CN100351263C - Pyrazole derivative, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof - Google Patents
Pyrazole derivative, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof Download PDFInfo
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- CN100351263C CN100351263C CNB038239299A CN03823929A CN100351263C CN 100351263 C CN100351263 C CN 100351263C CN B038239299 A CNB038239299 A CN B038239299A CN 03823929 A CN03823929 A CN 03823929A CN 100351263 C CN100351263 C CN 100351263C
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Abstract
A pyrazole derivative represented by the general formula (I) (wherein R<1> is H, optionally substituted C1-6 alkyl, etc.; either of Q and T is the group of the formula (II) or the formula (III) and the other is optionally substituted C1-6 alkyl, etc.; R<2> is H, halogeno, OH, optionally substituted C1-6 alkyl, etc.; X is a single bond, O, or S; Y is a single bond, C1-6 alkylene, etc.; Z is CO or SO2; R<4> and R<5> each is H, optionally substituted C1-6 alkyl, etc.; and R<3>, R<6>, and R<7> each is H, halogeno, etc.), a pharmacologically acceptable salt of the derivative, or a prodrug of either. They have excellent human SGLT1 inhibitory activity and are useful as a preventive or therapeutic agent for diseases attributable to hyperglycemia such as diabetes, complications of diabetes, and obesity.
Description
Technical field
The present invention relates to the pyrazole derivatives of useful as drug, its pharmacy acceptable salt or its prodrug contain their pharmaceutical composition, its pharmaceutical use and be used to produce their intermediate.
More specifically, the present invention relates in people SGLT1, have the active pyrazole derivatives of inhibition, its pharmacy acceptable salt or its prodrug, their useful as drug are with prevention or treatment and hyperglycemia diseases associated (as diabetes, impaired glucose tolerance, the too much obstacle of fasting plasma glucose, diabetic complication or obesity), also relate to the pharmaceutical composition that contains them, its pharmaceutical use and be used to produce their intermediate.
Background technology
Diabetes are and one of mode of life diseases associated that its background is the change of food habits and lacks motion.Therefore, in diabetic, carry out diet and kinesitherapy.In addition, when being difficult to fully control and persistent movement, pharmacological agent can be carried out simultaneously.In addition, large-scale clinical trial is verified, is necessary to carry out the strictness control of secular glucose level, so that prevent diabetic because receive treatment and take place or develop diabetic complication (document 1 and 2 of face as follows).In addition, the many epidemiological studies at impaired glucose tolerance and macroscopical vascular disease (macroangiopathy) show that impaired glucose tolerance also is the Hazard Factor of macroscopical vascular disease and diabetes as a kind of boundary types.Therefore, need improve postprandial hyperglycemia and become focus (the face document 3 as follows).
In recent years, under the background that diabetic increases fast, the exploitation of various antidiabetic medicines is underway.For example, alpha-glucosidase inhibitor (it can postpone the digestion of carbohydrate and the absorption in small intestine) is used to improve postprandial hyperglycemia.Report that also when acarbose (a kind of alpha-glucosidase inhibitor) when being used to suffer from the patient of impaired glucose tolerance, it has prevention or postpones the effect (the face document 4 as follows) of the morbidity of diabetes.Yet, form the high glucose level (the face document 5 as follows) that causes because alpha-glucosidase inhibitor can not influence because of the sugar that changes recently in ingestion of glucose monose and the meal, therefore need exploitation to have the active medicine that suppresses carbohydrate absorption more widely.
Simultaneously, know that sodium dependent glucose vehicle 1 (SGLT1) is present in the small intestine, the absorption of its control carbohydrate.Also report,, have the incomplete absorption (row document 6-8 as follows) of glucose and semi-lactosi because of congenital people SGLT1 has among the handicapped patient unusually.In addition, verified, SGLT1 relates to the absorption (row document 9 and 10 as follows) of glucose and semi-lactosi.
In addition, confirm that OLETF rat and suffering from the rat of U-9889 inductive diabetic symptom, the mRNA of SGLT1 and albumen increase, and (row document 11 and 12 as follows) accelerated in the absorption of glucose.Usually, in diabetic, the digestion and the absorption of carbohydrate increase.For example, confirm that the mRNA of SGLT1 and albumen are (the face document 13 as follows) that roll up in people's small intestine.
Therefore, blocking-up people SGLT1 activity can suppress carbohydrate such as the absorption of glucose in small intestine, can prevent the rising of glucose level subsequently.Especially, think, postpone the absorption of glucose, can make postprandial hyperglycemia normalizing effectively based on above-mentioned mechanism.In addition, because the increase of SGLT1 is considered to cause the increase of carbohydrate absorption in the small intestine,, has needed to develop as early as possible people SGLT1 has been had the active medicine of effective inhibition therefore in order to prevent or treat diabetes.
Reference 1: diabetes contrast and complication experimental study group (The Diabetes Control andComplications Trial Research Group), N.Engl.J.Med., 1993.9, Vol.329, No.14, pp.977-986;
Reference 2: the following diabetes study group (UK Prospective Diabetes Study Group) of Britain, Lancet, 1998.9, Vol.352, No.9131, pp.837-853;
Reference 3:Makoto, TOMINAGA, Endocrinology ﹠amp; Diabetology, 2001.11, Vol.13, No.5, pp.534-542;
Reference 4:Jean-Louis Chiasson and 5 people, Lancet, 2002.6, Vol.359, No.9323, pp.2072-2077;
Reference 5:Hiroyuki, ODAKA and 3 people, Journal of Japanese Society ofNutrition and Food Science, 1992, Vol.45, No.1, pp.27-31;
Reference 6:Tadao, BABA and 1 people, Supplementary volume of Nippon Rinsho, Ryoikibetsu Shokogun, 1998, No.19, pp.552-554;
Reference 7:Michihiro, KASAHARA and 2 people, Saishin Igaku, 1996.1, Vol.51, No.1, pp.84-90;
Reference 8:Tomofusa, TSUCHIYA and 1 people, Nippon Rinsho, 1997.8, Vol.55, No.8, pp.2131-2139;
Reference 9:Yoshikatsu, KANAI, Kidney and Dialysis, 1998.12, Vol.45, supplementary issue, pp.232-237;
Reference 10:E.Turk and 4 people, Nature, 1991.3, Vol.350, pp.354-356;
Reference 11:Y.Fujita and 5 people, Diabetologia, 1998, Vol.41, pp.1459-1466;
Reference 12:J.Dyer and 5 people, Biochemical Society Transactions, 1997, Vol.25, p.479S;
Reference 13:J.Dyer and 4 people, American Journal of Physiology, 2002.2, Vol.282, No.2, pp.G241-G248.
Summary of the invention
The inventor studies in earnest, to seek the SGLT1 that finds the right person the active compound of inhibition is arranged.As a result, found that the pyrazole derivatives shown in some following general formula (I) has the activity that suppresses people SGLT1 in small intestine, and as follows glucose level is raise there is excellent inhibition activity, constituted basis of the present invention thus.
The invention provides novel pyrazole derivatives, this derivative is by the absorption of carbohydrate such as glucose in and the inhibition small intestine active to the inhibition of people SGLT1, thereby the activity that the excellent inhibition glucose level of performance raises, its pharmacy acceptable salt or its prodrug also are provided, also provide the pharmaceutical composition that contains them, its pharmaceutical use and be used to produce their intermediate.
So, the present invention relates to
[1] pyrazole derivatives shown in the following general formula:
In the formula,
R
1Expression hydrogen atom, C
1-6Alkyl, C
2-6Alkenyl, hydroxyl C
2-6Alkyl, C
3-7Cycloalkyl, C
3-7The C of cycloalkyl substituted
1-6Alkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group, or can on ring, have identical or different 1-3 substituent aryl C
1-6Alkyl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group;
A group among Q and the T is the group shown in the following formula:
Or the group shown in the following formula:
And another group is C
1-6Alkyl, halo C
1-6Alkyl, C
1-6The C that alkoxyl group replaces
1-6Alkyl or C
3-7Cycloalkyl;
R
2Expression hydrogen atom, halogen atom, hydroxyl, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halo C
1-6Alkyl, halo C
1-6Alkoxyl group, C
1-6The C that alkoxyl group replaces
1-6Alkoxyl group, C
3-7The C of cycloalkyl substituted
2-6Group shown in alkoxyl group or the following general formula:
-A-R
8
Wherein A be singly-bound, Sauerstoffatom, methylene radical, ethylidene ,-OCH
2-or-CH
2O-; And R
8Be C
3-7Cycloalkyl, C
2-6Heterocyclylalkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Alkenyloxy, halo C
1-6Alkyl, hydroxyl C
1-6Alkyl, carboxyl, C
2-7Alkoxy carbonyl, cyano group and nitro maybe can have to be selected from down and organize substituent heteroaryl: halogen atom and C
1-6Alkyl;
X is singly-bound, Sauerstoffatom or sulphur atom;
Y is singly-bound, C
1-6Alkylidene group or C
2-6Alkylene group, condition are that X is a singly-bound when Y is singly-bound;
Z is carbonyl or alkylsulfonyl;
R
4And R
5Can be identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have the substituting group that identical or different 1-3 is selected from following substituting group group (i), or they with adjacent nitrogen-atoms in conjunction with constituting C
2-6Ring is amino, and this ring is amino can to have the substituting group of group: C down
1-6Alkyl and hydroxyl C
1-6Alkyl;
R
3, R
6And R
7Can be identical or different, and each hydrogen atom, halogen atom, C naturally
1-6Alkyl or C
1-6Alkoxyl group; And
Substituting group group (i) is made of following: hydroxyl, amino, list or two (C
1-6Alkyl) amino, single or two [hydroxyl (C
1-6Alkyl)] amino, urea groups, sulfoamido, list or two (C
1-6Alkyl) urea groups, list or two (C
1-6) sulfoamido, C
2-7Acyl amino, C
1-6Group shown in alkyl sulfonyl-amino, the following general formula:
-CON (R
9) R
10R in the formula
9And R
10Can be identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have identical or different 1-3 and be selected from down the substituting group of organizing: hydroxyl, amino, list or two (C
1-6Alkyl) amino, single or two [hydroxyl (C
1-6Alkyl)] amino, urea groups, list or two (C
1-6Alkyl) urea groups, C
2-7Acyl amino, C
1-6Alkyl sulfonyl-amino and formamyl; Or they constitute C with adjacent nitrogen-atoms combination
2-6Ring is amino, and this ring is amino can to have the substituting group of group: C down
1-6Alkyl and hydroxyl C
1-6Alkyl, C
3-7Cycloalkyl, C
2-6Heterocyclylalkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom and C
1-6Alkyl, the substituent C that can have the group of being selected from down
2-6Ring is amino: C
1-6Alkyl and hydroxyl C
1-6Alkyl, and can have C
1-6Alkyl is as substituent C
1-4Aromatic ring amino,
Or its pharmacy acceptable salt;
[2] pyrazole derivatives in [1] above a kind of being described in, Y is C in the formula
1-6Alkylidene group or C
2-6Alkylene group; R
4And R
5In one be C
1-6Alkyl, it can have identical or different 1-3 substituting group that is selected from following substituting group group (i), and another is hydrogen atom or C
1-6Alkyl, it can have identical or different 1-3 substituting group that is selected from following substituting group group (i); And substituting group group (i) is made of following: hydroxyl, amino, list or two (C
1-6Alkyl) amino, single or two [hydroxyl (C
1-6Alkyl)] amino, urea groups, sulfoamido, list or two (C
1-6Alkyl) urea groups, list or two (C
1-6) sulfoamido, C
2-7Acyl amino, C
1-6Group shown in alkyl sulfonyl-amino, the following general formula:
-CON (R
9) R
10, R in the formula
9And R
10Can be identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have identical or different 1-3 and be selected from down the substituting group of organizing: hydroxyl, amino, list or two (C
1-6Alkyl) amino, single or two [hydroxyl (C
1-6Alkyl)] amino, urea groups, list or two (C
1-6Alkyl) urea groups, C
2-7Acyl amino, C
1-6Alkyl sulfonyl-amino and formamyl, or they constitute C with adjacent nitrogen-atoms combination
2-6Ring is amino, and this ring is amino can to have the substituting group of group: C down
1-6Alkyl and hydroxyl C
1-6Alkyl, C
3-7Cycloalkyl, C
2-6Heterocyclylalkyl, (described substituting group is selected from down group: halogen atom, hydroxyl, amino, C can to have identical or different 1-3 substituent aryl
1-6Alkyl and C
1-6The substituent heteroaryl that alkoxyl group), can have the group of being selected from down: halogen atom and C
1-6Alkyl, the substituent C that can have the group of being selected from down
2-6Ring is amino: C
1-6Alkyl and hydroxyl C
1-6Alkyl, and can have C
1-6Alkyl is as substituent C
1-4Aromatic ring amino, or its pharmacy acceptable salt;
[3] at the pyrazole derivatives described in above-mentioned [2], R in the formula
4And R
5In one be C
1-6Alkyl, this alkyl have the group that is selected from following (iA) substituting group group, and another is a hydrogen atom; And substituting group group (iA) is the group shown in the following general formula :-CON (R
9A) R
10A, R wherein
9AAnd R
10ABe combined together to form the substituent C that can have the group of being selected from down with adjacent nitrogen atom
2-6Ring is amino: C
1-6Alkyl and hydroxyl C
1-6Alkyl, or its pharmacy acceptable salt;
[4] arbitrary described pyrazole derivatives in above-mentioned [1]-[3], wherein X is a singly-bound; And Y is trimethylene or propenylene, or its pharmacy acceptable salt;
[5] arbitrary described pyrazole derivatives in above-mentioned [1]-[3], wherein X is a Sauerstoffatom; And Y is ethylene or trimethylene, or its pharmacy acceptable salt;
[6] pyrazole derivatives in [1] above a kind of being described in, wherein X is a singly-bound; Y is a singly-bound; R
4And R
5In one be to have the C that identical or different 1-3 is selected from the group of following substituting group group (iB)
1-6Alkyl, another is hydrogen or has identical or different 1-3 C that is selected from the group of following substituting group group (iB)
1-6Alkyl; And substituting group group (iB) is made of following group: urea groups, sulfoamido, list or two (C
1-6Alkyl) urea groups, list or two (C
1-6) sulfoamido, C
1-6Group shown in alkyl sulfonyl-amino, the following general formula :-CON (R
9B) R
10B, R wherein
9BAnd R
10BIn one be C
1-6Alkyl, described alkyl have identical or different 1-3 substituting group that is selected from down group: hydroxyl, amino, list or two (C
1-6Alkyl) amino, single or two [hydroxyl (C
1-6Alkyl)] amino, urea groups, list or two (C
1-6Alkyl) urea groups, C
2-7Acyl amino, C
1-6Alkyl sulfonyl-amino and formamyl, and another is hydrogen atom, C
1-6Alkyl, described alkyl can have identical or different 1-3 substituting group that is selected from down group: hydroxyl, amino, list or two (C
1-6Alkyl) amino, single or two [hydroxyl (C
1-6Alkyl)] amino, urea groups, list or two (C
1-6Alkyl) urea groups, C
2-7Acyl amino, C
1-6Alkyl sulfonyl-amino and formamyl, or they constitute C with adjacent nitrogen-atoms combination
2-6Ring is amino, and this ring is amino can to have the substituting group of group: C down
1-6Alkyl and hydroxyl C
1-6Alkyl, C
3-7Cycloalkyl, C
2-6Heterocyclylalkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom and C
1-6Alkyl, the substituent C that can have the group of being selected from down
2-6Ring is amino: C
1-6Alkyl and hydroxyl C
1-6Alkyl, and can have C
1-6Alkyl is as substituent C
1-4Aromatic ring amino, or its pharmacy acceptable salt;
[7] arbitrary described pyrazole derivatives in above-mentioned [1]-[6], R in the formula
1Be hydrogen atom or hydroxyl (C
2-6Alkyl) group; T represents the group shown in the following formula:
Or the group shown in the following formula:
Q is C
1-6Alkyl or halo (C
1-6Alkyl) group; And R
3, R
6And R
7Be hydrogen atom, or its pharmacy acceptable salt;
[8] arbitrary described pyrazole derivatives in above-mentioned [1]-[6], wherein among Q and the T is the group shown in the following formula:
Another is C
1-6Alkyl, halo C
1-6Alkyl, C
1-6The C that alkoxyl group replaces
1-6Alkyl or C
3-7Cycloalkyl or its pharmacy acceptable salt;
[9] at the pyrazole derivatives described in above-mentioned [7] or [8], wherein T is the group shown in the following formula:
Or its pharmacy acceptable salt;
[10] at the pyrazole derivatives described in above-mentioned [7] or [9], wherein Q is a sec.-propyl, or its pharmacy acceptable salt;
[11] prodrug of arbitrary described pyrazole derivatives or its pharmacy acceptable salt in above-mentioned [1] to [10];
[12] at the prodrug described in above-mentioned [11], wherein T is the group shown in the following formula:
Or the group shown in the following formula:
In the formula, replaced by glucopyranosyl or galactopyranose base, perhaps, replaced by following group: glucopyranosyl (glucopyranosyl), galactopyranose base (galactopyranosyl), C at 6 hydroxyls at 4 hydroxyls
2-7Acyl group, C
1-6The C that alkoxyl group replaces
2-7Acyl group, C
2-7The C that alkoxy carbonyl replaces
2-7Acyl group, C
2-7Alkoxy carbonyl, aryl C
2-7Alkoxy carbonyl or C
1-6The C that alkoxyl group replaces
2-7Alkoxy carbonyl;
[13] pyrazole derivatives in [1] above a kind of being described in, it is the compound that is selected from down group:
4-[(4-{3-[1-formamyl-1-(methyl) ethylamino formyl radical] propyl group }-the 2-aminomethyl phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-4-[(4-{3-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[2-(dimethylamino) ethylamino formyl radical]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles;
4-[(4-{3-[1-(2-aminoethylamino formyl radical)-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(4-methylpiperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(4-sec.-propyl piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[(S)-2-hydroxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-4-[(4-{ (1E)-3-[(S)-2-hydroxyl-1-(methyl) ethylamino formyl radical] propylene-1-yl } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(2-{1-[(4-methylpiperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } oxyethyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[2-hydroxyl-1,1-two-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(2-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } oxyethyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(4-methylpiperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-1-(3-hydroxypropyl)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
4-{[2-fluoro-4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-1H-pyrazoles;
4-{[2-chloro-4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles, and
Its pharmacy acceptable salt;
[14] in the above the pyrazole derivatives described in [13], it is the compound that is selected from down group:
3-(β-D-galactopyranose oxygen base)-4-[(4-{3-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(4-methylpiperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(2-{1-[(4-methylpiperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } oxyethyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(2-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } oxyethyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
4-{[2-fluoro-4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-1H-pyrazoles, and
Its pharmacy acceptable salt;
[15] a kind of pharmaceutical composition, it contains in top [1]-[14] arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug as activeconstituents;
[16] a kind of people SGLT1 inhibitor, it contains in top [1]-[14] arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug as activeconstituents;
[17] a kind of preparation that suppresses postprandial hyperglycemia, it contains in top [1]-[14] arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug as activeconstituents;
[18] preparation of a kind of prevention or treatment hyperglycemia relative disease, it contains in top [1]-[14] arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug as activeconstituents;
[19] in the above being used to described in [18] preparation that prevents or treat, wherein the hyperglycemia relative disease is the disease that is selected from down group: diabetes, impaired glucose tolerance, diabetic complication, obesity, hyperinsulinemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism imbalance, atherosclerosis, hypertension, congestive heart failure, oedema, hyperuricemia and gout;
[20] a kind of impaired glucose tolerance in the individuality or too much obstacle of fasting plasma glucose (impairedfasting glycemia) of preventing develops into the preparation of diabetes, and it contains in top [1]-[14] arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug as activeconstituents;
[21] a kind of prevention or treatment and the blood semi-lactosi level preparation of relevant disease that raises, it contains in top [1]-[14] arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug as activeconstituents;
[22] in the above being used to described in [21] preparation that prevents or treat, be galactosemia wherein with the blood semi-lactosi level relevant disease that raises;
[23] in the above the pharmaceutical composition described in [15], wherein formulation is a sustained release preparation;
[24] in the above arbitrary described preparation in [16]-[22], wherein formulation is a sustained release preparation;
[25] method of a kind of prevention or treatment hyperglycemia relative disease, it comprises: use arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug in top [1]-[14] of significant quantity;
[26] a kind of method that develops into diabetes in the individuality from impaired glucose tolerance that is suppressed at, it comprises: use arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug in top [1]-[14] of significant quantity;
[27] purposes of arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug in [1]-[14] above, they are used to make the pharmaceutical composition of prevention or treatment hyperglycemia relative disease;
[28] purposes of arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug in [1]-[14] above, they are used to prepare and are suppressed at the pharmaceutical composition that develops into diabetes in the individuality from impaired glucose tolerance;
[29] a kind of pharmaceutical composition; it contains arbitrary described pyrazole derivatives in (A) top [1]-[14]; its pharmacy acceptable salt or its prodrug, and (B) at least a be selected from down the group member's material: insulin sensitivity enhancer; glucose absorption inhibitor; biguanides; insulin secretion enhancers; the SGLT2 inhibitor; Regular Insulin or insulin analog; glucagon receptor antagonist; the insulin receptor kinase stimulant; three peptidyl peptase II inhibitor; inhibitors of dipeptidyl IV; Protein Tyrosine Phosphatases-1B inhibitor; glycogen phosphorylase inhibitors; the Robison ester enzyme inhibitors; the fructose diphosphate enzyme inhibitors; pyruvate dehydrogenase inhibitor; liver starch heteroplasia inhibitor; D-chiro-inositol (D-chiroinsitol); glycogen synthase kinase-3 inhibitor; glucagon-like-peptide-1; the glucagon-like-peptide-1 analogue; the glucagon-like-peptide-1 agonist; islet amyloid polypeptide; the islet amyloid polypeptide analogue; the islet amyloid polypeptide agonist; aldose reductase inhibitor; senior glycan end product (advanced glycation endproducts) synthetic inhibitor; inhibitors of protein kinase C; the gamma aminobutyric acid receptor antagonist; the sodium channel antagonist; the transcription factor NF-KB inhibitor; the lipid peroxidation enzyme inhibitors; acid-the Dipeptidase inhibitor of N-acetylize-α-connection; insulin like growth factor-1; Thr6 PDGF BB; the Thr6 PDGF BB analogue; Urogastron; nerve growth factor; carnitine derivative; uridine; 5-hydroxyl-1-methyl glycolylurea; EGB-761; than More (bimoclomol); sulosemide; Y-128; anti-diarrhea agents (antidiarrhoics); cathartic; the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; Carboxymethylcellulose (fibric acid) derivative; β
3-adrenoceptor agonist; the acetyl-CoA chole-sterol acyltransferase inhibitor; probucol (probcol); the Thyroid Hormone Receptors agonist; cholesterol absorption inhibitor; esterase inhibitor; the microsomal triglyceride transfer protein inhibitor; lipoxygenase inhibitors; the carnitine palmitoyl transferase inhibitors; inhibitor for squalene synthetic enzyme; the low density lipoprotein receptor toughener; nicotinic acid derivates; the bile acide intercalating agent; sodium/biliary salts cotransporter inhibitor; cholestery ester transfer protein inhibitors; appetite-inhibiting agent; angiotensin converting enzyme inhibitor; the neutral endopeptidase inhibitor; angiotensin II receptor antagonists; the endothelin converting enzyme inhibitor; endothelin-receptor antagonists; diuretic(s); calcium antagonist; the vasorelaxation hypotensive agent; sympathetic blocker; the hypotensive agent of central action; α
2-adrenoceptor agonist, anti-platelet agents (antiplatelets agent), uric acid synthetic inhibitor, uricosuric agent and urine basifier;
[30] method of a kind of prevention or treatment hyperglycemia relative disease; it comprises arbitrary described pyrazole derivatives in (A) that use significant quantity top [1]-[14]; its pharmacy acceptable salt or its prodrug, and (B) at least a be selected from down the group member's material: insulin sensitivity enhancer; glucose absorption inhibitor; biguanides; insulin secretion enhancers; the SGLT2 inhibitor; Regular Insulin or insulin analog; glucagon receptor antagonist; the insulin receptor kinase stimulant; three peptidyl peptase II inhibitor; inhibitors of dipeptidyl IV; Protein Tyrosine Phosphatases-1B inhibitor; glycogen phosphorylase inhibitors; the Robison ester enzyme inhibitors; the fructose diphosphate enzyme inhibitors; pyruvate dehydrogenase inhibitor; liver starch heteroplasia inhibitor; D-chiro-inositol (D-chiroinsitol); glycogen synthase kinase-3 inhibitor; glucagon-like-peptide-1; the glucagon-like-peptide-1 analogue; the glucagon-like-peptide-1 agonist; islet amyloid polypeptide; the islet amyloid polypeptide analogue; the islet amyloid polypeptide agonist; aldose reductase inhibitor; senior glycan end product (advanced glycationendproducts) synthetic inhibitor; inhibitors of protein kinase C; the gamma aminobutyric acid receptor antagonist; the sodium channel antagonist; the transcription factor NF-KB inhibitor; the lipid peroxidation enzyme inhibitors; acid-the Dipeptidase inhibitor of N-acetylize-α-connection; insulin like growth factor-1; Thr6 PDGF BB; the Thr6 PDGF BB analogue; Urogastron; nerve growth factor; carnitine derivative; uridine; 5-hydroxyl-1-methyl glycolylurea; EGB-761; than More (bimoclomol); sulosemide; Y-128; anti-diarrhea agents (antidiarrhoics); cathartic; the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; Carboxymethylcellulose (fibric acid) derivative; β
3-adrenoceptor agonist; the acetyl-CoA chole-sterol acyltransferase inhibitor; probucol; the Thyroid Hormone Receptors agonist; cholesterol absorption inhibitor; esterase inhibitor; the microsomal triglyceride transfer protein inhibitor; lipoxygenase inhibitors; the carnitine palmitoyl transferase inhibitors; inhibitor for squalene synthetic enzyme; the low density lipoprotein receptor toughener; nicotinic acid derivates; the bile acide intercalating agent; sodium/biliary salts cotransporter inhibitor; cholestery ester transfer protein inhibitors; appetite-inhibiting agent; angiotensin converting enzyme inhibitor; the neutral endopeptidase inhibitor; angiotensin II receptor antagonists; the endothelin converting enzyme inhibitor; endothelin-receptor antagonists; diuretic(s); calcium antagonist; the vasorelaxation hypotensive agent; sympathetic blocker; the hypotensive agent of central action; α
2-adrenoceptor agonist, anti-platelet agents (antiplatelets agent), uric acid synthetic inhibitor, uricosuric agent and urine basifier;
[31] a kind of method that develops into diabetes in the individuality from impaired glucose tolerance that is suppressed at; it comprises arbitrary described pyrazole derivatives in (A) that use significant quantity top [1]-[14]; its pharmacy acceptable salt or its prodrug, and (B) at least a be selected from down the group member's material: insulin sensitivity enhancer; glucose absorption inhibitor; biguanides; insulin secretion enhancers; the SGLT2 inhibitor; Regular Insulin or insulin analog; glucagon receptor antagonist; the insulin receptor kinase stimulant; three peptidyl peptase II inhibitor; inhibitors of dipeptidyl IV; Protein Tyrosine Phosphatases-1B inhibitor; glycogen phosphorylase inhibitors; the Robison ester enzyme inhibitors; the fructose diphosphate enzyme inhibitors; pyruvate dehydrogenase inhibitor; liver starch heteroplasia inhibitor; D-chiro-inositol (D-chiroinsitol); glycogen synthase kinase-3 inhibitor; glucagon-like-peptide-1; the glucagon-like-peptide-1 analogue; the glucagon-like-peptide-1 agonist; islet amyloid polypeptide; the islet amyloid polypeptide analogue; the islet amyloid polypeptide agonist; aldose reductase inhibitor; senior glycan end product (advanced glycation endproducts) synthetic inhibitor; inhibitors of protein kinase C; the gamma aminobutyric acid receptor antagonist; the sodium channel antagonist; the transcription factor NF-KB inhibitor; the lipid peroxidation enzyme inhibitors; the sour Dipeptidase inhibitor of N-acetylize-α-connection; insulin like growth factor-1; Thr6 PDGF BB; the Thr6 PDGF BB analogue; Urogastron; nerve growth factor; carnitine derivative; uridine; 5-hydroxyl-1-methyl glycolylurea; EGB-761; than More (bimoclomol); sulosemide; Y-128; anti-diarrhea agents (antidiarrhoics); cathartic; the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; Carboxymethylcellulose (fibricacid) derivative; β
3-adrenoceptor agonist; the acetyl-CoA chole-sterol acyltransferase inhibitor; probucol; the Thyroid Hormone Receptors agonist; cholesterol absorption inhibitor; esterase inhibitor; the microsomal triglyceride transfer protein inhibitor; lipoxygenase inhibitors; the carnitine palmitoyl transferase inhibitors; inhibitor for squalene synthetic enzyme; the low density lipoprotein receptor toughener; nicotinic acid derivates; the bile acide intercalating agent; sodium/biliary salts cotransporter inhibitor; cholestery ester transfer protein inhibitors; appetite-inhibiting agent; angiotensin converting enzyme inhibitor; the neutral endopeptidase inhibitor; angiotensin II receptor antagonists; the endothelin converting enzyme inhibitor; endothelin-receptor antagonists; diuretic(s); calcium antagonist; the vasorelaxation hypotensive agent; sympathetic blocker; the hypotensive agent of central action; α
2-adrenoceptor agonist, anti-platelet agents (antiplatelets agent), uric acid synthetic inhibitor, uricosuric agent and urine basifier;
[32] (A) above arbitrary described pyrazole derivatives in [1]-[14]; its pharmacy acceptable salt or its prodrug, and (B) at least a be selected from down group the purposes of member's material: insulin sensitivity enhancer; glucose absorption inhibitor; biguanides; insulin secretion enhancers; the SGLT2 inhibitor; Regular Insulin or insulin analog; glucagon receptor antagonist; the insulin receptor kinase stimulant; three peptidyl peptase II inhibitor; inhibitors of dipeptidyl IV; Protein Tyrosine Phosphatases-1B inhibitor; glycogen phosphorylase inhibitors; the Robison ester enzyme inhibitors; the fructose diphosphate enzyme inhibitors; pyruvate dehydrogenase inhibitor; liver starch heteroplasia inhibitor; D-chiro-inositol (D-chiroinsitol); glycogen synthase kinase-3 inhibitor; glucagon-like-peptide-1; the glucagon-like-peptide-1 analogue; the glucagon-like-peptide-1 agonist; islet amyloid polypeptide; the islet amyloid polypeptide analogue; the islet amyloid polypeptide agonist; aldose reductase inhibitor; senior glycan end product (advanced glycation endproducts) synthetic inhibitor; inhibitors of protein kinase C; the gamma aminobutyric acid receptor antagonist; the sodium channel antagonist; the transcription factor NF-KB inhibitor; the lipid peroxidation enzyme inhibitors; the sour Dipeptidase inhibitor of N-acetylize-α-connection; insulin like growth factor-1; Thr6 PDGF BB; the Thr6 PDGF BB analogue; Urogastron; nerve growth factor; carnitine derivative; uridine; 5-hydroxyl-1-methyl glycolylurea; EGB-761; than More (bimoclomol); sulosemide; Y-128; anti-diarrhea agents (antidiarrhoics); cathartic; the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; Carboxymethylcellulose (fibricacid) derivative; β
3-adrenoceptor agonist; the acetyl-CoA chole-sterol acyltransferase inhibitor; probucol; the Thyroid Hormone Receptors agonist; cholesterol absorption inhibitor; esterase inhibitor; the microsomal triglyceride transfer protein inhibitor; lipoxygenase inhibitors; the carnitine palmitoyl transferase inhibitors; inhibitor for squalene synthetic enzyme; the low density lipoprotein receptor toughener; nicotinic acid derivates; the bile acide intercalating agent; sodium/biliary salts cotransporter inhibitor; cholestery ester transfer protein inhibitors; appetite-inhibiting agent; angiotensin converting enzyme inhibitor; the neutral endopeptidase inhibitor; angiotensin II receptor antagonists; the endothelin converting enzyme inhibitor; endothelin-receptor antagonists; diuretic(s); calcium antagonist; the vasorelaxation hypotensive agent; sympathetic blocker; the hypotensive agent of central action; α
2-adrenoceptor agonist, anti-platelet agents (antiplatelets agent), uric acid synthetic inhibitor, uricosuric agent and urine basifier, they are used to make the pharmaceutical composition of prevention or treatment hyperglycemia relative disease;
[33] (A) above arbitrary described pyrazole derivatives in [1]-[14]; its pharmacy acceptable salt or its prodrug; and (B) at least a be selected from down group the purposes of member's material: insulin sensitivity enhancer; glucose absorption inhibitor; biguanides; insulin secretion enhancers; the SGLT2 inhibitor; Regular Insulin or insulin analog; glucagon receptor antagonist; the insulin receptor kinase stimulant; three peptidyl peptase II inhibitor; inhibitors of dipeptidyl IV; Protein Tyrosine Phosphatases-1B inhibitor; glycogen phosphorylase inhibitors; the Robison ester enzyme inhibitors; the fructose diphosphate enzyme inhibitors; pyruvate dehydrogenase inhibitor; liver starch heteroplasia inhibitor; D-chiro-inositol (D-chiroinsitol); glycogen synthase kinase-3 inhibitor; glucagon-like-peptide-1; the glucagon-like-peptide-1 analogue; the glucagon-like-peptide-1 agonist; islet amyloid polypeptide; the islet amyloid polypeptide analogue; the islet amyloid polypeptide agonist; aldose reductase inhibitor; senior glycan end product (advanced glycation endproducts) synthetic inhibitor; inhibitors of protein kinase C; the gamma aminobutyric acid receptor antagonist; the sodium channel antagonist; the transcription factor NF-KB inhibitor; the lipid peroxidation enzyme inhibitors; the sour Dipeptidase inhibitor of N-acetylize-α-connection, insulin like growth factor-1; Thr6 PDGF BB; the Thr6 PDGF BB analogue; Urogastron; nerve growth factor; carnitine derivative; uridine; 5-hydroxyl-1-methyl glycolylurea; EGB-761; than More (bimoclomol); sulosemide; Y-128; anti-diarrhea agents (antidiarrhoics); cathartic; the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; Carboxymethylcellulose (fibricacid) derivative; β
3-adrenoceptor agonist; the acetyl-CoA chole-sterol acyltransferase inhibitor; probucol; the Thyroid Hormone Receptors agonist; cholesterol absorption inhibitor; esterase inhibitor; the microsomal triglyceride transfer protein inhibitor; lipoxygenase inhibitors; the carnitine palmitoyl transferase inhibitors; inhibitor for squalene synthetic enzyme; the low density lipoprotein receptor toughener; nicotinic acid derivates; the bile acide intercalating agent; sodium/biliary salts cotransporter inhibitor; cholestery ester transfer protein inhibitors; appetite-inhibiting agent; angiotensin converting enzyme inhibitor; the neutral endopeptidase inhibitor; angiotensin II receptor antagonists; the endothelin converting enzyme inhibitor; endothelin-receptor antagonists; diuretic(s); calcium antagonist; the vasorelaxation hypotensive agent; sympathetic blocker; the hypotensive agent of central action; α
2-adrenoceptor agonist, anti-platelet agents (antiplatelets agent), uric acid synthetic inhibitor, uricosuric agent and urine basifier, they are used to make and are suppressed at the pharmaceutical composition that develops into diabetes in the individuality from impaired glucose tolerance;
[34] pyrazole derivatives shown in the following general formula:
In the formula
R
11Be hydrogen atom, C
1-6Alkyl, C
2-6Alkenyl, the hydroxyl (C that can have protecting group
2-6Alkyl) group, C
3-7Cycloalkyl, C
3-7The C of cycloalkyl substituted
1-6Alkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl and C
1-6Alkoxyl group perhaps can have identical or different 1-3 substituent aryl C on ring
1-6Alkyl, described substituting group is selected from down group: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl and C
1-6Alkoxyl group;
Q
2And T
2In one be 2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base group or 2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base group, and another group is C
1-6Alkyl, halo C
1-6Alkyl, C
1-6The C that alkoxyl group replaces
1-6Alkyl or C
3-7Cycloalkyl;
R
12Be hydrogen atom, halogen atom, the hydroxyl that can have protecting group, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6Alkylthio, halo C
1-6Alkyl, halo C
1-6Alkoxyl group, C
1-6The C that alkoxyl group replaces
1-6Alkoxyl group, C
3-7The C of cycloalkyl substituted
2-6Group shown in alkoxyl group or the following general formula :-A-R
18, in the formula A be singly-bound, Sauerstoffatom, methylene radical, ethylidene ,-OCH
2-or-CH
2O-; And R
18Be C
3-7Cycloalkyl, C
2-6Heterocyclylalkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl, C
1-6Alkoxyl group, C
2-6Alkenyloxy, halo C
1-6Alkyl, the hydroxyl C that can have protecting group
1-6Alkyl, the carboxyl that can have protecting group, C
2-7Alkoxy carbonyl, cyano group and nitro maybe can have to be selected from down and organize substituent heteroaryl: halogen atom and C
1-6Alkyl;
X is singly-bound, Sauerstoffatom or sulphur atom;
Y is singly-bound, C
1-6Alkylidene group or C
2-6Alkylene group, condition are that X is a singly-bound when Y is singly-bound;
Z is carbonyl or alkylsulfonyl;
R
14And R
15Can be identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have identical or different 1-3 and be selected from following substituting group group group (ii), or they constitute C with adjacent nitrogen-atoms combination
2-6Ring is amino, and this ring is amino can to have the substituting group of group: C down
1-6Alkyl and the hydroxyl C that can have protecting group
1-6Alkyl;
R
3, R
6And R
7Can be identical or different, and each hydrogen atom, halogen atom, C naturally
1-6Alkyl or C
1-6Alkoxyl group; With
The substituting group group (ii) is made of following: can have the hydroxyl of protecting group, the amino that can have protecting group, the list that can have protecting group or two (C
1-6Alkyl) amino, list or the two [hydroxyl (C that can have protecting group
1-6Alkyl)] amino, urea groups, sulfoamido, list or two (C
1-6Alkyl) urea groups, list or two (C
1-6) sulfoamido, C
2-7Acyl amino, C
1-6Group shown in alkyl sulfonyl-amino, the following general formula:
-CON (R
19) R
20, R wherein
19And R
20Can be identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have identical or different 1-3 and be selected from down the substituting group of organizing: can have the hydroxyl of protecting group, the amino that can have protecting group, the list that can have protecting group or two (C
1-6Alkyl) amino, list or the two [hydroxyl (C that can have protecting group
1-6Alkyl)] amino, urea groups, list or two (C
1-6Alkyl) urea groups, C
2-7Acyl amino, C
1-6Alkyl sulfonyl-amino and formamyl, or they constitute C with adjacent nitrogen-atoms combination
2-6Ring is amino, and this ring is amino can to have the substituting group of group: C down
1-6Alkyl and the hydroxyl C that can have protecting group
1-6Alkyl, C
3-7Cycloalkyl, C
2-6Heterocyclylalkyl, can have identical or different 1-3 substituent aryl, described substituting group is selected from down group: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl and C
1-6Alkoxyl group, the substituent heteroaryl that can have the group of being selected from down: halogen atom and C
1-6Alkyl, the substituent C that can have the group of being selected from down
2-6Ring is amino: C
1-6Alkyl and the hydroxyl C that can have protecting group
1-6Alkyl, and can have C
1-6Alkyl is as substituent C
1-4Aromatic ring amino, or its salt; Or the like.
