CN1366518A - Biphenyl butyric acid derivative as matrix metalloproteinase inhibitor - Google Patents
Biphenyl butyric acid derivative as matrix metalloproteinase inhibitor Download PDFInfo
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- CN1366518A CN1366518A CN01801067A CN01801067A CN1366518A CN 1366518 A CN1366518 A CN 1366518A CN 01801067 A CN01801067 A CN 01801067A CN 01801067 A CN01801067 A CN 01801067A CN 1366518 A CN1366518 A CN 1366518A
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Abstract
The present invention provides a novel biphenyl butyric acid derivative, isomer and pharmaceutically acceptable salts thereof which are useful as an inhibitor of matrix metalloproteinase (MMP) and a process for preparing the same. Since the biphenyl butyric acid derivative of the invention selectively inhibits the activity of MMP in vitro, it can be practically applied to the treatment and prevention of diseases caused by overexpression of MMP.
Description
Background of invention
Invention field
The present invention relates to biphenyl butyric acid derivative, specifically, relate to the new biphenyl butyric acid derivative, its pharmacologically acceptable salt that can be used as the matrix metallo-proteinase inhibitor use represented by following formula (I) and the method for preparing these compounds.
The description of prior art
Matrix metalloproteinase (MMP) is to contain zine ion (Zn at its avtive spot
2+) Ca
2+Dependent proteolytic enzyme.Up to the present, identify at least 18 kinds of matrix metalloproteinases in the art, comprised stromelysin, collagenase and gelatinase family.MMP makes the various extracellular matrix components degradeds of collagen, ln, Saliva Orthana, fibronectin, elastin and gelatin under the biology condition, this degraded causes the growth of joint tissue, bone tissue and reticular tissue and reinventing of tissue conversely again.MMP is secreted out with the zymogen forms of non-activity at first, and this proenzyme is activated with naturally occurring inhibitor TIMP (tissue depressant of metalloprotease) in the cell outside subsequently.
Simultaneously, the MMP inhibitor can be used for preventing and treats the various diseases that is caused by the crossing expression or overactivity of MMP.This class disease is, for example, the intrusion of similar rheumatism, arthrosteitis, unusual bone resorption, osteoporosis, periodontitis, intermittence ephritis, arteriosclerosis, pulmonary emphysema, liver cirrhosis, corneal injury, metastasis (metastases), tumour cell or growth, autoimmune disorder, move out or white corpuscle oozes disease that profit causes, arterialization (referring to Curr.Opin.Ther.Patents such as Beeley by vascular, 4 (1): 7-16,1994).For example, it is reported that in suffering from the mouse model of ovarian cancer, synthetic MMP inhibitor has the active and basement membrane reconstruction inhibition (referring to Cancer Res., 53:2087,1993) of vivo antitumor.Particularly, consider the following fact: MMP-2 in the above-mentioned mmp enzyme and MMP-9 play an important role (referring to Biochim.Biophys.Acta in the required vasculogenesis of growth of cancer cells, 695,1983), MMP-1 in the mmp enzyme and MMP-3 play an important role in arthritic progress, be higher than normal value far away (referring to Arthritis Rheum. because in the synovial membrane of patient with rheumatoid arthritis and cartilage, find their concentration, 35:35-42,1992), it is believed that, being chosen in of MMP-1/MMP-2 alleviated such as playing a crucial role in the arthralgic side effect.Therefore, the focus of research concentrates on the exploitation selective depressant, has designed and synthesized multiple MMP inhibitor (referring to J.Enzyme Inhibitors, 2:1-22,1987 under multiple situation; Currnt Medicinal Chemistry, 2:743-762,1995; Progress in Medicinal Chemistry, 29:271-334,1992; Exp.Opin.Ther.Patents, 5:1287-1296,1995; Drug Discovery Today, 1:16-26,1996; Chem.Rev., 99:2735-2776,1999; Drugs of the Future 2000,25 (6), 551-557; Exp.Opin.Invest.Drugs, 2000,2167-2177).
More known compounds have the inhibition activity to MMP.They have a group in conjunction with zinc (ZBG) usually, and this group is at the avtive spot of mmp enzyme and the zinc ion coordination of mmp enzyme.This ZBG comprises that hydroxamic acid, carboxylic acid, phosphoric acid, phospho acid, mercaptan etc. are (referring to WO 92/09564; WO 95/04033; WO 00/04030; WO 00/43404; WO95/13289; WO 96/11209; WO 95/09834; WO 95/09620; WO 00/40577; WO 00/40600; WO98/03166; Chem.Rev.99:2735-2776,1999).Especially, designed and synthesized several succinic acid derivatives based on the substrate main chain as peptide-simulation inhibitor (referring to WO 99/25693; WO 90/05719; WO 94/02446; WO95/09841; WO 95/19956; WO 95/19957; WO 95/19961; WO 96/06074; WO 96/16931; WO 98/43959; WO 98/24759; WO 98/30551; WO98/30541; WO 97/32846; WO 99/01428; EP 897908; WO 98/38179; JP 95002797; WO 99/18074; WO 99/19296; EP 641323).Known this peptide-simulation inhibitor contains hydroxamic acid and shows wide range figure as ZBG and to mmp enzyme.
Yet some above-mentioned peptide-simulation inhibitor cause that in clinical trial arthralgic side effect is (referring to Current Pharmaceutical Design, 5:787-819,1999; Current Opinionin Drug Discovery ﹠amp; Development, 3:353-361,2000).They also are difficult for absorbing usually, show low oral administration biaavailability, and, have lower selectivity (referring to Drugs of the Future, 21 (12): 1215-1220,1996) to MMP-1/MMP-2.
1994, to develop non--inhibitor peptides and solved the problems referred to above, its chemical structure is significantly different with above-mentioned peptide-simulation inhibitor, and it has simple sulfuryl amino acid derivative, is expressed from the next (referring to USP 5,506,242; J.Med.Chem., 40:2525-2532,1997).
CGS-27023A(Novartis)
Consider that micromolecular sulphonamide deutero-MMP inhibitor has the activity at the vitro inhibition mmp enzyme, and it has the advantage that surpasses described peptide-simulation inhibitor, synthesized multiple sulfonamide inhibitors and write down in the literature (referring to WO 98/50348; WO 97/20824; WO00/09485; WO 99/58531; WO 99/51572; WO 99/52889; WO 99/52910; WO 99/37625; WO 98/32748; WO 99/18076; WO 99/06410; WO99/07675; WO 98/27069; WO 97/22587; EP 979816; EP 895988; EP878467; EP 1041072).In order to improve the distribution curve of vitro enzyme activity, selectivity and pharmacokinetics, the P1 ' of the sulfonamide inhibitors by changing the above-mentioned S1 ' sublocus that is connected to enzyme designs and synthesizes new sulfone amide derivative.
Though above-mentioned sulfonamide inhibitors has the high relatively inhibition activity to MMP, to compare with previous peptide-simulation inhibitor, they do not possess the higher selectivity to MMP-1/MMP-2.Their wherein some also have arthralgic side effect (referring to Current Pharmaceutical Design, 5:787-819,1999 in clinical trial; Current Opinion in DrugDiscovery ﹠amp; Development, 3:353-361,2000; Exp.Opin.Invest.Drugs, 9:2159-2165,2000; SCRIP, 2467:19,1999; Drugs of the Future, 24 (1): 16-21,1999).Although containing hydroxamic acid contains carboxylic acid as the sulfonamide inhibitors of ZBG and those and compares as the sulfonamide inhibitors of ZBG and show very strong vitro inhibition activity usually, because bioavailability and metabolic stability in their lower bodies, they also show limitation in oral administration.(referring to J.Med.Chem., 41:640-649,1988; InvestigationalNew Drugs 16:303-313,1999; Exp.Opin.Ther.Patents, 10:111-115,2000; WO 00/63194; WO 00/27808; WO 99/18079; USP 6,117, and 869).
Non--inhibitor peptides (3-oxo-biphenyl butyric acid derivative) of finding other can address the above problem and improve selectivity, this inhibitor that contains the butyric acid group be expressed from the next (referring to WO96/15096).
Though comparing with peptide-simulation succinic acid derivative or sulfuryl amino acid derivative, above-mentioned inhibitor has low-down external inhibition activity to MMP; they have very high to the selectivity of MMP-1/MMP-2 and in clinical trial arthralgic side effect also very little (referring to Drugs of the Future; 24 (1): 16-21,1999).In order to improve the problem of above-mentioned inhibitor, design and reported multiple biphenyl butyric acid derivative as the MMP inhibitor (referring to USP5,789,434; USP 5,854, and 277; USP 5,859, and 047; USP 5,861, and 427; USP5,861,428; USP 5,874, and 473; USP 5,886, and 022; USP 5,886, and 024; USP5,886,043).
The butanoic acid derivative that the following formula that another kind is in the news is represented also has shortcoming, and that is exactly lower (referring to WO 98/09940 to the inhibition activity of MMP; WO 98/06711).
In this case, press for other compound active and that the selectivity of MMP-1/MMP-2 is improved of development, to reduce its side effect to the inhibition of MMP.
Summary of the invention
The inventor is devoted to develop that new compound active and that the selectivity of MMP-1/MMP-2 is improved has finally found at the external active new synthetic inhibitor of MMP--the biphenyl butyric acid derivative that optionally suppresses to reduce its side effect to the inhibition of MMP.
Main purpose of the present invention is to provide inhibition MMP active biphenyl butyric acid derivative.
