)-(4-{[(2,3-difluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 36)
Molecular weight: 495.04
(2S)-2-[(S)-(4-{[(3,5-dichlorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 37)
Molecular weight: 526.99
(2S)-2-[(S)-(4-{[(2,4-difluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 38)
Molecular weight: 495.04
(2S)-2-[(S)-(4-{[(2,6-difluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 39)
Molecular weight: 495.10
(2S)-2-[(S)-hydroxyl (4-{[(2-p-methoxy-phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 40)
Molecular weight: 489.16
(2S)-2-[(S)-the 4-[(cyclohexyl-carbonyl) amino] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 41)
Molecular weight: 465.20
(2S)-2-[(S)-(4-{[(4-ethoxyl phenenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 42)
Molecular weight: 503.20
(2S)-2-[(S)-(4-{[(3,4-difluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 43)
Molecular weight: 495.16
(2S)-2-{ (S)-hydroxyl [4-({ [4-(trifluoromethoxy) phenyl] carbonyl } amino) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 44)
Molecular weight: 545.15
(2S)-2-{ (S)-hydroxyl [4-({ [3-(trifluoromethyl) phenyl] carbonyl } amino) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 45)
Molecular weight: 527.15
(2S)-2-[(S)-(4-{[(3-chloro-2,6-difluoro phenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 47)
Molecular weight: 529.13
(2S)-2-{ (S)-hydroxyl [4-({ [4-(trifluoromethyl) phenyl] carbonyl } amino) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 48)
Molecular weight: 527.16
(2S)-2-[(S)-(4-{[(2,5-difluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 49)
Molecular weight: 495.15
(2S)-2-[(S)-(4-{[(2,3-two fluoro-4-aminomethyl phenyls) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 50)
Molecular weight: 509.18
(2S)-2-[(S)-[4-({ [4-fluoro-3-(trifluoromethyl) phenyl] carbonyl } amino) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 51)
Molecular weight: 545.15
(2S)-2-[(S)-the 4-[(cyclopropyl carbonyl) amino] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 52)
Molecular weight: 423.19
(2S)-2-[(S)-(4-{[(2-ethylphenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 53)
Molecular weight: 485.19
(2S)-2-[(S)-hydroxyl (4-{[(4-p-methoxy-phenyl) ethanoyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 54)
Molecular weight: 503.20
(2S)-2-[(S)-the 4-[(cyclobutyl carbonyl) amino] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 55)
Molecular weight: 437.21
Matrix metalloproteinase (MMP) test
New compound of the present invention and respective standard product used are prepared in 100%DMSO (10mM storing solution), then test damping fluid [50mM HEPES, 10mM CaCl with MMP
2, 150nMNaCl, 1 μ M zinc acetate, 600 μ M CHAPS (pH7.4)] and the preparation diluent.Use total length people MMP or its catalyst structure domain in test.Shear and activate collagenase (MMP-1), gelatinase (MMP-9), elastoser (MMP-12) and 1 type film (MMP-14) with reagent A PMA (4-aminophenyl mercuric acetate), obtain thus the active catalytic structural domain.In typical 100 μ l reaction test mixtures, 1.0 μ l NCE/ standard substance exist and non-existent condition under, in buffered soln with 1.0 μ l target mmp enzyme heat insulating culture 30 minutes.Target fluorogenic substrate with ultimate density 10 μ M/ every holes
FAM-TAMRA (
FAM-Thr-Pro-Gly-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-Arg-Lys-TAM RA-NH2)Start reaction, reaction was carried out 45 minutes, with the excitation wavelength of 495nm and the emission wavelength monitoring reaction speed (increase of RFU) of 525nm.Deduct blank speed of reaction (there is no enzyme) from each value.With following formula calculation control percentage:
Active %=(suppressing speed/contrast speed) * 100
Use the 5-6 dose point response curve under the inhibitor existence to adopt least square regression analysis Graph-Pad prism4.2 version computed in software IC
50Value.Obtain the IC of revision test data
50The mean value of value is listed each value in form.
The present invention relates to the compound with desirable living features of MMP-9/12 double inhibitor effect.
Compare with about 1.4nM to 3.2nM of Marimastat, in the present invention, the MMP-9 of disclosed compound is active (with IC
50Value representation) be about 10 micromoles to about 1nM or from about 1 micromole to about 1nM or from about 650nM to about 1nM or from about 300nM to about 1nM or from about 100nM to about 1nM or from about 50nM to about 1nM or from about 30nM to about 1nM or from about 20nM to about 1nM or from about 12nM to about 1nM.
Compare with the 0.2nM to 0.9nM of Marimastat, the MMP-12 of the disclosed compound of the present invention is active (with IC
50Value representation) be about 10 micromoles to about 1nM or from about 1 micromole to about 1nM or from about 300nM to about 1nM or from about 100nM to about 1nM or from about 50nM to about 1nM or from about 30nM to about 1nM or from about 20nM to about 1nM or from about 15nM to about 1nM or from about 7nM to about 1nM.