In the present invention, term " C
1-6Alkyl " refer to have the straight or branched alkyl of 1-6 carbon atom, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, hexyl or similar group; Term " C
1-6Alkylidene group " refer to have the straight or branched alkylidene group of 1-6 carbon atom, for example methylene radical, ethylidene, trimethylene, tetramethylene, trimethylene, 1,1-dimethyl ethylidene, or similar group; Term " hydroxyl (C
1-6Alkyl) group " refer to the above-mentioned C that replaced by hydroxyl
1-6Alkyl; Term " C
2-6Alkyl " refer to have the straight or branched alkyl of 2-6 carbon atom, for example ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, hexyl or similar group; Term " hydroxyl (C
2-6Alkyl) group " refer to the above-mentioned C that replaced by hydroxyl
2-6Alkyl, for example 2-hydroxyethyl, 3-hydroxypropyl or similar group; Term " C
1-6Alkoxyl group " refer to have the straight or branched alkoxyl group of 1-6 carbon atom, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, neopentyl oxygen, uncle's pentyloxy, hexyloxy or similar group; Term " C
1-6(the C that alkoxyl group replaces
1-6Alkyl) group " refer to by above-mentioned C
1-6The above-mentioned C that alkoxyl group replaces
1-6Alkyl; Term " C
1-6(the C that alkoxyl group replaces
1-6Alkoxyl group) group " refer to by above-mentioned C
1-6The above-mentioned C that alkoxyl group replaces
1-6Alkoxyl group, for example methoxymethoxy or similar group; Term " C
2-6Alkenyl " refer to have the alkenyl of the straight or branched of 2-6 carbon atom, for example vinyl, allyl group, 1-propenyl, pseudoallyl, 1-butylene base, crotyl, 2-methacrylic or similar group; Term " C
2-6Alkenylene " refer to have the alkenylene of the straight or branched of 2-6 carbon atom, for example vinylene, propenylene or similar group; Term " C
2-6The alkenyl oxo group " refer to have the above-mentioned C of unsaturated link(age)
1-6Alkoxyl group (except methoxyl group), for example allyloxy or similar group; Term " C
1-6Alkylthio " refer to have the alkylthio of the straight or branched of 1-6 carbon atom, for example methylthio group, ethylmercapto group, rosickyite base, iprotiazem base, butylthio, isobutyl sulfenyl, secondary butylthio, uncle's butylthio, penta sulfenyl, isoamyl sulfenyl, new penta sulfenyl, uncle's penta sulfenyl, own sulfenyl or similar group; Term " single or two (C
1-6Alkyl) amino " refer to by above-mentioned C
1-6Alkyl is mono-substituted or by identical or different above-mentioned C
1-6The dibasic amino of alkyl; Term " single or two [hydroxyl (C
1-6Alkyl)] amino " refer to by above-mentioned hydroxyl C
1-6Alkyl is mono-substituted or by identical or different above-mentioned hydroxyl C
1-6The dibasic amino of alkyl; Term " single or two (C
1-6Alkyl) urea groups " refer to by above-mentioned C
1-6Alkyl is mono-substituted or by identical or different above-mentioned C
1-6The dibasic urea groups of alkyl; Term " single or two (C
1-6Alkyl) sulfoamido " refer to by above-mentioned C
1-6Alkyl is mono-substituted or by identical or different above-mentioned C
1-6The dibasic sulfoamido of alkyl; Term " C
2-7Acyl amino " refer to have 2-7 carbon atom by the amino of straight or branched acyl substituted, for example ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, pivaloyl group, caproyl or similar group; Term " C
1-6Alkyl sulfonyl-amino " refer to have the amino that is replaced by the straight or branched alkyl sulphonyl of 1-6 carbon atom, for example methylsulfonyl, ethylsulfonyl or similar group; Term " C
3-7Cycloalkyl " finger ring propyl group, cyclobutyl, cyclopentyl, cyclohexyl or suberyl; Term " C
3-7(the C of cycloalkyl substituted
1-6Alkyl) group " refer to by above-mentioned C
3-7The C of cycloalkyl substituted
1-6Alkyl; Term " C
3-7(the C of cycloalkyl substituted
2-6Alkoxyl group) group " refer to by above-mentioned C
3-7The C of cycloalkyl substituted
1-6Alkoxyl group (except methoxyl group); Term " C
2-6Heterocyclylalkyl " refer on ring, except binding site, to have 1 or 2 the identical or different heteroatomic above-mentioned C that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom
3-7Cycloalkyl, it is derived from morpholine, parathiazan, tetrahydrofuran (THF), tetrahydropyrans, aziridine, azetidine, tetramethyleneimine, imidazolidine, oxazoline, piperidines, piperazine, pyrazolidine or similar group; Term " halogen atom " refers to fluorine atom, chlorine atom, bromine atoms or iodine atom; Term " halo (C
1-6Alkyl) group " refer to by the above-mentioned C of identical or different 1-5 above-mentioned halogen atom replacement
1-6Alkyl, for example trifluoromethyl, pentafluoroethyl group or similar group; Term " halo (C
1-6Alkoxyl group) group " refer to by the above-mentioned C of identical or different 1-5 above-mentioned halogen atom replacement
1-6Alkoxyl group; Term " C
2-7Alkoxy carbonyl " refer to have the straight or branched alkoxy carbonyl of 2-7 carbon atom, for example methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, sec-butoxy carbonyl, tert-butoxycarbonyl, pentyloxy carbonyl, isopentyloxy carbonyl, neopentyl oxygen carbonyl, tert-pentyloxy carbonyl, hexyloxy carbonyl or similar group; Term " aryl " refers to monocycle to the trinucleated aromatic hydrocarbyl, for example phenyl, naphthyl or similar group; Term " aryl (C
1-6Alkyl) group " refer to the C that replaced by above-mentioned aryl
1-6Alkyl; Term " heteroaryl " refers to have 1-4 identical or different heteroatomic 5 or 6 yuan of heteroaryls that are selected from nitrogen-atoms, Sauerstoffatom and sulphur atom except binding site on ring, it is derived from thiazole, oxazole, isothiazole, isoxazole, pyridine, pyrimidine, piperazine, pyridazine, pyrroles, thiophene, imidazoles, pyrazoles, oxadiazole, thiadiazoles, tetrazolium, furazan or similar group; Term " C
2-6Ring is amino " refer to have 5 or 6 yuan of monocycle amino of 2-6 carbon atom; and it can contain the heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom on encircling except the nitrogen-atoms that is positioned at binding site, for example morpholino, parathiazan generation, 1-'-aziridino, 1-azepine butane group, 1-pyrrolidyl, piperidino-(1-position only), 1-imidazolidyl, 1-piperazinyl, pyrazolidyl or similar group; Term " C
1-4Aromatic ring amino " refer to have the 5-unit aromatic monocyclic amino of 1-4 carbon atom, it can contain 1-3 nitrogen-atoms except the nitrogen-atoms that is positioned at link position, for example 1-imidazolyl, 1-pyrryl, pyrazolyl, 1-tetrazyl or similar group; Term " hydroxy-protective group " refers to the hydroxyl protecting group that uses, for example benzyl, methoxymethyl, ethanoyl, pivaloyl group, benzoyl, t-butyldimethylsilyl, triisopropyl silyl, allyl group or similar group in general organic synthesis; Term " amido protecting group " refers to the amino protecting group that uses, for example benzyloxycarbonyl, tert-butoxycarbonyl, benzyl, trifluoroacetyl group or similar group in general organic synthesis; And term " carboxy protective group " refers to the carboxyl-protecting group that uses, for example benzyl, t-butyldimethylsilyl, allyl group or similar group in general organic synthesis.
In the present invention, for example, R
1Preferably hydrogen atom or hydroxyl C
2-6Alkyl more preferably is a hydrogen atom; T is the following formula group preferably:
Perhaps following formula group:
Q is C preferably
1-6Alkyl or halo C
1-6Alkyl more preferably is C
1-6Alkyl; C among the Q
1-6Alkyl is ethyl or sec.-propyl preferably, more preferably is sec.-propyl; X is singly-bound or Sauerstoffatom preferably.In addition, when X was singly-bound, Y is C preferably
1-6Alkylidene group or C
2-6Alkylene group more preferably is trimethylene or propenylene; And when X was Sauerstoffatom, Y is C preferably
1-6Alkylidene group more preferably is ethylene or trimethylene.Z is carbonyl preferably; R
2Preferably hydrogen atom, halogen atom, C
1-6Alkyl, C
1-6Alkoxyl group, C
1-6The C that alkoxyl group replaces
2-6Alkoxyl group, C
3-7The C of cycloalkyl substituted
2-6Group shown in alkoxyl group or the following general formula :-A-R
8, A and R in the formula
8Have identical meanings as defined above, and more preferably be hydrogen atom, chlorine atom, fluorine atom or methyl; R
4And R
5In a C preferably
1-6Alkyl, this alkyl have the group shown in 1-3 hydroxyl or the following general formula :-CON (R
9) R
10, R wherein
9And R
10Can be identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have identical or different 1-3 and be selected from down the substituting group of organizing: hydroxyl, amino, list or two (C
1-6Alkyl) amino, single or two [hydroxyl (C
1-6Alkyl)] amino, urea groups, list or two (C
1-6Alkyl) urea groups, C
2-7Acyl amino, C
1-6Alkyl sulfonyl-amino and formamyl, or they constitute C with adjacent nitrogen-atoms combination
2-6Ring is amino, and this ring is amino can to have the substituting group of group: C down
1-6Alkyl and hydroxyl C
1-6Alkyl, and R
4And R
5In another hydrogen atom preferably; And R
4And R
5In one more preferably be C
1-6Alkyl, this alkyl has the group shown in the following general formula :-CON (R
9A) R
10A, R wherein
9AAnd R
10ABe combined together to form the substituent C that can have the group of being selected from down with adjacent nitrogen atom
2-6Ring is amino: C
1-6Alkyl and hydroxyl C
1-6Alkyl, and R
4And R
5In another more preferably be the hydrogen atom hydrogen atom; And R
3, R
6And R
7Preferably hydrogen atom or halogen atom, and all they more preferably all be hydrogen atom.
As particular compound of the present invention, the compound of describing in embodiment 1-116 is a representative example.Particularly, following compounds or its pharmacy acceptable salt are preferred,
[embodiment 44] [embodiment 48]
[embodiment 52] [embodiment 56]
[embodiment 57] [embodiment 59]
[embodiment 61] [embodiment 62]
[embodiment 66] [embodiment 73]
[embodiment 85] [embodiment 87]
[embodiment 89] [embodiment 99]
[embodiment 103] [embodiment 105]
[embodiment 106] [embodiment 107]
[embodiment 109] [embodiment 112]
[embodiment 115] [embodiment 116]
And 3-(β-D-galactopyranose oxygen base)-4-[(4-{3-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles; 3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles; 3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles; 3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(4-methylpiperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles; 3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(2-{1-[(4-methylpiperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } oxyethyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles; 3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles; 3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(2-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } oxyethyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles; 3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles; 3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles; 3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles; 4-{[2-fluoro-4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-1H-pyrazoles, or its pharmacy acceptable salt is preferred.
For example, the represented compound of general formula of the present invention (I), can be according to following flow preparation:
L wherein
1Expression leavings group, for example halogen atom, mesyloxy, tosyloxy or similar group; L
2Expression MgBr, MgCl, MgI, ZnI, ZnBr, ZnCl or lithium atom; R represents C
1-6Alkyl, halo C
1-6Alkyl, C
1-6The C that alkoxyl group replaces
1-6Alkyl or C
3-7Cycloalkyl; R
0Expression C
1-6Alkyl; Q
3And T
3In one be hydroxyl, another is C
1-6Alkyl, halo C
1-6Alkyl, C
1-6The C that alkoxyl group replaces
1-6Alkyl or C
3-7Cycloalkyl; And R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
11, R
12, R
14, R
15, Q, Q
2, T, T
2, X, Y and Z have identical meanings as defined above.
Flow process 1-1
Compound shown in the above-mentioned general formula (VI) can prepare like this: in inert solvent, in the presence of alkali such as sodium hydride or potassium tert.-butoxide, with benzyl derivative shown in the following formula (IV) and the pyruvate condensation shown in the last formula V.As the inert solvent that is used to react, for example, 1,2-glycol dimethyl ether, tetrahydrofuran (THF), N, dinethylformamide, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction is generally room temperature to reflux temperature, and the reaction times is generally 1 hour to 1 day, and this can change according to used raw material, solvent and temperature of reaction.
Flow process 1-2
Can prepare like this by the benzyl pyrazole derivative shown in the following formula (III): in inert solvent; in the alkali existence or not; hydrazine compound or its monohydrate shown in compound shown in the following formula (VI) and the following formula (VII) are carried out condensation, and under some occasion, introduce the hydrogen protection as required in the usual way.As the inert solvent that is used for condensation reaction, for example, toluene, tetrahydrofuran (THF), chloroform, methyl alcohol, ethanol, its mixed solvent etc. can be used as to be enumerated, and as alkali, for example triethylamine, N, N-diisopropylethylamine, pyridine, sodium methylate, sodium ethylate etc. can be used as to be enumerated.Temperature of reaction is generally room temperature to reflux temperature, and the reaction times is generally 1 hour to 1 day, and this can change according to used raw material, solvent and temperature of reaction.Benzyl pyrazole derivative shown in the following formula (III) that obtains after changing salify suitably with ordinary method, can be used for flow process subsequently.
Flow process 1-3
The compound of following formula (X) expression can prepare like this: in inert solvent, in the presence of alkali (as sodium amide), the ketone compound shown in dithiocarbonic acid ester cpds shown in the following formula (VII) and the following formula (IX) is carried out condensation.As the inert solvent that is used to react, for example, toluene etc. can be used as to be enumerated.Temperature of reaction usually can from-20 ℃ to room temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.
Flow process 1-4
The benzyloxy pyrazole derivatives of following formula (XI) expression can prepare like this: in inert solvent; at alkali (as triethylamine or N; the N-diisopropylethylamine) exists down; hydrazine compound shown in compound shown in the following formula (X) and the following formula (VII) or its monohydrate or its salt are carried out condensation, and under some occasion, introduce the hydrogen protection as required in the usual way.As the inert solvent that is used for condensation reaction, for example, acetonitrile etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times is generally 1 hour to 1 day, this can change according to used raw material, solvent and temperature of reaction.
Flow process 1-5
The pyrazoles aldehyde derivatives of following formula (XII) expression can prepare like this: in all kinds of SOLVENTS, with phosphoryl chloride and N, dinethylformamide carries out the Vilsmeier reaction to the compound shown in the following formula (XI).As the solvent that is used to react, for example, N, dinethylformamide etc. can be used as and enumerate.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.
Flow process 1-6
The compound of following formula (XIV) expression can prepare like this: in inert solvent, with the lithium reagent condensation shown in the compound shown in the following formula (XII) and Grignard reagent, Reformatsky reagent or the following formula (XIII).As the solvent that is used to react, for example, tetrahydrofuran (THF), ether, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction usually can from-78 ℃ to room temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.
Flow process 1-7
Can prepare like this by the benzyl pyrazole derivative shown in the following formula (III): in inert solvent, in existing or not existing under the acid (example hydrochloric acid), with the compound shown in the following formula (XIV) being carried out shortening with palladium catalyst (as palladium-carbon dust), and have at compound under the situation of the sulphur atom shown in the following formula (XIV), the compound that obtains is carried out acid treatment in the aqueous solution of trifluoroacetic acid and dimethyl thioether, usually 0 ℃ to reflux temperature reaction 30 minutes to 1 day, this can be according to actual needs.As the solvent that is used for catalytic hydrogenation reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), ethyl acetate, acetate, Virahol or its mixed solvent etc. can be used as to be enumerated.Temperature of reaction is generally room temperature to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.The benzyl pyrazole derivative of following formula (III) expression that obtains after changing salify suitably with ordinary method, can also be used for flow process subsequently.
Flow process 1-8
[1] in the benzyl pyrazole derivative of following formula (III) expression, works as Q
3And T
3In one be C
1-6Alkyl, C
1-6The C that alkoxyl group replaces
1-6Alkyl or C
3-7During cycloalkyl, the present invention can be prepared like this by the respective compound of following formula (II) expression: in inert solvent, in existing under the alkali (as silver carbonate, sodium hydride etc.), the corresponding benzyl pyrazole derivative of following formula (III) being represented with acetyl bromide-α-D-glucose or acetyl bromide-α-D-semi-lactosi carries out glycosidation.As the inert solvent that is used to react, for example, tetrahydrofuran (THF), glycol dimethyl ether, N, dinethylformamide, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction is generally room temperature to reflux temperature, and the reaction times is generally 1 hour to 1 day, and this can change according to used raw material, solvent and temperature of reaction.
[2] in the benzyl pyrazole derivative of following formula (III) expression, work as Q
3And T
3In one be halo (C
1-6Alkyl) during group, the present invention can be prepared like this by the respective compound of following formula (II) expression: in inert solvent, alkali (as salt of wormwood etc.) exist down, the corresponding benzyl pyrazole derivative of following formula (III) being represented with acetyl bromide-α-D-glucose or acetyl bromide-α-D-semi-lactosi carries out glycosidation.As the inert solvent that is used to react, for example, tetrahydrofuran (THF), acetonitrile, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction is generally room temperature to reflux temperature, and the reaction times is generally 1 hour to 1 day, and this can change according to used raw material, solvent and temperature of reaction.
[3] in the benzyl pyrazole derivative of following formula (III) expression, work as Q
3And T
3In one be C
2-6Alkyl, C
1-6The C that alkoxyl group replaces
1-6Alkyl or C
3-7During cycloalkyl, the present invention can be prepared like this by the respective compound of following formula (II) expression: in aqueous inert solvent, in alkali (as sodium hydroxide, potassium hydroxide, salt of wormwood, etc.) and phase-transfer catalyst (as zephiran chloride three (normal-butyl) ammonium, bromination benzyl three (normal-butyl) ammonium, hydrogen sulfate four (normal-butyl) ammonium, etc.) exist down, the corresponding benzyl pyrazole derivative of following formula (III) being represented with acetyl bromide-α-D-glucose or acetyl bromide-α-D-semi-lactosi carries out glycosidation.As the inert solvent that is used to react, methylene dichloride, toluene, its mixed solvent of phenylfluoroform etc. can be used as to be enumerated.Temperature of reaction usually can be from 0 to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.
The benzyl pyrazole derivative of the glycosidation of following formula (II) expression that obtains is changing salify and after separating suitably with ordinary method, can also be used for flow process subsequently.
Flow process 1-9
The pyrazole derivatives of following formula of the present invention (I) expression can prepare like this: the compound to following formula (II) expression carries out alkaline hydrolysis, removes blocking group then or the nitro in the compound that forms is reduced, and this can according to circumstances need.As the solvent that is used for hydrolysis reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), water, its mixed solvent etc. can be used as to be enumerated.As alkali, for example, sodium hydroxide, sodium methylate, sodium ethylate etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.As mentioned above, after hydrolysis compound at R
11, R
12, R
14And/or R
15In when having blocking group, protecting group can be removed suitably with ordinary method.In addition, after above-mentioned reaction is finished, following formula (I) expression at R
2In the compound of nitro is arranged, can be derivatized to by catalytic reduction and have amino compound accordingly, wherein use palladium catalyst (as palladous oxide) and in inert solvent (as ethyl acetate), according to a conventional method usually in room temperature reaction 30 minutes to 1 day to the reflux temperature.
In the compound of representing as the following formula (III) of raw material, can there be following 3 kinds of R
11Be the tautomer of hydrogen atom, they change along with the difference of reaction conditions, and the compound of following formula (III) expression comprises all these compounds:
Wherein R, R
3, R
6, R
7, R
12, R
14, R
15, X, Y and Z have identical meanings as defined above.
In the compound shown in the above-mentioned general formula of the present invention (I), a compounds (R in the formula
1Be C
1-6Alkyl, C
2-6Alkenyl, hydroxyl C
2-6Alkyl, C
3-7Cycloalkyl, C
3-7The C of cycloalkyl substituted
1-6The C that alkyl or aryl replaces
1-6Alkyl, they can have identical or different 1-3 substituting group that is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group), for example, according to following flow preparation:
L wherein
3Expression leavings group, for example halogen atom, mesyloxy, tosyloxy or similar group; R
21Expression C
1-6Alkyl, C
2-6Alkenyl, the hydroxyl (C that can have protecting group
2-6Alkyl) group, C
3-7Cycloalkyl, C
3-7The C of cycloalkyl substituted
1-6The C that alkyl or aryl replaces
1-6Alkyl, they can have identical or different 1-3 substituting group that is selected from down group: halogen atom, the hydroxyl that can have protecting group, the amino that can have protecting group, C
1-6Alkyl and C
1-6Alkoxyl group; R
31Expression C
1-6Alkyl, C
2-6Alkenyl, hydroxyl C
2-6Alkyl, C
3-7Cycloalkyl, C
3-7The C of cycloalkyl substituted
1-6The C that alkyl or aryl replaces
1-6Alkyl, they can have identical or different 1-3 substituting group that is selected from down group: halogen atom, hydroxyl, amino, C
1-6Alkyl and C
1-6Alkoxyl group; And R
2, R
3, R
4, R
5, R
6, R
7, R
12, R
14, R
15, Q, Q
2, T, T
2, X, Y and Z have identical meanings as defined above.
Flow process 2
The pyrazole derivatives of following formula of the present invention (Ia) expression can prepare like this: press and the similar approach described in the above-mentioned flow process 1-9; compound to following formula (IIa) expression is hydrolyzed; then in inert solvent; in existing under the alkali (as cesium carbonate or salt of wormwood); N-alkylating agent with following formula (XV) expression carries out the N-alkanisation; and and have at compound under the situation of blocking group, according to circumstances need blocking group to be removed suitably with ordinary method.As the inert solvent that is used for the N-alkanisation, for example, acetonitrile, ethanol, 1,2-glycol dimethyl ether, tetrahydrofuran (THF), N, dinethylformamide, methyl-sulphoxide, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction is generally room temperature to reflux temperature, and the reaction times usually from 10 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.
In the compound shown in the above-mentioned general formula of the present invention (I), R in the formula
1Be the compound of hydrogen atom, for example, also can be according to following flow preparation:
R wherein
2, R
3, R
4, R
5, R
6, R
7, R
12, R
14, R
15, Q, Q
2, T, T
2, X, Y and Z have identical meanings as defined above.
Flow process 3-1
The compound of following formula (XVII) expression can prepare like this: in inert solvent, the compound of following formula (XVI) being represented with palladium catalyst (as palladium-carbon dust) carries out shortening, so that remove benzyl.As the solvent that is used for catalytic hydrogenation reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), ethyl acetate, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 1 hour to 2 days, this can change according to used raw material, solvent and temperature of reaction.
Flow process 3-2
The compound of following formula of the present invention (IIa) expression can prepare like this: the compound of following formula (XVII) expression and the sulfonamide derivatives of following formula (XVIII) expression are carried out condensation, wherein be reflected in the inert solvent, in having condensing agent (as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride) or dicyclohexyl carbodiimide) and having or do not exist alkali such as triethylamine or N, the N-diisopropylethylamine) under, and according to circumstances needs to carry out after adding I-hydroxybenzotriazole suitably.As the solvent that is used for condensation reaction, for example, N, dinethylformamide, methylene dichloride, tetrahydrofuran (THF), its mixed solvent etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 1 hour to 2 days, this can change according to used raw material, solvent and temperature of reaction.
Flow process 3-3
The pyrazole derivatives of following formula of the present invention (Ib) expression can prepare like this: the compound to following formula (IIa) expression carries out alkaline hydrolysis, according to circumstances needs then to remove blocking group with ordinary method.As the solvent that is used for hydrolysis reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), water, its mixed solvent etc. can be used as to be enumerated.As alkali, for example, sodium hydroxide, sodium methylate, sodium ethylate etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.Compound is at R after hydrolysis
12, R
14And/or R
15In have under the situation of blocking group, protecting group can be removed with ordinary method as flow process 1-9 suitably.
In the compound shown in the above-mentioned general formula of the present invention (I), R in the formula
1Be hydrogen atom; X is a singly-bound; And Y is C
2-6Alkylidene group or C
2-6The compound of alkylene group, for example, can be according to following flow preparation:
2) remove protecting group once in a while
L wherein
4Expression leavings group, for example chlorine atom, bromine atoms, iodine atom, trifluoro-methanesulfonyl oxy or similar group; Y
1Expression singly-bound or C
1-4Alkenyl; And R
2, R
3, R
4, R
5, R
6, R
7, R
12, R
14, R
15, Q, Q
2, T, T
2Has identical meanings as defined above with Z.
Flow process 4-1
The pyrazole derivatives of following formula (XXI) expression can prepare like this: the pyrazole derivatives of following formula (XIX) expression and the alkene derivatives of following formula (XX) expression are carried out the Heck reaction, wherein use palladium catalyst (close palladium, dibenzylideneacetonepalladium palladium or dichloride two (triphenylphosphine) as palladium-carbon dust, acid chloride, four (triphenylphosphine) and close palladium), exist or do not exist phosphine ligand (as three (2-aminomethyl phenyl) phosphine or triphenylphosphines and exist under the alkali (as triethylamine, sodium tert-butoxide, potassium tert.-butoxide or cesium fluoride), in inert solvent, to react.As the solvent that is used to react, for example, acetonitrile, toluene, tetrahydrofuran (THF), its mixed solvent etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 1 hour to 2 days, this can change according to used raw material, solvent and temperature of reaction.
Flow process 4-2
The compound of following formula (XXII) expression can prepare like this: in inert solvent, the compound of following formula (XXI) being represented with palladium catalyst (as palladium-carbon dust) carries out shortening.As the solvent that is used for catalytic hydrogenation reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), ethyl acetate, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 1 hour to 2 days, this can change according to used raw material, solvent and temperature of reaction.
Flow process 4-3
The The compounds of this invention of following formula (IIb) expression can prepare like this: in inert solvent (according to circumstances need after adding I-hydroxybenzotriazole suitably); there is condensing agent (as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride or dicyclohexyl carbodiimide) and existing alkali (as triethylamine or N; the N-diisopropylethylamine) under; the compound of following formula (XXII) expression and the sulfonamide derivatives of following formula (XVIII) are carried out condensation; then, according to circumstances need to remove blocking group suitably with ordinary method.As the solvent that is used for condensation reaction, for example, N, dinethylformamide, methylene dichloride, tetrahydrofuran (THF), its mixed solvent etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 1 hour to 2 days, this can change according to used raw material, solvent and temperature of reaction.
Flow process 4-4
The pyrazole derivatives of following formula of the present invention (Ic) expression can prepare like this: the compound to following formula (IIb) expression carries out alkaline hydrolysis, according to circumstances needs then to remove blocking group suitably with ordinary method.As the solvent that is used for hydrolysis reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), water, its mixed solvent etc. can be used as to be enumerated.As alkali, for example, sodium hydroxide, sodium methylate, sodium ethylate etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.Compound is at R after hydrolysis
12, R
14And/or R
15In have under the situation of blocking group, protecting group can be removed with ordinary method as flow process 1-9 suitably.
In the formula, L
4, R
2, R
3, R
4, R
5, R
6, R
7, R
12, R
14, R
15, Q, Q
2, T, T
2, Y
1Has identical meanings as defined above with Z.