Another object of the present invention is to provide the preparation method of described compound.Detailed description of the present invention
The invention provides by the active biphenyl butyric acid derivative of inhibition MMP, its isomer, the pharmacologically acceptable salt of following formula (I) expression and prepare the method for these compounds.
Wherein, R
1Be hydrogen, alkyl, cycloalkyl, halogen, nitro, cyano group ,-OCF
3,-OCH
2F,
-OR
4,-SR
4,-S (O) R
4Or-S (O)
2, R wherein
4And R
4 aCan be identical or different and be alkyl, aryl, aralkyl, heteroaryl or cycloalkyl;
R
2And R
3Can be identical or different, and be hydrogen, alkyl, aryl, aralkyl, heteroaryl or cycloalkyl; With
N is 1 or 2.
In following formula, R
2And R
3Form C with carbon, nitrogen, oxygen or sulphur
5-6Ring comprises the following ring:
Wherein
R
8Be hydrogen, alkyl, aryl, aralkyl, heteroaryl or cycloalkyl; With
X is O or S.And, at R
3When being hydrogen, R
2Can also comprise the substituting group shown in the following structural formula:
Wherein
R
5Be hydrogen, alkyl, aryl, aralkyl, heteroaryl, hydroxyalkyl, alkoxyalkyl, alkylthio alkyl, arylthio alkyl, alkyl sulfurous base alkyl, alkyl sulphonyl alkyl, aryl sulfurous base alkyl, aryl sulfonyl alkyl or cycloalkyl; With
R
6And R
7Can be identical or different, and be hydrogen, alkyl, aryl, aralkyl, heteroaryl or cycloalkyl.
At R
3When being not hydrogen, R
3And the R in the following formula (I)
5Form C with carbon, nitrogen, oxygen or sulphur
5-6Ring, wherein
Part comprises following groups:
Wherein
R
6And R
7Same as described above;
R
9Be hydrogen, hydroxyl, alkoxyl group, aryloxy, thiol or alkylthio;
R
10Be oxo, oxyamine or hydrazone;
R
11And R
12Be hydrogen or C
1-6Low alkyl group; With
Y is CH
2, O or S.
In addition, R
6And R
7Form C with carbon, nitrogen, oxygen or sulphur
5-6Ring comprises the following ring:
Wherein
R
8Same as described above with X.
Situation unless otherwise noted, the isomer of the biphenyl butyric acid derivative of all kinds all falls within the scope of protection of the present invention.
Pharmacologically acceptable salt of the present invention comprises acid salt and hydrate.The compound of general formula of the present invention (I) can be converted into and they corresponding salt, the non-toxic salt and the water-soluble salt of preferred as alkali salt (sodium salt, sylvite etc.), alkaline earth salt (calcium salt, magnesium salts etc.), ammonium salt, medicinal organic amine.The compound of general formula (I) can be converted into inorganic acid salt (hydrochloride, hydrogen bromide, hydrogen iodide, vitriol, phosphoric acid salt, nitrate etc.) and organic acid salt (acetate, lactic acid salt, tartrate, oxalate, fumarate, glucuronate etc.), preferred non-toxic salt and water-soluble salt.The compound of general formula (I) and salt thereof also can be converted into and they corresponding hydrates by conventional known method in this area.
Two kinds of preparation methods of the compound of general formula (I) are described through the following steps.At first, can be by following method 1 preparation above-claimed cpd.
Method 1
Wherein
R
1, R
2And R
3Same as described above.Step 1: tertiary butyl ester compound (IV) synthetic
Compound (II) and compound (III) reaction are obtained tertiary butyl ester compound (IV): compound (II) can be purchased or make by conventional known method, compound (III) can by with conventional known method in addition part change and make (referring to VOGEL ' s Textbook ofPractical Organic Chemistry such as B.S.Furniss, the 5th edition, the 942-943 page or leaf, 1988; WO96/15096).Step 2: compound (V) synthetic
The compound (V) that tertiary butyl ester compound (IV) deprotection is not contained the butyl ester base: deprotection reaction is preferably by using TFA or anhydrous HCl to finish.Step 3: compound (VI) synthetic
Compound (V) and amine compound condensation are obtained containing the compound (VI) of diethyl-ester group: amine compound comprises the R of above-mentioned definition
2And R
3, can be undertaken by several different methods with the condensation reaction of amine compound, for example acid chloride method, active ester method, mixed anhydride method etc.Step 4: compound (I) synthetic
The diethyl-ester group of compound (VI) is hydrolyzed to carboxyl, then this compound decarboxylation is obtained compound (I).
Also can be by the compound of following method 2 preparation general formulas (I).
Method 2
Wherein
R
1, R
2And R
3Same as described above.Step 1: tertiary butyl ester compound (IV) synthetic
Compound (II) and compound (III) reaction are obtained tertiary butyl ester compound (IV): compound (II) can be purchased or make by conventional known method, compound (III) can by with conventional known method in addition part change and make (referring to VOGEL ' s Textbook ofPractical Organic Chemistry such as B.S.Furniss, the 5th edition, the 942-943 page or leaf, 1988; WO96/15096).Step 2: compound (VII) synthetic
An ethoxycarbonyl of tertiary butyl ester compound (IV) is hydrolyzed to carboxyl, and then this compound decarboxylation is obtained compound (VII): hydrolysis reaction carries out in the presence of alkali, and decarboxylic reaction carries out in the presence of organic solvent; And described alkali preferably includes but is not limited to 1 normal KOH/EtOH, and organic solvent preferably includes 1, the 4-diox.Step 3: compound (VIII) synthetic
The compound (VIII) that compound (VII) deprotection is not contained the butyl ester base: preferably use TFA or anhydrous HCl to carry out deprotection reaction.Step 4: compound (IX) synthetic
Compound (VIII) and amine compound condensation are obtained containing the compound (IX) of ethoxycarbonyl: amine compound comprises the R of above-mentioned definition
2And R
3, can be undertaken by several different methods with the condensation reaction of amine compound, for example acid chloride method, active ester method, mixed anhydride method etc., most preferably active ester method.Step 5: compound (I) synthetic
The ethoxycarbonyl of compound (IX) is hydrolyzed to carboxyl, to obtain compound (I) (referring to WO96/15096).
In the following embodiments the present invention has been made further instruction, should not think that this embodiment can be construed as limiting scope of the present invention.Embodiment 1:5-(xenyl-4-yl)-5-oxo-3, the 3-diethoxy carbonyl valeric acid tert-butyl ester (IV, R
1=H) preparation
(95%, 505mg 20.0mmol) with highly purified THF (15mL), is reduced to temperature-10 ℃ to add NaH in the flask of 100ml.Then, (III, 4.9g 18.17mmol), at room temperature stirred 30 minutes to add the tert-butoxycarbonyl methyl-malonic ester that is dissolved in THF (10mL) lentamente.Then, add 4-phenyl-α-bromoacetyl benzene (II, the R that is dissolved in THF (15mL) lentamente
1=H, 5g 18.17mmol), at room temperature stirred 1 hour 30 minutes, with 1N HCl (30mL) and ethyl acetate (30mL) extraction.Water (10mL) washing organic phase adds anhydrous MgSO
4, stirred 5 minutes, filter and underpressure distillation, obtain title compound (8.65g, 95%).
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 6H), 1.38 (s, 9H), 3.39 (s, 2H), 3.97 (s, 2H), 4.24 (q, 4H), 7.45 (m, 3H), 7.61 (d, 2H), 7.69 (d, 2H), 8.04 (d, 2H) embodiment 2:5-(4 '-methoxyl biphenyl base-4-yl)-5-oxo-3, the 3-diethoxy carbonyl valeric acid tert-butyl ester (IV, R
1=OMe) preparation
Except using 4-(4 '-p-methoxy-phenyl)-α-bromoacetyl benzene (II, R
1=OMe) outside, prepare title compound according to embodiment 1 similar mode.
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 6H), 1.38 (s, 9H), 3.21 (s, 2H), 3.86 (s, 3H), 3.94 (s, 2H), 4.24 (q, 4H), 7.0 (d, 2H), 7.58 (d, 2H), 7.65 (d, 2H), 8.02 (d, 2H) embodiment 3:5-(4 '-bromo biphenyl base-4-yl)-5-oxo-3, the 3-diethoxy carbonyl valeric acid tert-butyl ester (IV, R
1=Br) preparation
Except using 4-(4 '-bromophenyl)-α-bromoacetyl benzene (II, R
1=Br) outside, prepare title compound according to embodiment 1 similar mode.
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 6H), 1.39 (s, 9H), 3.21 (s, 2H), 3.95 (s, 2H), 4.24 (q, 4H), 7.48 (d, 2H), 7.60 (d, 2H), 7.65 (d, 2H), 8.04 (d, 2H) embodiment 4:5-(4 '-chlorodiphenyl-4-yl)-5-oxo-3, the 3-diethoxy carbonyl valeric acid tert-butyl ester (IV, R
1=Cl) preparation
Except using 4-(4 '-chloro-phenyl-)-α-bromoacetyl benzene (II, R
1=Cl) outside, prepare title compound according to embodiment 1 similar mode.