Claims (12)
1. compound shown in a structural formula I:
Structural formula I
Comprise their racemic modification, enantiomer and diastereomer or their pharmaceutically-acceptable salts, wherein,
U be Lian Jian ,-NH-,-C (=O)-,-(CH
2)
n-,-C (=S)-,-O-,-SO
2-or-S-, wherein n is zero or 1 or 2 integer;
V be Lian Jian ,-NH-,-C (=O)-,-C (=S)-or-SO
2-;
W be Lian Jian ,-NH-,-C (=O)-, (CH
2)
n-,-C (=S)-,-O-,-S-or-SO
2-;
R
1Alkyl, thiazolinyl, alkynyl, cyano group, nitro, halogen, halo-C
1-C
6Alkyl, halo-C
1-C
6Alkoxyl group, azido-, sulfydryl, alkylthio ,-(CH
2)
n-OR
f,-C (=O)-R
f,-COOR
f,-NR
fR
q,-(CH
2)
n-C (=O) NR
fR
q,-(CH
2)
n-NHC (=O) R
f,-(CH
2)
n-O-C (=O)-NR
fR
q, (CH
2)
nNHC (=O) NR
fR
q,-(CH
2)
n-O-C (=O)-R
f,-(CH
2)
n-NH-C (=O)-R
fPerhaps-(CH
2)
nS (=O)
m-NR
fR
q{ R wherein
fAnd R
qBe selected from separately hydrogen, alkyl, thiazolinyl, cycloalkyl aryl, heteroaryl, heterocyclic radical, alkylaryl, miscellaneous alkyl aryl, alkyl heterocyclic, n as previously mentioned, m is the integer of 0-2 };
2. compound as claimed in claim 1, described compound has structure shown in structural formula Ia
Structural formula Ia
Comprise their racemic modification, enantiomer and diastereomer or their pharmaceutically-acceptable salts, wherein,
L
1Be Lian Jian ,-(CH
2)
n-,-NHCO (CH
2)
n-,-(CH
2)
nC (=O) NH-,-NHC (=O) NH-,-SO
2NH-,-NHSO
2-,-SO
2-,-NHC (=O) (O)-,-O-(CH
2)
n-,-(CH
2)
n-O-,-(CH
2)
nOC (=O) NH-,-C (=S) NH-,-NHC (=S)-or-NHC (=S) NH-, wherein n is zero or 1 or 2 integer;
R
1Alkyl, thiazolinyl, alkynyl, cyano group, nitro, halogen, halo-C
1-C
6Alkyl, halo-C
1-C
6Alkoxyl group, azido-, sulfydryl, alkylthio ,-(CH
2)
n-OR
f,-C (=O)-R
f,-COOR
f,-NR
fR
q,-(CH
2)
n-C (=O) NR
fR
q,-(CH
2)
n-NHC (=O)-R
f,-(CH
2)
n-O-C (=O)-NR
fR
q, (CH
2)
nNHC (=O)
nR
fR
q,-(CH
2)
n-O-C (=O)-R
f,-(CH
2)
n-NH-C (=O)-R
fPerhaps-(CH
2)
nS (=O)
m-NR
fR
q{ R wherein
fAnd R
qBe selected from separately hydrogen, alkyl, thiazolinyl, cycloalkyl aryl, heteroaryl, heterocyclic radical, alkylaryl, miscellaneous alkyl aryl, alkyl heterocyclic, n as previously mentioned, m is the integer of 0-2 };
3. compound as claimed in claim 1, described compound has structure shown in structural formula Ib
Structural formula Ib
Comprise their racemic modification, enantiomer and diastereomer or their pharmaceutically-acceptable salts, wherein,
V is the integer of zero or 1-4,
Ra is hydrogen or fluorine;
R
1, L
1With
As defined in claim 1.
4. compound as claimed in claim 1, described compound has structure shown in structural formula Ic
Structural formula Ic
Comprise their racemic modification, enantiomer and diastereomer or their pharmaceutically-acceptable salts, wherein,
L
1aBe selected from S (O)
n, NHCO (CH
2)
nAnd NHCO (O);
Ra,
With
As defined in claim 1.