Flow process 5-1
The compound of following formula of the present invention (IIc) expression can prepare like this:
In inert solvent (according to circumstances need after adding I-hydroxybenzotriazole suitably); there is condensing agent (as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride or dicyclohexyl carbodiimide) and existing alkali (as triethylamine or N; the N-diisopropylethylamine) under; the compound of following formula (XXI) expression and the sulfonamide derivatives of following formula (XVIII) are carried out condensation; then, according to circumstances need to remove blocking group suitably with ordinary method.As the solvent that is used for condensation reaction, for example, N, dinethylformamide, methylene dichloride, tetrahydrofuran (THF), its mixed solvent etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 1 hour to 2 days, this can change according to used raw material, solvent and temperature of reaction.
Flow process 5-2
The pyrazole derivatives that following formula of the present invention (IIc) is expressed can prepare like this: the pyrazole derivatives of following formula (XIX) expression and the alkene derivatives of following formula (XXIII) expression are carried out the Heck reaction, wherein use palladium catalyst (close palladium, dibenzylideneacetonepalladium palladium or dichloride two (triphenylphosphine) as palladium-carbon dust, acid chloride, four (triphenylphosphine) and close palladium), existing or not having phosphine ligand (as three (2-aminomethyl phenyl) phosphine or triphenylphosphine) and exist under the alkali (as triethylamine, sodium tert-butoxide, potassium tert.-butoxide or cesium fluoride), in inert solvent, react.As the solvent that is used to react, for example, acetonitrile, toluene, tetrahydrofuran (THF), its mixed solvent etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 1 hour to 2 days, this can change according to used raw material, solvent and temperature of reaction.
Flow process 5-3
The pyrazole derivatives of following formula of the present invention (Id) expression can prepare like this: the compound to following formula (IIc) expression carries out alkaline hydrolysis, according to circumstances needs then to remove blocking group suitably with ordinary method.As the solvent that is used for hydrolysis reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), water, its mixed solvent etc. can be used as to be enumerated.As alkali, for example, sodium hydroxide, sodium methylate, sodium ethylate etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.Compound is at R after hydrolysis
12, R
14And/or R
15In have under the situation of blocking group, protecting group can be removed with ordinary method as flow process 1-9 suitably.
Flow process 5-4
The compound of following formula (IIb) expression can prepare like this: in inert solvent, the compound of following formula (IIc) being represented with palladium catalyst (as palladium-carbon dust) carries out shortening.As the solvent that is used for catalytic hydrogenation reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), ethyl acetate, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 1 hour to 2 days, this can change according to used raw material, solvent and temperature of reaction.
Flow process 5-5
The compound of following formula of the present invention (Ic) expression can prepare like this: in inert solvent, the compound of following formula (Id) being represented with palladium catalyst (as palladium-carbon dust) carries out shortening.As the solvent that is used for catalytic hydrogenation reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), ethyl acetate, its mixed solvent etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 1 hour to 2 days, this can change according to used raw material, solvent and temperature of reaction.
Flow process 5-6
The pyrazole derivatives of following formula of the present invention (Ic) expression can prepare like this: the compound to following formula (IIb) expression carries out alkaline hydrolysis, according to circumstances needs then to remove blocking group suitably with ordinary method.As the solvent that is used for hydrolysis reaction, for example, methyl alcohol, ethanol, tetrahydrofuran (THF), water, its mixed solvent etc. can be used as to be enumerated.As alkali, for example, sodium hydroxide, sodium methylate, sodium ethylate etc. can be used as to be enumerated.Temperature of reaction usually can from 0 ℃ to reflux temperature, and the reaction times usually from 30 minutes to 1 day, this can change according to used raw material, solvent and temperature of reaction.Compound is at R after hydrolysis
12, R
14And/or R
15In have under the situation of blocking group, protecting group can be removed with ordinary method as flow process 1-9 suitably.
With the The compounds of this invention that the following formula (I) of above-mentioned Production Flow Chart acquisition is represented, available conventional separation means is separated and purifying, as fractional recrystallization (fractional recrystallization), usefulness chromatography purification, solvent extraction and Solid-Phase Extraction.
The pyrazole derivatives of following formula of the present invention (I) expression, available ordinary method changes pharmacy acceptable salt into.The example of these salt comprises and mineral acid (example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, nitric acid, phosphoric acid etc.) acid salt of Xing Chenging, with organic acid (as arboxylic acid, methylsulfonic acid, Phenylsulfonic acid, tosic acid, propionic acid, citric acid, succsinic acid, tartrate, fumaric acid, butyric acid, oxalic acid, propanedioic acid, toxilic acid, lactic acid, oxysuccinic acid, carbonic acid, L-glutamic acid, aspartic acid etc.) acid salt of Xing Chenging, the salt that forms with mineral alkali is (as sodium salt, sylvite etc.), and with organic bases (as N-methyl D glucosamine, N, N '-dibenzyl-ethylenediamin, the 2-monoethanolamine, three (methylol) aminomethane, arginine, Methionin etc.) salt of Xing Chenging.
The compound of following formula of the present invention (I) expression comprises the solvate that forms with pharmaceutically acceptable solvent (as the second alcohol and water).
In the pyrazole derivatives of following formula of the present invention (I) expression and prodrug thereof, have in each compound of unsaturated link(age) and have two kinds of isomer.In the present invention, can adopt cis (Z)-isomer or trans (E)-isomer.
In the pyrazole derivatives and prodrug thereof of following formula of the present invention (I) expression, in having each compound of unsymmetrical carbon, there are two kinds of rotational isomerisms of R isomer and S isomer (except pyranoglucose oxygen base section or galactopyranose oxygen base section).In the present invention, can use any one or two kinds of mixture of isomers in the isomer.
The preparation of the prodrug of the compound of following formula of the present invention (I) expression, can be according to a conventional method, use reagent corresponding, any one that organize under being selected from by compound shown in the proper group introducing following formula (I) that will form prodrug or a plurality of group: hydroxyl (is positioned at pyranoglucose base section or galactopyranose base section or randomly is positioned at R
1, R
2, R
4Or R
5), ring is amino (works as R
1When being hydrogen atom) and amino (work as R
1, R
2, R
4Or R
5Be when having amino substituting group), thus prodrug (as halogenide etc.) produced, according to circumstances need then to separate suitably and purifying with ordinary method.As the group that is used at hydroxyl or amino formation prodrug, for example, C
2-7Acyl group, C
1-6The C that alkoxyl group replaces
2-7Acyl group, C
2-7The C that alkoxy carbonyl replaces
2-7Acyl group, C
2-7The C that alkoxy carbonyl, aryl replace
2-7Alkoxy carbonyl, C
1-6The C that alkoxyl group replaces
2-7Alkoxy carbonyls etc. can be used as to be enumerated.As the group that is used for forming prodrug at ring amino, for example, C
2-7Acyl group, C
1-6The C that alkoxyl group replaces
2-7Acyl group, C
2-7The C that alkoxy carbonyl replaces
2-7Acyl group, C
2-7Alkoxy carbonyl, C
1-6The C that alkoxyl group replaces
2-7Alkoxy carbonyl, (C
2-7Acyloxy) methyl, 1-(C
2-7Acyloxy) ethyl, (C
2-7Alkoxy carbonyl) oxo methyl, 1-[(C
2-7Alkoxy carbonyl) oxo] ethyl, (C
3-7Cycloalkyl) the oxo ketonic oxygen is for methyl, 1-[(C
3-7Cycloalkyl) oxo ketonic oxygen generation] ethyl etc. can be used as and enumerate.Term " C
2-7Acyl group " refer to have the straight or branched acyl group of 2-7 carbon atom, for example ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, pivaloyl group, caproyl etc.; And term " C
1-6The C that alkoxyl group replaces
2-7Acyl group " refer to by above-mentioned C
1-6The above-mentioned C that alkoxyl group replaces
2-7Acyl group; Term " C
2-7The C that alkoxy carbonyl replaces
2-7Acyl group " refer to by above-mentioned C
2-7The above-mentioned C that alkoxy carbonyl replaces
2-7Acyl group; Term " the C that aryl replaces
2-7Alkoxy carbonyl " refer to by the above-mentioned C of above-mentioned acyl substituted
2-7Alkoxy carbonyl is as benzyloxycarbonyl; Term " C
1-6The C that alkoxyl group replaces
2-7Alkoxy carbonyl " refer to by above-mentioned C
1-6The above-mentioned C that alkoxyl group replaces
2-7Alkoxy carbonyl; Term " (C
2-7Acyloxy) methyl " refer to by above-mentioned C
2-7The methylol that acyl group replaces at O-; Term " 1-(C
2-7Acyloxy) ethyl " refer to by above-mentioned C
2-7The 1-hydroxyethyl that acyl group replaces at O-; Term " (C
2-7Alkoxy carbonyl) oxo methyl " refer to by above-mentioned C
2-7The methylol that alkoxy carbonyl replaces; And term " 1-[(C
2-7Alkoxy carbonyl) oxo] ethyl " refer to by above-mentioned C
2-7The 1-hydroxyethyl that alkoxy carbonyl replaces at O-.In addition, term " (C
3-7Cycloalkyl) oxo carbonyl " refer to have above-mentioned C
3-7The cyclo alkoxy carbonyl of cycloalkyl; Term " (C
3-7Cycloalkyl) the oxo ketonic oxygen is for methyl " refer to by above-mentioned (C
3-7Cycloalkyl) the oxo carbonyl is at the methylol of O-replacement; And term " 1-[(C
3-7Cycloalkyl) oxo ketonic oxygen generation] ethyl " refer to by above-mentioned (C
3-7Cycloalkyl) the oxo carbonyl is at the 1-hydroxyethyl of O-replacement.In addition, as the group that forms prodrug, glucopyranosyl or galactopyranose base can be used as to be enumerated.For example, these groups should be introduced in glucopyranosyl or the galactopyranose base 4 or 6 hydroxyl, more preferably are introduced in the glucopyranosyl 4 or 6 hydroxyl.
The pyrazole derivatives of following formula of the present invention (I) expression, for example, as described belowly suppress active at people SGLT1 and confirm to show in the test potent people SGLT1 and suppress active, and raise at the rat serum glucose level and to suppress the active activity that excellent inhibition blood glucose level raises that confirms to show in the test.Therefore, the pyrazole derivatives that following formula of the present invention (I) is represented shows excellent SGLT1 and suppresses active in small intestine, and can significantly suppress the rising of blood glucose level and/or reduce blood semi-lactosi level by the absorption that postpones glucose and semi-lactosi.Therefore, the pyrazole derivatives that contains following formula of the present invention (I) expression, its pharmacy acceptable salt or prodrug are as the pharmaceutical composition of activeconstituents, extremely be suitable for as the medicine that suppresses postprandial hyperglycemia, suppress in the individuality to develop into the medicine of diabetes from impaired glucose tolerance (IGT) or the too much obstacle of fasting plasma glucose (IFG), and the medicine of prevention or treatment hyperglycemia relative disease is [as diabetes, impaired glucose tolerance, the too much obstacle of fasting plasma glucose, diabetic complication is (as retinopathy, neuropathy, ephrosis, ulcer, the macroscopic view vascular disease), obesity, hyperinsulinemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, the lipid metabolism imbalance, atherosclerosis, hypertension, congestive heart failure, oedema, hyperuricemia, gout etc., these diseases relate to the SGLT1 activity in the small intestine], and the medicine of prevention or treatment and blood semi-lactosi level rising diseases associated (as galactosemia).
In addition, The compounds of this invention is fit to and at least a drug combination except the SGLT2 inhibitor.Can comprise with the example of the medicine of The compounds of this invention coupling: insulin sensitivity enhancer; glucose absorption inhibitor; biguanides; insulin secretion enhancers; the SGLT2 inhibitor; Regular Insulin or insulin analog; glucagon receptor antagonist; the insulin receptor kinase stimulant; three peptidyl peptase II inhibitor; inhibitors of dipeptidyl IV; Protein Tyrosine Phosphatases-1B inhibitor; glycogen phosphorylase inhibitors; the Robison ester enzyme inhibitors; the fructose diphosphate enzyme inhibitors; pyruvate dehydrogenase inhibitor; liver starch heteroplasia inhibitor; D-chiro-inositol (D-chiroinsitol); glycogen synthase kinase-3 inhibitor; glucagon-like-peptide-1; the glucagon-like-peptide-1 analogue; the glucagon-like-peptide-1 agonist; islet amyloid polypeptide; the islet amyloid polypeptide analogue; the islet amyloid polypeptide agonist; aldose reductase inhibitor; senior glycan end product (advancedglycation endproducts) synthetic inhibitor; inhibitors of protein kinase C; the gamma aminobutyric acid receptor antagonist; the sodium channel antagonist; the transcription factor NF-KB inhibitor; the lipid peroxidation enzyme inhibitors; acid-the Dipeptidase inhibitor of N-acetylize-α-connection; insulin like growth factor-1; Thr6 PDGF BB (PDGF); Thr6 PDGF BB (PDGF) analogue is (as PDGF-AA; PDGF-BB; PDGF-AB); Urogastron (EGF); nerve growth factor; carnitine derivative; uridine; 5-hydroxyl-1-methyl glycolylurea; EGB-761; than More (bimoclomol); sulosemide; Y-128; anti-diarrhea agents (antidiarrhoics); cathartic; the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; Carboxymethylcellulose (fibric acid) derivative; β
3-adrenoceptor agonist; the acetyl-CoA chole-sterol acyltransferase inhibitor; probucol; the Thyroid Hormone Receptors agonist; cholesterol absorption inhibitor; esterase inhibitor; the microsomal triglyceride transfer protein inhibitor; lipoxygenase inhibitors; the carnitine palmitoyl transferase inhibitors; inhibitor for squalene synthetic enzyme; the low density lipoprotein receptor toughener; nicotinic acid derivates; the bile acide intercalating agent; sodium/biliary salts cotransporter inhibitor; cholestery ester transfer protein inhibitors; appetite-inhibiting agent; angiotensin converting enzyme inhibitor; the neutral endopeptidase inhibitor; angiotensin II receptor antagonists; the endothelin converting enzyme inhibitor; endothelin-receptor antagonists; diuretic(s); calcium antagonist; the vasorelaxation hypotensive agent; sympathetic blocker; the hypotensive agent of central action; α
2-adrenoceptor agonist, anti-platelet agents (antiplatelets agent), uric acid synthetic inhibitor, uricosuric agent and urine basifier.
With The compounds of this invention and above-mentioned one or more drug combinations the time, the formulation that the present invention includes administration simultaneously (perhaps is single agent, perhaps for the preparation that separates of identical or different route of administration administration), and by the preparation that separates (with identical or different route of administration administration) of various dose administration pitch time.The pharmaceutical composition that contains The compounds of this invention and said medicine comprises the formulation as single agent or the preparation that separates, so that carry out coupling as mentioned above.
When with above-mentioned one or more medicines suitably during coupling, The compounds of this invention can or be treated in prevention and be obtained the effect more favourable than additive effect aspect the above-mentioned disease.In addition, compare with only using a kind of medicine, dosage can descend, and perhaps uses the adverse effect of the medicine except the SGLT1 inhibitor jointly and can be avoided or reduce.
Being used for the particular compound of coupling and preferred disease to be treated enumerates below.Yet the present invention is not limited thereto, and particular compound comprise its free cpds and they or other pharmacy acceptable salt.
The example of insulin sensitivity enhancer has, peroxisome proliferator-activated receptor-gamma agonists such as troglitazone, the hydrochloric acid U-721017E, rosiglitazone (rosiglitazone) maleate, darglitazone sodium, GI-262570, Netoglitazone (rosiglitazone), LG-100641, NC-2100, T-174, DRF-2189, CLX-0921, CS-011, GW-1929, ciglitazone, englitazone sodium and NIP-221, peroxisome proliferator-activated acceptor-alfa agonists such as GW-9578 and BM-170744, peroxisome proliferator-activated acceptor-α/gamma agonist such as GW-409544, KRP-297, NN-622, CLX-0940, LR-90, SB-219994, DRF-4158 and DRF-MDX8, retinoids X receptor stimulant such as ALRT-268, AGN-4204, MX-6054, AGN-194204, LG-100754 and hundred Sha Luoting (bexarotene), and if other insulin sensitivity enhancer lattice give birth to (reglixane), ONO-5816, MBX-102, CRE-1625, FK-614, CLX-0901, CRE-1633, NN-2344, BM-13125, BM-501050, HQL-975, CLX-0900, MBX-668, MBX-675, S-15261, GW-544, AZ-242, LY-510929, AR-H049020 and GW-501516.Insulin sensitivity enhancer is preferred for diabetes, impaired glucose tolerance, diabetic complication, obesity, hyperinsulinemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, lipodystrophy or arteriosclerosis, more preferably be used for diabetes, impaired glucose tolerance or hyperinsulinemia, this is because improved the disorderly situation of insulin signaling transduction in the surrounding tissue and strengthened that ingestion of glucose enters tissue from blood, thereby has reduced glucose level.
Example as glucose absorption inhibitor, compound except the SGLT1 inhibitor, alpha-glucosidase inhibitor such as acarbose, voglibose, miglitol, CKD-711, emiglitate, MDL-25 are arranged, 637, Camiglibose and MDL-73,945, alpha-amylase inhibitor such as AZM-127.Glucose absorption inhibitor is preferred for diabetes, impaired glucose tolerance, diabetic complication, obesity or hyperinsulinemia, more preferably be used for impaired glucose tolerance, this is because suppressed the enzymolysis of the enzyme of intestines and stomach to carbohydrate in the food, and suppresses or delayed the absorption of health to glucose.
The example of two guanidines has phenformin, hydrochloric acid buformin, hydrochloric acid metformin etc.Biguanides is preferred for diabetes, impaired glucose tolerance, diabetic complication or hyperinsulinemia, more preferably be used for diabetes, impaired glucose tolerance or hyperinsulinemia, this is because the restraining effect of liver glyconeogenesis has been reduced glucose level, has promoted the glucolytic influence of anaerobism in the tissue or has improved in the surrounding tissue effect to insulin resistance.
The example of insulin secretion enhancers has tolbutamide; P-607; first sulphur nitrogen grass urea; acetohexamide; U26452; glyburide (Glyburide); gliclazide; 1-butyl-3-metanilyl urine; invenol; glibornuride; Glipizide; gliquidone; glisoxepide; Glybuthiazole; glybuzole; glyhexamide; glymidine sodium; glypinamide; R-131; metahexamide; glimepiride; nateglinide (nateglinide); mitiglinide hydrate of calcium (mitiglinide calcium hydrate); repaglinide etc.In addition, insulin secretion enhancers comprises sugared kinase activator agent such as RO-28-1675.Insulin secretion enhancers is preferred for diabetes, impaired glucose tolerance or diabetic complication, more preferably be used for diabetes or impaired glucose tolerance, thereby this is because reduced glucose level and strengthened insulin secretion by acting on the pancreas beta cell.
The example of SGLT2 inhibitor, T-1095 is arranged and be described in compound in the following patent publications: Japanese patent application publication No.Hei10-237089 and 2001-288178, and international application publication No.WO01/16147, WO01/27128, WO01/68660, WO01/74834, WO01/74835, WO02/28872, WO02/36602, WO02/44192, WO02/53573 etc.The SGLT2 inhibitor is preferred for diabetes, impaired glucose tolerance, diabetic complication, obesity or hyperinsulinemia, more preferably be used for diabetes, impaired glucose tolerance, obesity or hyperinsulinemia are because they can absorb the level that reduces blood glucose again by what suppress glucose at kidney proximal tubule place.
The example of Regular Insulin or insulin analog has the analogue of insulin human, animal insulin, human or animal's Regular Insulin etc.These preparations are preferred for diabetes, impaired glucose tolerance or diabetic complication, more preferably are used for diabetes or impaired glucose tolerance.
The example of glucagon receptor antagonist has BAY-27-9955, NNC-92-1687 etc.; The example of insulin receptor kinase stimulant has TER-17411, L-783281, KRX-613 etc.; The example of three peptidyl peptase II inhibitor has UCL-1397 etc.; The example of inhibitors of dipeptidyl IV has NVP-DPP728A, TSL-225, P-32/98 etc.; The example of Protein-tyrosine-phosphatase-1B inhibitor has PTP-112, OC-86839, PNU-177496 etc.; The example of glycogen phosphorylase inhibitors has NN-4201, CP-368296 etc.; The example of fructose-diphosphatase inhibitor has R-132917 etc.; The example of pyruvate dehydrogenase inhibitor has AZD-7545 etc.; The example of glycogen heteroplasia inhibitor has FR-225659 etc.; The example of glucagon-like-peptide-1 analogue has exendin-4, CJC-1131 etc.; The example of glucagon-like-peptide-1 agonist has AZM-134, LY-315902 etc.; The example of islet amyloid polypeptide, islet amyloid polypeptide analogue, islet amyloid polypeptide agonist has tripro-amylin acetate etc.In these medicines, G-6-Pase inhibitor, D-chiro-inositol, glycogen synthase kinase-3 inhibitors, glucagon-like-peptide-1 are preferred for diabetes, impaired glucose tolerance, diabetic complication or hyperinsulinemia, more preferably are used for diabetes or impaired glucose tolerance.
The example of aldose reductase inhibitor has ascorbyl gamolenate, tolrestatin, epalrestat, ADN-138, BAL-ARI8, ZD-5522, ADN-311, GP-1447, IDD-598, fidarestat (fidarestat), sorbinil, Statyl, Li Sasita (risarestat), zenarestat, minalrestat (minalrestat), Mei Suonier (methosorbinil), AL-1567, Mi Ruisita, M-16209, TAT, AD-5467, zopolrestat, AS-3201, NZ-314, SG-210, JTT-811, Lin Duosita (lindolrestat) etc.Aldose reductase inhibitor is preferred for diabetic complication, and this is that it is present in the lasting hyperglycemia state of diabetic complication tissue because it can suppress the excessive intracellular accumulation that aldose reductase also can reduce Sorbitol Powder in the accelerating type poly-hydroxy approach.
The example that senior glycan end product forms inhibitor has Pyridoxylamine, OPB-9195, ALT-946, ALT-711, pimagedine hydrochloride etc.Senior glycan end product forms inhibitor and is preferred for diabetic complication, and this is because it can suppress the formation of senior glycan end product, increases under the lasting hyperglycemia state of this end product in diabetes, and can alleviate the damage of pair cell.
The example of inhibitors of protein kinase C has LY-333531, Mi Duosilin (midostaurin) etc.Inhibitors of protein kinase C is preferred for diabetic complication, but this is the activity because of its arrestin kinase c, and it continues to keep hyperglycemia state in diabetes.
The example of gamma-aminobutyric acid receptor antagonist has topiramate etc.; The example of sodium channel antagonist has mexiletine hydrochloride, O'Casey equality; The example of the transcription factor NF-KB inhibitor Pu Tan (dexlipotam) etc. that gets profit; The example of lipid peroxide enzyme inhibitors has Tiritazad (tirilazad) methylsulfonyl ester etc.; The example of the acid-Dipeptidase inhibitor of N-acetylize-α-connection has GPI-5693 etc.; The example of carnitine derivative has carnitine, hydrochloric acid L-carnitine, L-carnitine muriate, L-carnitine, ST-261 etc.In these medicines, insulin-like growth factor I, Thr6 PDGF BB, Thr6 PDGF BB analogue, Urogastron, nerve growth factor, uridine, 5-hydroxyl-1-methylhydantoi, EGB-761, ratio More, sulosemide, Y-128 are preferred for diabetic complication.
The example of anti-diarrhea agents or cathartic has polycarbophil calcium, albumin tannate, Vikaline etc.These medicines are preferred for following dysentery, the constipation and other diseases in diseases such as diabetes.
The example of methylol-glutaryl CoA reductase inhibitor has cerivastatin sodium, Pravastatin sodium, lovastatin, Simvastatin, fluvastatin sodium, the atorvastatin hydrate of calcium, SC-45355, SQ-33600, CP-83101, BB-476, L-669262, S-2468, DMP-565, U-20685, BAY-x-2678, BAY-10-2987, Da Tating calcium (calcium pitavastatin), Luo Shatating calcium (calciumrosuvastatin), Colestolone, Dalvastatin, acitemate, mevastatin, crilvastatin, BMS-180431, BMY-21950, the lattice logical sequence is cut down his spit of fland, his spit of fland (carvastatin) of block-regulations, BMY-22089, Bervastatin etc.Methylol-glutaryl CoA reductase inhibitor is preferred for hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, lipodystrophy or arteriosclerosis, more preferably be used for hyperlipidaemia, hypercholesterolemia or arteriosclerosis, thereby this is to reduce blood cholesterol levels because it can suppress 3-hydroxy-3-methylglutaryl coenzyme A reductase.
The example of fiber acid derivative has bezafibrate, Sgd-24774, binifibrate, Win-35833, S-8527, chlorine Bei Te, the special aluminium of chlorine shellfish, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pirifibrate, Ronifibrate, simfibrate, Sai Oubeite (theofibrate), AHL-157 etc.Fiber acid derivative is preferred for hyperinsulinemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, lipodystrophy or arteriosclerosis, more preferably be used for hyperlipidaemia, hypertriglyceridemia or arteriosclerosis, this is because it can activate the lipoprotein lipase of liver and strengthen oxidation of fatty acids, thereby has reduced the triglyceride levels of blood.
β
3The example of-adrenoceptor agonists has BRL-28410, SR-58611A, ICI-198157, ZD-2079, BMS-194449, BRL-37344, CP-331679, CP-114271, L-750355, BMS-187413, SR-59062A, BMS-210285, LY-377604, SWR-0342SA, AZ-40140, SB-226552, D-7114, BRL-35135, FR-149175, BRL-26830A, CL-316243, AJ-9677, GW-427353, N-5984, GW-2696, YM178 etc.β
3-adrenoceptor agonists is preferred for obesity, hyperinsulinemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia or lipodystrophy, more preferably is used for obesity or hyperinsulinemia, and this is because it can stimulate β in the fatty tissue
3-adrenoceptor also strengthens oxidation of fatty acids, thereby causes consumed energy.
The example of acyl group-coenzyme A chole-sterol acyltransferase inhibitor has NTE-122; MCC-147; PD-132301-2; DUP-129; U-73482; U-76807; RP-70676; P-06139; CP-113818; RP-73163; FR-129169; FY-038; EAB-309; KY-455; LS-3115; FR-145237; T-2591; J-104127; R-755; FCE-28654; YIC-C8-434; A Wamite (avasimibe); CI-976; RP-64477; F-1394; Ai Demite (eldacimibe); CS-505; CL-283546; YM-17E; lecimibide; 447C88; YM-750; E-5324; KW-3033; HL-004; Ai Fumite (eflucimibe) etc.Acyl group-coenzyme A chole-sterol acyltransferase inhibitor is preferred for hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia or lipodystrophy; more preferably be used for hyperlipidaemia or hypercholesterolemia, thereby this is to reduce blood cholesterol levels because it can suppress acyl group-coenzyme A cholesterol acetyl transferase.
The example of thyroid hormone receptor agonists has sodium triiodothyronine, levothyroxine sodium, KB-2611 etc.; The example of cholesterol absorption inhibitor has Yi Zhami than (ezetimibe), SCH-48461 etc.; The example of esterase inhibitor has orlistat, ATL-962, AZM-131, RED-103004 etc.; The example of Carnitine palmitoyltransferase inhibitor has etomoxir etc.; The example of squalene synthase inhibitor has SDZ-268-198, BMS-188494, A-87049, RPR-101821, ZD-9720, RPR-107393, ER-27856 etc.; The example of nicotinic acid derivates has nicotinic acid, niacinamide, nicomol, pentaerythritol tetranicotinate, Olbetam, Nicoril etc.; The example of bile acid chelating agent has Colestyramine, Colestilan, examines tretamine hydrochloride (colesevelamhydrochloride), GT-102-279 etc.; The example of sodium/bile acide cotransporter inhibitor has 264W94, S-8921, SD-5613 etc.; The example of cholestery ester transfer protein inhibitors has PNU-107368E, SC-795, JTT-705, CP-529414 etc.In these medicines, probucol, microsome tri-glyceride transporter inhibitors, lipoxygenase inhibitor, low density lipoprotein receptor toughener are preferred for hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia or lipodystrophy.
The example of appetite suppressant has monoamine reuptake inhibitors, thrombotonin reuptake inhibitor, thrombotonin release of irritants, combination of serotonin agonist (5HT especially
2C-agonist), norepinephrine reuptake inhibitor, norepinephrine release of irritants, α
1-adrenoceptor agonists, β
2-adrenoceptor agonists, dopamine agonist, hemp ester (cannabinoid) receptor antagonist, gamma-aminobutyric acid receptor antagonist, H
3-histamine antagonist, the L-histamine, obesity inhibin (leptin), the obesity inhibin analogue, the obesity inhibin receptor agonist, melanocortin (melanocortin) receptor stimulant (MC3-R agonist especially, the MC4-R agonist), α-melanocyte stimulates hormone, the transcript of Cocaine and Amphetamine control, redwood albumen (mahogany protein), enterostatin (enterostatin) agonist, thyrocalcitonin, the peptide relevant with calcitonin gene, sandfly toad peptide, cholecystokinin agonist (especially CCK-A agonist), corticotropin releasing hormone, the corticotropin releasing hormone analogue, the corticotropin releasing hormone agonist, Urocortin (urocortin), somatostatin, somatostatin analogs, the somatostatin receptor agonist, pituitary adenylate cyclase activation peptide, brain derived neurotrophic factor, ciliary neurotrophic factor, thyrotrophin-releasing hormone, neurotensin, sauvagine, the neuropeptide tyrosine antagonist, the opioid peptide antagonists, the galanin antagonist, the melanin concentration hormone antagonist, agouti associated protein inhibitor and orexin receptor antagonists etc.Specifically, monoamine reuptake inhibitors has Mazindol etc.; The example of thrombotonin reuptake inhibitor has Dexfenfluramine Hudrochlorid, Phenfluoramine, Sibutramine hydrochloride, fluvoxamine maleate, sertraline hydrochloride etc.; The example of combination of serotonin agonist has Ying Nuo Qu Tan (inotriptan), (+)-go cresol fluorine Lamine etc.; The example of norepinephrine reuptake inhibitor has Bupropion, GW-320659 etc.; The example of norepinephrine release of irritants has rolipram, YM-992 etc.; β
2The example of-adrenoceptor agonists has Amphetamine, dexamphetamine, phentermine, Benzphetamine, meth, phendimetrazine, Preludin, Diethylpropion, Phenylpropanolamine, clobenzorex etc.; The example of dopamine agonist has ER-230, many Pulis new (doprexin), bromocriptine methylsulfonyl ester etc.; The favourable Mo Nata of example (rimonabant) of hemp ester receptor antagonist etc.; The example of gamma-aminobutyric acid receptor antagonist has topiramate etc.; H
3The example of-histamine antagonist has GT-2394 etc.; The example of obesity inhibin, obesity inhibin analogue or obesity inhibin receptor agonist has LY-355101 etc.; The example of cholecystokinin agonist (especially CCK-A agonist) has SR-146131, SSR-125180, BP-3.200, A-71623, FPL-15849, GI-248573, GW-7178, GI-181771, GW-7854, A-71378 etc.; The example of neuropeptide tyrosine antagonist has SR-120819-A, PD-160170, NGD-95-1, BIBP-3226,1229-U-91, CGP-71683, BIBO-3304, CP-671906-01, J-115814 etc.Appetite-inhibiting agent is preferred for diabetes, impaired glucose tolerance, diabetic complication, obesity, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, lipodystrophy, arteriosclerosis, hypertension, congestive heart failure, oedema, hyperuricemia or gout, more preferably be used for obesity, this is because it can activate or suppress the active and depress appetite of the biologically active peptides in IC monoamine or the maincenter appetite Controlling System, takes in thereby reduce energy.
The example of angiotensin-convertion enzyme inhibitor has captopril, enalapril maleate, alacepril, delapril hydrochloride, Ramipril, lisinopril, hydrochloric acid imidapril, benazepril hydrochloride, SQ-29852 monohydrate, Yipingshu, fosinopril sodium, perindopril erbumine, moveltipril calcium, quinapril hydrochloride, spirapril hydrochloride, temocapril hydrochloride, Trolapril, zofenopril calcium, hydrochloric acid not glycosides Puli, rentiapril etc.Angiotensin-convertion enzyme inhibitor is preferred for diabetic complication or hypertension.
The example of neutral endopeptidase inhibitor has Ou Puqu to draw (omapatrilat), MDL-100240, Fasidotril, Sampatrilat, GW-660511X, rice Sha pula (mixanpril), SA-7060, E-4030, SLV-306, ecadotril etc.The neutral endopeptidase inhibitor is preferred for diabetic complication or hypertension.
The example of angiotensin II receptor antagonists has Candesartan hila west to carry (cilexetil), Candesartan hila west to carry/HCTZ, Losartan Potassium, Eprosartan methylsulfonyl ester, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, Ao Mishatan (olmesartan), Tasosartan, KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701 etc.Angiotensin II receptor antagonists is preferred for diabetic complication or hypertension.
The example of inhibitors of endothelin-converting enzyme has CGS-31447, CGS-35066, SM-19712 etc.; The example of endothelin receptor antagonists has L-749805, TBC-3214, BMS-182874, BQ-610, TA-0201, SB-215355, PD-180988, sitaxsentan sodium (sodium sitaxsentan), BMS-193884, reach as giving birth to smooth (darusentan), TBC-3711, bosentan, he gives birth to smooth sodium (sodium tezosentan) by azoles, J-104132, YM-598, S-0139, SB-234551, RPR-118031A, ATZ-1993, RO-61-1790, ABT-546, enrasentan (enlasentan), BMS-207940 etc.These medicines are preferred for diabetic complication or hypertension, more preferably are used for hypertension.