1H NMR (300MHz, CDCl
3): δ 1.25 (t, 6H), 1.39 (s, 9H), 3.21 (s, 2H), 3.95 (s, 2H), 4.24 (q, 4H), 7.44 (d, 2H), 7.56 (d, 2H), 7.65 (d, 2H), 8.06 (d, 2H) embodiment 5:5-(xenyl-4-yl)-5-oxo-3,3-diethoxy carbonyl valeric acid (V, R
1=H) preparation
To being dispersed in 5-(xenyl-4-the yl)-5-oxo-3 of methylene dichloride (MC) in (20mL), the 3-diethoxy carbonyl valeric acid tert-butyl ester (IV, R
1=H, 1.5g, 3.2mmol) the middle TFA (2mL) that adds at room temperature stirred 24 hours.After MC is removed in decompression, add ethyl acetate (20mL) and 1N NaOH lentamente, the organic layer of water extracting and separating.Then, collect the aqueous solution, handle and use ethyl acetate extraction with 1N HCl (30mL).Use anhydrous MgSO
4Dry isolating organic layer filters and underpressure distillation, obtains title compound (1.2g, 91%).
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 6H), 3.39 (s, 2H), 3.97 (s, 2H), 4.24 (q, 4H), 7.45 (m, 3H), 7.61 (d, 2H), 7.69 (d, 2H), 8.04 (d, 2H) embodiment 6:5-(4 '-methoxyl biphenyl base-4-yl)-5-oxo-3,3-diethoxy carbonyl valeric acid (V, R
1=OMe) preparation
Except using 5-(4 '-methoxyl biphenyl base-4-yl)-5-oxo-3, the 3-diethoxy carbonyl valeric acid tert-butyl ester (IV, R
1=OMe) outside, prepare title compound according to embodiment 5 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 6H), 3.21 (s, 2H), 3.86 (s, 3H), 3.94 (s, 2H), 4.24 (q, 4H), 7.0 (d, 2H), 7.58 (d, 2H), 7.65 (d, 2H), 8.02 (d, 2H) embodiment 7:5-(4 '-bromo biphenyl base-4-yl)-5-oxo-3,3-diethoxy carbonyl valeric acid (V, R
1=Br) preparation
Except using 5-(4 '-bromo biphenyl base-4-yl)-5-oxo-3, the 3-diethoxy carbonyl valeric acid tert-butyl ester (IV, R
1=Br) outside, prepare title compound according to embodiment 5 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 6H), 3.21 (s, 2H), 3.95 (s, 2H), 4.24 (q, 4H), 7.48 (d, 2H), 7.60 (d, 2H), 7.65 (d, 2H), 8.04 (d, 2H) embodiment 8:N-phenyl-5-(xenyl-4-yl)-5-oxo-3,3-diethoxy carbonyl valeramide (VI, R
1=H) preparation
With 5-(xenyl-4-yl)-5-oxo-3,3-diethoxy carbonyl valeric acid (V, R
1=H, 0.5g, 1.2mmol), EDC (0.23g, 1.2mmol) and HOBt (0.16g 1.2mmol) is dissolved among the MC (5mL), and temperature is reduced to 0 ℃.(170mL 1.2mmol), stirred 10 minutes, and (122mL 1.3mmol) also at room temperature stirred 2 hours 30 minutes to add aniline then to add TEA.Then, add 1N HCl and, use anhydrous MgSO with the MC extraction
4Drying is filtered and underpressure distillation, and (Hx/EA=4/1, v/v) separation obtains title compound (0.365g, 62%) through column chromatography.
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 6H), 3.32 (s, 2H), 4.05 (s, 2H), 4.24 (q, 4H), 7.07 (t, 1H), 7.26 (m, 1H), 7.45 (m, 5H), 7.65 (m, 5H), 8.04 (d, 2H) embodiment 9:N-cyclopropyl-5-(xenyl-4-yl)-5-oxo-3,3-diethoxy carbonyl valeramide (VI, R
1=H) preparation
Except using 5-(xenyl-4-yl)-5-oxo-3,3-diethoxy carbonyl valeric acid (V, R
1=H) and cyclopropylamine outside, prepare title compound according to embodiment 8 similar modes.
1H NMR (300MHz, CDCl
3): δ 0.41 (m, 2H), 0.69 (m, 2H), 2.62 (m, 1H), 3.08 (s, 2H), 4.00 (s, 2H), 4.24 (q, 4H), 5.9 (s, 1H), 7.45 (m, 3H), 7.61 (d, 2H), 7.69 (d, 2H), 8.04 (d, 2H) embodiment 10:N-(α-Jia Jibianji)-5-(xenyl-4-yl)-5-oxo-3,3-diethoxy carbonyl valeramide (VI, R
1=H) the preparation of (VI)
Except using 5-(xenyl-4-yl)-5-oxo-3,3-diethoxy carbonyl valeric acid (V, R
1=H) and α-Jia Jibianji amine outside, prepare title compound according to embodiment 8 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 6H), 1.41 (d, 3H), 3.17 (d, 2H), 3.97 (d, 2H), 4.21 (q, 4H), 5.0 (m, 1H), 5.95 (d, 1H), 7.19 (m, 5H), 7.46 (m, 3H), 7.61 (d, 2H), 7.67 (d, 2H), 8.04 (d, 2H) embodiment 11:N-phenyl-5-(4 '-methoxyl biphenyl base-4-yl)-5-oxo-3,3-diethoxy carbonyl valeramide (VI, R
1=OMe) preparation
Except using 5-(4 '-methoxyl biphenyl base-4-yl)-5-oxo-3,3-diethoxy carbonyl valeric acid (V, R
1=OMe) and aniline outside, prepare title compound according to embodiment 8 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 6H), 3.34 (s, 2H), 3.86 (s, 3H), 4.04 (s, 2H), 4.24 (q, 4H), 7.0 (d, 2H), 7.05 (t, 1H), 7.26 (t, 2H), 7.44 (d, 2H), 7.54 (d, 2H), 7.62 (d, 2H), 8.02 (d, 2H) embodiment 12:N-[1,5-dioxo-5-(4 '-methoxyl biphenyl base-4-yl)-3,3-diethoxy carbonyl pentane-1-yl]-4-methylpiperazine (VI, R
1=OMe) the preparation of (VI)
Except using 5-(4 '-methoxyl biphenyl base-4-yl)-5-oxo-3,3-diethoxy carbonyl valeric acid (V, R
1=OMe) and N methyl piperazine outside, prepare title compound according to embodiment 8 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 6H), 2.30 (s, 3H), 2.34 (br, 4H), 3.35 (s, 2H), 3.55 (br, 4H), 3.86 (s, 3H), 4.10 (s, 2H), 4.24 (q, 4H), 7.0 (d, 2H), 7.58 (d, 2H), 7.65 (d, 2H), 8.02 (d, 2H) embodiment 13:N-[1,5-dioxo-5-(4 '-bromo biphenyl base-4-yl)-3,3-diethoxy carbonyl pentane-1-yl] piperidines (VI, R
1=Br) preparation
Except using 5-(4 '-bromo biphenyl base-4-yl)-5-oxo-3,3-diethoxy carbonyl valeric acid (V, R
1=Br) and piperidines outside, prepare title compound according to embodiment 8 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 6H), 2.85 (Br, 4H); 3.37 (s, 2H), 3.64 (br, 4H); 4.00 (s, 2H), 4.26 (q, 4H); 7.48 (d, 2H), 7.59 (d, 2H); 7.66 (d, 2H), 8.04 (d, 2H) embodiment 14:N-[1; 5-dioxo-5-(4 '-bromo biphenyl base-4-yl)-3,3-diethoxy carbonyl pentane-1-yl]-4-benzoyl-piperazine (VI, R
1=Br) preparation
Except use the N-benzoyl-piperazine (referring to Kondo, J.Chem.Soc such as K., PerkinTrans 1,1998,2973-2974) and 5-(4 '-bromo biphenyl base-4-yl)-5-oxo-3,3-diethoxy carbonyl valeric acid (V, R
1=Br) outside, prepare title compound according to embodiment 8 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 6H), 3.18 (s, 2H), 3.54 (br; 4H), 3.75 (br, 4H), 4.00 (s; 2H), 4.24 (q, 4H), 7.40 (m; 4H), 7.42 (d, 2H), 7.62 (m; 4H), 7.86 (d, 1H), 8.02 (d; 2H) embodiment 15:1,5-dioxo-1-(1-phenyl amino formyl radical-1-ethylamino)-5-(4 '-bromo biphenyl base-4-yl)-3,3-diethoxy carbonyl pentane (VI, R
1=Br) preparation
With 5-(4 '-bromo biphenyl base-4-yl)-5-oxo-3,3-diethoxy carbonyl valeric acid (V, R
1=Br, 140mg, 0.285mmol), EDC (60mg, 0.313mmol) and HOBt (42.4mg 0.313mmol) is dissolved among the MC (5mL), and temperature is reduced to 0 ℃.(44.3mL 0.313mmol), stirred 10 minutes, and (56mg 0.342mmol) also at room temperature stirred 12 hours to add L-L-Ala-CONH-benzene then to add TEA.Then, add 1N HCl and, use anhydrous MgSO with the MC extraction
4Drying is filtered and underpressure distillation, through column chromatography (CHCl
3/ MeOH=19/1, v/v) separation obtains title compound (120mg, 69%).
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 6H), 1.43 (d, 3H), 3.06 (d, 1H), 3.17 (d, 1H), 3.94 (s, 2H), 4.23 (q, 4H), 4.60 (m, 1H), 6.15 (d, 1H), 7.07 (t, 1H), 7.27 (m, 1H), 7.45 (d, 2H), 7.58 (m, 6H), 7.97 (d, 2H), 8.60 (s, 1H) embodiment 16:N-phenyl-5-(xenyl-4-yl)-5-oxo-3-carboxyl valeramide (I, R
1=H) preparation
N-phenyl-5-in being dissolved in ethanol (10mL) (xenyl-4-yl)-5-oxo-3,3-diethoxy carbonyl valeramide (VI, R
1=H, 0.36g, 0.74mmol) (1.55mL 1.55mmol), at room temperature stirred 2 hours middle adding 1N NaOH.After ethanol is removed in decompression, add entry and, add 1N HCl then and carry out acidifying with ethyl acetate washing, use ethyl acetate extraction, use anhydrous MgSO
4Drying is filtered and underpressure distillation.The product of gained is dissolved in 1, in the 4-diox (10mL), refluxed 3 hours, under reduced pressure solvent evaporation is removed, use MC/MeOH (19/1v/v) and hexane, obtain title compound (0.17g, 60%) the resistates recrystallization.