5. compound shown in a structural formula I, described compound is:
(2S)-2-[(S)-the 4-[(4-chloro-phenyl-) sulfinyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 1);
(2S)-2-[(S)-the 4-[(4-chloro-phenyl-) alkylsulfonyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 2);
(2S)-2-[(S)-4-[(3,4-difluorophenyl) sulfinyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 3);
(2S)-2-[(S)-4-[(2,3-dichlorophenyl) sulfinyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 4);
(2S)-2-[(S)-4-[(2,4-3,5-dimethylphenyl) sulfinyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 5);
(2S)-2-[(S)-the 4-[(4-fluorophenyl) alkylsulfonyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 6);
(2S)-2-[(S)-4-[(3,4-difluorophenyl) alkylsulfonyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 7);
2-[{4-[(2, the 3-dichlorophenyl) alkylsulfonyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 8);
(2S)-2-[(S)-4-[(2,4-3,5-dimethylphenyl) alkylsulfonyl] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 9);
(2S)-2-[(S)-(4-{[(4-ethylphenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 10);
(2S)-2-[(S)-(4-{[(4-chloro-phenyl-) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 11);
(2S)-2-[(S)-(4-{[(3,4-dichlorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 12);
(2S)-2-[(S)-hydroxyl (4-{[(4-p-methoxy-phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 13);
(2S)-2-[(S)-hydroxyl (4-{[(3-p-methoxy-phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 14);
(2S)-2-[(S)-hydroxyl (4-{[(4-aminomethyl phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 15);
(2S)-2-[(S)-(4-{[(4-fluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 16);
(2S)-2-{ (S)-hydroxyl [4-({ [4-methoxyl group-3-(trifluoromethyl) phenyl] carbonyl } amino) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 17);
(2S)-2-[(S)-hydroxyl (4-{[(5-methyl isophthalic acid, 2-oxazole-3-yl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 18);
(2S)-2-[(S)-(4-{[(3-chloro-4-fluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 19);
(2S)-2-[(S)-hydroxyl the 4-[(phenylcarbonyl group) and amino] phenyl } methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 20);
(2S)-2-[(S)-hydroxyl (4-{[(4-propyl group phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 21);
(2S)-2-[(S)-hydroxyl the 4-[(phenyloxycarbonyl) and amino] phenyl } methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 22);
(2S)-2-[(S)-hydroxyl the 4-[(phenyl acetyl) and amino] phenyl } methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 23);
(2S)-2-[(S)-(4-{[(2,4-dichlorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 24);
(2S)-2-[(S)-hydroxyl (4-{[(2-aminomethyl phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 25);
(2S)-2-[(S)-(4-{[(2-fluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 26);
(2S)-2-[(S)-(4-{[(3-chloro-phenyl-) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 27);
(2S)-2-[(S)-hydroxyl (4-{[(3-aminomethyl phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 28);
(2S)-2-[(S)-(4-{[(3-fluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 29);
(2S)-2-[(S)-(4-{[(2,6-Dimethoxyphenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 30);
(2S)-2-[(S)-the 4-[(cyclopentylcarbonyl) amino] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 31);
(2S)-2-[(S)-hydroxyl (4-{[(2,4,5-, three fluoro-3-p-methoxy-phenyls) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 32);
(2S)-2-[(S)-hydroxyl (4-{[(2,3,4-trifluorophenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 33);
(2S)-2-{ (S)-hydroxyl [4-({ [2-(trifluoromethyl) phenyl] carbonyl } amino) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 34);
(2S)-2-[(S)-(4-{[(3,5-Dimethoxyphenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 35);
(2S)-2-[(S)-(4-{[(2,3-difluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 36);
(2S)-2-[(S)-(4-{[(3,5-dichlorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 37);
(2S)-2-[(S)-(4-{[(2,4-difluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 38);
(2S)-2-[(S)-(4-{[(2,6-difluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 39);
(2S)-2-[(S)-hydroxyl (4-{[(2-p-methoxy-phenyl) carbonyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 40);
(2S)-2-[(S)-the 4-[(cyclohexyl-carbonyl) amino] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 41);
(2S)-2-[(S)-(4-{[(4-ethoxyl phenenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 42);
(2S)-2-[(S)-(4-{[(3,4-difluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 43);
(2S)-2-{ (S)-hydroxyl [4-({ [4-(trifluoromethoxy) phenyl] carbonyl } amino) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 44);
(2S)-2-{ (S)-hydroxyl [4-({ [3-(trifluoromethyl) phenyl] carbonyl } amino) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 45);
(2S)-2-[(S)-[4-({ [2-fluoro-4-(trifluoromethyl) phenyl] carbonyl } amino) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 46);
(2S)-2-[(S)-(4-{[(3-chloro-2,6-difluoro phenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 47);
(2S)-2-{ (S)-hydroxyl [4-({ [4-(trifluoromethyl) phenyl] carbonyl } amino) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 48);
(2S)-2-[(S)-(4-{[(2,5-difluorophenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 49);
(2S)-2-[(S)-(4-{[(2,3-two fluoro-4-aminomethyl phenyls) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 50);
(2S)-2-[(S)-[4-({ [4-fluoro-3-(trifluoromethyl) phenyl] carbonyl } amino) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 51);
(2S)-2-[(S)-the 4-[(cyclopropyl carbonyl) amino] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 52);