The example of diuretic(s) has chlorthalidone, metolazone, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, Hydroflumethiazide, the benzylic hydrogens chlorothiazide, Pentylhydroflumethiazide, Methyclothiazide, indapamide, tripamide, mefruside, azosemide, Ethacrynic, torasemide, piretanide, Furosemide, bumetanide, meticrane, potassium canrenoate, spironolactone, triamterene, aminophylline, BN-1270, LLU-α, PNU-80873A, Isosorbide, D-N.F,USP MANNITOL, the D-Sorbitol Powder, fructose, glycerine, acetazolamide, Methalthiazide, FR-179544, OPC-31260, Li Xi cuts down smooth (lixivaptan), hydrochloric acid health Buddhist nun cuts down smooth (conivaptan hydrochloride) etc.Diuretic(s) is preferred for diabetic complication, hypertension, congestive heart failure or oedema, more preferably is used for hypertension, congestive heart failure or oedema, thereby this is to bring high blood pressure down or improve oedema because it can increase to urinate.
The example of calcium antagonist has Aranidipine, efonidipine, nicardipine hydrochloride, Bamidipine Hydrochloride, KW-3049, CV-4093, cilnidipineb, nisoldipine, nitrendipine, nifedipine, nilvadipine, felodipine, the amlodipine esilate, pranidipine, R-75, Isrodipine, elgodipine, Azelnidipine, Lacidipine (62, his Horizon (vatanidipine) hydrochloride of method, Lemildipine, diltiazem hydrochloride, Crane sulphur Zhuo (clentiazem) maleate, verapamil hydrochloride, the S-verapamil, Fasudil Hydrochloride, Bepridil hydrochloride, Algocor (Ravizza) etc.; The example that causes vasodilative antihypertensive drug has indapamide, hydrochloric acid todralazine, hydralazine hydrochloride, cadralazine, budralazine etc.; The example of sympathetic blocking agent has amosulalol hydrochloride, Vasocard, E-643, PRAZOSINI HYDROCHLORIDE, Doxazosin methylsulfonyl ester, propranolol hydrochloride, atenolol USP 23, metoprolol tartrate, carvedilol, nipradolol, Celiprolol Hydrochorid, nebivolol, betaxolol hydrochloride, pindolol, Tertatolol Hydrochloride, bevantolol hydrochloride, timolol maleate, carteolol hydrochloride, the bisoprolol hemifumarate, the Bopindolol malonate, nipradolol, penbutolol vitriol, Acebutolol, N-696, the many Luo Er of sodium, urapidil, Indoramine etc.; Act on the favourable blood equality of example of the antihypertensive drug of nervus centralis; α
2The example of-adrenoceptor agonists has Tenso-Timelets, methyldopa, CHF-1035, guanabenz acetate, Guanfacine Hydrochloride, moxonidine, lofexidine, hydrochloric acid talipexole etc.These medicines are preferred for hypertension.
The example of anti-platelet agents has hydrochloric acid Ticlopidine, Dipyridamole, Cilostazole, ethyl Yi Sha spray ester (icosapentate), Sarpogrelatehydrochloride, Indoramine dihydrochloride, trapidil, beraprost sodium, Asprin etc.Anti-platelet agents is preferred for arteriosclerosis or congestive heart failure.
The example of uric acid synthetic inhibitor has Zyloric, oxipurinol etc.; The example of uricosuric has benzbromarone, probenecid etc.; The example of urine basifier has sodium bicarbonate, Tripotassium Citrate, Trisodium Citrate etc.These medicines are preferred for hyperuricemia or gout.
When with drug combination except the SGLT2 inhibitor, when for example being used for diabetes, be preferred with being selected from down at least a drug combination of organizing: insulin sensitivity enhancer, glucose absorption inhibitor, biguanides, insulin secretion enhancers, the SGLT2 inhibitor, Regular Insulin or insulin analog, glucagon receptor antagonist, the insulin receptor kinase stimulant, three peptidyl peptase II inhibitor, inhibitors of dipeptidyl IV, Protein Tyrosine Phosphatases-1B inhibitor, glycogen phosphorylase inhibitors, the Robison ester enzyme inhibitors, the fructose diphosphate enzyme inhibitors, pyruvate dehydrogenase inhibitor, liver starch heteroplasia inhibitor, D-chiro-inositol (D-chiroinsitol), glycogen synthase kinase-3 inhibitor, glucagon-like-peptide-1, the glucagon-like-peptide-1 analogue, the glucagon-like-peptide-1 agonist, islet amyloid polypeptide, the islet amyloid polypeptide analogue, islet amyloid polypeptide (amylin) agonist and appetite-inhibiting agent; With being selected from down at least a drug combination of organizing is preferred: insulin sensitivity enhancer, biguanides, insulin secretion enhancers, the SGLT2 inhibitor, Regular Insulin or insulin analog, glucagon receptor antagonist, the insulin receptor kinase stimulant, three peptidyl peptase II inhibitor, inhibitors of dipeptidyl IV, Protein Tyrosine Phosphatases-1B inhibitor, glycogen phosphorylase inhibitors, the Robison ester enzyme inhibitors, the fructose diphosphate enzyme inhibitors, pyruvate dehydrogenase inhibitor, liver starch heteroplasia inhibitor, D-chiro-inositol (D-chiroinsitol), glycogen synthase kinase-3 inhibitor, glucagon-like-peptide-1, the glucagon-like-peptide-1 analogue, the glucagon-like-peptide-1 agonist, islet amyloid polypeptide, islet amyloid polypeptide (amylin) analogue and islet amyloid polypeptide (amylin) agonist; With being selected from down at least a drug combination of organizing is preferred: insulin sensitivity enhancer, biguanides, insulin secretion enhancers, SGLT2 inhibitor and Regular Insulin or insulin analog.Similarly, when being used for diabetic complication, with being selected from down at least a drug combination of organizing is preferred: insulin sensitivity enhancer, glucose absorption inhibitor, biguanides, insulin secretion enhancers, the SGLT2 inhibitor, Regular Insulin or insulin analog, glucagon receptor antagonist, the insulin receptor kinase stimulant, three peptidyl peptase II inhibitor, inhibitors of dipeptidyl IV, Protein Tyrosine Phosphatases-1B inhibitor, glycogen phosphorylase inhibitors, the Robison ester enzyme inhibitors, the fructose diphosphate enzyme inhibitors, pyruvate dehydrogenase inhibitor, liver starch heteroplasia inhibitor, D-chiro-inositol (D-chiroinsitol), the Glycogen Synthase kinase 3 inhibitor, glucagon-like-peptide-1, the glucagon-like-peptide-1 analogue, the glucagon-like-peptide-1 agonist, islet amyloid polypeptide, the islet amyloid polypeptide analogue, the islet amyloid polypeptide agonist, aldose reductase inhibitor, senior glycan end product (advanced glycation endproducts) synthetic inhibitor, inhibitors of protein kinase C, the gamma aminobutyric acid antagonist, the sodium channel antagonist, the transcription factor NF-KB inhibitor, the lipid peroxidation enzyme inhibitors, the sour Dipeptidase inhibitor of N-acetylize-α-connection, insulin like growth factor-1, Thr6 PDGF BB, the Thr6 PDGF BB analogue, Urogastron, nerve growth factor, carnitine derivative, uridine, 5-hydroxyl-1-methylhydantoi (methylhidantoin), EGB-761, than More (bimoclomol), sulosemide, Y-128, angiotensin converting enzyme inhibitor, the neutral endopeptidase inhibitor, angiotensin II receptor antagonists, the endothelin converting enzyme inhibitor, endothelin-receptor antagonists and diuretic(s); With being selected from down at least a drug combination of organizing is preferred: aldose reductase inhibitor, angiotensin converting enzyme inhibitor, nerve (neutrality) endopeptidase inhibitor and angiotensin II receptor antagonists.In addition, when being used for obesity, be preferred with being selected from down at least a drug combination of organizing: insulin sensitivity enhancer, glucose absorption inhibitor, biguanides, insulin secretion enhancers, the SGLT2 inhibitor, Regular Insulin or insulin analog, glucagon receptor antagonist, the insulin receptor kinase stimulant, three peptidyl peptase II inhibitor, inhibitors of dipeptidyl IV, Protein Tyrosine Phosphatases-1B inhibitor, glycogen phosphorylase inhibitors, the Robison ester enzyme inhibitors, the fructose diphosphate enzyme inhibitors, pyruvate dehydrogenase inhibitor, liver starch heteroplasia inhibitor, D-chiro-inositol (D-chiroinsitol), glycogen synthase kinase-3 inhibitor, glucagon-like-peptide-1, the glucagon-like-peptide-1 analogue, the glucagon-like-peptide-1 agonist, islet amyloid polypeptide, the islet amyloid polypeptide analogue, the islet amyloid polypeptide agonist, β
3-adrenoceptor and appetite-inhibiting agent; With being selected from down at least a drug combination of organizing is preferred: SGLT2 inhibitor, β
3-adrenoceptor and appetite-inhibiting agent.
When pharmaceutical composition of the present invention is used for actual therapeutic, can use various formulations according to its purposes.The example of these formulations has pulvis, granule, micro mist agent, dry syrup, tablet, capsule, injection, solution, ointment, suppository, plaster etc., and they are oral or parenteral administration.Pharmaceutical composition of the present invention also comprises sustained release preparation, comprises intestines and stomach mucous membrane absorption preparation (for example international publication No:WO99/10010, WO99/26606, and Japanese Patent publication No:2001-2567).
These preparation of drug combination can be by with suitable medicine additives mixed or by dilution be dissolved in suitable additive, these additives have vehicle, disintegrating agent, tackiness agent, lubricant, thinner, buffer reagent, isotonic agent, antiseptic, wetting agent, emulsifying agent, dispersion agent, stablizer, solubilizing agent etc., and dispose this mixture according to ordinary method.When the drug combination beyond compound of the present invention and the SGLT1 inhibitor, can be with various activeconstituentss built in making various activeconstituentss together or respectively, thus make pharmaceutical composition.
When pharmaceutical composition of the present invention is used for actual therapeutic, can suitably determine as the compound of the above-mentioned general formula of the usefulness of activeconstituents (I) expression or the dosage of its pharmacy acceptable salt or prodrug according to the degree of each patient's age, sex, body weight and symptom and treatment, this dosage is approximately each grownup 0.1-1 every day when dosage forms for oral administration, 000mg, this dosage is approximately each grownup 0.01-300mg every day when parenteral administration, and daily dosage can be divided into once a day or several times and medication in suitable.Simultaneously, when the drug combination beyond compound of the present invention and the SGLT1 inhibitor, can reduce the dosage of The compounds of this invention, this depends on the dosage of the medicine beyond the SGLT1 inhibitor usually.
Embodiment
By following comparative example, embodiment and test case, further illustrate in greater detail the present invention.Yet the present invention is not subjected to the restriction of these examples.
The comparative example 1
2-amino-2-methyl propionic acid amide
To 2-benzyloxycarbonyl amino-2-methyl propionic acid (1g) at N, solution in the dinethylformamide (10mL), add I-hydroxybenzotriazole (0.63g), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (1.21g), triethylamine (1.76mL) and 28% ammonia soln (2mL), mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Organic layer is used 0.5mol/L hydrochloric acid, water, 1mol/L aqueous sodium hydroxide solution, water and salt water washing successively, uses anhydrous sodium sulfate drying then.Solvent is removed in decompression, obtains 2-benzyloxycarbonyl amino-2-methyl propionic acid amide (0.26g).This material is dissolved in methyl alcohol (5mL).Add 10% palladium-carbon dust (30mg) in this solution, mixture stirred 3 hours under hydrogen atmosphere then.Insoluble substance is removed by filtering, and then filtrate is carried out concentrating under reduced pressure, obtains title compound (0.11g).
1H-NMR(DMSO-d
6)δppm：
1.15(6H，s)，1.9(2H，brs)，6.83(1H，brs)，7.26(1H，brs)
The comparative example 2
The 4-[(4-bromophenyl) methyl]-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone
To sodium hydride (60%, 3.85g) in the suspension in tetrahydrofuran (THF) (250mL), add 4-methyl-3-oxopentanoic acid ethyl ester (15.2g), mixture stirred 10 minutes at 0 ℃ then.In reaction mixture, add the solution of 4-bromo benzyl bromo (20g) in tetrahydrofuran (THF) (100mL), mixture is in stirred overnight at room temperature then.In reaction mixture, add entry, and the mixture ethyl acetate extraction that forms.The organic layer anhydrous sodium sulfate drying, solvent is removed in decompression then.To the solution of residue in toluene (10mL), add hydrazine monohydrate (8.01g), mixture spends the night 100 ℃ of stirrings then.After reaction mixture was cooled to room temperature, solvent was removed in decompression.Add ethyl acetate (20mL) in residue, mixture was stirring at room 2 hours then.Sedimentary crystal is collected by filtration.The crystal of collecting is water and normal hexane washing successively, then at 40 ℃ of drying under reduced pressure, obtains title compound (11.5g).
1H-NMR(DMSO-d
6)δppm：
1.07(6H，d，J＝7.1Hz)，2.75-2.9(1H，m)，3.55(2H，s)，7.05-7.15(2H，m)，7.35-7.45(2H，m)
The comparative example 3
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-bromophenyl) methyl]-5-sec.-propyl-1H-pyrazoles
To the 4-[(4-bromophenyl) methyl]-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone (5.0g) is in the solution of methylene dichloride (50mL), add acetyl bromide-α-D-glucose (7.0g), zephiran chloride three (normal-butyl) ammonium (5.3g) and 5mol/L aqueous sodium hydroxide solution (8.5mL), mixture is in stirred overnight at room temperature then.Separate organic layer, solvent is removed in decompression then.Residue carries out purifying (eluent: n-hexane/ethyl acetate=1/1), obtain title compound (4.12g) by silica gel column chromatography.
1H-NMR(CDCl
3)δppm：
1.1-1.25(6H，m)，1.86(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.85-2.95(1H，m)，3.58(1H，d，J＝16.2Hz)，3.64(1H，d，J＝16.2Hz)，3.8-3.95(1H，m)，4.15(1H，dd，J＝12.4Hz，2.2Hz)，4.32(1H，dd，J＝12.4Hz，3.9Hz)，5.15-5.35(3H，m)，5.53(1H，d，J＝7.5Hz)，6.95-7.05(2H，m)，7.3-7.4(2H，m)
The comparative example 4
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and the 4-[(4-bromophenyl) methyl]-5-sec.-propyl-1H-pyrazoles (3.0g) and the solution of 3-butenoic acid (1.0g) in acetonitrile (15mL); add triethylamine (2.4g), acid chloride (II) (0.11g) and three (2-aminomethyl phenyl) phosphines (0.29g), mixture flows through night next time in shading then.Solvent is removed in decompression, and residue carries out purifying (eluent: ethyl acetate-methylene chloride=10/1), obtain title compound (1.74g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.84(3H，s)，2.01(3H，s)，2.02(3H，s)，2.05(3H，s)，2.8-2.95(1H，m)，3.2-3.3(2H，m)，3.59(1H，d，J＝16.0Hz)，3.66(1H，d，J＝16.0Hz)，3.8-3.9(1H，m)，4.18(1H，dd，J＝12.3Hz，1.8Hz)，4.33(1H，dd，J＝12.3Hz，3.8Hz)，5.15-5.35(3H，m)，5.4-5.5(1H，m)，6.2-6.3(1H，m)，6.4-6.5(1H，m)，7.0-7.1(2H，m)，7.2-7.3(2H，m)
The comparative example 5
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-the 2-carboxy vinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 4, wherein replaces the 3-butenoic acid with vinylformic acid.
1H-NMR(CDCl
3)δppm：
1.19(6H，d，J＝7.3Hz)，1.84(3H，s)，2.01(3H，s)，2.04(3H，s)，2.05(3H，s)，2.85-3.0(1H，m)，3.66(1H，d，J＝16.2Hz)，3.73(1H，d，J＝16.2Hz)，3.85-3.95(1H，m)，4.2(1H，dd，J＝12.6Hz，2.2Hz)，4.34(1H，dd，J＝12.6Hz，4.1Hz)，5.15-5.35(3H，m)，5.5(1H，d，J＝7.7Hz)，6.4(1H，d，J＝15.7Hz)，7.15-7.2(2H，m)，7.4-7.5(2H，m)，7.71(1H，d，J＝15.7Hz)
Embodiment 1
4-(4-[3-(formamyl methylamino formyl radical) propyl group] and phenyl } methyl)-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-({ 4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles (0.34g) is at N; solution in the dinethylformamide (1mL); add glycyl amide hydrochloride (0.12g), I-hydroxybenzotriazole (0.09g), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.15g) and triethylamine (0.27g), mixture is in stirred overnight at room temperature then.Insoluble substance is removed by filtering.In filtrate, add 5mol/L aqueous sodium hydroxide solution (0.5mL), mixture was stirring at room 1 hour then.Insoluble substance is removed by filtering; filtrate is by the reverse column chromatography purifying of preparation property (Shiseido CAPCELL PAK UG120 ODS then; 5 μ m; 120 ; 20 * 50mm; flow velocity 30mL/ minute linear gradient, water/acetonitrile=90/10-10/90) obtains 4-({ 4-[(1E)-3-(formamyl methylamino formyl radical) third-1-thiazolinyl] phenyl } methyl)-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles (0.03g).This material is dissolved in methyl alcohol (1mL).Add 10% palladium-carbon dust (0.01g) in this solution, mixture stirred 3 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and the solvent of filtrate is removed in decompression then, obtains title compound (0.02g).
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.85-1.95(2H，m)，2.25(2H，t，J＝7.6Hz)，2.6(2H，t，J＝7.5Hz)，2.85-2.95(1H，m)，3.25-3.4(4H，m)，3.6-3.9(6H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 2
4-{[4-(3-formamyl propyl group) phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses ammonium chloride to replace glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.8-1.95(2H，m)，2.19(2H，t，J＝7.6Hz)，2.58(2H，t，J＝7.5Hz)，2.85-2.95(1H，m)，3.3-3.45(4H，m)，3.6-3.8(3H，m)，3.8-3.9(1H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 3
4-(4-[3-(2-formamyl ethylamino formyl radical) propyl group] and phenyl } methyl)-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses the amino propionic acid amide of 3-to replace glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.8-1.95(2H，m)，2.15(2H，t，J＝7.3Hz)，2.4(2H，t，J＝6.7Hz)，2.56(2H，t，J＝7.5Hz)，2.85-2.95(1H，m)，3.25-3.45(6H，m)，3.6-3.9(4H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 4
4-(4-[3-(2-aminoethylamino formyl radical) propyl group] and phenyl } methyl)-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses N-benzyloxycarbonyl-1 hydrochloride to replace glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.85-1.95(2H，m)，2.19(2H，t，J＝7.6Hz)，2.58(2H，t，J＝7.5Hz)，2.8(2H，t，J＝6.1Hz)，2.85-2.95(1H，m)，3.2-3.4(6H，m)，3.6-3.9(4H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 5
4-(4-[3-(3-amino propyl amino formyl radical) propyl group] and phenyl } methyl)-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses N-benzyloxycarbonyl-1, and 3-diaminopropanes hydrochloride is replaced glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.6-1.7(2H，m)，1.8-1.95(2H，m)，2.17(2H，t，J＝7.7Hz)，2.57(2H，t，J＝7.5Hz)，2.68(2H，t，J＝7.1Hz)，2.85-2.95(1H，m)，3.22(2H，t，J＝6.7Hz)，3.25-3.45(4H，m)，3.6-3.9(4H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 6
4-(4-[3-(the amino butyl formamyl of 4-) propyl group] and phenyl } methyl)-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses N-benzyloxycarbonyl-1, and 4-diaminobutane hydrochloride is replaced glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.45-1.65(4H，m)，1.8-1.95(2H，m)，2.16(2H，t，J＝7.5Hz)，2.57(2H，t，J＝7.7Hz)，2.83(2H，t，J＝7.0Hz)，2.85-3.0(1H，m)，3.17(2H，t，J＝6.6Hz)，3.25-3.45(4H，m)，3.6-3.9(4H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 7
4-[(4-{3-[(S)-and 1-formamyl-2-(4-hydroxy phenyl) ethylamino formyl radical] propyl group } phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses L-tyramine amide hydrochloride to replace glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.7-1.8(2H，m)，2.1-2.2(2H，m)，2.44(2H，t，J＝7.5Hz)，2.76(1H，dd，J＝13.9Hz，9.3Hz)，2.85-2.95(1H，m)，3.04(1H，dd，J＝13.9Hz，5.5Hz)，3.25-3.45(4H，m)，3.6-3.9(4H，m)，4.57(1H，dd，J＝9.3Hz，5.5Hz)，5.0-5.1(1H，m)，6.65-6.75(2H，m)，6.95-7.15(6H，m)
Embodiment 8
4-{[4-(3-benzylamino formyl radical propyl group) phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses benzene methanamine to replace glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.85-1.95(2H，m)，2.22(2H，t，J＝7.5Hz)，2.57(2H，t，J＝7.5Hz)，2.8-2.95(1H，m)，3.25-3.45(4H，m)，3.6-3.9(4H，m)，4.33(2H，s)，5.0-5.1(1H，m)，7.0-7.15(4H，m)，7.15-7.45(5H，m)
Embodiment 9
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3 styroyl formamyl propyl group) phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses phenylethylamine to replace glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.75-1.9(2H，m)，2.12(2H，t，J＝7.5Hz)，2.51(2H，t，J＝7.7Hz)，2.77(2H，t，J＝7.5Hz)，2.8-2.95(1H，m)，3.25-3.45(6H，m)，3.6-3.9(4H，m)，5.0-5.15(1H，m)，6.95-7.05(2H，m)，7.05-7.3(7H，m)
Embodiment 10
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-(4-[3-(3-pyridylmethyl formamyl) propyl group] and phenyl } methyl)-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses 3-picoline amine to replace glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.85-1.95(2H，m)，2.22(2H，t，J＝7.6Hz)，2.56(2H，t，J＝7.6Hz)，2.85-2.95(1H，m)，3.25-3.45(4H，m)，3.6-3.9(4H，m)，4.37(2H，s)，5.0-5.1(1H，m)，7.0-7.15(4H，m)，7.35-7.45(1H，m)，7.7-7.8(1H，m)，8.4-8.45(1H，m)，8.45-8.5(1H，m)
Embodiment 11
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-[(4-{3-[2-(2-pyridyl) ethylamino formyl radical] propyl group } phenyl) methyl]-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses 2-(2-amino-ethyl) pyridine to replace glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.75-1.9(2H，m)，2.11(2H，t，J＝7.5Hz)，2.51(2H，t，J＝7.6Hz)，2.85-3.0(3H，m)，3.25-3.45(4H，m)，3.52(2H，t，J＝6.9Hz)，3.6-3.9(4H，m)，5.0-5.1(1H，m)，6.95-7.15(4H，m)，7.2-7.35(2H，m)，7.7-7.8(1H，m)，8.4-8.5(1H，m)
Embodiment 12
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-[(4-{3-[2-(dimethylamino) ethylamino formyl radical] propyl group } phenyl) methyl]-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses N, and the N-dimethyl-ethylenediamine is replaced glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.8-1.95(2H，m)，2.17(2H，t，J＝7.6Hz)，2.25(6H，s)，2.42(2H，t，J＝6.9Hz)，2.57(2H，t，J＝7.5Hz)，2.85-2.95(1H，m)，3.25-3.4(6H，m)，3.6-3.9(4H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 13
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-[(4-{3-[2-(morpholine-4-yl) ethylamino formyl radical] propyl group } phenyl) methyl]-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses 4-(2-amino-ethyl) morpholine to replace glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.8-1.95(2H，m)，2.17(2H，t，J＝7.6Hz)，2.4-2.55(6H，m)，2.58(2H，t，J＝7.6Hz)，2.85-2.95(1H，m)，3.25-3.45(6H，m)，3.6-3.9(8H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 14
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-{2-[bis (2-hydroxyethyl) amino] the ethylamino formyl radical } propyl group) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses N, and N-two (2-hydroxyethyl) quadrol is replaced glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.8-1.95(2H，m)，2.18(2H，t，J＝7.5Hz)，2.5-2.7(8H，m)，2.85-2.95(1H，m)，3.25(2H，t，J＝6.4Hz)，3.3-3.4(4H，m)，3.5-3.9(8H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 15
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{3-[bis (2-hydroxyethyl) amino] the propyl group formamyl } propyl group) phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses N, N-bis (2-hydroxyethyl)-1, and the 3-diaminopropanes is replaced glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.6-1.75(2H，m)，1.8-1.95(2H，m)，2.17(2H，t，J＝7.5Hz)，2.5-2.75(8H，m)，2.8-2.95(1H，m)，3.21(2H，t，J＝6.7Hz)，3.25-3.45(4H，m)，3.5-3.9(8H，m)，5.0-5.15(1H，m)，7.0-7.2(4H，m)
Embodiment 16
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-[(4-{3-[3-(dimethylamino) propyl group formamyl] propyl group } phenyl) methyl]-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses N, N-dimethyl-1, and the 3-diaminopropanes is replaced glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.6-1.75(2H，m)，1.8-1.95(2H，m)，2.16(2H，t，J＝7.5Hz)，2.22(6H，s)，2.3-2.35(2H，m)，2.57(2H，t，J＝7.6Hz)，2.85-2.95(1H，m)，3.17(2H，t，J＝6.9Hz)，3.25-3.45(4H，m)，3.6-3.9(4H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 17
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[2-(imidazoles-1-yl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses 1-(2-amino-ethyl) imidazoles to replace glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.8-2.0(4H，m)，2.17(2H，t，J＝7.6Hz)，2.57(2H，t，J＝7.7Hz)，2.85-2.95(1H，m)，3.14(2H，t，J＝6.8Hz)，3.3-3.45(4H，m)，3.6-3.9(4H，m)，4.03(2H，t，J＝7.0Hz)，5.0-5.1(1H，m)，6.9-7.0(1H，m)，7.0-7.15(5H，m)，7.6-7.7(1H，m)
Embodiment 18
3-(β-D-pyranoglucose oxygen base)-4-(4-[3-(2-hydroxyethyl) formamyl propyl group] and phenyl } methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses the 2-monoethanolamine to replace glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.8-1.95(2H，m)，2.18(2H，t，J＝7.5Hz)，2.57(2H，t，J＝7.5Hz)，2.85-2.95(1H，m)，3.27(2H，t，J＝5.8Hz)，3.3-3.5(4H，m)，3.57(2H，t，J＝5.9Hz)，3.6-3.9(4H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 19
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[2-hydroxyl-1-(methylol) ethyl] the formamyl propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses 2-amino-1, and ammediol is replaced glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.8-1.95(2H，m)，2.21(2H，t，J＝7.6Hz)，2.58(2H，t，J＝7.6Hz)，2.85-2.95(1H，m)，3.3-3.45(4H，m)，3.55-3.95(9H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 20
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[2-hydroxyl-1-methylol-1-(methyl) ethyl] the formamyl propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses 2-amino-2-methyl-1, and ammediol is replaced glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.22(3H，s)，1.8-1.95(2H，m)，2.19(2H，t，J＝7.7Hz)，2.58(2H，t，J＝7.5Hz)，2.85-2.95(1H，m)，3.25-3.45(4H，m)，3.55-3.9(8H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 21
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[2-hydroxyl-1,1-two (methylol) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses three (methylol) aminomethane to replace glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.8-1.95(2H，m)，2.23(2H，t，J＝7.5Hz)，2.59(2H，t，J＝7.6Hz)，2.85-2.95(1H，m)，3.25-3.45(4H，m)，3.6-3.9(10H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 22
4-[(4-{3-[(S)-and 1-(formamyl) ethylamino formyl radical] propyl group } phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses L-alanimamides hydrochloride to replace glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.32(3H，d，J＝7.2Hz)，1.8-1.95(2H，m)，2.15-2.25(2H，m)，2.58(2H，t，J＝7.5Hz)，2.85-2.95(1H，m)，3.25-3.45(4H，m)，3.6-3.9(4H，m)，4.32(1H，q，J＝7.2Hz)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 23
4-[(4-{3-[(S)-and 1-formamyl-2-hydroxyethylamino formyl radical] propyl group } phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses L-silk amide hydrochloride to replace glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.85-1.95(2H，m)，2.2-2.3(2H，m)，2.59(2H，t，J＝7.4Hz)，2.85-2.95(1H，m)，3.25-3.45(4H，m)，3.6-3.9(6H，m)，4.4(1H，t，J＝5.2Hz)，5.0-5.1(1H，m)，7.05-7.15(4H，m)
Embodiment 24
4-[(4-{3-[1-formamyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses 2-amino-2-methyl propionic acid amide to replace glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.44(6H，s)，1.8-1.95(2H，m)，2.18(2H，t，J＝7.5Hz)，2.58(2H，t，J＝7.4Hz)，2.85-2.95(1H，m)，3.25-3.45(4H，m)，3.6-3.9(4H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 25
4-[(4-{3-[2-(acetylamino) ethylamino formyl radical] propyl group } phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses the N-acetylethylenediamine to replace glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.8-1.95(5H，m)，2.16(2H，t，J＝7.6Hz)，2.57(2H，t，J＝7.6Hz)，2.85-2.95(1H，m)，3.2-3.45(8H，m)，3.6-3.9(4H，m)，5.0-5.15(1H，m)，7.0-7.15(4H，m)
Embodiment 26
4-(4-[(1E)-3-formamyl third-1-thiazolinyl] phenyl } methyl)-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-({ 4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles (32mg) is at N; solution in the dinethylformamide (1mL); add ammonium chloride (8mg), hydroxybenzotriazole (9mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (15mg) and triethylamine (21mg), mixture is in stirred overnight at room temperature then.Insoluble substance is removed by filtering, and 5mol/L aqueous sodium hydroxide solution (0.5mL) is added filtrate, will stir 1 hour under the mixture room temperature that form then.Insoluble substance is removed by filtering, and filtrate is by the reverse column chromatography purifying of preparation property (Shiseido CAPCELL PAK UG120 ODS, 5 μ m then, 120,20 * 50mm, flow velocity 30mL/ minute linear gradient, water/acetonitrile=90/10-10/90), obtain title compound (7mg).
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，2.8-2.95(1H，m)，3.05-3.15(2H，m)，3.25-3.45(4H，m)，3.6-3.9(4H，m)，5.0-5.15(1H，m)，6.15-6.35(1H，m)，6.48(1H，d，J＝15.6Hz)，7.1-7.2(2H，m)，7.2-7.3(2H，m)
Embodiment 27
3-(β-D-pyranoglucose oxygen base)-4-[(4-{ (1E)-2-[2-hydroxyl-1-methylol-1-(methyl) ethylamino formyl radical] vinyl } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 26; wherein use 2-amino-2-methyl-1; ammediol and 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-the 2-carboxy vinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles; replace ammonium chloride and 3-(2 respectively; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.3(3H，s)，2.85-2.95(1H，m)，3.25-3.45(4H，m)，3.6-3.9(8H，m)，5.05-5.15(1H，m)，6.64(1H，d，J＝15.9Hz)，7.2-7.3(2H，m)，7.4-7.5(3H，m)
Embodiment 28
3-(β-D-pyranoglucose oxygen base)-4-[(4-{ (1E)-2-[2-hydroxyl-1,1-two (methylol) ethylamino formyl radical] vinyl } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 26; wherein use three (methylol) aminomethanes and 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-the 2-carboxy vinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles, replace ammonium chloride and 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，2.85-2.95(1H，m)，3.25-3.45(4H，m)，3.67(1H，dd，J＝12.1Hz，5.3Hz)，3.7-3.9(9H，m)，5.05-5.15(1H，m)，6.69(1H，d，J＝15.7Hz)，7.24(2H，d，J＝8.3Hz)，7.45(2H，d，J＝8.3Hz)，7.48(1H，d，J＝15.7Hz)
Embodiment 29
4-[(4-{ (1E)-2-[1-formamyl-1-(methyl) ethylamino formyl radical] vinyl } phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 26; wherein use 2-amino-2-methyl propionic acid amide and 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-the 2-carboxy vinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles, replace ammonium chloride and 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.52(6H，s)，2.85-2.95(1H，m)，3.25-3.45(4H，m)，3.67(1H，dd，J＝11.9Hz，5.1Hz)，3.7-3.9(3H，m)，5.0-5.15(1H，m)，6.6(1H，d，J＝15.8Hz)，7.24(2H，d，J＝8.4Hz)，7.4-7.5(3H，m)
Embodiment 30
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-(2-hydroxyethylamino formyl radical)-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
To the solution of 2-benzyloxycarbonyl amino-2-methyl propionic acid (0.5g) in methylene dichloride (5mL), add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.61g), I-hydroxybenzotriazole (0.43g) and 2-monoethanolamine (1.16g), mixture is in stirred overnight at room temperature then.In reaction mixture, add entry, then the mixture dichloromethane extraction of Xing Chenging.Organic layer is used saturated sodium bicarbonate aqueous solution and salt water washing successively, uses anhydrous sodium sulfate drying then.Solvent is removed in decompression, then residue is dissolved in methyl alcohol (5mL).Add 10% palladium-carbon dust (0.10g) in this solution, mixture stirred 4 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and the solvent of filtrate is removed in decompression then, obtains 2-(2-amino-2-methyl propionyl amino) ethanol (0.11g).To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-({ 4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles (70mg) is at N; solution in the dinethylformamide (0.5mL); add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (32mg), I-hydroxybenzotriazole (23mg) and 2-(2-amino-2-methyl propionyl amino) ethanol (0.11g), mixture is in stirred overnight at room temperature then.Insoluble substance is removed by filtering, and 5mol/L aqueous sodium hydroxide solution (0.25mL) is added filtrate, and the mixture of Xing Chenging at room temperature stirred 1 hour then.In mixture, add acetate (0.09mL), mixture dilute with water (1mL) then.Insoluble substance is removed by filtering; filtrate is by the reverse column chromatography purifying of preparation property (Shiseido CAPCELL PAK UG120 ODS then; 5 μ L; 120 ; 20 * 50mm; flow velocity 30mL/ minute linear gradient, water/methyl alcohol=90/10-10/90) obtains 3-(β-D-pyranoglucose oxygen base)-4-(4-{ (1E)-3-[1-(2-hydroxyethylamino formyl radical)-1-methylethyl formamyl] propylene-1-yl } phenyl) methyl)-5-sec.-propyl-1H-pyrazoles (14mg).This material is dissolved in methyl alcohol (0.5mL).Add 10% palladium-carbon dust (7mg) in this solution, mixture stirred 2 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and the solvent of filtrate is removed in decompression then, obtains title compound (11mg).