1H NMR (300MHz, CDCl
3): δ 2.76 (dd, 1H), 2.90 (dd, 1H), 3.42 (dd, 1H), 3.49 (m, 1H), 3.58 (dd, 1H), 7.10 (t, 1H), 7.26 (m, 1H), 7.45 (m, 5H), 7.65 (m, 5H), 8.07 (d, 2H) embodiment 17:N-cyclopropyl-5-(xenyl-4-yl)-5-oxo-3-carboxyl valeramide (I, R
1=H) preparation
Except using N-cyclopropyl-5-(xenyl-4-yl)-5-oxo-3,3-diethoxy carbonyl valeramide (VI, R
1=H) outside, prepare title compound according to embodiment 16 similar modes.
1H NMR (300MHz, CDCl
3): δ 0.47 (m, 2H), 0.73 (m, 2H), 2.48 (dd, 1H), 2.68 (m, 2H), 3.39 (m, 2H), 3.54 (dd, 1H), 7.40 (m, 3H), 7.61 (d, 2H), 7.69 (d, 2H), 8.02 (d, 2H) embodiment 18:N-(α-Jia Jibianji)-5-(xenyl-4-yl)-5-oxo-3-carboxyl valeramide (I, R
1=H) preparation
Except using N-(α-Jia Jibianji)-5-(xenyl-4-yl)-5-oxo-3,3-diethoxy carbonyl valeramide (VI, R
1=H) outside, prepare title compound according to embodiment 16 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.44 (d, 3H), 2.48 (dd, 1H), 2.68 (m, 2H), 3.39 (m, 2H), 3.54 (dd, 1H), 4.98 (m, 1H), 7.40 (m, 3H), 7.61 (d, 2H), 7.69 (d, 2H), 8.02 (d, 2H) embodiment 19:N-phenyl-5-(4 '-methoxymethyl biphenyl base-4-yl)-5-oxo-3-carboxyl valeramide (I, R
1=OMe) preparation
Except using N-phenyl-5-(xenyl-4-yl)-5-oxo-3,3-diethoxy carbonyl valeramide (VI, R
1=OMe) outside, prepare title compound according to embodiment 16 similar modes.
1H NMR (300MHz, CDCl
3): δ 2.70 (dd, 1H), 2.91 (dd, 1H), 3.40 (dd, 1H), 3.49 (m, 1H), 3.55 (dd, 1H), 3.84 (s, 3H), 6.98 (d, 2H), 7.06 (t, 1H), 7.30 (m, 2H), 7.50 (m, 4H), 7.62 (d, 2H), 8.01 (d, 2H) embodiment 20:N-[1,5-dioxo-5-(4 '-methoxyl biphenyl base-4-yl)-3-carboxyl pentane-1-yl]-4-methylpiperazine (I, R
1=OMe) the preparation of (VI)
Except use N-[1,5-dioxo-5-(4 '-methoxyl biphenyl base-4-yl)-3,3-diethoxy carbonyl pentane-1-yl]-4-methylpiperazine (VI, R
1=OMe) outside, prepare title compound according to embodiment 16 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.20 (s, 3H), 2.45 (s, 1H), 2.65 (m, 4H), 2.82 (dd, 1H), 3.28 (dd, 1H), 3.39 (br, 4H), 3.65 (dd, 1H), 3.84 (s, 3H), 4.13 (m, 1H), 6.98 (d, 2H), 7.54 (d, 2H), 7.62 (d, 2H), 8.00 (d, 2H) embodiment 21:N-phenyl-5-(4 '-bromo biphenyl base-4-yl)-5-oxo-3-carboxyl valeramide I, R
1=OMe) the preparation of (I)
Except using N-phenyl-5-(4 '-bromo biphenyl base-4-yl)-5-oxo-3,3-diethoxy carbonyl valeramide (VI, R
1=Br) outside, prepare title compound according to embodiment 16 similar modes.
1H NMR (300MHz, CDCl
3+ DMSO): δ 2.73 (dd, 1H), 2.89 (dd, 1H), 3.33 (dd, 2H), 3.55 (m, 1H), 7.05 (t, 1H), 7.28 (t, 2H), 7.52 (m, 6H), 7.65 (d, 2H), 8.04 (d, 2H) embodiment 22:N-[1,5-dioxo-5-(4 '-bromo biphenyl base-4-yl)-3-carboxyl pentane-1-yl] piperidines (I, R
1=Br) preparation
Except use N-[1,5-dioxo-5-(4 '-bromo biphenyl base-4-yl)-3,3-diethoxy carbonyl pentane-1-yl] piperidines (VI, R
1=Br) outside, prepare title compound according to embodiment 16 similar modes.
1H NMR (300MHz, CDCl
3): δ 2.85 (Br, 4H), 3.37 (m, 2H); 3.64 (br, 4H), 4.00 (m, 2H); 4.13 (m, 1H), 7.48 (d; 2H), 7.59 (d, 2H); 7.66 (d, 2H), 8.04 (d; 2H) embodiment 23:N-[1,5-dioxo-5-(4 '-bromo biphenyl base-4-yl)-3-carboxyl pentane-1-yl]-4-benzoyl-piperazine (I, R
1=Br) preparation
Except use N-[1,5-dioxo-5-(4 '-bromo biphenyl base-4-yl)-3,3-diethoxy carbonyl pentane-1-yl]-4-benzoyl-piperazine (VI, R
1=Br) outside, prepare title compound according to embodiment 16 similar modes.
1H NMR (300MHz, CDCl
3): δ 2.59 (dd, 1H), 2.86 (br, 4H); 3.10 (dd, 1H), 3.42 (dd, 2H); 3.62 (Br, 4H), 3.80 (m, 1H); 7.40 (m, 4H), 7.42 (d, 2H); 7.62 (m, 4H), 7.86 (d, 1H); 8.02 (d, 2H) embodiment 24:1,5-dioxo-1-(1-phenyl amino formyl radical-1-ethylamino)-5-(4 '-bromo biphenyl base-4-yl)-3-carboxyl pentane (I, R
1=Br) preparation
In being dissolved in ethanol (5mL) 1,5-dioxo-1-(1-phenyl amino formyl radical-1-ethylamino)-5-(4 '-bromo biphenyl base-4-yl)-3,3-diethoxy carbonyl pentane (VI, R
1=Br, 120mg, 0.197mmol) (1mL 1mmol), at room temperature stirred 5 hours middle adding 1N NaOH.After ethanol is removed in decompression, add entry and, add 1N HCl then and carry out acidifying with ethyl acetate washing, use ethyl acetate extraction, use anhydrous MgSO
4Drying is filtered and underpressure distillation.The product of gained is dissolved in 1, in the 4-diox (10mL), refluxed 2 hours, under reduced pressure solvent evaporation is removed, use MC/MeOH (19/1 v/v) and hexane, obtain title compound (64mg, 60%) the resistates recrystallization.
1H NMR (300MHz, CDCl
3): δ 1.43 (d, 3H), 3.06 (d, 1H), 3.17 (d, 1H), 3.40 (dd, 1H), 3.53 (m, 3H), 4.56 (m, 1H), 6.15 (d, 1H), 7.07 (t, 1H), 7.27 (m, 1H), 7.45 (d, 2H), 7.58 (m, 6H), 7.97 (d, 2H), 8.60 (s, 1H) embodiment 25:5-(4 '-chlorodiphenyl-4-yl)-5-oxo-3-ethoxycarbonyl valeric acid tert-butyl ester (VII, R
1=Cl) preparation
(85%, 0.72g 11.0mmol) adds the 5-that is dissolved in ethanol (30mL) (4 '-chlorodiphenyl-4-yl)-5-oxo-3, the 3-diethoxy carbonyl valeric acid tert-butyl ester (IV, R lentamente will to be dissolved in KOH in the ethanol (30mL)
1=Cl, 5.26g, 10.46mmol) in.Reaction mixture was at room temperature stirred 6 hours.Add 1N HCl and carry out acidifying, also use anhydrous MgSO with ethyl acetate extraction
4Drying is filtered and underpressure distillation.Resultant is dissolved in 1, in the 4-diox (10mL), refluxed 3 hours, under reduced pressure solvent evaporation is removed, obtain title compound (3.51g, 78%).
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 3H), 1.45 (s, 9H), 2.66 (ddd, 2H), 3.24 (dd, 1H), 3.45 (m, 1H), 3.53 (dd, 1H), 4.16 (q, 2H), 7.42 (d, 2H), 7.55 (d, 2H), 7.65 (m, 2H), 8.03 (d, 2H) embodiment 26:5-(xenyl-4-the yl)-5-oxo-3-ethoxycarbonyl valeric acid tert-butyl ester (VII, R
1=H) preparation
Prepare title compound according to embodiment 25 similar modes, except using 5-(xenyl-4-yl)-5-oxo-3, the 3-diethoxy carbonyl valeric acid tert-butyl ester (IV, R
1=H).