(2S)-2-[(S)-(4-{[(2-ethylphenyl) carbonyl] amino } phenyl) (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 53);
(2S)-2-[(S)-hydroxyl (4-{[(4-p-methoxy-phenyl) ethanoyl] amino } phenyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 54);
(2S)-2-[(S)-the 4-[(cyclobutyl carbonyl) amino] phenyl } (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 55);
(2S)-2-{ (S)-hydroxyl [4-(4-methoxyphenoxy) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 56);
(2S)-2-[(S)-[4-(3-chloro-4-fluorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 57);
(2S)-2-[(S)-[4-(4-chloro-3-methylphenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 58);
(2S)-2-[(S)-[4-(4-chloro-2-fluorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 59);
(2S)-2-[(S)-[4-(4-fluorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 60);
(2S)-2-[(S)-[4-(3,4-difluoro phenoxy group) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 61);
(2S)-2-[(S)-[4-(2-chlorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 62);
(2S)-2-[(S)-[4-(3-chlorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 63);
(2S)-2-[(S)-[4-(2,6-difluoro phenoxy group) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 64);
(2S)-2-[(S)-[4-(2,5-dichlorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 65);
(2S)-2-[(S)-[4-(2-chloro-4-fluorophenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 66);
(2S)-2-{ (S)-hydroxyl [4-(3-methoxyphenoxy) phenyl] methyl }-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 67);
(2S)-2-[(S)-[4-(2-chloro-4-methoxy phenoxy group) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 68);
(2S)-2-[(S)-[4-(2,4 difluorobenzene oxygen base) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 69);
(2S)-2-[(S)-[3-fluoro-4-(4-methylphenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 70);
(2S)-2-[(S)-[3-fluoro-4-(3-methylphenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 71);
(2S)-2-[(S)-[4-(3,4-dimethyl phenoxy)-3-fluorophenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 72);
(2S)-2-[(S)-[4-(3,4-dichlorophenoxy)-3-fluorophenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 73);
(2S)-2-[(S)-[4-(4-tertiary butyl phenoxy group)-3-fluorophenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 74);
(2S)-2-[(S)-[3-fluoro-4-(4-methoxyphenoxy) phenyl] (hydroxyl) methyl]-4-(4-oxo-1,2,3-phentriazine-3 (4H)-yl) butyric acid (compound 75);
Comprise their racemic modification, enantiomer and diastereomer or their pharmaceutically-acceptable salts.
6. pharmaceutical composition, described pharmaceutical composition comprises compound as described in any one in claim 1 to 5 and pharmaceutically acceptable carrier, vehicle or the thinner for the treatment of significant quantity.
7. be used for the treatment of or prevent to suffer from the animal or human's of diseases associated with inflammation or allergic disorder compound as described in any one in claim 1 to 5.
8. compound as claimed in claim 7, wherein said diseases associated with inflammation or allergic disorder are asthma, rheumatoid arthritis, chronic obstructive pulmonary disease, rhinitis, osteoarthritis, psoriatic arthritis, psoriatic, pulmonary fibrosis, pneumonia, adult respiratory distress syndrome, periodontitis, multiple sclerosis, gingivitis, atherosclerosis, xerophthalmia, intimal hyperplasia, apoplexy, ephrosis or the metastases relevant with ischemic cardiac exhaustion to restenosis.
9. pharmaceutical composition as claimed in claim 6 also comprises other activeconstituents that one or more are selected from following medicament:
(a) anti-inflammatory agent, (i) such as non-steroidal anti-inflammatory agent, piroxicam, diclofenac, phenoxy propionic acid, fragrant that esters of gallic acid, the pyrazoline ketone, the salicylate class, phosphodiesterase inhibitor (comprising the PDE-4 inhibitor), p38MAP kinases/cathepsin inhibitors, the CCR-3 antagonist, the iNOS inhibitor, tryptase and elastase inhibitor, the Beta 2 integrin antagonist, cell adhension inhibitors (particularly ICAM), adenosine 2a agonist, (ii) leukotriene LTC4/LTD4/LTE4/LTB4 inhibitor, the 5-lipoxidase inhibitor, and paf receptor antagonists, (iii) Cox-2 inhibitor, (iv) other MMP inhibitor, (v) interleukin--I inhibitor, (vi) reflunomide is such as Modrasone, amcinonide, Amelometasone, beclometasone, Betamethasone Valerate, budesonide, ciclesonide, clobetasol, cloticasone, Telocort, deflazacort, deprodone, dexbudesonide, diflorasone, difluprednate, fluticasone, flunisolide, halometasone, the halogen pyrrone, hydrocortisone, methylprednisolone, Mometasone, prednicarbate, prednisolone, rimexolone, tixocortol, triamcinolone, ulobetasol, Rofleponide, GW215864, KSR592, ST-126, dexamethasone, and their pharmaceutically-acceptable salts, solvate, preferred reflunomide for example comprises: flunisolide, beclometasone, triamcinolone, budesonide, fluticasone, Mometasone, ciclesonide, dexamethasone,
(b) beta-2-agonists, suitable β 2-agonist for example comprises: one or more in salbutamol, salbutamol, bitolterol, pirbuterol, Levalbuterol, Tulobuterol, terbutaline, bambuterol, Racemic isoproterenol, Partusisten, Salmeterol, Ka Moteluo, Afromoterol, formoterol and their pharmaceutically-acceptable salts or solvate;
(c) antihypertensive drug, (i) ACE inhibitor, for example: enalapril, lisinopril, valsartan, telmisartan, quinapril, (ii) angiotensin II receptor antagonists and agonist, for example: losartan, Candesartan, Irb, valsartan, Eprosartan, (iii) beta-Blocking agent, and (iv) calcium channel blocker;
(d) immunosuppressor: S-Neoral, azathioprine and methotrexate, antiphlogistic corticoid; And
(e) anti-infection agent.