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.42(6H，s)，1.8-1.95(2H，m)，2.19(2H，t，J＝7.6Hz)，2.58(2H，t，J＝7.6Hz)，2.85-2.95(1H，m)，3.25-3.45(6H，m)，3.56(2H，t，J＝5.8Hz)，3.6-3.9(4H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 31
4-[(4-{3-[1-formamyl methylamino formyl radical-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 30, wherein uses glycyl amide hydrochloride and triethylamine to replace the 2-monoethanolamine.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.42(6H，s)，1.8-1.95(2H，m)，2.22(2H，t，J＝7.5Hz)，2.58(2H，t，J＝7.7Hz)，2.85-2.95(1H，m)，3.25-3.45(4H，m)，3.6-3.9(6H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
The comparative example 6
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-bromophenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 3, wherein uses acetyl bromide-α-D-semi-lactosi to replace acetyl bromide-α-D-glucose.
1H-NMR(CDCl
3)δppm：
1.17(6H，d，J＝7.3Hz)，1.88(3H，s)，1.99(3H，s)，2.02(3H，s)，2.17(3H，s)，2.8-2.95(1H，m)，3.59(1H，d，J＝16.0Hz)，3.66(1H，d，J＝16.0Hz)，4.05-4.25(3H，m)，5.1(1H，dd，J＝10.4Hz，3.5Hz)，5.35-5.45(2H，m)，5.57(1H，d，J＝8.2Hz)，6.95-7.05(2H，m)，7.3-7.4(2H，m)
The comparative example 7
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 4; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and the 4-[(4-bromophenyl) methyl]-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-the 4-[(4-bromophenyl) methyl]-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.83(3H，s)，1.99(3H，s)，2.00(3H，s)，2.17(3H，s)，2.8-2.95(1H，m)，3.26(2H，d，J＝6.9Hz)，3.6(1H，d，J＝16.2Hz)，3.69(1H，d，J＝16.2Hz)，4.05-4.3(3H，m)，5.1(1H，dd，J＝10.1Hz，3.5Hz)，5.3-5.5(3H，m)，6.2-6.3(1H，m)，6.45(1H，d，J＝15.9Hz)，7.0-7.1(2H，m)，7.2-7.3(2H，m)，10.0-12.0(1H，br)
Embodiment 32
3-(β-D-galactopyranose oxygen base)-4-[(4-{3-[2-hydroxyl-1-methylol-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1; wherein use 3-(2; 3; 4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl-1, ammediol; replace 3-(2 respectively; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.22(3H，s)，1.8-1.95(2H，m)，2.19(2H，t，J＝7.4Hz)，2.58(2H，t，J＝7.5Hz)，2.85-2.95(1H，m)，3.52(1H，dd，J＝9.8Hz，3.6Hz)，3.55-3.8(10H，m)，3.85-3.9(1H，m)，5.05-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 33
4-[(4-{3-[1-formamyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl propionic acid amide, replace 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.44(6H，s)，1.8-1.95(2H，m)，2.19(2H，t，J＝7.6Hz)，2.57(2H，t，J＝7.6Hz)，2.85-2.95(1H，m)，3.52(1H，dd，J＝9.7Hz，3.4Hz)，3.55-3.65(1H，m)，3.65-3.8(5H，m)，3.85-3.9(1H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 34
4-({ 4-[3-(2-amino-ethyl sulfamyl) propyl group] phenyl } methyl)-3-) β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
With the suspension of sodium allyl sulfonate (2.0g) in thionyl chloride (10.4mL), under 70 ℃, heat and stirred 1.5 days.Insoluble substance is removed by filtering, and the solvent of filtrate is removed in decompression then.The residue that obtains is dissolved in anhydrous tetrahydrofuran (THF) (10mL), and solvent is removed in decompression then.The residue that obtains is dissolved in anhydrous tetrahydrofuran (THF) (10mL) once more, and solvent is removed in decompression then, obtains allyl group thionyl chloride (1.26g).The suspension in methylene dichloride (5mL) to N-benzyloxycarbonyl-1 hydrochloride (0.82g) and triethylamine (0.63g) at room temperature adds allyl group thionyl chloride (0.25g), and mixture stirs and spends the night then.Reaction stops by adding entry, and the organic layer in the mixture that forms is separated.Organic layer is used 1mol/L hydrochloric acid, saturated sodium bicarbonate aqueous solution and salt water washing successively, uses anhydrous sodium sulfate drying then.Solvent is removed in decompression, obtains N-(2-benzyloxycarbonyl amino-ethyl) allyl group sulfanilamide (SN) (82mg).With this substance dissolves in acetonitrile (0.25mL).In this solution; add 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-the 4-[(4-bromophenyl) methyl]-5-sec.-propyl-1H-pyrazoles (70mg), triethylamine (57mg), acid chloride (II) (3mg) and three (2-aminomethyl phenyl) phosphines (7mg), mixture flows through night next time in shading then.Solvent is removed in decompression, then residue is dissolved in methyl alcohol (0.5mL).In this solution, add 5mol/L aqueous sodium hydroxide solution (0.25mL), mixture was stirring at room 1 hour then.Insoluble substance is removed by filtering, filtrate is by the reverse column chromatography purifying of preparation property (Shiseido CAPCELL PAK UG120 ODS then, 5 μ L, 120 , 20 * 50mm, flow velocity 30mL/ minute linear gradient, water/methyl alcohol=90/10-10/90) obtains 4-({ 4-[(1E)-3-(2-benzyloxycarbonyl amino-ethyl sulphonamide) third-1-thiazolinyl] phenyl } methyl)-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles (14mg).This material is dissolved in methyl alcohol (0.5mL).Add 10% palladium-carbon dust (5mg) in this solution, mixture stirred 3 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and the solvent of filtrate is removed in decompression then, obtains title compound (10mg).
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，2.0-2.1(2H，m)，2.65-2.75(4H，m)，2.85-2.95(1H，m)，2.95-3.05(4H，m)，3.25-3.45(4H，m)，3.6-3.9(4H，m)，5.0-5.1(1H，m)，7.05-7.2(4H，m)
Embodiment 35
4-[(4-{3-[1-formamyl-1-(methyl) ethyl sulphonamide] propyl group } phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
To benzyl methylpropanoate right-tosylate (Tetrahedron, 1991, Vol.47, No.2, pp.259-270; 3.9g) and the suspension of triethylamine (2.7g) in methylene dichloride (15mL), at room temperature adding allyl group thionyl chloride (0.75g), mixture stirs and spends the night then.Reaction stops by adding entry, separates the organic layer in the mixture that forms then.Organic layer is used 1mol/L hydrochloric acid, saturated sodium bicarbonate aqueous solution and salt water washing successively, uses anhydrous sodium sulfate drying then.Solvent is removed in decompression, obtains N-[1-benzyloxycarbonyl-1-(methyl) ethyl] allyl group sulfanilamide (SN) (0.48g).To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and the 4-[(4-bromophenyl) methyl]-5-sec.-propyl-1H-pyrazoles (0.40g), N-[1-benzyloxycarbonyl-1-(methyl) ethyl] solution of allyl group sulfanilamide (SN) (0.48g) in acetonitrile (1mL); add triethylamine (0.32g), acid chloride (II) (14mg) and three (2-aminomethyl phenyl) phosphines (39mg), mixture flows through night next time in shading then.Solvent is removed in decompression; residue carries out purifying (eluent: n-hexane/ethyl acetate=1/1-ethyl acetate) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{ (1E)-3-[1-benzyloxycarbonyl-1-(methyl) ethyl sulphonamide] propylene-1-yl } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (0.11g).This material is dissolved in methyl alcohol (1mL).Add 10% palladium-carbon dust (50mg) in this solution, mixture stirred 2 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering; the solvent of filtrate is removed in decompression then, obtains 3-(2,3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-carboxyl-1-(methyl) ethyl sulphonamide] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (95mg).To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{3-[1-carboxyl-1-(methyl) ethyl sulphonamide] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (50mg) is at N; solution in the dinethylformamide (0.5mL) adds 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (19mg) and I-hydroxybenzotriazole (13mg).Ammonia was frothed into mixture about 2 minutes, and the mixture of Xing Chenging at room temperature stirs and spends the night then.Insoluble substance is removed by filtering.In filtrate, add 5mol/L aqueous sodium hydroxide solution (0.25mL), mixture was stirring at room 1 hour then.In reaction mixture, add acetate (0.09mL), mixture dilute with water (1mL) then.Insoluble substance is removed by filtering, and filtrate is by the reverse column chromatography purifying of preparation property (Shiseido CAPCELL PAK UG120 ODS, 5 μ L then, 120 , 20 * 50mm, flow velocity 30mL/ minute linear gradient, water/methyl alcohol=90/10-10/90), obtain title compound (14mg).
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.43(6H，s)，2.0-2.15(2H，m)，2.7(2H，t，J＝7.4Hz)，2.8-2.95(1H，m)，2.95-3.1(2H，m)，3.25-3.45(4H，m)，3.6-3.9(4H，m)，5.0-5.15(1H，m)，7.05-7.2(4H，m)
The comparative example 8
Hydroxy new pentane acid benzyl ester
At N, the suspension in the dinethylformamide (25mL) adds cylite (2.9mL) to hydroxy new pentane acid (3g) and salt of wormwood (3.9g), and mixture was stirring at room 5 hours then.Reaction mixture is poured in the water, then the mixture extracted with diethyl ether of Xing Chenging.Organic layer washes with water 2 times and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression, obtains title compound (4.7g).
1H-NMR(CDCl
3)δppm：
1.22(6H，s)，2.33(1H，t，J＝6.7Hz)，3.58(2H，d，J＝6.7Hz)，5.15(2H，s)，7.3-7.4(5H，m)
The comparative example 9
4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl aldehyde
To 4-hydroxy benzaldehyde (2.7g), hydroxy new pentane acid benzyl ester (4.7g) and the solution of triphenylphosphine (6.4g) in tetrahydrofuran (THF) (22mL), add diethylazodicarboxylate (diethyl azodicarboxylate) (40% toluene solution, 11mL), then mixture stirring at room 2 days.Reaction mixture is poured in the water, then the mixture extracted with diethyl ether of Xing Chenging.Organic layer washes and uses anhydrous magnesium sulfate drying with water.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=6/1-4/1), obtain title compound (0.97g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.36(6H，s)，4.07(2H，s)，5.15(2H，s)，6.9-7.0(2H，m)，7.2-7.35(5H，m)，7.75-7.85(2H，m)，9.89(1H，s)
The comparative example 10
[4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl] methyl alcohol
To 4-(2-benzyloxycarbonyl-2-methyl propoxy-) solution of phenyl aldehyde (0.97g) in tetrahydrofuran (THF) (20mL), add sodium borohydride (59mg), mixture was stirring at room 3 hours then.Pour reaction mixture into 0.5mol/L hydrochloric acid, then the mixture extracted with diethyl ether of Xing Chenging.Organic layer is water and salt water washing successively, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=6/1-3/2), obtain title compound (0.95g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.34(6H，s)，1.51(1H，t，J＝5.9Hz)，3.99(2H，s)，4.62(2H，d，J＝5.9Hz)，5.15(2H，s)，6.8-6.9(2H，m)，7.25-7.35(7H，m)
The comparative example 11
4-{[4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone
To [4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl] solution of methyl alcohol (0.95g) in tetrahydrofuran (THF) (8mL),, stirred the mixture then 1 hour at ice-cooled triethylamine (0.48mL) and the methylsulfonyl chloride (0.26mL) of adding down.Insoluble substance is removed by filtering.Methylsulfonic acid [4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl] solution of methyl esters in tetrahydrofuran (THF) that obtains, be added to sodium hydride (60%, 139mg) with the 4-methyl-suspension of 3-oxopentanoic acid ethyl ester (0.52g) in tetrahydrofuran (THF) (15mL), the reflux mixture is 15 hours then.In reaction mixture, add 1mol/L hydrochloric acid, then the mixture extracted with diethyl ether of Xing Chenging.Organic layer washes and uses anhydrous magnesium sulfate drying with water.Solvent is removed in decompression.To the solution of residue in ethanol (10mL), add hydrazine monohydrate (0.16mL), mixture was stirring at room 2 days then.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (eluent: methylene chloride=30/1-20/1), obtain title compound (0.25g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.15(6H，d，J＝6.9Hz)，1.32(6H，s)，2.85-2.95(1H，m)，3.66(2H，s)，3.94(2H，s)，5.13(2H，s)，6.7-6.8(2H，m)，7.05-7.15(2H，m)，7.2-7.35(5H，m)
The comparative example 12
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
To 4-{[4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone (0.25g), acetyl bromide-α-D-glucose (0.48g) and the solution of zephiran chloride three (normal-butyl) ammonium (0.18g) in methylene dichloride (5mL), add 5mol/L aqueous sodium hydroxide solution (0.35mL), mixture was stirring at room 3 hours then.Reaction mixture is purifying (eluent: n-hexane/ethyl acetate=1/1-1/3), obtain title compound (0.28g) by the column chromatography of carrying out on aminopropyl silica gel.
1H-NMR(CDCl
3)δppm：
1.16(6H，d，J＝7.1Hz)，1.32(6H，s)，1.86(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.85-2.95(1H，m)，3.56(1H，d，J＝16.0Hz)，3.62(1H，d，J＝16.0Hz)，3.8-3.9(1H，m)，3.92(1H，d，J＝8.7Hz)，3.94(1H，d，J＝8.7Hz)，4.15(1H，dd，J＝12.5Hz，2.4Hz)，4.31(1H，dd，J＝12.5Hz，4.2Hz)，5.13(2H，s)，5.15-5.3(3H，m)，5.55-5.65(1H，m)，6.7-6.75(2H，m)，6.95-7.05(2H，m)，7.25-7.35(5H，m)
The comparative example 13
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl-2-methyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
With 3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (0.28g) is dissolved in methyl alcohol (6mL).In this solution, add 10% palladium-carbon dust (54mg), under hydrogen atmosphere, mixture at room temperature stirred then and spend the night.Insoluble substance is removed by filtering, and the solvent of filtrate is removed in decompression then, obtains title compound (0.25g).
1H-NMR(CDCl
3)δppm：
1.16(6H，d，J＝6.7Hz)，1.33(6H，s)，1.88(3H，s)，2.01(3H，s)，2.03(3H，s)，2.05(3H，s)，2.85-3.0(1H，m)，3.54(1H，d，J＝15.8Hz)，3.6(1H，d，J＝15.8Hz)，3.8-3.9(1H，m)，3.91(1H，d，J＝8.8Hz)，3.93(1H，d，J＝8.8Hz)，4.15(1H，dd，J＝12.5Hz，2.0Hz)，4.32(1H，dd，J＝12.5H，4.0Hz)，5.15-5.3(3H，m)，5.4-5.45(1H，m)，6.7-6.8(2H，m)，6.95-7.05(2H，m)
Embodiment 36
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[(S)-1-(formamyl) ethylamino formyl radical]-2-methyl propoxy-} phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-carboxyl-2-methyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (0.13g) is at N; solution in the dinethylformamide (2mL); add L-alanimamides hydrochloride (46mg), triethylamine (0.08mL), I-hydroxybenzotriazole (38mg) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.11g), mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Organic layer is water, saturated sodium bicarbonate aqueous solution, water and salt water washing successively, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression, and residue carries out purifying (eluent: methylene chloride=20/1-10/1), obtain title compound (0.14g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.29(3H，s)，1.32(3H，s)，1.38(3H，d，J＝7.5Hz)，1.89(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.85-2.95(1H，m)，3.57(1H，d，J＝16.0Hz)，3.62(1H，d，J＝16.0Hz)，3.8-3.9(2H，m)，3.94(1H，d，J＝9.1Hz)，4.14(1H，dd，J＝12.5Hz，2.4Hz)，4.3(1H，dd，J＝12.5Hz，4.1Hz)，4.4-4.55(1H，m)，5.15-5.4(4H，m)，5.58(1H，d，J＝8.0Hz)，6.2-6.35(1H，br)，6.67(1H，d，J＝7.3Hz)，6.7-6.8(2H，m)，7.0-7.1(2H，m)
Embodiment 37
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[2-hydroxyl-1,1-two (methyl) ethylamino formyl radical]-2-methyl propoxy-} phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 36, wherein uses 2-amino-2-methyl-1-propanol to replace L-alanimamides hydrochloride.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.25(6H，s)，1.27(6H，s)，1.89(3H，s)，1.97(3H，s)，2.01(3H，s)，2.02(3H，s)，2.85-3.0(1H，m)，3.5(2H，s)，3.6(2H，s)，3.89(2H，s)，3.9-4.0(1H，m)，4.11(1H，dd，J＝12.3Hz，2.2Hz)，4.3(1H，dd，J＝12.3Hz，4.0Hz)，5.05-5.15(2H，m)，5.25-5.35(1H，m)，5.48(1H，d，J＝7.9Hz)，6.75-6.9(3H，m)，7.0-7.1(2H，m)
Embodiment 38
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-formamyl-1-(methyl) ethylamino formyl radical]-2-methyl propoxy-} phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 36, wherein uses 2-amino-2-methyl propionic acid amide to replace L-alanimamides hydrochloride.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.27(6H，s)，1.49(6H，s)，1.89(3H，s)，1.97(3H，s)，2.01(3H，s)，2.02(3H，s)，2.85-3.0(1H，m)，3.6(2H，s)，3.9-4.0(3H，m)，4.11(1H，dd，J＝12.3Hz，2.4Hz)，4.3(1H，dd，J＝12.3Hz，4.0Hz)，5.05-5.15(2H，m)，5.25-5.35(1H，m)，5.48(1H，d，J＝8.4Hz)，6.75-6.85(2H，m)，7.0-7.1(2H，m)
Embodiment 39
4-[(4-{2-[(S)-1-(formamyl) ethylamino formyl radical]-2-methyl propoxy-} phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[(S)-1-(formamyl) ethylamino formyl radical]-2-methyl propoxy-} phenyl) methyl]-the 5-sec.-propyl-solution of 1H-pyrazoles (0.14g) in methyl alcohol (4mL); add sodium methylate (28% methanol solution; 0.04mL), mixture was stirring at room 1 hour then.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (94mg) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.29(3H，s)，1.3(3H，s)，1.35(3H，d，J＝7.5Hz)，2.8-2.95(1H，m)，3.25-3.45(4H，m)，3.6-3.8(3H，m)，3.8-3.9(1H，m)，3.94(2H，s)，4.3-4.45(1H，m)，5.0-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 40
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[2-hydroxyl-1,1-two (methyl) ethylamino formyl radical]-2-methyl propoxy-} phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 39; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[2-hydroxyl-1; 1-(dimethyl) ethylamino formyl radical]-2-methyl propoxy-} phenyl) methyl]-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[(S)-1-(formamyl) ethylamino formyl radical]-2-methyl propoxy-} phenyl) methyl]-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.25(6H，s)，1.27(6H，s)，2.8-2.95(1H，m)，3.25-3.45(4H，m)，3.5(2H，s)，3.6-3.7(2H，m)，3.74(1H，d，J＝16.0Hz)，3.8-3.95(3H，m)，5.0-5.15(1H，m)，6.75-6.9(2H，m)，7.05-7.15(2H，m)
Embodiment 41
4-[(4-{2-[1-formamyl-1-(methyl) ethylamino formyl radical]-2-methyl propoxy-} phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 39; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-formamyl-1-(methyl) ethylamino formyl radical]-2-methyl propoxy-} phenyl) methyl]-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[(S)-1-(formamyl) ethylamino formyl radical]-2-methyl propoxy-} phenyl) methyl]-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.27(6H，s)，1.49(6H，s)，2.8-2.95(1H，m)，3.25-3.45(4H，m)，3.6-3.8(3H，m)，3.8-3.9(1H，m)，3.93(2H，s)，5.0-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 42
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-{1-[2-hydroxyl-1-(methylol) ethylamino formyl radical]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 30, wherein uses 2-amino-1, and ammediol is replaced the 2-monoethanolamine.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.43(6H，s)，1.8-1.95(2H，m)，2.19(2H，t，J＝7.5Hz)，2.58(2H，t，J＝7.5Hz)，2.85-2.95(1H，m)，3.25-3.45(4H，m)，3.5-3.95(9H，m)，5.0-5.15(1H，m)，7.0-7.2(4H，m)
Embodiment 43
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-{1-[2-hydroxyl-1,1-two (methylol) ethylamino formyl radical]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 30, wherein uses three (methylol) aminomethane to replace the 2-monoethanolamine.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.42(6H，s)，1.8-1.95(2H，m)，2.18(2H，t，J＝7.5Hz)，2.58(2H，t，J＝7.5Hz)，2.85-3.0(1H，m)，3.25-3.45(4H，m)，3.6-3.9(10H，m)，5.0-5.15(1H，m)，7.0-7.2(4H，m)
The comparative example 14
4-bromo-2-methylbenzyl alcohol
To the solution of 4-bromo-2-tolyl acid (10g) in tetrahydrofuran (THF) (60mL), at the ice-cooled borane-dimethyl sulphide mixture (7.07g) that adds down.Reaction mixture at room temperature stirred 5 minutes, and stirred 2 days at 75 ℃.Reaction mixture is cooled to room temperature.Saturated wet chemical is added in the reaction mixture, separate organic layer then.Organic layer water and salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression, obtains title compound (9.0g).
1H-NMR(CDCl
3)δppm：
1.55-1.65(1H，m)，2.36(3H，s)，4.64(2H，d，J＝5.4Hz)，7.2-7.25(1H，m)，7.3-7.35(2H，m)
The comparative example 15
4-[(4-bromo-2-aminomethyl phenyl) methyl]-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone
To the solution of 4-bromo-2-methylbenzyl alcohol (9.0g) in methylene dichloride (50mL), at the ice-cooled thionyl chloride (3.8mL) that adds down, at room temperature stirred reaction mixture spends the night then.Reaction mixture carries out concentrating under reduced pressure, obtains 4-bromo-2-methyl-benzyl chlorine (9.8g).(60%, the 2.1g) suspension in tetrahydrofuran (THF) (90mL) adds 4-methyl-3-oxopentanoic acid ethyl ester (7.5g) under ice-cooled, and reaction mixture at room temperature stirred 1 hour then to sodium hydride.With 4-bromo-2-methyl-benzyl chlorine (9.8g), add in the reaction mixture, the mixture of Xing Chenging stirred 3 days at 70 ℃ then.Pour reaction mixture into saturated aqueous ammonium chloride solution, then the mixture extracted with diethyl ether.Organic layer water and salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression.To the solution of residue in toluene (20mL), add hydrazine monohydrate (5.4mL), mixture spends the night 90 ℃ of stirrings then.To the reaction mixture concentrating under reduced pressure, residue is used normal hexane/ether (10/1) thereby is handled crystallization then.Crystal is collected and is washed with normal hexane, water and normal hexane successively by filtering, and drying under reduced pressure, obtains title compound (12.4g).
1H-NMR(DMSO-d
6)δppm：
1.05(6H，d，J＝6.8Hz)，2.28(3H，s)，2.65-2.8(1H，m)，3.45(2H，s)，6.82(1H，d，J＝8.2Hz)，7.24(1H，dd，J＝8.2Hz，1.8Hz)，7.33(1H，d，J＝1.8Hz)，8.5-12.0(2H，br)
The comparative example 16
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-bromo-2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 3, wherein uses 4-[(4-bromo-2-aminomethyl phenyl) methyl]-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone is replaced the 4-[(4-bromophenyl) methyl]-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.81(3H，s)，1.99(3H，s)，2.02(3H，s)，2.06(3H，s)，2.28(3H，s)，2.75-2.9(1H，m)，3.49(1H，d，J＝16.7Hz)，3.59(1H，d，J＝16.7Hz)，3.8-3.9(1H，m)，4.05-4.2(1H，m)，4.3(1H，dd，J＝12.4Hz，4.0Hz)，5.1-5.3(3H，m)，5.5-5.6(1H，m)，6.76(1H，d，J＝8.2Hz)，7.1-7.2(1H，m)，7.25-7.3(1H，m)
The comparative example 17
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 4; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-bromo-2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-the 4-[(4-bromophenyl) methyl]-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.78(3H，s)，1.99(3H，s)，2.02(3H，s)，2.06(3H，s)，2.29(3H，s)，2.75-2.9(1H，m)，3.13(2H，d，J＝7.3Hz)，3.54(1H，d，J＝16.8Hz)，3.64(1H，d，J＝16.8Hz)，3.8-3.9(1H，m)，4.05-4.15(1H，m)，4.25-4.35(1H，m)，5.1-5.3(3H，m)，5.5-5.6(1H，m)，6.15-6.25(1H，m)，6.46(1H，d，J＝16.1Hz)，6.85(1H，d，J＝7.9Hz)，7.05(1H，d，J＝7.9Hz)，7.15(1H，s)
The comparative example 18
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-the 2-carboxy vinyl]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 4; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-bromo-2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and vinylformic acid, replace 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-the 4-[(4-bromophenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 3-butenoic acid.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.73(3H，s)，1.99(3H，s)，2.04(3H，s)，2.06(3H，s)，2.35(3H，s)，2.8-2.9(1H，m)，3.58(1H，d，J＝17.2Hz)，3.69(1H，d，J＝17.2Hz)，3.85-3.95(1H，m)，4.21(1H，dd，J＝12.4Hz，2.2Hz)，4.35(1H，dd，J＝12.4Hz，3.9Hz)，5.15-5.3(3H，m)，5.45(1H，d，J＝7.8Hz)，6.4(1H，d，J＝15.8Hz)，6.93(1H，d，J＝7.8Hz)，7.2-7.3(1H，m)，7.3-7.4(1H，m)，7.69(1H，d，J＝15.8Hz)
Embodiment 44
4-[(4-{3-[1-formamyl-1-(methyl) ethylamino formyl radical] propyl group }-the 2-aminomethyl phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl propionic acid amide, replace 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.44(6H，s)，1.8-1.9(2H，m)，2.2(2H，t，J＝7.6Hz)，2.3(3H，S)，2.55(2H，t，J＝7.6Hz)，2.75-2.9(1H，m)，3.2-3.4(4H，m)，3.6-3.9(4H，m)，4.95-5.1(1H，m)，6.8-6.9(2H，m)，6.9-7.0(1H，m)
Embodiment 45
4-[(4-{ (1E)-2-[1-formamyl-1-(methyl) ethylamino formyl radical] vinyl }-the 2-aminomethyl phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 26; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-the 2-carboxy vinyl]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl propionic acid amide, replace 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and ammonium chloride.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.52(6H，s)，2.36(3H，s)，2.75-2.9(1H，m)，3.2-3.4(4H，m)，3.6-3.85(4H，m)，5.0-5.1(1H，m)，6.58(1H，d，J＝15.8Hz)，7.0(1H，d，J＝7.9Hz)，7.2-7.3(1H，m)，7.33(1H，s)，7.43(1H，d，J＝15.8Hz)
Embodiment 46
3-(β-D-pyranoglucose oxygen base)-4-[(4-{ (1E)-2-[2-hydroxyl-1-methylol-1-(methyl) ethylamino formyl radical] vinyl }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 26; wherein use 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-the 2-carboxy vinyl]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl-1, ammediol; replace 3-(2 respectively; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and ammonium chloride.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.3(3H，s)，2.36(3H，s)，2.75-2.9(1H，m)，3.25-3.45(4H，m)，3.6-3.85(8H，m)，5.04(1H，d，J＝6.1Hz)，6.62(1H，d，J＝15.5Hz)，6.99(1H，d，J＝7.6Hz)，7.26(1H，d，J＝7.6Hz)，7.32(1H，s)，7.42(1H，d，J＝15.5Hz)
Embodiment 47
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-[(4-{ (1E)-2-[2-(sulfamoylamino group) ethylamino formyl radical] vinyl }-the 2-aminomethyl phenyl) methyl]-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 26; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-the 2-carboxy vinyl]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and N-sulphonamide quadrol, replace 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and ammonium chloride.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，2.36(3H，s)，2.75-2.9(1H，m)，3.19(2H，t，J＝6.3Hz)，3.25-3.4(4H，m)，3.47(2H，t，J＝6.3Hz)，3.6-3.7(1H，m)，3.7-3.9(3H，m)，5.04(1H，d，J＝7.3Hz)，6.54(1H，d，J＝15.7Hz)，7.0(1H，d，J＝7.9Hz)，7.27(1H，d，J＝7.9Hz)，7.33(1H，s)，7.47(1H，d，J＝15.7Hz)
The comparative example 19
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-({ 4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles (0.4g) is at N; solution in the dinethylformamide (2mL); at room temperature add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.18g), I-hydroxybenzotriazole (0.13g), benzyl methylpropanoate right-tosylate (1.16g) and triethylamine (0.64g), mixture stirs and spends the night then.In reaction mixture, add entry, then the mixture dichloromethane extraction of Xing Chenging.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent is removed in decompression; residue carries out purifying (eluent: n-hexane/ethyl acetate=1/1-ethyl acetate) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-{ (1E)-3-[1-benzyloxycarbonyl-1-(methyl) ethylamino formyl radical] propylene-1-yl } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (0.18g).This material is dissolved in methyl alcohol (2mL).Add 10% palladium-carbon dust (50mg) in this solution, mixture stirred 4 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and the solvent of filtrate is removed in decompression then, obtains title compound (0.15g).
1H-NMR(CDCl
3)δppm：
1.05-1.2(6H，m)，1.57(3H，s)，1.59(3H，s)，1.85(3H，s)，1.85-1.95(2H，m)，1.99(3H，s)，2.02(3H，s)，2.1-2.2(5H，m)，2.6(2H，t，J＝7.4Hz)，2.8-2.95(1H，m)，3.59(1H，d，J＝16.1Hz)，3.68(1H，d，J＝16.1Hz)，4.0-4.1(1H，m)，4.14(1H，dd，J＝11.0Hz，8.2Hz)，4.27(1H，dd，J＝11.0Hz，5.6Hz)，5.08(1H，dd，J＝10.3Hz，3.5Hz)，5.37(1H，d，J＝8.1Hz)，5.4-5.5(2H，m)，6.19(1H，s)，6.95-7.1(4H，m)
The comparative example 20
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 19; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.05-1.2(6H，m)，1.57(3H，s)，1.58(3H，s)，1.85(3H，s)，1.85-1.95(2H，m)，2.0(3H，s)，2.03(3H，s)，2.05(3H，s)，2.15(2H，t，J＝7.6Hz)，2.6(2H，t，J＝7.5Hz)，2.8-2.95(1H，m)，3.58(1H，d，J＝15.7Hz)，3.66(1H，d，J＝15.7Hz)，3.8-3.9(1H，m)，4,17(1H，dd，J＝11.9Hz，2.2Hz)，4.34(1H，dd，J＝11.9Hz，3.4Hz)，5.15-5.3(3H，m)，5.35-5.45(1H，m)，6.18(1H，s)，6.95-7.1(4H，m)
The comparative example 21
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 19; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.05-1.15(6H，m)，1.57(3H，s)，1.58(3H，s)，1.76(3H，s)，1.85-1.95(2H，m)，1.99(3H，s)，2.02(3H，s)，2.05(3H，s)，2.1-2.2(2H，m)，2.25(3H，s)，2.5-2.6(2H，m)，2.7-2.85(1H，m)，3.51(1H，d，J＝16.8Hz)，3.61(1H，d，J＝16.8Hz)，3.8-3.9(1H，m)，4.1-4.2(1H，m)，4.32(1H，dd，J＝12.2Hz，3.4Hz)，5.15-5.3(3H，m)，5.38(1H，d，J＝8.1Hz)，6.23(1H，s)，6.77(1H，d，J＝7.8Hz)，6.85(1H，d，J＝7.8Hz)，6.93(1H，s)
Embodiment 48
3-(β-D-galactopyranose oxygen base)-4-[(4-{3-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (30mg) is at N; solution in the dinethylformamide (0.5mL); add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (12mg), I-hydroxybenzotriazole (9mg) and 1-(2-hydroxyethyl) piperazine (54mg), mixture is in stirred overnight at room temperature then.In reaction mixture, add 5mol/L aqueous sodium hydroxide solution (0.25mL), the mixture of Xing Chenging at room temperature stirred 1 hour then.In reaction mixture, add acetate (0.1mL), mixture dilute with water (1mL) then.Insoluble substance is removed by filtering, and filtrate is by the reverse column chromatography purifying of preparation property (Shiseido CAPCELL PAK UG120 ODS, 5 μ L then, 120 , 20 * 50mm, flow velocity 30mL/ minute linear gradient, water/acetonitrile=90/10-10/60), obtain title compound (4mg).