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 3H), 1.45 (s, 9H), 2.66 (ddd, 2H), 3.24 (dd, 1H), 3.45 (m, 1H), 3.53 (dd, 1H), 4.16 (q, 2H), 7.45 (m, 3H), 7.61 (d, 2H), 7.69 (d, 2H), 8.04 (d, 2H) embodiment 27:5-(4 '-bromo biphenyl base-4-yl)-5-oxo-3-ethoxycarbonyl valeric acid tert-butyl ester (VII, R
1=Br) preparation
Except using 5-(4 '-bromo biphenyl base-4-yl)-5-oxo-3, the 3-diethoxy carbonyl valeric acid tert-butyl ester (IV, R
1=Br) outside, prepare title compound according to embodiment 25 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 3H), 1.45 (s, 9H), 2.66 (ddd, 2H), 3.24 (dd, 1H), 3.45 (m, 1H), 3.53 (dd, 1H), 4.16 (q, 2H), 7.48 (d, 2H), 7.60 (d, 2H), 7.65 (d, 2H), 8.04 (d, 2H) embodiment 28:5-(4 '-chlorodiphenyl-4-yl)-5-oxo-3-ethoxycarbonyl valeric acid (VIII, R
1=Cl) preparation
5-in being dispersed in MC (50mL) (4 '-chlorodiphenyl-4-yl)-the 5-oxo-3-ethoxycarbonyl valeric acid tert-butyl ester (VII, R
1=Cl, 3.51g, 8.14mmol) the middle TFA (7.4mL) that adds at room temperature stirred 24 hours.MC is removed in decompression, adds ethyl acetate (20mL).Add 1N NaOH then lentamente and stirred the organic layer of water extracting and separating 10 minutes.Collect the aqueous solution then, handle and use ethyl acetate extraction with 1N HCl (30mL).Use anhydrous MgSO
4Dry isolating organic layer filters and underpressure distillation.Use CHCl
3With hexane with the resistates recrystallization, obtain title compound (2.7g, 88%)
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 3H), 2.84 (ddd, 2H), 3.30 (dd, 1H), 3.48 (m, 1H), 3.57 (dd, 1H), 4.18 (q, 2H), 7.42 (d, 2H), 7.55 (d, 2H), 7.65 (m, 2H), 8.03 (d, 2H) embodiment 29:5-(xenyl-4-yl)-5-oxo-3-ethoxycarbonyl valeric acid (VIII, R
1=H) preparation
Except using 5-(xenyl-4-the yl)-5-oxo-3-ethoxycarbonyl valeric acid tert-butyl ester (VII, R
1=H) outside, prepare title compound according to embodiment 28 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 3H), 2.84 (ddd, 2H), 3.30 (dd, 1H), 3.48 (m, 1H), 3.57 (dd, 1H), 4.18 (q, 2H), 7.45 (m, 3H), 7.61 (d, 2H), 7.69 (d, 2H), 8.04 (d, 2H) embodiment 30:5-(4 '-bromo biphenyl base-4-yl)-5-oxo-3-ethoxycarbonyl valeric acid (VIII, R
1=Br) preparation
Except using 5-(4 '-bromo biphenyl base-4-yl)-5-oxo-3-ethoxycarbonyl valeric acid tert-butyl ester (VII, R
1=Br) outside, prepare title compound according to embodiment 28 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 3H), 2.84 (ddd, 2H), 3.30 (dd, 1H), 3.48 (m, 1H), 3.57 (dd, 1H), 4.18 (q, 2H), 7.48 (d, 2H), 7.60 (d, 2H), 7.65 (d, 2H), 8.04 (d, 2H) embodiment 31:N-(3-cyano-phenyl)-5-(xenyl-4-yl)-5-oxo-3-ethoxycarbonyl valeramide (IX, R
1=H) preparation
With 5-(xenyl-4-yl)-5-oxo-3-ethoxycarbonyl valeric acid (VIII, R
1=H, 50mg 0.147mmol) is dissolved in THF (3mL), and temperature is reduced to 0 ℃.Add lentamente N-methylmorpholine (35mL, 0.323mmol) and Vinyl chloroformate (16mL 0.162mmol), at room temperature stirred 30 minutes.Add the 3-aminobenzonitrile that is dissolved in THF (1mL) then, stirred 3 hours 30 minutes, filter and underpressure distillation.After the chloroform dilution, use 1N HCl, 10%NaHCO successively
3And water washing, the anhydrous MgSO of gains
4Drying is filtered and underpressure distillation, obtains title compound (55.5mg, 86%)
1H NMR (300MHz, CDCl
3): δ 1.22 (t, 3H), 2.74 (dd, 1H); 3.01 (dd, 1H), 3.54 (m; 3H), 4.22 (q, 2H); 7.42 (m, 4H), 7.65 (m; 5H), 8.01 (m, 3H); (8.20 s, 1H) embodiment 32:N-(3-acetylphenyl)-5-[(xenyl-4-yl)]-5-oxo-3-ethoxycarbonyl valeramide (IX, R
1=H) the preparation of (IX)
Except using 5-(xenyl-4-yl)-5-oxo-3-ethoxycarbonyl valeric acid (VIII, R
1=H) and the 3-aminoacetophenone outside, prepare title compound according to embodiment 31 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.23 (t, 3H), 2.59 (s, 3H); 2.80 (dd, 1H), 3.00 (dd, 1H); 3.56 (m, 3H), 4.20 (q, 2H); 7.40 (m, 4H), 7.60 (m; 5H), 8.03 (m, 3H); (8.20 s, 1H) embodiment 33:N-(3-acetylphenyl)-5-[(4 '-chlorodiphenyl-4-yl)]-5-oxo-3-ethoxycarbonyl valeramide (IX, R
1=Cl) preparation
Except using 5-[(4 '-chlorodiphenyl-4-yl)]-5-oxo-3-ethoxycarbonyl valeric acid (VIII, R
1=Cl) and the 3-aminoacetophenone outside, prepare title compound according to embodiment 31 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 3H), 2.60 (s, 3H), 2.80 (dd, 1H), 2.94 (dd, 1H), 3.56 (m, 3H), 4.20 (q, 2H), 7.44 (m, 3H), 7.54 (d, 2H), 7.66 (m, 3H), 7.82 (s, 1H), (8.04 m, 3H) embodiment 34:N-(2-chloro-phenyl-)-5-[(xenyl-4-yl)]-5-oxo-3-ethoxycarbonyl valeramide (IX, R
1=H) preparation
Except using 5-[(xenyl-4-yl)]-5-oxo-3-ethoxycarbonyl valeric acid (VIII, R
1=H) and the 2-chloroaniline outside, prepare title compound according to embodiment 31 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.24 (t, 3H), 2.88 (dd, 1H), 3.03 (dd, 1H), 3.48～3.66 (m, 3H), 4.24 (q, 2H), 7.05 (t, 1H), 7.43 (m, 4H), 7.62 (d, 2H), 7.70 (d, 2H), 7.90 (s, 1H), 8.06 (d, 2H), 8.30 (s, 1H) embodiment 35:N-(3-chloro-phenyl-)-5-[(xenyl-4-yls)]-5-oxo-3-ethoxycarbonyl valeramide (IX, R
1=H) preparation
Except using 5-[(xenyl-4-yl)]-5-oxo-3-ethoxycarbonyl valeric acid (VIII, R
1=H) and the 3-chloroaniline outside, prepare title compound according to embodiment 31 similar modes.
1H NMR (300MHz, MeOH-d
4): δ 1.24 (t, 3H), 2.88 (dd, 1H), 3.03 (dd, 1H), 3.48～3.66 (m, 3H), 4.24 (q, 2H), 7.23 (d, 2H), 7.42 (m, 3H), 7.48 (d, 2H), 7.62 (d, 2H), 7.69 (d, 2H), (8.04 d, 2H) embodiment 36:N-(4-chloro-phenyl-)-5-[(xenyl-4-yl)]-5-oxo-3-ethoxycarbonyl valeramide (IX, R
1=H) the preparation of (IX)
Except using 5-[(xenyl-4-yl)]-5-oxo-3-ethoxycarbonyl valeric acid (VIII, R
1=H) and the 4-chloroaniline outside, prepare title compound according to embodiment 31 similar modes.