One kind for the preparation of structural formula VIII (ring A be that phenyl, U are-SO
2-, V and W be the structural formula I of Lian Jian) and structural formula IX (ring A be phenyl, U be-O-, V and W are the structural formula I of Lian Jian) shown in the method for compound,
Structural formula VIII structural formula IX
Comprise:
A) compound shown in the structural formula II
React with compound shown in structural formula II I
Structural formula II I
Get compound shown in structural formula IV
Structural formula IV
B) reaction of compound shown in compound shown in structural formula IV and structural formula V
Structural formula V
Get compound shown in structural formula VI,
Structural formula VI
C) with compound shown in structural formula VI (when X is S) hydrolysis, get compound shown in structural formula VII
Structural formula VII
D) with compound oxidation shown in structural formula VII, get compound shown in structural formula VIII, perhaps
E) with compound shown in structural formula VI (when X is O) hydrolysis, get compound shown in structural formula IX, wherein,
R
1Alkyl, thiazolinyl, alkynyl, cyano group, nitro, halogen, halo-C
1-C
6Alkyl, halo-C
1-C
6Alkoxyl group, azido-, sulfydryl, alkylthio ,-(CH
2)
n-OR
f,-C (=O)-R
f,-COOR
f,-NR
fR
q,-(CH
2)
n-C (=O) NR
fR
q,-(CH
2)
n-NHC (=O) R
f,-(CH
2)
n-O-C (=O) NR
fR
q, (CH
2)
nNHC (=O) NR
fR
q,-(CH
2)
n-O-C (=O)-R
f,-(CH
2)
n-NH-C (=O)-R
fPerhaps (CH
2)
nS (=O)
m-NR
fR
q{ R wherein
fAnd R
qBe selected from separately hydrogen, alkyl, thiazolinyl, cycloalkyl aryl, heteroaryl, heterocyclic radical, alkylaryl, miscellaneous alkyl aryl, alkyl heterocyclic, n as previously mentioned and m be the integer of 0-2;
X is O or S;
Rk is H, halogen, alkyl, alkoxyl group, cyano group, halo-C
1-C
6Alkyl or halo-C
1-C
6Alkoxyl group;
Z is 0-4;
L and W are respectively O or S; And
Rx is alkyl, aryl or aralkyl.
11. one kind for the preparation of structural formula XV (ring A be phenyl, U be-NH-, V be-CO-and W be-the structural formula I of NH-) and XVIII (encircle A and be phenyl, U and be-NH-, V and W combine the structural formula I into Rj) shown in the method for compound
Structural formula XV structural formula XVIII
Comprise:
A) addition reaction of compound generation aldol shown in compound shown in structural formula X and structural formula V
Structural formula X structural formula V
Get compound shown in structural formula XI
Structural formula XI
B) with the reduction of compound shown in structural formula XI, get compound shown in structural formula XII
Structural formula XII
C) shown in structural formula XII, compound (is worked as G
1When being amino) with structural formula XIII shown in compound generation linked reaction
Structural formula XII (works as G
1Be NH
2The time) structural formula XIII
Get compound shown in structural formula XIV
Structural formula XIV
D) with compound hydrolysis shown in structural formula XIV, get compound shown in structural formula XV, perhaps
E) compound generation linked reaction shown in compound shown in structural formula XII and structural formula XVI
Structural formula XVI
Get compound shown in structural formula XVII,
Structural formula XVII
F) with compound hydrolysis shown in structural formula XVII, get compound shown in structural formula XVIII, wherein,
R
1Alkyl, thiazolinyl, alkynyl, cyano group, nitro, halogen, halo-C
1-C
6Alkyl, halo-C
1-C
6Alkoxyl group, azido-, sulfydryl, alkylthio ,-(CH
2)
n-OR
f,-C (=O)-R
f,-COOR
f,-NR
fR
q,-(CH
2)
n-C (=O) NR
fR
q,-(CH
2)
n-NHC (=O)-R
f,-(CH
2)
n-O-C (=O)-NR
fR
q, (CH
2)
n-NHC (=O) NR
fR
q,-(CH
2)
n-O-C (=O)-R
f,-(CH
2)
n-NH-C (=O)-R
fPerhaps (CH
2)
nS (=O)
m-NR
fR
q{ R wherein
fAnd R
qBe selected from separately hydrogen, alkyl, thiazolinyl, cycloalkyl aryl, heteroaryl, heterocyclic radical, alkylaryl, miscellaneous alkyl aryl, alkyl heterocyclic, n as previously mentioned, m is the integer of 0-2 };
Rk is H, halogen, alkyl, alkoxyl group, cyano group, halo-C
1-C
6Alkyl or halo-C
1-C
6Alkoxyl group;
Z is 0-4;
L and W are respectively O or S;
Rx is alkyl, aryl or aralkyl;
G is nitro or C (O) O-benzyl;
G
1Amino or COOH;
X is leavings group, for example halogen; And
R
jBe-(CH
2)
0-1-CO-,-C (O) O-,-SO
2-.