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.42(6H，s)，1.8-1.95(2H，m)，2.17(2H，t，J＝7.7Hz)，2.35-2.55(6H，m)，2.58(2H，t，J＝7.6Hz)，2.8-2.95(1H，m)，3.52(1H，dd，J＝9.7Hz，3.4Hz)，3.55-3.8(12H，m)，3.87(1H，d，J＝3.4Hz)，5.08(1H，d，J＝8.0Hz)，7.0-7.15(4H，m)
Embodiment 49
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-{1-[2-hydroxyl-1-(methylol) ethylamino formyl radical]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 48; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 2-amino-1; ammediol; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-(2-hydroxyethyl) piperazine.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.43(6H，s)，1.8-1.95(2H，m)，2.19(2H，t，J＝7.5Hz)，2.58(2H，t，J＝7.5Hz)，2.85-2.95(1H，m)，3.25-3.45(4H，m)，3.5-3.95(9H，m)，5.0-5.15(1H，m)，7.0-7.2(4H，m)
Embodiment 50
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-{1-[2-hydroxyl-1,1-two (methylol) ethylamino formyl radical]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 48; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and three (methylol) aminomethane; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-(2-hydroxyethyl) piperazine.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.42(6H，s)，1.8-1.95(2H，m)，2.18(2H，t，J＝7.5Hz)，2.58(2H，t，J＝7.5Hz)，2.85-3.0(1H，m)，3.25-3.45(4H，m)，3.6-3.9(10H，m)，5.0-5.15(1H，m)，7.0-7.2(4H，m)
Embodiment 51
3-(β-D-galactopyranose oxygen base)-4-[(4-{3-[1-(2-hydroxyethylamino formyl radical)-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 48, wherein uses the 2-monoethanolamine to replace 1-(2-hydroxyethyl) piperazine.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.42(6H，s)，1.8-1.9(2H，m)，2.19(2H，t，J＝7.6Hz)，2.57(2H，t，J＝7.6Hz)，2.8-2.95(1H，m)，3.28(2H，t，J＝5.8Hz)，3.45-3.65(4H，m)，3.65-3.8(5H，m)，3.86(1H，d，J＝2.7Hz)，5.08(1H，d，J＝7.9Hz)，7.0-7.15(4H，m)
Embodiment 52
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[2-(dimethylamino) ethylamino formyl radical]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 48, wherein uses N, and the N-dimethyl-ethylenediamine is replaced 1-(2-hydroxyethyl) piperazine.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.41(6H，s)，1.8-1.9(2H，m)，2.19(2H，t，J＝7.7Hz)，2.24(6H，s)，2.42(2H，t，J＝6.8Hz)，2.58(2H，t，J＝7.6Hz)，2.8-2.95(1H，m)，3.28(2H，t，J＝6.8Hz)，3.52(1H，dd，J＝9.7Hz，3.3Hz)，3.55-3.65(1H，m)，3.65-3.8(5H，m)，3.8-3.9(1H，m)，5.08(1H，d，J＝7.4Hz)，7.0-7.15(4H，m)
Embodiment 53
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[2-(dimethylamino) ethylamino formyl radical]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 48; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and N; the N-dimethyl-ethylenediamine; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-(2-hydroxyethyl) piperazine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.41(6H，s)，1.8-1.9(2H，m)，2.18(2H，t，J＝7.5Hz)，2.23(6H，s)，2.41(2H，t，J＝6.8Hz)，2.57(2H，t，J＝7.6Hz)，2.8-2.95(1H，m)，3.2-3.45(6H，m)，3.6-3.9(4H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 54
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[3-(dimethylamino) propyl group formamyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 48; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and N; N-dimethyl-1; the 3-propylene diamine is replaced 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-(2-hydroxyethyl) piperazine.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.41(6H，s)，1.6-1.7(2H，m)，1.8-1.9(2H，m)，2.19(2H，t，J＝7.7Hz)，2.22(6H，s)，2.35(2H，t，J＝7.6Hz)，2.57(2H，t，J＝7.6Hz)，2.85-2.95(1H，m)，3.18(2H，t，J＝6.6Hz)，3.3-3.45(4H，m)，3.6-3.8(3H，m)，3.8-3.9(1H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 55
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 48; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.42(6H，s)，1.8-1.95(2H，m)，2.16(2H，t，J＝7.5Hz)，2.35-2.55(6H，m)，2.58(2H，t，J＝7.3Hz)，2.85-3.0(1H，m)，3.25-3.45(4H，m)，3.55-3.9(10H，m)，5.0-5.15(1H，m)，7.0-7.15(4H，m)
Embodiment 56
4-[(4-{3-[1-(2-aminoethylamino formyl radical)-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 48, wherein uses quadrol to replace 1-(2-hydroxyethyl) piperazine.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.41(6H，s)，1.8-1.9(2H，m)，2.19(2H，t，J＝7.5Hz)，2.58(2H，t，J＝7.6Hz)，2.7(2H，t，J＝5.9Hz)，2.85-2.95(1H，m)，3.24(2H，t，J＝5.9Hz)，3.51(1H，dd，J＝9.8Hz，3.2Hz)，3.55-3.65(1H，m)，3.65-3.8(5H，m)，3.86(1H，d，J＝3.2Hz)，5.07(1H，d，J＝7.9Hz)，7.0-7.15(4H，m)
Embodiment 57
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 48, wherein uses piperazine to replace 1-(2-hydroxyethyl) piperazine.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.42(6H，s)，1.8-1.95(2H，m)，2.1-2.2(2H，m)，2.58(2H，t，J＝7.4Hz)，2.65-2.8(4H，m)，2.85-2.95(1H，m)，3.45-3.8(11H，m)，3.8-3.9(1H，m)，5.08(1H，d，J＝8.0Hz)，7.0-7.15(4H，m)
Embodiment 58
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 48; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and piperazine; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-(2-hydroxyethyl) piperazine.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.42(6H，s)，1.8-1.95(2H，m)，2.17(2H，t，J＝7.6Hz)，2.5-2.85(6H，m)，2.85-3.0(1H，m)，3.25-3.45(4H，m)，3.5-3.9(8H，m)，5.0-5.15(1H，m)，7.0-7.15(4H，m)
Embodiment 59
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 48; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.42(6H，s)，1.8-1.9(2H，m)，2.1-2.2(2H，m)，2.3(3H，s)，2.35-2.6(8H，m)，2.75-2.9(1H，m)，3.25-3.4(4H，m)，3.45-3.75(9H，m)，3.8(1H，d，J＝11.1Hz)，4.95-5.05(1H，m)，6.8-7.0(3H，m)
Embodiment 60
3-(β-D-galactopyranose oxygen base)-4-{[4-(3-{1-[2-hydroxyl-1,1-two (methylol) ethylamino formyl radical]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 48, wherein uses three (methylol) aminomethane to replace 1-(2-hydroxyethyl) piperazine.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.42(6H，s)，1.8-1.95(2H，m)，2.18(2H，t，J＝7.5Hz)，2.58(2H，t，J＝7.6Hz)，2.8-2.95(1H，m)，3.52(1H，dd，J＝9.7Hz，3.4Hz)，3.55-3.9(13H，m)，5.07(1H，d，J＝7.5Hz)，7.0-7.15(4H，m)
Embodiment 61
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(4-methylpiperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 48, wherein uses the 1-methylpiperazine to replace 1-(2-hydroxyethyl) piperazine.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.42(6H，s)，1.8-1.9(2H，m)，2.1-2.2(2H，m)，2.25(3H，s)，2.3-2.45(4H，m)，2.58(2H，t，J＝7.4Hz)，2.85-2.95(1H，m)，3.52(1H，dd，J＝9.6Hz，3.2Hz)，3.55-3.8(10H，m)，3.8-3.9(1H，m)，5.08(1H，d，J＝7.4Hz)，7.0-7.15(4H，m)
Embodiment 62
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(4-sec.-propyl piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 48, wherein uses 1-sec.-propyl piperazine to replace 1-(2-hydroxyethyl) piperazine.
1H-NMR(CD
3OD)δppm：
1.03(6H，d，J＝6.6Hz)，1.05-1.15(6H，m)，1.42(6H，s)，1.8-1.95(2H，m)，2.1-2.2(2H，m)，2.35-2.7(7H，m)，2.8-2.95(1H，m)，3.52(1H，dd，J＝9.8Hz，3.4Hz)，3.55-3.8(10H，m)，3.8-3.9(1H，m)，5.08(1H，d，J＝7.8Hz)，7.0-7.15(4H，m)
Embodiment 63
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-(4-[(1E)-2-{1-[2-(dimethylamino) ethylamino formyl radical]-1-(methyl) ethylamino formyl radical } vinyl] phenyl } methyl)-the 1H-pyrazoles
To 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-({ 4-[(1E)-2-carboxy vinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles (1.2g) is at N; solution in dinethylformamide (15mL) and the methylene dichloride (10mL) adds triethylamine (15mL).In mixture, add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.56g), I-hydroxybenzotriazole (0.4g) and the solution of 2-amino-2-methyl propionic acid (2.0g) in water (15mL), mixture is in stirred overnight at room temperature then.Reaction mixture neutralizes by adding the 2mol/L acetic acid aqueous solution, then the mixture ethyl acetate extraction.Organic layer is water and salt water washing successively, uses anhydrous sodium sulfate drying then.Solvent is removed in decompression; residue carries out purifying (eluent: ethyl acetate-methylene chloride=7/1-3/1) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{ (1E)-2-[1-carboxyl-1-(methyl) ethylamino formyl radical] vinyl } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (0.44g).With this substance dissolves in N, dinethylformamide (0.3mL).In this solution, add 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.18g), I-hydroxybenzotriazole (0.13g) and N, N-dimethyl-ethylenediamine (0.55g), mixture is in stirred overnight at room temperature then.In reaction mixture, add 5mol/L aqueous sodium hydroxide solution (1.5mL), mixture was stirring at room 1 hour then.In reaction mixture, add acetate (1mL), mixture dilute with water (3mL) then.Insoluble substance is removed by filtering, and filtrate is by the reverse column chromatography purifying of preparation property (Shiseido CAPCELL PAK UG120 ODS, 5 μ L then, 120 , 20 * 50mm, flow velocity 30mL/ minute linear gradient, water/acetonitrile=90/10-10/60), obtain title compound (71mg).
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.49(6H，s)，2.27(6H，s)，2.46(2H，t，J＝6.7Hz)，2.8-2.95(1H，m)，3.25-3.45(6H，m)，3.6-3.9(4H，m)，5.05-5.15(1H，m)，6.61(1H，d，J＝15.7Hz)，7.2-7.3(2H，m)，7.35-7.5(3H，m)
Embodiment 64
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-(4-[(1E)-2-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } vinyl] phenyl } methyl)-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 63, wherein uses piperazine to replace N, N-dimethyl-ethylenediamine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.51(6H，s)，2.65-2.8(4H，m)，2.85-2.95(1H，m)，3.25-3.45(4H，m)，3.5-3.9(8H，m)，5.05-5.15(1H，m)，6.55(1H，d，J＝15.8Hz)，7.2-7.3(2H，m)，7.4-7.55(3H，m)
Embodiment 65
3-(β-D-pyranoglucose oxygen base)-4-[(4-{ (1E)-2-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] vinyl } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 63, wherein uses 1-(2-hydroxyethyl) piperazine to replace N, N-dimethyl-ethylenediamine.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.51(6H，s)，2.35-2.65(6H，m)，2.85-2.95(1H，m)，3.25-3.45(4H，m)，3.55-3.9(10H，m)，5.05-5.15(1H，m)，6.55(1H，d，J＝15.8Hz)，7.2-7.3(2H，m)，7.4-7.5(3H，m)
Embodiment 66
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[(S)-2-hydroxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1, wherein uses (S)-2-amino-1-propyl alcohol to replace glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.2(9H，m)，1.8-1.95(2H，m)，2.17(2H，t，J＝7.7Hz)，2.57(2H，t，J＝7.6Hz)，2.8-2.95(1H，m)，3.25-3.5(6H，m)，3.6-3.8(3H，m)，3.83(1H，d，J＝11.9Hz)，3.85-4.0(1H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 67
3-(β-D-galactopyranose oxygen base)-4-[(4-{3-[(S)-2-hydroxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-({ 4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and (S)-2-amino-1-propyl alcohol, replace 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.2(9H，m)，1.8-1.95(2H，m)，2.17(2H，t，J＝7.6Hz)，2.57(2H，t，J＝7.6Hz)，2.85-2.95(1H，m)，3.35-3.55(3H，m)，3.55-3.65(1H，m)，3.65-4.0(7H，m)，5.0-5.15(1H，m)，7.0-7.15(4H，m)
Embodiment 68
3-(β-D-galactopyranose oxygen base)-4-[(4-{3-[2-hydroxyl-1,1-two (methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl-1-propanol, replace 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.25(6H，s)，1.8-1.9(2H，m)，2.15(2H，t，J＝7.6Hz)，2.56(2H，t，J＝7.5Hz)，2.8-2.95(1H，m)，3.45-3.65(4H，m)，3.65-3.8(5H，m)，3.8-3.9(1H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 69
4-[(4-{3-[(S)-and 5-amino-5-(formamyl) amyl group formamyl] propyl group } phenyl) methyl]-3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-({ 4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and (S)-2-benzyloxycarbonyl amino-6-aminocaproamide hydrochloride; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.3-1.6(5H，m)，1.6-1.75(1H，m)，1.8-1.9(2H，m)，2.15(2H，t，J＝7.7Hz)，2.56(2H，t，J＝7.3Hz)，2.8-2.95(1H，m)，3.15(2H，t，J＝7.0Hz)，3.28(1H，t，J＝6.4Hz)，3.52(1H，dd，J＝9.8Hz，3.1Hz)，3.55-3.65(1H，m)，3.65-3.8(5H，m)，3.8-3.9(1H，m)，5.08(1H，d，J＝7.9Hz)，7.0-7.15(4H，m)
Embodiment 70
4-[(4-{3-[(S)-and 2-amino-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-the 5-sec.-propyl-solution of 1H-pyrazoles (1.6g) in methyl alcohol (20mL); add 10% palladium-carbon dust, mixture stirred 3 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and then filtrate is carried out concentrating under reduced pressure, obtains 3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(3-carboxylic propyl group) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (1.5g).With this substance dissolves in N, dinethylformamide (15mL).In this solution, add (S)-2-amino-1-propyl alcohol (0.89g), I-hydroxybenzotriazole (0.48g) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.68g), mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water into the mixture that forms dichloromethane extraction 2 times then.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, obtains 3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[(S)-2-hydroxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (1.64g).With 3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[(S)-2-hydroxyl-1-(methyl) ethylamino formyl radical that obtains] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (0.19g) is dissolved in methylene dichloride (2mL).In this solution, at ice-cooled triethylamine (0.058mL) and the methylsulfonyl chloride (0.032mL) of adding down, mixture was stirring at room 1 hour then.Reaction mixture is poured in the water into the mixture that forms dichloromethane extraction 2 times then.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression.Residue is dissolved in N, dinethylformamide (1mL).Add sodiumazide (0.18g) in this solution, mixture spends the night 100 ℃ of stirrings then.Reaction mixture is cooled to room temperature.(1.5mL) adds to mixture with the 5mol/L aqueous sodium hydroxide solution, stirs the mixture then 1 hour.Acetate (1mL) and water (2mL) are added in the reaction mixture.Insoluble substance is removed by filtering; filtrate is by the reverse column chromatography purifying of preparation property (ShiseidoCAPCELL PAK UG120 ODS then; 5 μ m; 120 ; 20 * 50mm; flow velocity 30mL/ minute linear gradient, water/acetonitrile=90/10-10/90), obtain 4-[(4-{3-[(1S)-2-azido-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles (18mg).This material is dissolved in methyl alcohol (1mL).Add 10% palladium-carbon dust (0.01g) in this solution, mixture stirred 4 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and then filtrate is carried out concentrating under reduced pressure, obtains title compound (12mg).
1H-NMR(CD
3OD)δppm：
1.05-1.2(9H，m)，1.8-1.95(2H，m)，2.1-2.25(2H，m)，2.5-2.65(4H，m)，2.8-2.95(1H，m)，3.25-3.45(4H，m)，3.6-3.9(5H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 71
4-[(4-{3-[2-amino-1,1-two (methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and 2-amino-1-benzyloxycarbonyl amino-2-(methyl) propane; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.27(6H，s)，1.8-1.9(2H，m)，2.16(2H，t，J＝7.7Hz)，2.57(2H，t，J＝7.6Hz)，2.8-2.95(3H，m)，3.51(1H，dd，J＝9.8Hz，3.7Hz)，3.55-3.65(1H，m)，3.65-3.8(5H，m)，3.8-3.9(1H，m)，5.08(1H，d，J＝7.7Hz)，7.0-7.15(4H，m)
Embodiment 72
4-[(4-{3-[(R)-and 5-amino-1-(methylol) amyl group formamyl] propyl group } phenyl) methyl]-3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 1; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-({ 4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and (R)-2-amino-6-benzyloxycarbonyl amino-1-hexanol; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles and glycyl amide hydrochloride.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.2-1.7(6H，m)，1.8-1.95(2H，m)，2.2(2H，t，J＝7.5Hz)，2.57(2H，t，J＝7.6Hz)，2.65(2H，t，J＝7.3z)，2.8-3.0(1H，m)，3.4-3.65(4H，m)，3.65-3.95(7H，m)，5.0-5.15(1H，m)，7.0-7.15(4H，m)
Embodiment 73
3-(β-D-pyranoglucose oxygen base)-4-[(4-{ (1E)-3-[(S)-2-hydroxyl-1-(methyl) ethylamino formyl radical] propylene-1-yl } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 26, wherein uses (S)-2-amino-1-propyl alcohol to replace ammonium chloride.
1H-NMR(CD
3OD)δppm：
1.05-1.2(9H，m)，2.8-2.95(1H，m)，3.09(2H，d，J＝7.4Hz)，3.25-3.55(6H，m)，3.6-3.9(4H，m)，3.9-4.0(1H，m)，5.05-5.15(1H，m)，6.2-6.3(1H，m)，6.47(1H，d，J＝15.9Hz)，7.1-7.2(2H，m)，7.2-7.3(2H，m)
Embodiment 74
3-(β-D-pyranoglucose oxygen base)-4-{[4-(3-{ (S)-1-[2-hydroxyl-1-(methylol) ethylamino formyl radical] the ethylamino formyl radical } propyl group) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-({ 4-[(1E)-3-carboxyl third-1-thiazolinyl] phenyl } methyl)-5-sec.-propyl-1H-pyrazoles (7.13g) is at N; solution in the dinethylformamide (30mL); add I-hydroxybenzotriazole (2.31g), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (3.25g) and (S)-2-alanine benzyl ester (8.34g), mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water into the mixture that forms ethyl acetate extraction 2 times then.Extract is water and salt water washing successively, uses dried over sodium sulfate then.Solvent is removed in decompression; residue carries out purifying (eluent: n-hexane/ethyl acetate=1/2) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{ (1E)-3-[(S)-1-(benzyloxycarbonyl) ethylamino formyl radical] propylene-1-yl } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (3.25g).This material is dissolved in methyl alcohol (40mL).In this solution, add 10% palladium-carbon dust (1.0g), under hydrogen atmosphere, mixture at room temperature stirred then and spend the night.Insoluble substance is removed by filtering; then filtrate is carried out concentrating under reduced pressure, obtain 3-(2,3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[(S)-and 1-(carboxyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (2.25g).To the 3-(2 that obtains; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{3-[(S)-and 1-(carboxyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (0.09g) is at N; solution in the dinethylformamide (0.5mL); add I-hydroxybenzotriazole (0.026g), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.037g) and 2-amino-1; ammediol (0.12g), mixture was stirring at room 1 hour then.In reaction mixture, add 5mol/L aqueous sodium hydroxide solution (0.5mL), mixture was stirring at room 1 hour then.Acetate (0.3mL) and water (1mL) are added in the reaction mixture.Insoluble substance is removed by filtering, and filtrate is by the reverse column chromatography purifying of preparation property (Shiseido CAPCELL PAK UG120 ODS, 5 μ L then, 120 , 20 * 50mm, flow velocity 30mL/ minute linear gradient, water/acetonitrile=90/10-10/90), obtain title compound (0.017g).
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.32(3H，d，J＝6.8Hz)，1.8-1.95(2H，m)，2.15-2.3(2H，m)，2.58(2H，t，J＝7.5Hz)，2.85-2.95(1H，m)，3.25-3.45(4H，m)，3.5-3.95(9H，m)，4.25-4.35(1H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 75
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[(S)-1-(2-hydroxyethylamino formyl radical) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 74, wherein uses the 2-monoethanolamine to replace 2-amino-1, ammediol.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.31(3H，d，J＝7.0Hz)，1.8-1.95(2H，m)，2.15-2.25(2H，m)，2.58(2H，t，J＝7.6Hz)，2.85-2.95(1H，m)，3.25-3.45(6H，m)，3.58(2H，t，J＝5.7Hz)，3.6-3.8(3H，m)，3.83(1H，d，J＝11.9Hz)，4.25-4.35(1H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 76
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{ (S)-1-[(4-methylpiperazine-1-yl) carbonyl] the ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 74, wherein uses the 1-methylpiperazine to replace 2-amino-1, ammediol.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.26(3H，d，J＝7.0Hz)，1.8-1.95(2H，m)，2.2(2H，t，J＝7.4Hz)，2.25-2.55(7H，m)，2.57(2H，t，J＝7.6Hz)，2.8-2.95(1H，m)，3.25-3.45(4H，m)，3.45-3.75(6H，m)，3.77(1H，d，J＝16.0Hz)，3.83(1H，d，J＝11.7Hz)，4.75-4.9(1H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
Embodiment 77
3-(β-D-pyranoglucose oxygen base-4-[(4-{3-[(S)-1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl } the ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 74, wherein uses 1-(2-hydroxyethyl) piperazine to replace 2-amino-1, ammediol.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.26(3H，d，J＝6.9Hz)，1.8-1.95(2H，m)，2.2(2H，t，J＝7.4Hz)，2.4-2.65(8H，m)，2.85-2.95(1H，m)，3.2-3.45(4H，m)，3.45-3.75(8H，m)，3.77(1H，d，J＝16.4Hz)，3.83(1H，d，J＝11.9Hz)，4.75-4.9(1H，m)，5.0-5.1(1H，m)，7.0-7.15(4H，m)
To embodiment 22
(4-benzyloxy-2-aminomethyl phenyl) methyl alcohol
At N, the solution in the dinethylformamide (50mL) adds salt of wormwood (8.87g) and cylite (6.36mL) to 4-bromo-3-methylphenol (10g), and mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water, then the mixture extracted with diethyl ether of Xing Chenging.Organic layer washes and uses anhydrous magnesium sulfate drying with water.Solvent is removed in decompression, obtains 4-benzyloxy-1-bromo-2 toluene (14.6g).This material is dissolved in tetrahydrofuran (THF) (200mL).Under-78 ℃ and argon gas atmosphere, (the 2.66mol/L hexane solution 21.7mL), stirred the mixture 10 minutes then to add n-Butyl Lithium in this solution.In reaction mixture, add N, dinethylformamide (10.1mL) allows mixture be warmed to 0 ℃ and stirred 30 minutes then.Reaction mixture is poured in the water, then the mixture extracted with diethyl ether of Xing Chenging.Organic layer washes and uses anhydrous magnesium sulfate drying with water.Solvent is removed in decompression, obtains 4-benzyloxy-2-tolyl aldehyde.With this substance dissolves in ethanol (100mL).Add sodium borohydride (1.99g) in this solution, mixture is in stirred overnight at room temperature then.In reaction mixture, add methyl alcohol, then the mixture that forms is carried out concentrating under reduced pressure.In residue, add saturated sodium bicarbonate aqueous solution, then the mixture extracted with diethyl ether.Organic layer is used saturated sodium bicarbonate aqueous solution, water and salt water washing successively, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=6/1-3/1-1/1), obtain title compound (10.5g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.37(1H，t，J＝5.8Hz)，2.36(3H，s)，4.64(2H，d，J＝5.8Hz)，5.06(2H，s)，6.79(1H，dd，J＝8.4Hz，2.4Hz)，6.84(1H，d，J＝2.4Hz)，7.23(1H，d，J＝8.4Hz)，7.25-7.45(5H，m)
The comparative example 23
4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone
To the solution of (4-benzyloxy-2-aminomethyl phenyl) methyl alcohol (10.5g) in tetrahydrofuran (THF) (80mL), at ice-cooled triethylamine (7.36mL) and the methylsulfonyl chloride (3.91mL) of adding down.After stirring the mixture 1 hour, insoluble substance is removed by filtering.With methylsulfonic acid (4-benzyloxy-2-aminomethyl phenyl) solution of methyl esters in tetrahydrofuran (THF) that obtains, add to sodium hydride (60%, 2.11g) and the 4-methyl-suspension of 3-oxopentanoic acid ethyl ester (7.99g) in tetrahydrofuran (THF) (160mL), mixture refluxed 15 hours then.In reaction mixture, add 1mol/L hydrochloric acid, then the mixture extracted with diethyl ether of Xing Chenging.Organic layer washes and uses anhydrous magnesium sulfate drying with water.Solvent is removed in decompression.Residue is dissolved in toluene (30mL).(6.68mL) adds in the solution with the hydrazine monohydrate, and mixture spends the night 100 ℃ of stirrings then.Reaction mixture is poured in the water, then the mixture ethyl acetate extraction.Organic layer is with the salt water washing and use anhydrous magnesium sulfate drying.Solvent is removed in decompression, and residue is handled with hexane then.Sedimentary crystal is collected by filtering, and drying under reduced pressure, obtains title compound (12.3g).
1H-NMR(DMSO-d
6)δppm：
1.04(6H，d，J＝6.8Hz)，2.24(3H，s)，2.65-2.8(1H，m)，3.44(2H，s)，5.02(2H，s)，6.69(1H，dd，J＝8.7Hz，2.4Hz)，6.75-6.85(2H，m)，7.25-7.45(5H，m)
The comparative example 24
4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
The preparation method of title compound is similar to comparative example 12, wherein uses 4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and 2,3,4,6-four-O-pivaloyl group-α-D-glucopyranosyl bromine (Kunz, H.; Harreus, A.Liebigs Ann.Chem.1982,41-48 Velarde, S.; Urbina, J.; Pena, M.R.J.Org.Chem.1996,61,9541-9545), replace 4-{[4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl respectively] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and acetyl bromide-α-D-glucose.
1H-NMR(CDCl
3)δppm：
1.04(9H，s)，1.05-1.2(33H，m)，2.27(3H，s)，2.7-2.85(1H，m)，3.45-3.6(2H，m)，3.8-3.9(1H，m)，4.11(1H，dd，J＝12.6Hz，4.8Hz)，4.17(1H，dd，J＝12.6Hz，1.8Hz)，5.0(2H，s)，5.15-5.3(2H，m)，5.37(1H，t，J＝9.5Hz)，5.65(1H，d，J＝7.8Hz)，6.64(1H，dd，J＝8.4Hz，2.8Hz)，6.77(1H，d，J＝2.8Hz)，6.83(1H，d，J＝8.4Hz)，7.25-7.45(5H，m)
The comparative example 25
4-[(4-hydroxy-2-methyl phenyl) methyl]-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
With 4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles (5g) is dissolved in tetrahydrofuran (THF) (18mL).Add 10% palladium-carbon dust (500mg) in this solution, mixture stirred 3 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and the solvent of filtrate is removed in decompression then, obtains title compound (4.45g).
1H-NMR(CDCl
3)δppm：
1.0-1.2(42H，m)，2.24(3H，s)，2.7-2.85(1H，m)，3.52(2H，s)，3.8-3.9(1H，m)，4.09(1H，dd，J＝12.4Hz，4.7Hz)，4.15(1H，dd，J＝12.4Hz，1.9Hz)，4.6(1H，s)，5.15-5.25(2H，m)，5.36(1H，t，J＝9.2Hz)，5.65(1H，d，J＝8.0Hz)，6.5(1H，dd，J＝8.3Hz，2.9Hz)，6.61(1H，d，J＝2.9Hz)，6.78(1H，d，J＝8.3Hz)
The comparative example 26
4-bromo-butyric acid benzyl ester
To 4-bromo-butyric acid (1g), phenylcarbinol (0.65g) and the mixture of triphenylphosphine (1.57g) in tetrahydrofuran (THF) (12mL), add diethylazodicarboxylate (diethyl azodicarboxylate) (40% toluene solution, 2.88mL), mixture was stirring at room 3 hours then.Reaction mixture is poured in the water, then the mixture extracted with diethyl ether of Xing Chenging.Extract water and salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=20/1), obtain title compound (0.69g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
2.15-2.25(2H，m)，2.56(2H，t，J＝7.1Hz)，3.46(2H，t，J＝6.5Hz)，5.13(2H，s)，7.25-7.4(5H，m)
The comparative example 27
4-(4-[3-(benzyloxycarbonyl) propoxy-]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
To 4-[(4-hydroxy-2-methyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles (0.2g) is at N; solution in the dinethylformamide (3mL); add the sodium iodide of 4-bromo-butyric acid benzyl ester (0.1g), cesium carbonate (0.18g) and catalytic amount, mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Extract water and salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=3/1-2/1), obtain title compound (0.16g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.04(9H，s)，1.05-1.2(33H，m)，2.05-2.15(2H，m)，2.25(3H，s)，2.56(2H，t，J＝7.3Hz)，2.7-2.85(1H，m)，3.53(2H，s)，3.8-3.9(1H，m)，3.94(2H，t，J＝6.2Hz)，4.1(1H，dd，J＝12.5Hz，4.1Hz)，4.16(1H，dd，J＝12.5Hz，2.0Hz)，5.13(2H，s)，5.15-5.25(2H，m)，5.36(1H，t，J＝9.6Hz)，5.65(1H，d，J＝8.1Hz)，6.54(1H，dd，J＝8.5Hz，2.7Hz)，6.64(1H，d，J＝2.7Hz)，6.81(1H，d，J＝8.5Hz)，7.25-7.4(5H，m)
The comparative example 28
1,2-dihydro-4-[(4-iodophenyl) methyl]-5-sec.-propyl-3H-pyrazoles-3-ketone
The preparation method of title compound is similar to comparative example 23, wherein uses 4-iodine benzylalcohol to replace (4-benzyloxy-2-aminomethyl phenyl) methyl alcohol.
1H-NMR(CD
3OD)δppm：
1.12(6H，d，J＝7.3Hz)，2.8-2.95(1H，m)，3.63(2H，s)，6.9-7.0(2H，m)，7.5-7.6(2H，m)
The comparative example 29
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-iodophenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 12, wherein use 1,2-dihydro-4-[(4-iodophenyl) methyl]-5-sec.-propyl-3H-pyrazoles-3-ketone and acetyl bromide-α-D-semi-lactosi, replace 4-{[4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl respectively] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and acetyl bromide-α-D-glucose.
1H-NMR(CDCl
3)δppm：
1.15-1.2(6H，m)，1.88(3H，s)，1.99(3H，s)，2.03(3H，s)，2.18(3H，s)，2.8-2.95(1H，m)，3.58(1H，d，J＝16.0Hz)，3.65(1H，d，J＝16.0Hz)，4.0-4.1(1H，m)，4.15-4.25(2H，m)，5.09(1H，dd，J＝10.7Hz，3.5Hz)，5.35-5.45(2H，m)，5.56(1H，d，J＝8.3Hz)，6.85-6.95(2H，m)，7.5-7.6(2H，m)
The comparative example 30
4-[2-(benzyloxycarbonyl) oxyethyl group] and phenyl } methyl alcohol
To 3-[4-(methylol) phenoxy group] propionic acid (0.98g) and salt of wormwood (0.9g) are at N, and the mixture in the dinethylformamide (5mL) adds cylite (0.65mL), and mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water, then the mixture extracted with diethyl ether of Xing Chenging.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=2/1-1/1), obtain title compound (1.1g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.5-1.55(1H，m)，2.85(2H，t，J＝6.4Hz)，4.28(2H，t，J＝6.4Hz)，4.62(2H，d，J＝5.9Hz)，5.18(2H，s)，6.85-6.9(2H，m)，7.25-7.4(7H，m)
The comparative example 31
4-hydroxy-2-methyl phenyl aldehyde
To 4-bromo-3-methylphenol (14g) and N, the solution of N-Diisopropylamine (39.1mL) in methylene dichloride (150mL), at the ice-cooled chloromethyl methyl ether (11.4mL) that adds down, mixture was stirring at room 5 days then.Pour reaction mixture into saturated aqueous citric acid solution, then the mixture extracted with diethyl ether of Xing Chenging.Extract is water, 1mol/L aqueous sodium hydroxide solution successively, and anhydrous sodium sulfate drying is used in water and salt water washing then.Solvent is removed in decompression, obtains 4-bromo-3-methyl isophthalic acid-(methoxymethoxy) benzene (16.7g).This material is dissolved in tetrahydrofuran (THF) (250mL).Under-78 ℃ and argon gas atmosphere, (the 2.64mol/L hexane solution, 32.7mL), mixture stirred 15 minutes under uniform temp then to add n-Butyl Lithium in this solution.In reaction mixture, add N, dinethylformamide (16.6mL), mixture stirred 1 hour down ice-cooled then.Pour reaction mixture into saturated aqueous ammonium chloride solution, then the mixture extracted with diethyl ether of Xing Chenging.Extract is used anhydrous sodium sulfate drying then with saturated sodium bicarbonate aqueous solution and salt water washing.Solvent is removed in decompression, obtains 2-methyl-4-(methoxymethoxy) phenyl aldehyde (12.9g).This material is dissolved in tetrahydrofuran (THF) (70mL)-methyl alcohol (10mL).Add concentrated hydrochloric acid (6mL) in this solution, mixture stirred 1.5 hours down at 50 ℃ then.Pour reaction mixture into saturated sodium bicarbonate aqueous solution, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract salt water washing then.Solvent is removed in decompression.Under 60 ℃ of heating, residue is dissolved in ethyl acetate (30mL).(100mL) gently adds to solution with normal hexane, and mixture stirred 10 minutes under uniform temp then.Mixture is cooled to food.(170mL) adds to mixture with normal hexane, stirs the mixture overnight that forms then.Sedimentary crystal is collected by filtration, with normal hexane washing and drying under reduced pressure, obtains title compound (5.6g) then.