1H NMR (300MHz, DMSO-d
6): δ 1.24 (t, 3H), 2.76 (dd, 1H); 2.90 (dd, 1H), 3.53 (m, 3H); 4.20 (q, 2H), 7.06 (d, 2H); 7.21 (t, 1H), 7.44 (m, 4H); 7.62 (d, 2H), 7.68 (d, 2H); 8.04 (d, 2H) embodiment 37:N-[3-(N, N-diethylamino formyl radical) phenyl]-5-(4 '-chlorodiphenyl-4-yl)-5-oxo-3-ethoxycarbonyl valeramide (IX, R
1=Cl) the preparation of (IX)
Except using 5-[(4 '-chlorodiphenyl-4-yl)]-5-oxo-3-ethoxycarbonyl valeric acid (VIII, R
1=Cl) and outside 3-(N, the N-diethylamino formyl radical) aniline, prepare title compound according to embodiment 31 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.11 (t, 3H), 1.23 (t, 6H), 2.73 (dd; 1H), 2.90 (dd, 1H), 3.26 (br, 2H); 3.52 (m, 5H), 4.22 (q, 2H), 7.08 (d; 1H), 7.32 (t, 1H), 7.44 (d, 2H); 7.54 (m, 3H), 7.65 (d, 2H), 7.80 (s; 1H), 8.03 (d, 2H) embodiment 38:N-[3-(N-phenyl amino formyl radical) phenyl]-5-[(4 '-chlorodiphenyl-4-yl)]-5-oxo-3-ethoxycarbonyl valeramide (IX, R
1=Cl) preparation
Except using 5-[(4 '-chlorodiphenyl-4-yl)]-5-oxo-3-ethoxycarbonyl valeric acid (VIII, R
1=Cl) and outside 3-(the N-phenyl amino formyl radical) aniline, prepare title compound according to embodiment 31 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.17 (t, 3H), 2.85 (dd, 1H), 3.10 (dd; 1H), 3.56 (d, 2H), 3.65 (m, 1H); 4.15 (q, 2H), 7.15 (t, 1H), 7.34 (m; 4H), 7.50 (d, 3H), 7.61 (d, 3H); 7.75 (d, 3H), 8.00 (d, 2H), 8.35 (s; 1H), 8.50 (s, 1H) embodiment 39:(L)-1,5-dioxo-1-(1-phenyl amino formyl radical-1-ethylamino)-5-(xenyl-4-yl)-3-ethoxycarbonyl pentane (IX, R
1=H) preparation
With 5-(xenyl-4-yl)-5-oxo-3-ethoxycarbonyl valeric acid (VIII, R
1=H, 100mg 0.29mmol) is dissolved in THF (5mL), and temperature is reduced to 0 ℃.Add N-methylmorpholine (70mL, 0.65mmol) and Vinyl chloroformate (31mL 0.32mmol), stirred 30 minutes.Add then the L-L-Ala-CONH-benzene be dissolved among the THF (1mL) (referring to Kruse, J.Org.Chem. such as C.H., 50:2792,1985; Fink, Bioorg.Med.Chem. such as C.A., Lett., 9:195-200,1999), stirred 3 hours 30 minutes, filter and underpressure distillation.After the chloroform dilution, use 1N HCl, 10%NaHCO successively
3And water washing, the anhydrous MgSO of gains
4Drying is filtered and underpressure distillation, obtains title compound (105mg, 73%).
1H NMR (300MHz, CDCl
3): δ 1.20 (dt, 3H), 1.47 (dd, 3H), 2.55 (ddd; 1H), 2.75 (ddd, 1H), 3.48 (m, 3H); 4.14 (m, 2H), 4.63 (m, 1H), 6.15 (dd; 1H), 7.07 (t, 1H), 7.27 (m, 1H); 7.45 (m, 3H), 7.58 (m, 6H), 7.97 (t; 2H), 8.40～8.60 (d, 1H) embodiment 40:(D)-1,5-dioxo-1-(1-phenyl amino formyl radical-1-ethylamino)-5-(xenyl-4-yl)-3-ethoxycarbonyl pentane (IX, R
1=H) preparation
Except using 5-(xenyl-4-yl)-5-oxo-3-ethoxycarbonyl valeric acid and D-L-Ala-CONH-benzene, prepare title compound (105mg, 73%) according to embodiment 39 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.20 (dt, 3H), 1.47 (dd, 3H), 2.55 (ddd; 1H), 2.75 (ddd, 1H), 3.48 (m, 3H); 4.14 (m, 2H), 4.63 (m, 1H), 6.15 (dd; 1H), 7.07 (t, 1H), 7.27 (m, 1H); 7.45 (m, 3H), 7.58 (m, 6H), 7.97 (t; 2H), 8.40～8.60 (d, 1H) embodiment 41:1,5-dioxo-1-[1-(Chloro-O-Phenyl) formamyl-1-ethylamino]-5-(xenyl-4-yl)-3-ethoxycarbonyl pentane (IX, R
1=H) the preparation of (IX)
Except using 5-(xenyl-4-yl)-5-oxo-3-ethoxycarbonyl valeric acid (VIII, R
1=H) and the L-L-Ala-the adjacent chlorobenzene of CONH-outside, prepare title compound according to embodiment 39 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.20 (dt, 3H), 1.47 (dd, 3H), 2.55 (ddd, 1H); 2.75 (ddd, 1H), 3.48 (m, 3H), 4.14 (m, 2H); 4.63 (m, 1H), 6.15 (dd, 1H), 7.08 (t; 1H), 7.29 (t, 2H), 7.45 (m, 3H); 7.58 (m, 4H), 7.70 (d, 2H), 7.97 (t; 2H), 8.60 (d, 1H) embodiment 42:1,5-dioxo-1-[1-(chloro-phenyl-) formamyl-1-ethylamino]-5-(xenyl-4-yl)-3-ethoxycarbonyl pentane (IX, R
1=H) the preparation of (IX)
Except using 5-(xenyl-4-yl)-5-oxo-3-ethoxycarbonyl valeric acid (VIII, R
1=H) and between L-L-Ala-CONH-outside the chlorobenzene, prepare title compound according to embodiment 39 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.20 (dt, 3H), 1.47 (dd, 3H), 2.55 (ddd, 1H); 2.75 (ddd, 1H), 3.48 (m, 3H), 4.14 (m, 2H); 4.63 (m, 1H), 6.15 (dd, 1H), 7.07 (t; 1H), 7.30 (t, 2H), 7.45 (m, 3H); 7.58 (m, 4H), 7.68 (d, 2H), 7.97 (t; 2H), 8.60 (d, 1H) embodiment 43:1,5-dioxo-1-[1-(rubigan) formamyl-1-ethylamino]-5-(xenyl-4-yl)-3-ethoxycarbonyl pentane (IX, R
1=H) the preparation of (IX)
Except using 5-(xenyl-4-yl)-5-oxo-3-ethoxycarbonyl valeric acid (VIII, R
1=H) and L-L-Ala-CONH-to outside the chlorobenzene, prepare title compound according to embodiment 39 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.20 (dt, 3H), 1.47 (dd, 3H), 2.55 (ddd, 1H); 2.75 (ddd, 1H), 3.48 (m, 3H), 4.14 (m, 2H); 4.63 (m, 1H), 6.15 (dd, 1H), 7.08 (t; 1H), 7.29 (t, 2H), 7.45 (m, 3H); 7.58 (m, 4H), 7.70 (d, 2H), 7.97 (t; 2H), 8.60 (d, 1H) embodiment 44:N-{1,5-dioxo-5-[(xenyl-4-yl)]-3-ethoxycarbonyl pentane-1-yl }-2-(N-phenyl amino formyl radical) tetramethyleneimine (IX, R
1=H) preparation
Except using 5-(xenyl-4-yl)-5-oxo-3-ethoxycarbonyl valeric acid (VIII, R
1=H) and L-proline(Pro)-CONH-benzene outside, prepare title compound according to embodiment 39 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.17 (t, 3H), 1.90 (m, 1H); 2.06 (m, 1H), 2.58 (br, 2H); 2.70～3.00 (m, 2H), 3.50 (m, 2H); 3.57 (m, 2H), 3.70 (m, 1H); 4.15 (m, 2H), 4.78 (m; 1H), 7.05 (t, 1H); 7.27 (m, 2H), 7.45 (m; 3H), 7.58 (m, 5H); 8.03 (d, 2H), 9.2～9.4 (d; 1H) embodiment 45:1,5-dioxo-1-[1-phenyl amino formyl radical-2-phenyl-1-ethylamino]-5-(xenyl-4-yl)-3-ethoxycarbonyl pentane (IX, R
1=H) preparation
Except using 5-(xenyl-4-yl)-5-oxo-3-ethoxycarbonyl valeric acid (VIII, R
1=H) and L-phenylalanine-CONH-benzene outside, prepare title compound according to embodiment 39 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.17 (dt, 3H), 2.38～2.55 (ddd, 1H), 2.70 (ddd, 1H), 3.20 (m, 2H), 3.45 (m, 3H), 4.13 (dq, 2H), 4.75～4.90 (dq, 1H), 6.10～6.30 (dd, 1H), 7.08 (t, 1H), 7.24 (m, 6H), 7.42 (m, 4H), 7.63 (m, 5H), 8.00 (d, 2H), 7.90 ﹠amp; (8.30 d, 1H) embodiment 46:N-{1,5-dioxo-5-[(4 '-chlorodiphenyl-4-yl)]-3-ethoxycarbonyl pentane-1-yl }-2-(N-phenyl amino formyl radical) tetramethyleneimine (IX, R
1=H) preparation
Except using 5-(4 '-chlorodiphenyl-4-yl)-5-oxo-3-ethoxycarbonyl valeric acid (VIII, R
1=Cl) and L-proline(Pro)-CONH-benzene outside, prepare title compound according to embodiment 39 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.20 (t, 3H), 1.90 (m, 1H); 2.06 (m, 1H), 2.58 (br, 2H); 2.70～3.00 (m, 2H), 3.50 (m, 2H); 3.57 (m, 2H), 3.70 (m, 1H); 4.15 (m, 2H), 4.78 (m; 1H), 7.05 (t, 1H); 7.27 (m, 2H), 7.45 (m; 2H), 7.58 (m, 5H); 8.03 (d, 2H), 9.2～9.4 (d; 1H) embodiment 47:1,5-dioxo-1-[1-phenyl amino formyl radical-2-phenyl-1-ethylamino]-5-(4 '-chlorodiphenyl-4-yl)-3-ethoxycarbonyl pentane (IX, R
1=Cl) preparation
Except using 5-(4 '-chlorodiphenyl-4-yl)-5-oxo-3-ethoxycarbonyl valeric acid (VIII, R
1=Cl) and L-phenylalanine-CONH-benzene outside, prepare title compound according to embodiment 39 similar modes.