12. one kind for the preparation of compound shown in structural formula XXI (ring A be phenyl, U be-CO-, V be-NH-and W are the structural formula I of Lian Jian) method
Structural formula XXI
Comprise:
A) shown in structural formula XII, compound (is worked as G
1When being COOH)
Structural formula XII (works as G
1During for COOH)
With the linked reaction of compound generation shown in structural formula XIX
Structural formula XIX
Get compound shown in structural formula XX
Structural formula XX
B) will be hydrolyzed compound hydrolysis shown in structural formula XX, get compound shown in structural formula XXI, wherein,
Be aryl, cycloalkyl, heteroaryl or heterocyclic radical, they separately can be further by one or more R that are independently selected from
1Substituting group replace;
R
1Alkyl, thiazolinyl, alkynyl, cyano group, nitro, halogen, halo-C
1-C
6Alkyl, halo C
1-C
6Alkoxyl group, azido-, sulfydryl, alkylthio ,-(CH
2)
n-OR
f,-C (=O)-R
f,-COOR
f,-NR
fR
q,-(CH
2)
n-C (=O) NR
fR
q,-(CH
2)
n-NHC (=O)-R
f,-(CH
2)
n-O-C (=O)-NR
fR
q, (CH
2)
nNHC (=O) NR
fR
q,-(CH
2)
n-O-C (=O)-R
f,-(CH
2)
n-NH-C (=O)-R
fPerhaps (CH
2)
nS (=O)
m-NR
fR
q{ R wherein
fAnd R
qBe selected from separately hydrogen, alkyl, thiazolinyl, cycloalkyl aryl, heteroaryl, heterocyclic radical, alkylaryl, miscellaneous alkyl aryl, alkyl heterocyclic, n as previously mentioned, m is the integer of 0-2 };
Be selected from heteroaryl or heterocyclic radical;
Rk is H, halogen, alkyl, alkoxyl group, cyano group, halo-C
1-C
6Alkyl or halo-C
1-C
6Alkoxyl group;
Z is 0-4;
L and W are respectively O or S;
Rx is alkyl, aryl or aralkyl.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1810DE2010 | 2010-07-30 | ||
| IN1810/DEL/2010 | 2010-07-30 | ||
| PCT/IB2011/053155 WO2012014114A1 (en) | 2010-07-30 | 2011-07-14 | Matrix metalloproteinase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103119030A true CN103119030A (en) | 2013-05-22 |
Family
ID=44720049
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011800461515A Pending CN103119030A (en) | 2010-07-30 | 2011-07-14 | Matrix metalloproteinase inhibitors |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP2598493A1 (en) |
| JP (1) | JP2013537533A (en) |
| KR (1) | KR20130042590A (en) |
| CN (1) | CN103119030A (en) |
| AU (1) | AU2011284397A1 (en) |
| BR (1) | BR112013002370A2 (en) |
| CA (1) | CA2807097A1 (en) |
| CO (1) | CO6680674A2 (en) |
| MX (1) | MX2013001240A (en) |
| SG (1) | SG187654A1 (en) |
| WO (1) | WO2012014114A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103254290A (en) * | 2013-05-30 | 2013-08-21 | 苏州普罗达生物科技有限公司 | Matrix metal proteinase-2 polypeptide inhibitors and application thereof |
| CN103304634A (en) * | 2013-05-30 | 2013-09-18 | 苏州普罗达生物科技有限公司 | Matrix metalloproteinase-2 polypeptide inhibitor and application |
Families Citing this family (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102154880B1 (en) | 2012-05-03 | 2020-09-10 | 칼라 파마슈티컬스, 인크. | Pharmaceutical nanoparticles showing improved mucosal transport |
| EP2844295A1 (en) | 2012-05-03 | 2015-03-11 | Kala Pharmaceuticals, Inc. | Pharmaceutical nanoparticles showing improved mucosal transport |
| US9827191B2 (en) | 2012-05-03 | 2017-11-28 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
| US11596599B2 (en) | 2012-05-03 | 2023-03-07 | The Johns Hopkins University | Compositions and methods for ophthalmic and/or other applications |
| AU2014216178B2 (en) | 2013-02-15 | 2018-06-28 | KALA BIO, Inc. | Therapeutic compounds and uses thereof |
| US9688688B2 (en) | 2013-02-20 | 2017-06-27 | Kala Pharmaceuticals, Inc. | Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof |
| EP2958895B1 (en) | 2013-02-20 | 2020-08-19 | Kala Pharmaceuticals, Inc. | Therapeutic compounds and uses thereof |
| CN106061261B (en) | 2013-11-01 | 2018-04-24 | 卡拉制药公司 | Crystal form of therapeutic compounds and application thereof |