1H-NMR(CDCl
3)δppm：
2.63(3H，s)，5.47(1H，s)，6.7(1H，d，J＝2.3Hz)，6.79(1H，dd，J＝8.4Hz，2.3Hz)，7.73(1H，d，J＝8.4Hz)，10.11(1H，s)
The comparative example 32
4-(2-carboxyl oxyethyl group)-2-tolyl aldehyde
The mixture in tetrahydrofuran (THF) (60mL) to 4-hydroxy-2-methyl phenyl aldehyde (5g) and potassium tert.-butoxide (4.12g) adds beta-propiolactone (4.6mL), and mixture was stirring at room 4 hours then.Pour reaction mixture into 1mol/L hydrochloric acid, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression.Residue is suspended in ethyl acetate (20mL)-normal hexane (100mL).Insoluble substance is collected by filtration, with normal hexane washing and drying under reduced pressure, obtains title compound (7.2g) then.
1H-NMR(CDCl
3)δppm：
2.65(3H，s)，2.89(2H，t，J＝6.4Hz)，4.32(2H，t，J＝6.4Hz)，6.76(1H，d，J＝2.5Hz)，6.85(1H，dd，J＝8.7Hz，2.5Hz)，7.76(1H，d，J＝8.7Hz)，10.12(1H，s)
The comparative example 33
4-[2-(benzyloxycarbonyl) oxyethyl group]-the 2-tolyl aldehyde
At N, the suspension in the dinethylformamide (70mL) at room temperature adds cylite (8.2mL) to 4-(2-carboxyl oxyethyl group)-2-tolyl aldehyde (7.2g) and salt of wormwood (14.3g), and mixture stirs and spends the night then.Reaction mixture is poured in the water, then the mixture extracted with diethyl ether of Xing Chenging.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=4/1-3/1), obtain title compound (6.47g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
2.64(3H，s)，2.88(2H，t，J＝6.3Hz)，4.34(2H，t，J＝6.3Hz)，5.19(2H，s)，6.73(1H，d，J＝2.4Hz)，6.83(1H，dd，J＝8.5Hz，2.4Hz)，7.3-7.4(5H，m)，7.75(1H，d，J＝8.5Hz)，10.12(1H，s)
The comparative example 34
4-[2-(benzyloxycarbonyl) oxyethyl group]-the 2-aminomethyl phenyl } methyl alcohol
The preparation method of title compound is similar to comparative example 10, wherein uses 4-[2-(benzyloxycarbonyl) oxyethyl group]-2-tolyl aldehyde replacement 4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl aldehyde.
1H-NMR(CDCl
3)δppm：
1.38(1H，t，J＝5.7Hz)，2.35(3H，s)，2.84(2H，t，J＝6.4Hz)，4.26(2H，t，J＝6.4Hz)，4.63(2H，d，J＝5.7Hz)，5.18(2H，s)，6.7-6.75(2H，m)，7.22(1H，d，J＝8.2Hz)，7.3-7.4(5H，m)
The comparative example 35
4-(4-[2-(benzyloxycarbonyl) oxyethyl group] and phenyl } methyl)-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone
The preparation method of title compound is similar to comparative example 11, wherein use 4-[2-(benzyloxycarbonyl) oxyethyl group] phenyl methyl alcohol replacement [4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl] methyl alcohol.
1H-NMR(DMSO-d
6)δppm：
1.05-1.1(6H，m)，2.75-2.85(3H，m)，3.5(2H，s)，4.16(2H，t，J＝5.9Hz)，5.14(2H，s)，6.75-6.8(2H，m)，7.0-7.05(2H，m)，7.3-7.4(5H，m)
The comparative example 36
4-(4-[2-(benzyloxycarbonyl) oxyethyl group]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-3H-pyrazoles-3-ketone
The preparation method of title compound is similar to comparative example 11, wherein use 4-[2-(benzyloxycarbonyl) oxyethyl group]-the 2-aminomethyl phenyl } methyl alcohol replacement [4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl] methyl alcohol.
1H-NMR(CDCl
3)δppm：
1.12(6H，d，J＝6.8Hz)，2.3(3H，s)，2.75-2.9(3H，m)，3.6(2H，s)，4.23(2H，t，J＝6.2Hz)，5.17(2H，s)，6.62(1H，dd，J＝8.5Hz，2.7Hz)，6.7(1H，d，J＝2.7Hz)，6.94(1H，d，J＝8.5Hz)，7.25-7.4(5H，m)
The comparative example 37
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[2-(benzyloxycarbonyl) oxyethyl group] and phenyl } methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 12, wherein use 4-({ 4-[2-(benzyloxycarbonyl) oxyethyl group] phenyl } methyl)-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone is replaced 4-{[4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.87(3H，s)，2.01(3H，s)，2.03(3H，s)，2.06(3H，s)，2.82(2H，t，J＝6.4Hz)，2.85-2.95(1H，m)，3.57(1H，d，J＝15.9Hz)，3.63(1H，d，J＝15.9Hz)，3.8-3.9(1H，m)，4.1-4.15(1H，m)，4.22(2H，t，J＝6.4Hz)，4.31(1H，dd，J＝12.4Hz，4.0Hz)，5.16(2H，s)，5.2-5.3(3H，m)，5.58(1H，d，J＝7.6Hz)，6.7-6.8(2H，m)，7.0-7.05(2H，m)，7.3-7.4(5H，m)
The comparative example 38
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-(4-[2-(benzyloxycarbonyl) oxyethyl group] and phenyl } methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 12, wherein use 4-({ 4-[2-(benzyloxycarbonyl) oxyethyl group] phenyl } methyl)-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and acetyl bromide-α-D-semi-lactosi, replace 4-{[4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl respectively] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and acetyl bromide-α-D-glucose.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.88(3H，s)，1.99(3H，s)，2.02(3H，s)，2.17(3H，s)，2.8-2.9(3H，m)，3.58(1H，d，J＝16.1Hz)，3.65(1H，d，J＝16.1Hz)，4.0-4.25(5H，m)，5.09(1H，dd，J＝10.4Hz，3.5Hz)，5.17(2H，s)，5.4-5.45(2H，m)，5.55(1H，d，J＝8.2Hz)，6.7-6.8(2H，m)，7.0-7.05(2H，m)，7.25-7.35(5H，m)
The comparative example 39
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[2-(benzyloxycarbonyl) oxyethyl group]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 12, wherein use 4-({ 4-[2-(benzyloxycarbonyl) oxyethyl group]-2-aminomethyl phenyl } methyl)-5-sec.-propyl-3H-pyrazoles-3-ketone to replace 4-{[4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone.
1H-NMR(CDCl
3)δppm：
1.05-1.15(6H，m)，1.8(3H，s)，1.99(3H，s)，2.02(3H，s)，2.06(3H，s)，2.25(3H，s)，2.7-2.85(3H，m)，3.49(1H，d，J＝16.2Hz)，3.59(1H，d，J＝16.2Hz)，3.8-3.9(1H，m)，4.12(1H，dd，J＝12.4Hz，2.3Hz)，4.21(2H，t，J＝6.6Hz)，4.3(1H，dd，J＝12.4Hz，4.0Hz)，5.15-5.3(5H，m)，5.56(1H，d，J＝8.0Hz)，6.57(1H，dd，J＝8.5Hz，2.4Hz)，6.67(1H，d，J＝2.4Hz)，6.8(1H，d，J＝8.5Hz)，7.25-7.4(5H，m)
The comparative example 40
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 13; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[2-(benzyloxycarbonyl) oxyethyl group] and phenyl } methyl)-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.89(3H，s)，1.97(3H，s)，2.0(3H，s)，2.02(3H，s)，2.71(2H，t，J＝6.2Hz)，2.85-2.95(1H，m)，3.6(2H，s)，3.9-3.95(1H，m)，4.1-4.15(1H，m)，4.18(2H，t，J＝6.2Hz)，4.3(1H，dd，J＝12.4Hz，4.0Hz)，5.05-5.15(2H，m)，5.25-5.35(1H，m)，5.48(1H，d，J＝8.0Hz)，6.75-6.8(2H，m)，7.0-7.05(2H，m)
The comparative example 41
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-{[4-(2-carboxyl oxyethyl group) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 13; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-(4-[2-(benzyloxycarbonyl) oxyethyl group] and phenyl } methyl)-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.9(3H，s)，1.95(3H，s)，1.99(3H，s)，2.16(3H，s)，2.71(2H，t，J＝6.1Hz)，2.85-2.95(1H，m)，3.61(2H，s)，4.05-4.2(5H，m)，5.19(1H，dd，J＝10.4Hz，3.5Hz)，5.25-5.35(1H，m)，5.4-5.45(1H，m)，5.46(1H，d，J＝8.1Hz)，6.75-6.8(2H，m)，7.0-7.05(2H，m)
The comparative example 42
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 13; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[2-(benzyloxycarbonyl) oxyethyl group]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.82(3H，s)，1.96(3H，s)，2.0(3H，s)，2.02(3H，s)，2.26(3H，s)，2.7(2H，t，J＝6.2Hz)，2.75-2.9(1H，m)，3.53(1H，d，J＝16.4Hz)，3.58(1H，d，J＝16.4Hz)，3.85-3.95(1H，m)，4.08(1H，dd，J＝12.4Hz，2.4Hz)，4.17(2H，t，J＝6.2Hz)，4.28(1H，dd，J＝12.4Hz，4.1Hz)，5.0-5.15(2H，m)，5.27(1H，t，J＝9.6Hz)，5.43(1H，d，J＝7.9Hz)，6.61(1H，dd，J＝8.5Hz，2.5Hz)，6.71(1H，d，J＝2.5Hz)，6.77(1H，d，J＝8.5Hz)
The comparative example 43
4-{[4-(3-carboxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
The preparation method of title compound is similar to comparative example 25; wherein use 4-({ 4-[3-(benzyloxycarbonyl) propoxy-]-2-aminomethyl phenyl } methyl)-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles replacement 4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.04(9H，s)，1.05-1.2(33H，m)，2.05-2.15(2H，m)，2.25(3H，s)，2.5-2.6(2H，m)，2.7-2.8(1H，m)，3.52(2H，s)，3.8-3.9(1H，m)，3.95-4.0(2H，m)，4.05-4.15(1H，m)，4.17(1H，dd，J＝12.4Hz，1.9Hz)，5.15-5.3(2H，m)，5.36(1H，t，J＝9.4Hz)，5.53(1H，d，J＝8.3Hz)，6.57(1H，dd，J＝8.4Hz，2.7Hz)，6.67(1H，d，J＝2.7Hz)，6.81(1H，d，J＝8.4Hz)
The comparative example 44
Hydrochlorinate 2-amino-2-methyl benzyl propionate
At N, the solution in the dinethylformamide (40mL) adds salt of wormwood (4.15g) and cylite (2.85mL) to 2-(tert-butoxycarbonyl amino)-2 Methylpropionic acid (4.06g), and mixture was stirring at room 2 hours then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression.Residue (solid) is handled with normal hexane, collects by filtration then.Crystal is carried out drying under reduced pressure, obtain 2-(tert-butoxycarbonyl amino)-benzyl 2-methylpropanoate (4.44g).(4mol/L 1, and the 4-dioxane solution 15mL) adds to 2-(tert-butoxycarbonyl the amino)-benzyl 2-methylpropanoate (4.44g) of acquisition, and mixture is in stirred overnight at room temperature then with hydrochloric acid.Reaction mixture dilutes with ether, and the mixture of stirring formation is 1 hour then.Insoluble substance is collected by filtration, with ether washing and drying under reduced pressure, obtains title compound (3.4g) then.
1H-NMR(DMSO-d
6)δppm：
1.49(6H，s)，5.25(2H，s)，7.3-7.45(5H，m)，8.54(3H，brs)
The comparative example 45
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-benzyloxycarbonyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (0.14g) is at N; solution in the dinethylformamide (3mL); add hydrochlorinate benzyl methylpropanoate (57mg), I-hydroxybenzotriazole (31mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (60mg) and triethylamine (0.087mL), mixture was stirring at room 4 hours then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, and residue carries out purifying (eluent: methylene chloride=40/1-20/1), obtain title compound (0.15g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.1-1.15(6H，m)，1.56(6H，s)，1.81(3H，s)，1.99(3H，s)，2.02(3H，s)，2.05(3H，s)，2.25(3H，s)，2.6(2H，t，J＝6.1Hz)，2.75-2.85(1H，m)，3.5(1H，d，J＝16.7Hz)，3.59(1H，d，J＝16.7Hz)，3.8-3.9(1H，m)，4.05-4.2(3H，m)，4.29(1H，dd，J＝12.5Hz，4.0Hz)，5.1-5.3(5H，m)，5.56(1H，d，J＝8.1Hz)，6.53(1H，brs)，6.57(1H，dd，J＝8.5Hz，2.5Hz)，6.67(1H，d，J＝2.5Hz)，6.8(1H，d，J＝8.5Hz)，7.25-7.4(5H，m)
The comparative example 46
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[(S)-1-(benzyloxycarbonyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 45, wherein use (S)-2-alanine benzyl ester right-tosylate replaces the hydrochlorinate benzyl methylpropanoate.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.38(3H，d，J＝7.3Hz)，1.82(3H，s)，1.95(3H，s)，2.0(3H，s)，2.01(3H，s)，2.25(3H，s)，2.6-2.7(2H，m)，2.75-2.9(1H，m)，3.52(1H，d，J＝16.5Hz)，3.58(1H，d，J＝16.5Hz)，3.85-3.95(1H，m)，4.07(1H，dd，J＝12.2Hz，2.5Hz)，4.1-4.2(2H，m)，4.27(1H，dd，J＝12.2Hz，4.2Hz)，4.4-4.5(1H，m)，5.0-5.2(4H，m)，5.28(1H，t，J＝9.5Hz)，5.43(1H，d，J＝7.9Hz)，6.58(1H，dd，J＝8.5Hz，2.2Hz)，6.69(1H，d，J＝2.2Hz)，6.76(1H，d，J＝8.5Hz)，7.25-7.4(5H，m)
The comparative example 47
4-[(4-{3-[1-benzyloxycarbonyl-1-(methyl) ethylamino formyl radical] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
The preparation method of title compound is similar to comparative example 45; wherein use 4-{[4-(3-carboxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.0-1.2(42H，m)，1.52(6H，s)，1.95-2.1(2H，m)，2.25(3H，s)，2.34(2H，t，J＝7.3Hz)，2.7-2.85(1H，m)，3.52(2H，s)，3.8-3.95(3H，m)，4.05-4.2(2H，m)，5.1-5.25(4H，m)，5.36(1H，t，J＝9.1Hz)，5.65(1H，d，J＝8.3Hz)，6.05(1H，brs)，6.53(1H，dd，J＝8.2Hz，2.5Hz)，6.65(1H，d，J＝2.5Hz)，6.81(1H，d，J＝8.2Hz)，7.25-7.4(5H，m)
The comparative example 48
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-carboxyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-benzyloxycarbonyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (0.15g) is dissolved in methyl alcohol (5mL).In this solution, add 10% palladium-carbon dust (50mg), under hydrogen atmosphere, mixture at room temperature stirred then and spend the night.Insoluble substance is removed by filtering, and the solvent of filtrate is removed in decompression then, obtains title compound (0.13g).
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.47(6H，s)，1.82(3H，s)，1.96(3H，s)，2.0(3H，s)，2.02(3H，s)，2.26(3H，s)，2.6(2H，t，J＝6.3Hz)，2.75-2.9(1H，m)，3.52(1H，d，J＝16.4Hz)，3.58(1H，d，J＝16.4Hz)，3.85-3.95(1H，m)，4.07(1H，dd，J＝12.4Hz，2.2Hz)，4.16(2H，t，J＝6.3Hz)，4.27(1H，dd，J＝12.4Hz，4.0Hz)，5.0-5.15(2H，m)，5.28(1H，t，J＝9.5Hz)，5.43(1H，d，J＝8.2Hz)，6.61(1H，dd，J＝8.5Hz，2.6Hz)，6.71(1H，d，J＝2.6Hz)，6.77(1H，d，J＝8.5Hz)
The comparative example 49
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[(S)-1-(carboxyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 48; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[(S)-and 1-(benzyloxycarbonyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-benzyloxycarbonyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.39(3H，d，J＝7.3Hz)，1.82(3H，s)，1.96(3H，s)，2.0(3H，s)，2.02(3H，s)，2.26(3H，s)，2.6-2.7(2H，m)，2.75-2.9(1H，m)，3.52(1H，d，J＝16.6Hz)，3.58(1H，d，J＝16.6Hz)，3.85-3.95(1H，m)，4.07(1H，dd，J＝12.4Hz，2.5Hz)，4.1-4.25(2H，m)，4.27(1H，dd，J＝12.4Hz，4.0Hz)，4.4(1H，q，J＝7.3Hz)，5.0-5.15(2H，m)，5.28(1H，t，J＝9.4Hz)，5.43(1H，d，J＝8.0Hz)，6.62(1H，dd，J＝8.3Hz，2.7Hz)，6.72(1H，d，J＝2.7Hz)，6.77(1H，d，J＝8.3Hz)
The comparative example 50
4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
The preparation method of title compound is similar to comparative example 48; wherein use 4-[(4-{3-[1-benzyloxycarbonyl-1-(methyl) ethylamino formyl radical] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles replacement 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-benzyloxycarbonyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.2(42H，m)，1.44(6H，s)，1.95-2.05(2H，m)，2.26(3H，s)，2.35(2H，t，J＝7.4Hz)，2.75-2.85(1H，m)，3.5-3.6(2H，m)，3.9-4.0(3H，m)，4.09(1H，dd，J＝12.4Hz，1.8Hz)，4.17(1H，dd，J＝12.4Hz，4.2Hz)，5.05-5.2(2H，m)，5.39(1H，t，J＝9.5Hz)，5.58(1H，d，J＝7.9Hz)，6.58(1H，dd，J＝8.4Hz，2.6Hz)，6.7(1H，d，J＝2.6Hz)，6.8(1H，d，J＝8.4Hz)
The comparative example 51
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-{4-[1-carboxyl-1-(methyl) ethylamino formyl radical] butyl } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
With 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-the 4-[(4-iodophenyl) methyl]-5-sec.-propyl-1H-pyrazoles (0.43g), 4-pentynoic acid (94mg), four (triphenylphosphines) close palladium (0) (37mg), cuprous iodide (I) (12mg) and the mixture of triethylamine (0.45mL) in tetrahydrofuran (THF) (5mL), under room temperature and argon gas atmosphere, stir and spend the night.Pour reaction mixture into 0.5mol/L hydrochloric acid, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression; residue carries out purifying (eluent: n-hexane/ethyl acetate=1/2-ethyl acetate) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-{[4-(4-carboxyl fourth-1-alkynyl) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (0.37g).With this substance dissolves in N, dinethylformamide (6mL).In this solution, add hydrochlorinate benzyl methylpropanoate (0.15g), I-hydroxybenzotriazole (86mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.22g) and triethylamine (0.32mL), mixture is in stirred overnight at room temperature then.Pour reaction mixture into 0.5mol/L hydrochloric acid, and the mixture ethyl acetate extraction that forms.Extract is water, saturated sodium bicarbonate aqueous solution and salt water washing successively, uses anhydrous sodium sulfate drying then.Solvent is removed in decompression; residue carries out purifying (eluent: methylene chloride=20/1) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-{4-[1-benzyloxycarbonyl-1-(methyl) ethylamino formyl radical] fourth-1-alkynyl } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (0.36g).This material is dissolved in methyl alcohol (5mL).Add 10% palladium-carbon dust (50mg) in this solution, mixture stirred 2 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and the solvent of filtrate is removed in decompression then, obtains title compound (0.31g).
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.44(6H，s)，1.55-1.65(4H，m)，1.88(3H，s)，1.95(3H，s)，1.99(3H，s)，2.1-2.2(5H，m)，2.5-2.6(2H，m)，2.85-3.0(1H，m)，3.55-3.7(2H，m)，4.05-4.2(3H，m)，5.19(1H，dd，J＝10.4Hz，3.5Hz)，5.25-5.35(1H，m)，5.4-5.45(1H，m)，5.46(1H，d，J＝8.1Hz)，7.0-7.1(4H，m)
Embodiment 78
4-[(4-{2-[1-formamyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (0.2g) is at N; solution in the dinethylformamide (3mL); add 2-amino-2-methyl propionic acid amide (47mg), I-hydroxybenzotriazole (50mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (118mg) and triethylamine (0.13mL), mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression; residue carries out purifying (eluent: methylene chloride=20/1-10/1) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-formamyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (0.12g).This material is dissolved in methyl alcohol (3mL).In this solution, (28% methanol solution, 0.06mL), mixture was stirring at room 1 hour then to add sodium methylate.In reaction mixture, add acetate (0.1mL), the mixture of Xing Chenging is through concentrating under reduced pressure then.Residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (80mg) by Solid-Phase Extraction on ODS.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.47(6H，s)，2.29(3H，s)，2.62(2H，t，J＝6.1Hz)，2.75-2.85(1H，m)，3.25-3.4(4H，m)，3.6-3.75(3H，m)，3.81(1H，d，J＝11.9Hz)，4.18(2H，t，J＝6.1Hz)，4.95-5.05(1H，m)，6.63(1H，dd，J＝8.4Hz，2.4Hz)，6.72(1H，d，J＝2.4Hz)，6.86(1H，d，J＝8.4Hz)
Embodiment 79
4-[(4-{2-[1-formamyl-1-(methyl) ethylamino formyl radical] oxyethyl group } phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 78; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-carboxyl oxyethyl group) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.5-1.15(6H，m)，1.47(6H，s)，2.63(2H，t，J＝6.2Hz)，2.85-2.95(1H，m)，3.3-3.4(4H，m)，3.6-3.75(3H，m)，3.8-3.85(1H，m)，4.19(2H，t，J＝6.2Hz)，5.05-5.1(1H，m)，6.8-6.85(2H，m)，7.1-7.15(2H，m)
Embodiment 80
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[2-hydroxyl-1,1-two (methyl) ethylamino formyl radical] oxyethyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 78; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-carboxyl oxyethyl group) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl-1-propanol, replace 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.27(6H，s)，2.59(2H，t，J＝6.2Hz)，2.85-2.95(1H，m)，3.3-3.4(4H，m)，3.57(2H，s)，3.6-3.85(4H，m)，4.16(2H，t，J＝6.2Hz)，5.05-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
The comparative example 52
1-(2-amino-2-methyl propionyl)-4-methylpiperazine
To the solution of 2-benzyloxycarbonyl amino-2-methyl propionic acid (2.37g) in tetrahydrofuran (THF) (20mL), add 1,1 '-carbonyl diurethane-1H-imidazoles (1.78g), mixture was stirring at room 1 hour then.In reaction mixture, add 1-methylpiperazine (2.0mL), mixture stirred 3.5 days at 40 ℃ then.In reaction mixture, add methyl alcohol, then the mixture that forms is carried out concentrating under reduced pressure.Residue carries out purifying (eluent: methylene chloride=20/1), obtain 1-(2-benzyloxycarbonyl amino-2-methyl propionyl)-4-methylpiperazine (1.99g) by silica gel column chromatography.This material is dissolved in methyl alcohol (10mL).Add 10% palladium-carbon dust (0.4g) in this solution, mixture stirred 3 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and the solvent of filtrate is removed in decompression then, obtains title compound (1.14g).
1H-NMR(CD
3OD)δppm：
1.39(6H，s)，2.3(3H，s)，2.44(4H，t，J＝5.1Hz)，3.77(4H，brs)
The comparative example 53
2-(2-amino-2-methyl propionyl amino) ethanol
The preparation method of title compound is similar to comparative example 52, wherein uses the 2-monoethanolamine to replace the 1-methylpiperazine.
1H-NMR(CD
3OD)δppm：
1.31(6H，s)，3.25-3.35(2H，m)，3.6(2H，t，J＝5.8Hz)
Embodiment 81
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(2-{1-[(4-methylpiperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } oxyethyl group) phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 78; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-carboxyl oxyethyl group) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 1-(2-amino-2-methyl propionyl)-4-methylpiperazine; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.45(6H，s)，2.2(3H，s)，2.3-2.5(4H，m)，2.6(2H，t，J＝5.7Hz)，2.85-2.95(1H，m)，3.3-3.4(4H，m)，3.6-3.9(8H，m)，4.18(2H，t，J＝5.7Hz)，5.05-5.1(1H，m)，6.75-6.85(2H，m)，7.1-7.15(2H，m)
Embodiment 82
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(2-{1-[(4-methylpiperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } oxyethyl group) phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 78; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-{[4-(2-carboxyl oxyethyl group) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 1-(2-amino-2-methyl propionyl)-4-methylpiperazine; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.45(6H，s)，2.17(3H，s)，2.35(4H，brs)，2.6(2H，t，J＝5.6Hz)，2.85-2.95(1H，m)，3.52(1H，dd，J＝9.7Hz，3.2Hz)，3.55-3.9(11H，m)，4.18(2H，t，J＝5.6Hz)，5.08(1H，d，J＝7.6Hz)，6.75-6.85(2H，m)，7.05-7.2(2H，m)
Embodiment 83
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-(2-hydroxyethylamino formyl radical)-1-(methyl) ethylamino formyl radical] oxyethyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 78; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-carboxyl oxyethyl group) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-(2-amino-2-methyl propionyl amino) ethanol, replace 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.45(6H，s)，2.63(2H，t，J＝6.2Hz)，2.85-2.95(1H，m)，3.24(2H，t，J＝5.9Hz)，3.3-3.4(4H，m)，3.51(2H，t，J＝5.9Hz)，3.6-3.85(4H，m)，4.19(2H，t，J＝6.2Hz)，5.05-5.1(1H，m)，6.8-6.85(2H，m)，7.1-7.15(2H，m)
Embodiment 84
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[(S)-2-hydroxyl-1-(methyl) ethylamino formyl radical] oxyethyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 78; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-carboxyl oxyethyl group) phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and (S)-2-amino-1-propyl alcohol, replace 3-(2,3 respectively; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.1-1.15(9H，m)，2.55-2.65(2H，m)，2.85-2.95(1H，m)，3.3-3.4(4H，m)，3.44(1H，dd，J＝10.9Hz，5.7Hz)，3.49(1H，dd，J＝10.9Hz，5.6Hz)，3.6-3.75(3H，m)，3.8-3.85(1H，m)，3.9-4.0(1H，m)，4.15-4.25(2H，m)，5.0-5.1(1H，m)，6.75-6.85(2H，m)，7.05-7.15(2H，m)
Embodiment 85
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(2-{1-[(4-methylpiperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } oxyethyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 78; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{2-[1-carboxyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-methylpiperazine; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.45(6H，s)，2.18(3H，s)，2.29(3H，s)，2.36(4H，brs)，2.6(2H，t，J＝5.7Hz)，2.75-2.85(1H，m)，3.25-3.4(4H，m)，3.55-3.75(7H，m)，3.82(1H，d，J＝11.8Hz)，4.17(2H，t，J＝5.7Hz)，5.0-5.15(1H，m)，6.63(1H，dd，J＝8.4Hz，2.5Hz)，6.71(1H，d，J＝2.5Hz)，6.87(1H，d，J＝8.4Hz)
Embodiment 86
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[2-hydroxyl-1,1-two (methylol) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 78, wherein uses three (methylol) aminomethane to replace 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，2.29(3H，s)，2.68(2H，t，J＝6.1Hz)，2.75-2.85(1H，m)，3.25-3.4(4H，m)，3.6-3.75(9H，m)，3.81(1H，d，J＝12.0Hz)，4.18(2H，t，J＝6.1Hz)，5.0-5.05(1H，m)，6.65(1H，dd，J＝8.4Hz，2.3Hz)，6.74(1H，d，J＝2.3Hz)，6.86(1H，d，J＝8.4Hz)
Embodiment 87
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[2-hydroxyl-1,1-two (methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 78, wherein uses 2-amino-2-methyl-1-propanol to replace 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.27(6H，s)，2.29(3H，s)，2.58(2H，t，J＝6.2Hz)，2.75-2.85(1H，m)，3.2-3.4(4H，m)，3.57(2H，s)，3.6-3.75(3H，m)，3.82(1H，d，J＝11.9Hz)，4.16(2H，t，J＝6.2Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.4Hz，2.0Hz)，6.72(1H，d，J＝2.0Hz)，6.86(1H，d，J＝8.4Hz)
Embodiment 88
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[2-hydroxyl-1-methylol-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 78, wherein uses 2-amino-2-methyl-1, and ammediol is replaced 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.25(3H，s)，2.29(3H，s)，2.63(2H，t，J＝6.2Hz)，2.75-2.85(1H，m)，3.25-3.4(4H，m)，3.6-3.7(7H，m)，3.81(1H，d，J＝11.8Hz)，4.17(2H，t，J＝6.2Hz)，5.0-5.05(1H，m)，6.63(1H，dd，J＝8.4Hz，2.4Hz)，6.73(1H，d，J＝2.4Hz)，6.86(1H，d，J＝8.4Hz)
Embodiment 89
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 78; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{2-[1-carboxyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-(2-hydroxyethyl) piperazine; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.45(6H，s)，2.3(3H，s)，2.35-2.55(6H，m)，2.6(2H，t，J＝5.7Hz)，2.75-2.9(1H，m)，3.25-3.4(4H，m)，3.57(2H，t，J＝5.8Hz)，3.6-3.8(7H，m)，3.82(1H，d，J＝11.9Hz)，4.17(2H，t，J＝5.7Hz)，5.0-5.05(1H，m)，6.63(1H，dd，J＝8.4Hz，2.4Hz)，6.71(1H，d，J＝2.4Hz)，6.87(1H，d，J＝8.4Hz)
Embodiment 90
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-(2-hydroxyethylamino formyl radical)-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 78; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{2-[1-carboxyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 2-monoethanolamine; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.45(6H，s)，2.29(3H，s)，2.63(2H，t，J＝6.2Hz)，2.75-2.85(1H，m)，3.24(2H，t，J＝5.9Hz)，3.3-3.4(4H，m)，3.51(2H，t，J＝5.9Hz)，3.6-3.7(3H，m)，3.82(1H，d，J＝12.0Hz)，4.18(2H，t，J＝6.2Hz)，5.0-5.05(1H，m)，6.64(1H，dd，J＝8.4Hz，2.4Hz)，6.74(1H，d，J＝2.4Hz)，6.86(1H，d，J＝8.4Hz)
Embodiment 91
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-(3-hydroxypropyl formamyl)-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 78; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{2-[1-carboxyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 3-amino-1-propyl alcohol; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.45(6H，s)，1.55-1.65(2H，m)，2.29(3H，s)，2.62(2H，t，J＝6.1Hz)，2.75-2.85(1H，m)，3.2(2H，t，J＝6.6Hz)，3.25-3.4(4H，m)，3.51(2H，t，J＝6.2Hz)，3.6-3.7(3H，m)，3.82(1H，d，J＝12.0Hz)，4.18(2H，t，J＝6.1Hz)，5.0-5.15(1H，m)，6.64(1H，dd，J＝8.4Hz，2.3Hz)，6.73(1H，d，J＝2.3Hz)，6.87(1H，d，J＝8.4Hz)
Embodiment 92
4-[(4-{2-[(S)-and 1-(formamyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 78, wherein uses L-alanimamides hydrochloride to replace 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.1-1.15(6H，m)，1.36(3H，d，J＝7.2Hz)，2.29(3H，s)，2.6-2.85(3H，m)，3.3-3.4(4H，m)，3.6-3.7(3H，m)，3.81(1H，d，J＝12.1Hz)，4.15-4.25(2H，m)，4.36(1H，q，J＝7.2Hz)，5.0-5.05(1H，m)，6.62(1H，dd，J＝8.4Hz，2.5Hz)，6.72(1H，d，J＝2.5Hz)，6.86(1H，d，J＝8.4Hz)
Embodiment 93
3-(β-D-pyranoglucose oxygen base)-4-[4-{2-[(S)-1-(2-hydroxyethylamino formyl radical) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 78; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[(S)-and 1-(carboxyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 2-monoethanolamine; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.34(3H，d，J＝7.2Hz)，2.29(3H，s)，2.67(2H，t，J＝6.1Hz)，2.75-2.85(1H，m)，3.2-3.4(6H，m)，3.55(2H，t，J＝5.8Hz)，3.6-3.7(3H，m)，3.82(1H，d，J＝12.0Hz)，4.19(2H，t，J＝6.1Hz)，4.35(1H，q，J＝7.2Hz)，4.95-5.05(1H，m)，6.63(1H，dd，J＝8.4Hz，2.3Hz)，6.73(1H，d，J＝2.3Hz)，6.86(1H，d，J＝8.4Hz)
Embodiment 94
4-[(4-{2-[(S)-and 1-formamyl-2-hydroxyethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 78, wherein uses L-silk amide hydrochloride to replace 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，2.29(3H，s)，2.65-2.9(3H，m)，3.25-3.4(4H，m)，3.55-3.9(6H，m)，4.21(2H，t，J＝6.0Hz)，4.4-4.5(1H，m)，4.95-5.05(1H，m)，6.64(1H，dd，J＝8.3Hz，2.2Hz)，6.73(1H，d，J＝2.2Hz)，6.86(1H，d，J＝8.3Hz)
Embodiment 95
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[2-hydroxyl-1-(methylol) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 78, wherein uses 2-amino-1, and ammediol is replaced 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，2.29(3H，s)，2.65(2H，t，J＝6.2Hz)，2.75-2.85(1H，m)，3.3-3.4(4H，m)，3.55-3.7(7H，m)，3.86(1H，d，J＝11.6Hz)，3.9-4.0(1H，m)，4.19(2H，t，J＝6.2Hz)，4.95-5.05(1H，m)，6.63(1H，dd，J＝8.4Hz，2.4Hz)，6.72(1H，d，J＝2.4Hz)，6.86(1H，d，J＝8.4Hz)
Embodiment 96
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[(S)-1-(3-hydroxypropyl formamyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 78; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[(S)-and 1-(carboxyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 3-amino-1-propyl alcohol; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.34(3H，d，J＝7.2Hz)，1.6-1.7(2H，m)，2.29(3H，s)，2.66(2H，t，J＝6.2Hz)，2.75-2.85(1H，m)，3.2-3.4(6H，m)，3.54(2H，t，J＝6.2Hz)，3.6-3.7(3H，m)，3.82(1H，d，J＝11.6Hz)，4.19(2H，t，J＝6.2Hz)，4.32(1H，q，J＝7.2Hz)，5.0-5.05(1H，m)，6.63(1H，dd，J＝8.4Hz，2.5Hz)，6.72(1H，d，J＝2.5Hz)，6.86(1H，d，J＝8.4Hz)
Embodiment 97
3-(β-D-galactopyranose oxygen base)-4-[(4-{4-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] butyl } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 78; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-[(4-{4-[1-carboxyl-1-(methyl) ethylamino formyl radical] butyl } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-(2-hydroxyethyl) piperazine; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.42(6H，s)，1.55-1.65(4H，m)，2.18(2H，t，J＝6.8Hz)，2.4-2.65(8H，m)，2.85-2.95(1H，m)，3.5-3.8(13H，m)，3.85-3.9(1H，m)，5.08(1H，d，J＝7.8Hz)，7.04(2H，d，J＝8.0Hz)，7.1(2H，d，J＝8.0Hz)
Embodiment 98
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(4-{1-[(4-methylpiperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } butyl) phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 78; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-[(4-{4-[1-carboxyl-1-(methyl) ethylamino formyl radical] butyl } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-methylpiperazine; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.41(6H，s)，1.55-1.65(4H，m)，2.18(2H，t，J＝6.9Hz)，2.24(3H，s)，2.35(4H，brs)，2.57(2H，t，J＝6.6Hz)，2.85-2.95(1H，m)，3.45-3.8(11H，m)，3.85-3.95(1H，m)，5.08(1H，d，J＝7.7Hz)，7.04(2H，d，J＝7.9Hz)，7.1(2H，d，J＝7.9Hz)
Embodiment 99
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(2-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } oxyethyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{2-[1-carboxyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (40mg) is at N; solution in the dinethylformamide (1mL); add 1-benzyl diethylenediamine (12mg); I-hydroxybenzotriazole (8mg); 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (16mg) and triethylamine (0.023mL), mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression; residue carries out purifying (eluent: methylene chloride=30/1-15/1) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-{1-[(4-benzyl diethylenediamine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } oxyethyl group)-the 2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles (31mg).This material is dissolved in methyl alcohol (3mL).In this solution, (28% methanol solution, 0.02mL), mixture was stirring at room 1 hour then to add sodium methylate.In reaction mixture, add acetate (0.04mL).The mixture that obtains is through concentrating under reduced pressure; residue carries out purifying (cleaning solvent: distilled water by Solid-Phase Extraction on ODS then; eluent: methyl alcohol), obtain 4-{[4-(2-{1-[(4-benzyl diethylenediamine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } oxyethyl group)-the 2-aminomethyl phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles (24mg).This material is dissolved in methyl alcohol (3mL).In this solution, add 10% palladium-carbon dust (10mg), under hydrogen atmosphere, mixture at room temperature stirred then and spend the night.Insoluble substance is removed decompression then through decompression and is removed the solvent of filtrate, obtains title compound (20mg).