1H NMR (300MHz, CDCl
3): δ 1.17 (dt, 3H), 2.38～2.55 (ddd, 1H), 2.70 (ddd, 1H), 3.20 (m, 2H), 3.45 (m, 3H), 4.13 (dq, 2H), 4.75～4.90 (dq, 1H), 6.10～6.30 (dd, 1H), 7.07 (t, 1H), 7.26 (m, 6H), 7.45 (m, 4H), 7.56 (m, 5H), 7.99 (d, 2H), 7.90 ﹠amp; (8.30 d, 1H) embodiment 48:N-(3-cyano-phenyl)-5-[(xenyl-4-yl)]-5-oxo-3-carboxyl valeramide (I, R
1=H) preparation
N-in being dissolved in ethanol (2mL) (3-cyano-phenyl)-5-[(xenyl-4-yl)]-5-oxo-3-ethoxycarbonyl valeramide (IX, R
1=H, 11.8mg, 0.0268mmol) the middle 1NNaOH (0.5mL) that adds at room temperature stirred 1 hour 30 minutes, added entry and with the ethyl acetate washing, added 1N HCl with the gains acidifying, with the MC extraction, used anhydrous MgSO
4Dry.Then gains are filtered and underpressure distillation, use CHCl
3/ MeOH (19/1 v/v) and hexane recrystallization obtain title compound (10.4mg, 94%).
1H NMR (300MHz, CDCl
3): δ 2.74 (dd, 1H), 3.01 (dd, 3H), 3.54 (m; 3H), 7.42 (m, 4H), 7.65 (m, 5H); 8.01 (m, 3H), 8.20 (s, 1H) embodiment 49:N-(3-acetylphenyl)-5-[(xenyl-4-yls)]-5-oxo-3-carboxyl valeramide (I, R
1=H) preparation
Except using N-(3-acetylphenyl)-5-(xenyl-4-yl)-5-oxo-3-ethoxycarbonyl valeramide (IX, R
1=H) outside, prepare title compound according to embodiment 48 similar modes.
1H NMR (300MHz, CDCl
3): δ 2.59 (s, 3H), 2.80 (dd, 1H), 3.00 (dd, 3H); 3.56 (m, 3H), 7.40 (m, 4H), 7.60 (m, 5H); 8.03 (m, 3H), 8.20 (s, 1H) embodiment 50:N-(3-acetylphenyl)-5-[(4 '-chlorodiphenyl-4-yls)]-5-oxo-3-carboxyl valeramide (I, R
1=H) preparation
Except using N-(3-acetylphenyl)-5-(4 '-chlorodiphenyl-4-yl)-5-oxo-3-ethoxycarbonyl valeramide (IX, R
1=H) outside, prepare title compound according to embodiment 48 similar modes.
1H NMR (300MHz, CDCl
3): δ 2.60 (s, 3H), 2.80 (dd, 1H), 2.94 (dd, 1H), 3.56 (m, 3H), 7.44 (m, 3H), 7.54 (d, 2H), 7.66 (m, 3H), 7.82 (s, 1H), (8.04 m, 3H) embodiment 51:N-(3-chloro-phenyl-)-5-[(xenyl-4-yl)]-5-oxo-3-carboxyl valeramide (I, R
1=H) preparation
Except using N-(3-chloro-phenyl-)-5-(xenyl-4-yl)-5-oxo-3-ethoxycarbonyl valeramide (IX, R
1=H) outside, prepare title compound according to embodiment 48 similar modes.
1H NMR (300MHz, MeOH-d4): δ 2.88 (dd, 1H), 3.03 (dd; 1H), 3.48～3.66 (m, 3H), 7.23 (d; 2H), 7.42 (m, 3H), 7.48 (d; 2H), 7.62 (d, 2H); 7.69 (d, 2H), 8.04 (d; 2H) embodiment 52:1,5-dioxo-1-(1-phenyl amino formyl radical-1-ethylamino)-5-(xenyl-4-yl)-3-carboxyl pentane (I, R
1=H) preparation
In being dissolved in ethanol (5mL) 1,5-dioxo-1-(1-phenyl amino formyl radical-1-ethylamino)-5-(xenyl-4-yl)-3-ethoxycarbonyl pentane (IX, R
1=H, 105mg, (1mL 1mmol), at room temperature stirred 90 minutes, added entry and washed with ethyl acetate to add 1N NaOH in 0.215mmol).Add 1N HCl then with the gains acidifying,, use anhydrous MgSO with the MC extraction
4Drying is filtered and underpressure distillation, uses CHCl
3/ MeOH (19/1, v/v) and hexane with the resistates recrystallization, obtain title compound (88mg, 89%).
1H NMR (300MHz, CDCl
3): δ 1.47 (dd, 3H), 2.55 (ddd, 1H), 2.75 (ddd; 1H), 3.48 (m, 3H), 4.63 (m, 1H); 6.15 (dd, 1H), 7.07 (t, 1H), 7.27 (m; 1H), 7.45 (m, 3H), 7.58 (m, 6H); 7.97 (t, 2H), 8.40～8.60 (d, 1H) embodiment 53:N-{1,5-dioxo-5-[(4 '-chlorodiphenyl-4-yl)]-3-carboxyl pentane-1-yl }-3-(N-phenyl amino formyl radical)-1; 2,3,4-tetrahydroisoquinoline (I, R
1=Cl) preparation
Except using N-{1,5-dioxo-5-[(4 '-chlorodiphenyl-4-yl)]-3-ethoxycarbonyl pentane-1-yl }-3-(N-phenyl amino formyl radical)-1,2,3,4-tetrahydroisoquinoline (IX, R
1=Cl) outside, prepare title compound according to embodiment 52 similar modes.
1H NMR (300MHz, CDCl
3): δ 2.70～3.20 (m, 2H) 3.38～3.57 (m, 4H), 4.11 (m, 1H), 4.66 (m, 2H), 5.33 (d, 1H), 6.92 (t, 1H), 7.15 (m, 4H), 7.45 (m, 7H), 7.93 (d, 2H), 8.66 (m, 1H) embodiment 54: to the vitro inhibition of gelatin enzyme A (MMP-2)
(fluorescence intensity of ayapanin-4-ethanoyl-Pro-Leu-Gly) is finished by measuring fluorescent material in this test; described fluorescent material is by the synthetic peptide substrates (ayapanin-4-ethanoyl-Pro-Leu-Gly-Leu-β-(2,4-dinitrophenyl amino) Ala-Ala-Arg-NH of fluorescence
2(Sigma Chem.Co., U.S.A.)) obtains by gelatin A (Boehringer Manneheim cat#1782916 is from human fiber's sarcoma cell) cracking.
Adopting the enzymic catalytic reaction of the synthetic substrate of fluorescence is following carrying out: place test compound in 96 hole flat boards, (25mM Tris-HCl, pH 7.5,0.1M NaCl, 0.01%Brij-35,5mM CaCl for TNBC buffered soln
2), (ultimate density in the hole is 4.17nM to gelatin enzyme A, before enzymic catalytic reaction, just down activate 30 minutes with the APMA (acetate aminophenyl mercury) of 1mM at 37 ℃) and substrate (be that fluorescence synthesizes peptide, ultimate density in the hole is 9.15 μ M), reacted 30 minutes down at 37 ℃ then, measure the exciting light of 328nm and the radiative fluorescence intensity under the 393nm with spectrofluorometer (Fmax (molecular device)).Calculate inhibiting rate (%) by following formula:
Wherein
A represents and the preceding fluorescence intensity of inhibitor reaction;
B represents and the reacted fluorescence intensity of inhibitor;
C is illustrated in the preceding fluorescence intensity of reaction that does not have inhibitor to exist; With
D is illustrated in the reacted fluorescence intensity that does not have inhibitor to exist.Embodiment 55: to the vitro inhibition of gelatinase B (MMP-9)
Except gelatinase B (the Boehringer Manneheim cat#1758896 that uses different concns (ultimate density in the hole is 2.715nM), come from human blood) and the substrate of different concns (be the synthetic peptide of fluorescence, ultimate density in the hole is 4.575 μ M) outside, according to measuring extracorporeal inhibiting rate to gelatinase B (MMP-9) with embodiment 54 similar modes.Embodiment 56: to the vitro inhibition of collagenase (MMP-1)
Except use in the hole ultimate density as the collagenase of 7.25nM (Angiolab.Co., Ltd) outside, according to measuring extracorporeal inhibiting rate to collagenase (MMP-1) with embodiment 54 similar modes.
Clearly describe and confirm as above, the invention provides and suppress the active new biphenyl butyric acid derivative of MMP, its isomer and pharmacologically acceptable salt, and the preparation method of these compounds.Because biphenyl butyric acid derivative of the present invention is in the external activity that optionally suppresses MMP, therefore in fact contains described biphenyl butyric acid derivative and can be used for treating and prevent as the MMP inhibitor of activeconstituents and express or the caused disease of excessive activation by crossing of MMP.
Although the present invention discloses preferred embodiment for illustrative purposes, those skilled in the art should be understood that it is possible making various modifications, interpolation and replacement under the prerequisite of the scope and spirit that do not deviate from the claims explanation.
Claims (8)
1. compound, its isomer and the pharmacologically acceptable salt of the expression of a kind as following general formula (I):
Wherein, R
1Be hydrogen, alkyl, cycloalkyl, halogen, nitro, cyano group ,-OCF
3,-OCH
2F,
-OR
4,-SR
4,-S (O) R
4Or-S (O)
2, R wherein
4And R
4 aCan be identical or different and be alkyl, aryl, aralkyl, heteroaryl or cycloalkyl;
R
2And R
3Can be identical or different, and be hydrogen, alkyl, aryl, aralkyl, heteroaryl or cycloalkyl; With
N is 1 or 2.