| US9890173B2 (en) | 2013-11-01 | 2018-02-13 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| WO2015150366A1 (en) * | 2014-04-03 | 2015-10-08 | Bayer Pharma Aktiengesellschaft | Cyclically substituted phenol ether derivatives and use thereof |
| WO2015150364A1 (en) * | 2014-04-03 | 2015-10-08 | Bayer Pharma Aktiengesellschaft | Substituted benzotriazinone butane acids and use thereof |
| EP3126358A1 (en) | 2014-04-03 | 2017-02-08 | Bayer Pharma Aktiengesellschaft | 2,5-disubstituted cyclopentane carboxylic acids for the treatment of respiratoy tract diseases |
| JP2017511319A (en) | 2014-04-03 | 2017-04-20 | バイエル ファーマ アクチエンゲゼルシャフト | Chiral 2,5-disubstituted cyclopentanecarboxylic acid derivatives and uses thereof |
| EP3126339A1 (en) | 2014-04-03 | 2017-02-08 | Bayer Pharma Aktiengesellschaft | 2,5-disubstituted cyclopentane carboxylic acids and use thereof |
| WO2015189117A1 (en) * | 2014-06-12 | 2015-12-17 | Bayer Pharma Aktiengesellschaft | Heterobicyclically substituted 4-oxobutane acid derivatives and use thereof |
| JOP20190024A1 (en) | 2016-08-26 | 2019-02-19 | Gilead Sciences Inc | Substituted pyrrolizine compounds and uses thereof |
| CA3036340A1 (en) | 2016-09-08 | 2018-03-15 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| AU2017324713B2 (en) | 2016-09-08 | 2020-08-13 | KALA BIO, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| EP3509421A4 (en) | 2016-09-08 | 2020-05-20 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
| WO2019165374A1 (en) | 2018-02-26 | 2019-08-29 | Gilead Sciences, Inc. | Substituted pyrrolizine compounds as hbv replication inhibitors |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1200886A (en) | 1966-09-23 | 1970-08-05 | Allen & Hanburys Ltd | Phenylaminoethanol derivatives |
| US3937838A (en) | 1966-10-19 | 1976-02-10 | Aktiebolaget Draco | Orally active bronchospasmolytic compounds and their preparation |
| US3700681A (en) | 1971-02-16 | 1972-10-24 | Pfizer | 2-hydroxymethyl-3-hydroxy-6-(1-hydroxy-2-aminoethyl)pyridines |
| US3994974A (en) | 1972-02-05 | 1976-11-30 | Yamanouchi Pharmaceutical Co., Ltd. | α-Aminomethylbenzyl alcohol derivatives |
| US4011258A (en) | 1973-06-21 | 1977-03-08 | Aktiebolaget Draco | Orally active bronchospasmolytic compounds |
| ATE7689T1 (en) | 1980-07-09 | 1984-06-15 | Aktiebolaget Draco | 1-(DIHYDROXYPHENYL)-2-AMINO-AETHANOL DERIVATIVES, PROCESSES AND MEANS FOR THEIR PREPARATION, AND AGENTS CONTAINING THESE DERIVATIVES. |
| ZW6584A1 (en) | 1983-04-18 | 1985-04-17 | Glaxo Group Ltd | Phenethanolamine derivatives |
| CA1240708A (en) | 1983-11-15 | 1988-08-16 | Johannes K. Minderhoud | Process for the preparation of hydrocarbons |
| GB9304919D0 (en) | 1993-03-10 | 1993-04-28 | Celltech Ltd | Chemical compounds |
| JP2003528082A (en) | 2000-03-21 | 2003-09-24 | ザ プロクター アンド ギャンブル カンパニー | Difluorobutyric acid metalloprotease inhibitor |
| BR0206771A (en) | 2001-01-30 | 2004-02-25 | Pfizer Prod Inc | Processes for the preparation of chromanylbenzoic acids |
| US6794510B2 (en) | 2002-08-08 | 2004-09-21 | Adolor Corporation | Processes for the preparation of peripheral opioid antagonist compounds and intermediates thereto |
| GB0312654D0 (en) | 2003-06-03 | 2003-07-09 | Glaxo Group Ltd | Therapeutically useful compounds |
| GB0314488D0 (en) | 2003-06-20 | 2003-07-23 | Glaxo Group Ltd | Therapeutically useful compounds |
| GB0321538D0 (en) | 2003-09-13 | 2003-10-15 | Glaxo Group Ltd | Therapeutically useful compounds |
| ES2381681T3 (en) | 2005-02-22 | 2012-05-30 | Ranbaxy Laboratories Limited | 5-Phenyl-pentanoic acid derivatives as inhibitors of matrix metalloproteinase for the treatment of asthma and other diseases |
| SG174089A1 (en) | 2006-08-22 | 2011-09-29 | Ranbaxy Lab Ltd | Matrix metalloproteinase inhibitors |
-
2011
- 2011-07-14 WO PCT/IB2011/053155 patent/WO2012014114A1/en active Application Filing