2. compound as claimed in claim 1, its isomer and pharmacologically acceptable salt, wherein R
2And R
3Form C with carbon, nitrogen, oxygen or sulphur
5-6Ring comprises ring as follows:
Wherein
R
8Be hydrogen, alkyl, aryl, aralkyl, heteroaryl or cycloalkyl; With
X is O or S.
3. compound as claimed in claim 1, its isomer and pharmacologically acceptable salt, wherein R
2Also comprise the substituting group shown in the following structural formula:
Wherein
R
5Be hydrogen, alkyl, aryl, aralkyl, heteroaryl, hydroxyalkyl, alkoxyalkyl, alkylthio alkyl, arylthio alkyl, alkyl sulfurous base alkyl, alkyl sulphonyl alkyl, aryl sulfurous base alkyl, aryl sulfonyl alkyl or cycloalkyl; With
R
6And R
7Can be identical or different, and be hydrogen, alkyl, aryl, aralkyl, heteroaryl or cycloalkyl.
4. compound as claimed in claim 3, its isomer and pharmacologically acceptable salt, wherein R
2With defined identical in the claim 3, its precondition is R
3Be hydrogen; If R
3Not hydrogen, then R
3And R
5Form C with carbon, nitrogen, oxygen or sulphur
5-6Ring, wherein
Part comprises following groups:
Wherein
R
6And R
7Same as described above;
R
9Be hydrogen, hydroxyl, alkoxyl group, aryloxy, thiol or alkyl sulfenyl;
R
10Be oxo, oxyamine or hydrazone;
R
11And R
12Be hydrogen or C
1-6Low alkyl group; With
Y is CH
2, O or S.
5. as claim 3 or 4 described compounds, its isomer and pharmacologically acceptable salt, wherein R
6And R
7Form ring compound with carbon, nitrogen, oxygen or sulphur, comprise ring as follows:
Wherein
R
8Same as described above with X.
6. as each described compound, its isomer and pharmacologically acceptable salt among the claim 1-5, it has the inhibition activity to matrix metalloproteinase.
7. the preparation method of compound shown in the general formula (I) comprises:
(i) compound (II) and compound (III) reaction are obtained tertiary butyl ester compound (IV);
The compound (V) that (ii) tertiary butyl ester compound (IV) deprotection is not contained the butyl ester base;
(iii) compound (V) and amine compound condensation are obtained containing the compound (VI) of diethyl-ester group; With
(iv) the diethyl-ester group with compound (VI) is hydrolyzed to carboxyl, decarboxylation then, to prepare compound (I):
Wherein
R
1, R
2And R
3Identical with the definition in claim 1.
8. the preparation method of compound shown in the general formula (I) comprises:
(i) compound (II) and compound (III) reaction are obtained tertiary butyl ester compound (IV);
(ii) an ethoxycarbonyl with tertiary butyl ester compound (IV) is hydrolyzed to carboxyl, and decarboxylation then obtains compound (VII);
The compound (VIII) that (iii) compound (VII) deprotection is not contained the butyl ester base;
(iv) compound (VIII) and amine compound condensation are obtained containing the compound (IX) of ethoxycarbonyl; With
(v) the ethoxycarbonyl with compound (IX) is hydrolyzed to carboxyl, to prepare compound (I):
Wherein
R
1, R
2And R
3Identical with the definition in claim 1.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2000-0021834A KR100405913B1 (en) | 2000-04-25 | 2000-04-25 | Biphenyl Butyric Acid Derivative as a Matrix Metalloproteinase Inhibitor |
| KR10-2000-0021835A KR100405914B1 (en) | 2000-04-25 | 2000-04-25 | Biphenyl Butyric Acid Derivative as a Matrix Metalloproteinase Inhibitor |
| KR21834/2000 | 2000-04-25 | ||
| KR21835/2000 | 2000-04-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1366518A true CN1366518A (en) | 2002-08-28 |
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ID=26637911
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN01801067A Pending CN1366518A (en) | 2000-04-25 | 2001-04-24 | Biphenyl butyric acid derivative as matrix metalloproteinase inhibitor |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1189882A1 (en) |
| JP (1) | JP2003531894A (en) |
| CN (1) | CN1366518A (en) |
| AU (1) | AU5275901A (en) |
| CA (1) | CA2377629A1 (en) |
| WO (1) | WO2001083445A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104955806A (en) * | 2013-02-06 | 2015-09-30 | 默克专利股份公司 | Substituted carboxylic acid derivatives as aggrecanase inhibitors for the treatment of osteoarthritis |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100405914B1 (en) * | 2000-04-25 | 2003-11-15 | 삼성전자주식회사 | Biphenyl Butyric Acid Derivative as a Matrix Metalloproteinase Inhibitor |
| KR100405913B1 (en) * | 2000-04-25 | 2003-11-14 | 삼성전자주식회사 | Biphenyl Butyric Acid Derivative as a Matrix Metalloproteinase Inhibitor |
| WO2006095922A1 (en) * | 2005-03-10 | 2006-09-14 | Kyoto Pharmaceutical Industries, Ltd. | Tetrahydroisoquinoline compound and medicinal use thereof |
| MY144590A (en) | 2005-07-11 | 2011-10-14 | Wyeth Corp | Glutamate aggrecanase inhibitors |
| TW200740729A (en) | 2005-10-13 | 2007-11-01 | Wyeth Corp | Methods for preparing glutamic acid derivatives |
| EP2089012A2 (en) * | 2006-11-09 | 2009-08-19 | Wyeth | Polymorphs of n²-(1,1'- biphenyl- 4-ylcarbonyl)-n¹-[2-(4-fluorophenyl)-1,1-dimethylethyl]-l-alpha -glutamine |
| CN101353320A (en) * | 2007-07-24 | 2009-01-28 | 中国人民解放军军事医学科学院毒物药物研究所 | Matrix metalloprotease inhibitors, medicinal composition containing the same, preparation and use thereof |
| EP3102576B8 (en) | 2014-02-03 | 2019-06-19 | Vitae Pharmaceuticals, LLC | Dihydropyrrolopyridine inhibitors of ror-gamma |
| PT3207043T (en) | 2014-10-14 | 2019-03-25 | Vitae Pharmaceuticals Llc | Dihydropyrrolopyridine inhibitors of ror-gamma |
| US9845308B2 (en) | 2014-11-05 | 2017-12-19 | Vitae Pharmaceuticals, Inc. | Isoindoline inhibitors of ROR-gamma |
| US9663515B2 (en) | 2014-11-05 | 2017-05-30 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| US10301261B2 (en) | 2015-08-05 | 2019-05-28 | Vitae Pharmaceuticals, Llc | Substituted indoles as modulators of ROR-gamma |
| MA53943A (en) | 2015-11-20 | 2021-08-25 | Vitae Pharmaceuticals Llc | ROR-GAMMA MODULATORS |
| TW202220968A (en) | 2016-01-29 | 2022-06-01 | 美商維它藥物有限責任公司 | Modulators of ror-gamma |
| US9481674B1 (en) | 2016-06-10 | 2016-11-01 | Vitae Pharmaceuticals, Inc. | Dihydropyrrolopyridine inhibitors of ROR-gamma |
| WO2019018975A1 (en) | 2017-07-24 | 2019-01-31 | Vitae Pharmaceuticals, Inc. | Inhibitors of ror gamma |
| AU2018307919B2 (en) | 2017-07-24 | 2022-12-01 | Vitae Pharmaceuticals, Llc | Inhibitors of RORϒ |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUT71401A (en) * | 1992-05-07 | 1995-11-28 | Merck & Co Inc | New quinazolines as inhibitors of hiv reverse transcriptase |
| US5536727A (en) * | 1992-05-20 | 1996-07-16 | Merck & Co., Inc. | 17-Ethers and thioethers of 4-aza-steroids |
| AU4159197A (en) * | 1996-09-04 | 1998-03-26 | Warner-Lambert Company | Biphenyl butyric acids and their derivatives as inhibitors of matrix metalloproteinases |
| AU9663798A (en) * | 1997-10-06 | 1999-04-27 | Warner-Lambert Company | Heteroaryl butyric acids and their derivatives as inhibitors of matrix metalloproteinases |
-
2001
- 2001-04-24 CA CA002377629A patent/CA2377629A1/en not_active Abandoned
- 2001-04-24 JP JP2001580874A patent/JP2003531894A/en not_active Ceased
- 2001-04-24 WO PCT/KR2001/000687 patent/WO2001083445A1/en not_active Application Discontinuation
- 2001-04-24 AU AU52759/01A patent/AU5275901A/en not_active Abandoned
- 2001-04-24 EP EP01926225A patent/EP1189882A1/en not_active Withdrawn
- 2001-04-24 CN CN01801067A patent/CN1366518A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104955806A (en) * | 2013-02-06 | 2015-09-30 | 默克专利股份公司 | Substituted carboxylic acid derivatives as aggrecanase inhibitors for the treatment of osteoarthritis |
| CN104955806B (en) * | 2013-02-06 | 2018-09-14 | 默克专利股份公司 | The substituted carboxylic acid derivative as polyprotein xylanase inhibitor for treating osteoarthritis |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1189882A1 (en) | 2002-03-27 |
| WO2001083445A1 (en) | 2001-11-08 |
| JP2003531894A (en) | 2003-10-28 |
| AU5275901A (en) | 2001-11-12 |
| CA2377629A1 (en) | 2001-11-08 |
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