- 2011-07-14 BR BR112013002370A patent/BR112013002370A2/en not_active IP Right Cessation
- 2011-07-14 AU AU2011284397A patent/AU2011284397A1/en not_active Abandoned
- 2011-07-14 CN CN2011800461515A patent/CN103119030A/en active Pending
- 2011-07-14 EP EP11763767.8A patent/EP2598493A1/en not_active Withdrawn
- 2011-07-14 KR KR1020137005055A patent/KR20130042590A/en not_active Application Discontinuation
- 2011-07-14 MX MX2013001240A patent/MX2013001240A/en not_active Application Discontinuation
- 2011-07-14 CA CA2807097A patent/CA2807097A1/en not_active Abandoned
- 2011-07-14 SG SG2013007448A patent/SG187654A1/en unknown
- 2011-07-14 JP JP2013522322A patent/JP2013537533A/en not_active Withdrawn
-
2013
- 2013-02-28 CO CO13040146A patent/CO6680674A2/en not_active Application Discontinuation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103254290A (en) * | 2013-05-30 | 2013-08-21 | 苏州普罗达生物科技有限公司 | Matrix metal proteinase-2 polypeptide inhibitors and application thereof |
| CN103304634A (en) * | 2013-05-30 | 2013-09-18 | 苏州普罗达生物科技有限公司 | Matrix metalloproteinase-2 polypeptide inhibitor and application |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2598493A1 (en) | 2013-06-05 |
| JP2013537533A (en) | 2013-10-03 |
| KR20130042590A (en) | 2013-04-26 |
| CA2807097A1 (en) | 2012-02-02 |
| BR112013002370A2 (en) | 2017-06-20 |
| WO2012014114A1 (en) | 2012-02-02 |
| AU2011284397A1 (en) | 2013-02-21 |
| SG187654A1 (en) | 2013-03-28 |
| MX2013001240A (en) | 2013-08-27 |
| CO6680674A2 (en) | 2013-05-31 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103119030A (en) | Matrix metalloproteinase inhibitors | |
| EP2368550B1 (en) | Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases | |
| CN103228634A (en) | Matrix metalloproteinase inhibitors | |
| CN101616925B (en) | Tricyclic compounds and their use as glucocorticoid receptor modulators | |
| CN103140479B (en) | Manufacturing process for pyrimidine derivatives | |
| CN102485721B (en) | 2，3-benzodiazine ketone compound replaced and uses thereof | |
| CN106715415A (en) | 3-amino-1,5,6,7-tetrahydro-4H-indol-4-ones | |
| HUT77608A (en) | Use of heterocyclic compounds as dopamines-d3-receptor ligands | |
| TW200413331A (en) | Small molecule PI 3-kinase inhibitors and methods of their use | |
| CN105727298A (en) | Reverse amide compounds as protein deacetylase inhibitors and methods of use thereof | |
| CN105130957A (en) | Aryl substituted carboxamide derivatives as calcium or sodium channel blockers | |
| CN101124201A (en) | PARP inhibitors | |
| CN103249719A (en) | Matrix metalloproteinase inhibitors | |
| CN103391932B (en) | For suppressing the heterogeneous ring compound of PASK | |
| EP2646435B1 (en) | 5-methyl-1-(naphthalen-2-yl)-1h-pyrazole derivatives and their use in potentiating the effect of opioid analgesics | |
| CN101500997A (en) | PARP inhibitors | |
| WO2011035174A1 (en) | Substituted heteroarylamine carboxamide analogs as mglur5 negative allosteric modulators and methods of making and using the same | |
| CN101490030A (en) | Novel chromene and thiochromene carboxamide derivatives, methods for preparing same and therapeutic applications of same | |
| CN103402995A (en) | Novel indole or indazole derivative or salt thereof | |
| JP2023518356A (en) | Methods for treatment of COVID-19 related conditions | |
| WO1990012001A1 (en) | Thionaphthalene derivatives, method of producing the same, and antiallergic agent containing the same | |
| CN101287712B (en) | Heterocyclic compounds | |
| CN105085436A (en) | Sulfonamide derivative and application thereof to medicament | |
| JP2004520399A (en) | Thrombin inhibitor | |
| JP2002513789A (en) | Fine particle size form of 1- (6-chloronaphth-2-ylsulfonyl) -4- [4- (4-pyridyl) benzoyl] piperazine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130522 |
|
| WD01 | Invention patent application deemed withdrawn after publication |