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.45(6H，s)，2.3(3H，s)，2.5-2.9(7H，m)，3.25-3.4(4H，m)，3.45-3.75(7H，m)，3.81(1H，d，J＝11.5Hz)，4.17(2H，t，J＝5.7Hz)，4.95-5.05(1H，m)，6.62(1H，dd，J＝8.4Hz，2.5Hz)，6.71(1H，d，J＝2.5Hz)，6.86(1H，d，J＝8.4Hz)
Embodiment 100
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(4-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } butyl) phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 99; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-[(4-{4-[1-carboxyl-1-(methyl) ethylamino formyl radical] butyl } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-carboxyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.41(6H，s)，1.5-1.65(4H，m)，2.17(2H，t，J＝7.1Hz)，2.58(2H，t，J＝6.8Hz)，2.72(4H，brs)，2.85-2.95(1H，m)，3.45-3.8(11H，m)，3.8-3.9(1H，m)，5.08(1H，d，J＝7.7Hz)，7.04(2H，d，J＝8.0Hz)，7.1(2H，d，J＝8.0Hz)
Embodiment 101
4-[(4-{2-[(S)-and 5-amino-1-(formamyl) amyl group formamyl] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 99; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and (S)-2-amino-6-(benzyloxycarbonyl amino) hexanamide hydrochloride; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-carboxyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-benzyl diethylenediamine.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.3-1.95(6H，m)，2.3(3H，s)，2.6-2.9(5H，m)，3.3-3.4(4H，m)，3.6-3.7(3H，m)，3.82(1H，d，J＝11.8Hz)，4.15-4.25(2H，m)，4.38(1H，dd，J＝9.3Hz，4.8Hz)，5.0-5.05(1H，m)，6.62(1H，dd，J＝8.4Hz，2.5Hz)，6.72(1H，d，J＝2.5Hz)，6.86(1H，d，J＝8.4Hz)
Embodiment 102
4-[(4-{2-[(S)-and 5-amino-5-(formamyl) amyl group formamyl] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 99; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and (S)-6-amino-2-(benzyloxycarbonyl amino) hexanamide hydrochloride; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-carboxyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-benzyl diethylenediamine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.3-1.8(6H，m)，2.29(3H，s)，2.59(2H，t，J＝6.1Hz)，2.75-2.85(1H，m)，3.21(2H，t，J＝6.9Hz)，3.3-3.4(5H，m)，3.6-3.7(3H，m)，3.81(1H，d，J＝11.5Hz)，4.18(2H，t，J＝6.1Hz)，5.0-5.05(1H，m)，6.62(1H，dd，J＝8.4Hz，2.4Hz)，6.71(1H，d，J＝2.4Hz)，6.86(1H，d，J＝8.4Hz)
Embodiment 103
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 99; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-(benzyloxycarbonyl) piperazine; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-carboxyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-benzyl diethylenediamine.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.42(6H，s)，1.8-1.95(2H，m)，2.16(2H，t，J＝7.2Hz)，2.3(3H，s)，2.55(2H，t，J＝7.5Hz)，2.65-2.9(5H，m)，3.2-3.45(4H，m)，3.5-3.9(8H，m)，4.95-5.05(1H，m)，6.8-6.9(2H，m)，6.9-7.0(1H，m)
Embodiment 104
4-{[4-(3-{1-[(S)-5-amino-5-(formamyl) amyl group formamyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 99; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and (S)-6-amino-2-(benzyloxycarbonyl amino) hexanamide hydrochloride; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-carboxyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-benzyl diethylenediamine.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.2-1.6(11H，m)，1.6-1.75(1H，m)，1.8-1.9(2H，m)，2.19(2H，t，J＝7.8Hz)，2.58(2H，t，J＝7.7Hz)，2.85-2.95(1H，m)，3.1-3.25(2H，m)，3.25-3.35(1H，m)，3.52(1H，dd，J＝9.7Hz，3.4Hz)，3.55-3.65(1H，m)，3.65-3.8(5H，m)，3.86(1H，d，J＝3.1Hz)，5.08(1H，d，J＝8.0Hz)，7.0-7.15(4H，m)
Embodiment 105
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles
To 4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles (0.12g) is at N; solution in the dinethylformamide (3mL); add 1-(benzyloxycarbonyl) piperazine (43mg), I-hydroxybenzotriazole (19mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (50mg) and triethylamine (0.027mL), mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water.Sedimentary crystal is collected by filtration; wash with water then and drying under reduced pressure; obtain 4-[(4-{3-[1-{[4-(benzyloxycarbonyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles (0.14g).With this substance dissolves in ethanol (4mL).Add 10% palladium-carbon dust (30mg) in this solution, mixture stirred 1.5 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering; the solvent of filtrate is removed in decompression then. and residue carries out purifying (eluent: methylene chloride=10/1-5/1) by silica gel column chromatography; obtain 5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propoxy-)-the 2-aminomethyl phenyl] methyl }-3-(2; 3; 4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles (89mg).This material is dissolved in methyl alcohol (6mL).In this solution, (28% methanol solution, 0.087mL), mixture stirred 3 hours down at 50 ℃ then to add sodium methylate.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (54mg) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.42(6H，s)，1.95-2.05(2H，m)，2.29(3H，s)，2.39(2H，t，J＝7.3Hz)，2.55-2.9(5H，m)，3.25-3.4(4H，m)，3.5-3.7(7H，m)，3.75-3.85(1H，m)，3.95(2H，t，J＝6.0Hz)，5.0-5.05(1H，m)，6.61(1H，dd，J＝8.4Hz，2.3Hz)，6.71(1H，d，J＝2.3Hz)，6.84(1H，d，J＝8.4Hz)
Embodiment 106
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
To 4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles (40mg) is at N; solution in the dinethylformamide (2mL); add 1-(2-hydroxyethyl) piperazine (7mg), I-hydroxybenzotriazole (7mg), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (13mg) and triethylamine (0.018mL), mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression; residue carries out purifying (eluent: methylene chloride=15/1) by silica gel column chromatography then; obtain 4-[(4-{3-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles (27mg).This material is dissolved in methyl alcohol (2mL).In this solution, (28% methanol solution, 0.015mL), mixture spends the night 50 ℃ of stirrings then to add sodium methylate.To the reaction mixture concentrating under reduced pressure, residue carries out purifying (cleaning solvent: distilled water, eluent: methyl alcohol), obtain title compound (12mg) by Solid-Phase Extraction on ODS then.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.42(6H，s)，1.95-2.05(2H，m)，2.29(3H，s)，2.35-2.5(8H，m)，2.75-2.85(1H，m)，3.25-3.4(4H，m)，3.55-3.75(9H，m)，3.75-3.85(1H，m)，3.94(2H，t，J＝6.1Hz)，5.0-5.05(1H，m)，6.61(1H，dd，J＝8.4Hz，2.4Hz)，6.7(1H，d，J＝2.4Hz)，6.85(1H，d，J＝8.4Hz)
Embodiment 107
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(4-methylpiperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 106, wherein uses the 1-methylpiperazine to replace 1-(2-hydroxyethyl) piperazine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.42(6H，s)，1.95-2.05(2H，m)，2.22(3H，s)，2.25-2.45(9H，m)，2.75-2.85(1H，m)，3.25-3.4(4H，m)，3.55-3.75(7H，m)，3.75-3.85(1H，m)，3.95(2H，t，J＝6.0Hz)，5.03(1H，d，J＝7.5Hz)，6.61(1H，dd，J＝8.3Hz，2.6Hz)，6.7(1H，d，J＝2.6Hz)，6.85(1H，d，J＝8.3Hz)
Embodiment 108
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-(2-hydroxyethylamino formyl radical)-1-(methyl) ethylamino formyl radical] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 106, wherein uses the 2-monoethanolamine to replace 1-(2-hydroxyethyl) piperazine.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.42(6H，s)，1.95-2.05(2H，m)，2.28(3H，s)，2.39(2H，t，J＝7.4Hz)，2.75-2.85(1H，m)，3.2-3.4(6H，m)，3.56(2H，t，J＝5.9Hz)，3.6-3.7(3H，m)，3.75-3.85(1H，m)，3.94(2H，t，J＝6.1Hz)，4.95-5.05(1H，m)，6.61(1H，dd，J＝8.4Hz，2.3Hz)，6.71(1H，d，J＝2.3Hz)，6.85(1H，d，J＝8.4Hz)
The comparative example 54
1-(3-benzoyloxy propyl group)-1,2-dihydro-4-[(4-iodophenyl) methyl]-5-sec.-propyl-3H-pyrazoles-3-ketone
To 1,2-dihydro-4-[(4-iodophenyl) methyl]-5-sec.-propyl-3H-pyrazoles-3-ketone (5g) and imidazoles (1.19g) be at N, solution in the dinethylformamide (20mL) at room temperature adds triisopropyl silyl chlorination thing (3.1g), stirs the mixture then 3 hours.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, obtains the 4-[(4-iodophenyl) methyl]-5-sec.-propyl-3-triisopropyl siloxy--1H-pyrazoles (7.27g).To the 4-[(4-iodophenyl that obtains) methyl]-5-sec.-propyl-3-triisopropyl siloxy--1H-pyrazoles (3g) is at N, solution in the dinethylformamide (10mL), ice-cooled add down sodium hydride (55%, 0.33g), stirred the mixture then 20 minutes.In reaction mixture, under uniform temp, add 1-benzoyloxy-3-chloropropane (3.0g) at N, solution in the dinethylformamide (10mL) and potassiumiodide (0.25g), the mixture of Xing Chenging at room temperature stirs and spends the night then.Reaction mixture is poured in the water, then the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, then residue by silica gel column chromatography carry out purifying (eluent: n-hexane/ethyl acetate=20/1-10/1), obtain 1-(3-benzoyloxy propyl group)-4-[(4-iodophenyl) methyl]-5-sec.-propyl-3-triisopropyl siloxy--1H-pyrazoles (2.55g).This material is dissolved in tetrahydrofuran (THF) (3mL).Adding 4mol/L hydrochloric acid in this solution (1, the 4-dioxane solution, 10mL), mixture is in stirred overnight at room temperature then.Reaction mixture dilutes with ethyl acetate, then the mixture that forms is poured in the water.Separate organic layer, anhydrous sodium sulfate drying is used in organic layer salt water washing then then.Solvent is removed in decompression.In residue, the mixed solvent (20/1) that adds normal hexane and ethyl acetate (10mL), mixture was stirring at room 1 hour then.Sedimentary crystal is collected by filtration, uses mixed solvent (20/1) washing and the drying under reduced pressure of normal hexane and ethyl acetate then, obtains title compound (0.85g).
1H-NMR(DMSO-d
6)δppm：
1.06(6H，d，J＝7.3Hz)，2.1-2.2(2H，m)，2.95-3.1(1H，m)，3.6(2H，s)，4.02(2H，t，J＝6.9Hz)，4.27(2H，t，J＝6.1Hz)，6.94(2H，d，J＝8.3Hz)，7.5-7.7(5H，m)，7.9-8.0(2H，m)，9.51(1H，s)
The comparative example 55
Benzyl methylpropanoate
Hydrochlorinate benzyl methylpropanoate (1.48g) is dissolved in ethyl acetate (60mL) and the saturated sodium bicarbonate aqueous solution (20mL), separates organic layer then.Organic layer salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression, obtains title compound (1.2g).
1H-NMR(CDCl
3)δppm：
1.37(6H，s)，5.14(2H，s)，7.3-7.45(5H，m)
The comparative example 56
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-1-(3-benzoyloxy propyl group)-4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
To 1-(3-benzoyloxy propyl group)-1,2-dihydro-4-[(4-iodophenyl) methyl]-5-sec.-propyl-3H-pyrazoles-3-ketone (0.85g), acetyl bromide-α-D-semi-lactosi (0.91g) and the mixture of zephiran chloride three (normal-butyl) ammonium (0.53g) in methylene dichloride (2.55mL), add 5mol/L aqueous sodium hydroxide solution (0.85mL), mixture was stirring at room 6 hours then.Reaction mixture dilutes with methylene dichloride, then mixture is poured in the water.Separate organic layer, use the salt water washing, use anhydrous sodium sulfate drying then.Solvent is removed in decompression.To the solution of residue in acetonitrile (2.5mL), add 3-butenoic acid (0.36g), triethylamine (1.71g), acid chloride (II) (38mg) and three (2-aminomethyl phenyl) phosphines (0.1g), mixture refluxed 3 hours then.Solvent is removed in decompression, and residue is dissolved in ethyl acetate then.The solution with water washing.The water layer ethyl acetate extraction.Anhydrous sodium sulfate drying is used in the organic layer water and the salt water washing that merge then.Solvent is removed in decompression, residue is dissolved at tetrahydrofuran (THF) (5mL) then.In this solution, add benzyl methylpropanoate (1.63g), I-hydroxybenzotriazole (0.46g) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.65g), mixture was stirring at room 2 days then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression; residue carries out purifying (eluent: n-hexane/ethyl acetate=1/1) by silica gel column chromatography then; obtain 3-(2; 3; 4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-1-(3-benzoyloxy propyl group)-4-[(4-{ (1E)-3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propylene-1-yl } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (0.55g).This material is dissolved in methyl alcohol (5mL).Add 10% palladium-carbon dust (0.15g) in this solution, mixture stirred 3 hours under hydrogen atmosphere in room temperature then.Insoluble substance is removed by filtering, and the solvent of filtrate is removed in decompression then, obtains title compound (0.48g).
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.53(3H，s)，1.54(3H，s)，1.85-2.2(16H，m)，2.25-2.35(2H，m)，2.61(2H，t，J＝7.1Hz)，2.95-3.05(1H，m)，3.67(1H，d，J＝16.7Hz)，3.71(1H，d，J＝16.7Hz)，3.95-4.05(1H，m)，4.05-4.2(4H，m)，4.36(2H，t，J＝5.7Hz)，5.0-5.1(1H，m)，5.3-5.45(2H，m)，5.51(1H，d，J＝8.2Hz)，6.19(1H，s)，6.95-7.05(4H，m)，7.4-7.5(2H，m)，7.5-7.6(1H，m)，8.0-8.1(2H，m)
Embodiment 109
3-(β-D-galactopyranose oxygen base)-1-(3-hydroxypropyl)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 99; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 1-(3-benzoyloxy propyl group)-4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-(benzyloxycarbonyl) piperazine; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-carboxyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-benzyl diethylenediamine.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.42(6H，s)，1.8-2.0(4H，m)，2.17(2H，t，J＝7.7Hz)，2.58(2H，t，J＝7.4Hz)，2.65-2.8(4H，m)，3.05-3.2(1H，m)，3.45-3.9(14H，m)，4.08(2H，t，J＝7.0Hz)，5.11(1H，d，J＝7.8Hz)，7.0-7.15(4H，m)
Embodiment 110
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-{3-[1-{[4-(benzyloxycarbonyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
With 3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles (37g) is dissolved in N, dinethylformamide (180mL).In this solution, add 1-(benzyloxycarbonyl) piperazine (28.4g), I-hydroxybenzotriazole (10.5g) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (14.8g), mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water into the mixture that forms ethyl acetate extraction 2 times then.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=1/2-ethyl acetate), obtain title compound (40.5g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.56(6H，s)，1.85-1.95(5H，m)，1.98(3H，s)，2.02(3H，s)，2.12(2H，t，J＝7.5Hz)，2.16(3H，s)，2.58(2H，t，J＝7.5Hz)，2.85-2.95(1H，m)，3.4-3.55(4H，m)，3.55-3.75(6H，m)，4.0-4.1(1H，m)，4.1-4.2(2H，m)，5.09(1H，dd，J＝10.6Hz，3.3Hz)，5.14(2H，s)，5.35-5.45(2H，m)，5.56(1H，d，J＝7.8Hz)，6.39(1H，s)，6.95-7.1(4H，m)，7.3-7.4(5H，m)
Embodiment 111
4-[(4-{3-[1-{[4-(benzyloxycarbonyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-1H-pyrazoles
To 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-[(4-{3-[1-{[4-(benzyloxycarbonyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-the 5-sec.-propyl-solution of 1H-pyrazoles (39.5g) in methyl alcohol (160mL); add sodium methylate (28% methanol solution; 8.24mL), mixture is in stirred overnight at room temperature then.In reaction mixture, add acetate (2.7mL), the mixture of Xing Chenging is through concentrating under reduced pressure then.Residue carries out purifying (eluent: methylene chloride=10/1), obtain title compound (21.3g) by silica gel column chromatography.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.42(6H，s)，1.8-1.9(2H，m)，2.16(2H，t，J＝7.8Hz)，2.57(2H，t，J＝7.6Hz)，2.8-2.95(1H，m)，3.35-3.8(15H，m)，3.85-3.9(1H，m)，5.07(1H，d，J＝7.9Hz)，5.12(2H，s)，7.04(2H，d，J＝8.2Hz)，7.11(2H，d，J＝8.2Hz)，7.25-7.4(5H，m)
The comparative example 57
[4-benzyloxy-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl alcohol
The solution in tetrahydrofuran (THF) (35mL) to tetrahydrochysene-4H-pyrans-4-alcohol (3.62g) and triethylamine (5.6mL), at the ice-cooled methylsulfonyl chloride (2.93mL) that adds down, mixture was stirring at room 1 hour then.Insoluble substance is removed by filtering.In this filtrate, add N, dinethylformamide (70mL), 4-benzyloxy-2-hydroxy benzaldehyde (5.39g) and cesium carbonate (23g), mixture stirred 12 hours at 80 ℃ then.Reaction mixture is poured in the water, then the mixture extracted with diethyl ether of Xing Chenging.Extract water and salt water washing, and use anhydrous magnesium sulfate drying.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=4/1-2/1), obtain 4-benzyloxy-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl aldehyde (4.58g) by silica gel column chromatography then.With this substance dissolves in ethanol (70mL).Down add sodium borohydride (0.28g) in this solution ice-cooled, mixture was stirring at room 3 hours then.In reaction mixture, add methyl alcohol, then the mixture that forms is carried out concentrating under reduced pressure.With saturated sodium bicarbonate aqueous solution, add residue, mixture extracted with diethyl ether then.Residue is used saturated sodium bicarbonate aqueous solution, water and salt water washing successively, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression, and residue carries out purifying (eluent: n-hexane/ethyl acetate=3/1-1/1), obtain title compound (4.45g) by silica gel column chromatography then.
1H-NMR(CDCl
3)δppm：
1.75-1.85(2H，m)，1.95-2.05(2H，m)，2.11(1H，t，J＝6.3Hz)，3.5-3.65(2H，m)，3.9-4.0(2H，m)，4.45-4.55(1H，m)，4.63(2H，d，J＝6.3Hz)，5.05(2H，s)，6.5-6.6(2H，m)，7.19(1H，d，J＝7.7Hz)，7.3-7.45(5H，m)
The comparative example 58
4-{[4-benzyloxy-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone
To [4-benzyloxy-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] solution of methyl alcohol (4.45g) in tetrahydrofuran (THF) (28mL), add triethylamine (2.27mL) and methylsulfonyl chloride (1.21mL) down ice-cooled, stirred the mixture then 1 hour.Insoluble substance is removed by filtering.To the methylsulfonic acid that obtains [4-benzyloxy-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] solution of methyl esters in tetrahydrofuran (THF), add sodium hydride (55%, 710mg) with the 4-methyl-suspension of 3-oxopentanoic acid methyl esters (2.25g) in tetrahydrofuran (THF) (56mL), the reflux mixture is 8 hours then.In reaction mixture, add 1mol/L hydrochloric acid, then the mixture extracted with diethyl ether of Xing Chenging.Organic layer washes with water, and uses anhydrous magnesium sulfate drying.Solvent is removed in decompression.To the solution of residue in toluene (8mL), add hydrazine monohydrate (3.43mL), mixture stirred 8 hours at 100 ℃ then.Reaction mixture carries out purifying (eluent: methylene chloride=20/1-10/1), obtain title compound (1.69g) by silica gel column chromatography.
1H-NMR(CDCl
3)δppm：
1.16(6H，d，J＝7.1Hz)，1.75-1.9(2H，m)，1.95-2.1(2H，m)，2.9-3.05(1H，m)，3.5-3.6(2H，m)，3.64(2H，s)，3.9-4.05(2H，m)，4.4-4.5(1H，m)，5.0(2H，s)，6.45-6.55(2H，m)，7.0(1H，d，J＝8.4Hz)，7.25-7.45(5H，m)
The comparative example 59
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 12, wherein use 4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and acetyl bromide-α-D-semi-lactosi, replace 4-{[4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl respectively] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and acetyl bromide-α-D-glucose.
1H-NMR(CDCl
3)δppm：
1.05-1.2(6H，m)，1.78(3H，s)，1.98(3H，s)，2.03(3H，s)，2.16(3H，s)，2.28(3H，s)，2.75-2.85(1H，m)，3.51(1H，d，J＝16.4Hz)，3.62(1H，d，J＝16.4Hz)，4.0-4.1(1H，m)，4.1-4.2(2H，m)，5.02(2H，s)，5.07(1H，dd，J＝10.4Hz，3.5Hz)，5.35-5.45(2H，m)，5.51(1H，d，J＝7.9Hz)，6.66(1H，dd，J＝8.3Hz，2.8Hz)，6.75-6.85(2H，m)，7.2-7.45(5H，m)
The comparative example 60
4-{[4-benzyloxy-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
The preparation method of title compound is similar to comparative example 12; wherein use 4-{[4-benzyloxy-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-1; 2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and 2; 3; 4; 6-four-O-pivaloyl group-α-D-glucopyranosyl bromine replaces 4-{[4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl respectively] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and acetyl bromide-α-D-glucose.
1H-NMR(CDCl
3)δppm：
1.0-1.2(42H，m)，1.7-1.85(2H，m)，1.95-2.05(2H，m)，2.85-2.95(1H，m)，3.5-3.65(4H，m)，3.8-3.9(1H，m)，3.9-4.0(2H，m)，4.12(1H，dd，J＝12.4Hz，5.1Hz)，4.19(1H，dd，J＝12.4Hz，1.8Hz)，4.4-4.5(1H，m)，4.99(2H，s)，5.15-5.3(2H，m)，5.36(1H，t，J＝9.4Hz)，5.66(1H，d，J＝8.0Hz)，6.42(1H，dd，J＝8.3Hz，2.3Hz)，6.47(1H，d，J＝2.3Hz)，6.86(1H，d，J＝8.3Hz)，7.25-7.45(5H，m)
The comparative example 61
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-hydroxy-2-methyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 25; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles replacement 4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.83(3H，s)，1.98(3H，s)，2.03(3H，s)，2.16(3H，s)，2.25(3H，s)，2.75-2.9(1H，m)，3.5(1H，d，J＝16.6Hz)，3.6(1H，d，J＝16.6Hz)，4.0-4.05(1H，m)，4.1-4.2(2H，m)，4.78(1H，brs)，5.06(1H，dd，J＝10.4Hz，3.5Hz)，5.35-5.45(2H，m)，5.5(1H，d，J＝8.2Hz)，6.52(1H，dd，J＝8.1Hz，2.6Hz)，6.62(1H，d，J＝2.6Hz)，6.76(1H，d，J＝8.1Hz)
The comparative example 62
4-{[4-hydroxyl-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
The preparation method of title compound is similar to comparative example 25; wherein use 4-{[4-benzyloxy-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles replacement 4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.0-1.2(42H，m)，1.75-1.9(2H，m)，1.95-2.1(2H，m)，2.8-2.95(1H，m)，3.52(1H，d，J＝16.5Hz)，3.55-3.65(3H，m)，3.8-3.9(1H，m)，3.9-4.05(2H，m)，4.05-4.2(2H，m)，4.4-4.5(1H，m)，5.14(1H，brs)，5.15-5.3(2H，m)，5.3-5.4(1H，m)，5.65(1H，d，J＝8.1Hz)，6.22(1H，dd，J＝8.2Hz，2.3Hz)，6.37(1H，d，J＝2.3Hz)，6.78(1H，d，J＝8.2Hz)
The comparative example 63
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-(4-[3-(benzyloxycarbonyl) propoxy-]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 27; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-[(4-hydroxy-2-methyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles replacement 4-[(4-hydroxy-2-methyl phenyl) methyl]-5-sec.-propyl-3-(2; 3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.05-1.15(6H，m)，1.81(3H，s)，1.98(3H，s)，2.02(3H，s)，2.05-2.15(2H，m)，2.16(3H，s)，2.26(3H，s)，2.56(2H，t，J＝7.1Hz)，2.7-2.85(1H，m)，3.5(1H，d，J＝16.5Hz)，3.6(1H，d，J＝16.5Hz)，3.9-4.0(2H，m)，4.0-4.1(1H，m)，4.1-4.2(2H，m)，5.07(1H，dd，J＝10.6Hz，3.6Hz)，5.13(2H，s)，5.35-5.45(2H，m)，5.52(1H，d，J＝8.2Hz)，6.55(1H，dd，J＝8.6Hz，2.5Hz)，6.66(1H，d，J＝2.5Hz)，6.79(1H，d，J＝8.6Hz)，7.25-7.4(5H，m)
The comparative example 64
4-(4-[3-(benzyloxycarbonyl) propoxy-]-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl } methyl)-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
The preparation method of title compound is similar to comparative example 27; wherein use 4-{[4-hydroxyl-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles replacement 4-[(4-hydroxy-2-methyl phenyl) methyl]-5-sec.-propyl-3-(2; 3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.0-1.2(42H，m)，1.75-1.85(2H，m)，1.95-2.15(4H，m)，2.56(2H，t，J＝7.3Hz)，2.8-2.95(1H，m)，3.5-3.65(4H，m)，3.8-3.9(1H，m)，3.9-4.05(4H，m)，4.05-4.25(2H，m)，4.4-4.5(1H，m)，5.13(2H，s)，5.15-5.3(2H，m)，5.36(1H，t，J＝9.5Hz)，5.66(1H，d，J＝8.1Hz)，6.3(1H，dd，J＝8.4Hz，2.5Hz)，6.38(1H，d，J＝2.5Hz)，6.84(1H，d，J＝8.4Hz)，7.25-7.4(5H，m)
The comparative example 65
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-{[4-(3-carboxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 25; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-(4-[3-(benzyloxycarbonyl) propoxy-]-the 2-aminomethyl phenyl } methyl)-5-sec.-propyl-1H-pyrazoles replacement 4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.05-1.15(6H，m)，1.78(3H，s)，1.98(3H，s)，2.02(3H，s)，2.05-2.15(2H，m)，2.16(3H，s)，2,27(3H，s)，2.45-2.6(2H，m)，2.75-2.85(1H，m)，3.49(1H，d，J＝16.8Hz)，3.6(1H，d，J＝16.8Hz)，3.98(2H，t，J＝6.3Hz)，4.0-4.1(1H，m)，4.1-4.25(2H，m)，5.06(1H，dd，J＝10.3Hz，3.4Hz)，5.3-5.45(3H，m)，6.58(1H，dd，J＝8.6Hz，2.4Hz)，6.68(1H，d，J＝2.4Hz)，6.78(1H，d，J＝8.6Hz)
The comparative example 66
4-{[4-(3-carboxyl propoxy-)-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
The preparation method of title compound is similar to comparative example 25; wherein use 4-({ 4-[3-(benzyloxycarbonyl) propoxy-]-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl } methyl)-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles replacement 4-[(4-benzyloxy-2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.0-1.2(42H，m)，1.75-1.9(2H，m)，1.95-2.15(4H，m)，2.5-2.6(2H，m)，2.8-2.95(1H，m)，3.45-3.65(4H，m)，3.8-3.9(1H，m)，3.9-4.05(4H，m)，4.1-4.25(2H，m)，4.4-4.55(1H，m)，5.2-5.3(2H，m)，5.36(1H，t，J＝9.2Hz)，5.52(1H，d，J＝7.7Hz)，6.33(1H，dd，J＝8.1Hz，2.1Hz)，6.41(1H，d，J＝2.1Hz)，6.84(1H，d，J＝8.1Hz)
The comparative example 67
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-{3-[1-benzyloxycarbonyl-1-(methyl) ethylamino formyl radical] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 45; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-{[4-(3-carboxyl propoxy-)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.05-1.15(6H，m)，1.53(6H，s)，1.83(3H，s)，1.95-2.1(8H，m)，2.15(3H，s)，2.26(3H，s)，2.34(2H，t，J＝7.2Hz)，2.7-2.85(1H，m)，3.5(1H，d，J＝16.6Hz)，3.6(1H，d，J＝16.6Hz)，3.85-3.95(2H，m)，4.0-4.1(1H，m)，4.1-4.2(2H，m)，5.07(1H，dd，J＝10.4Hz，3.5Hz)，5.15(2H，s)，5.35-5.45(2H，m)，5.52(1H，d，J＝8.1Hz)，6.06(1H，s)，6.55(1H，dd，J＝8.5Hz，2.6Hz)，6.66(1H，d，J＝2.6Hz)，6.79(1H，d，J＝8.5Hz)，7.25-7.4(5H，m)
The comparative example 68
4-{[4-{3-[1-benzyloxycarbonyl-1-(methyl) ethylamino formyl radical] propoxy-}-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
The preparation method of title compound is similar to comparative example 45; wherein use 4-{[4-(3-carboxyl propoxy-)-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.0-1.2(42H，m)，1.54(6H，s)，1.75-1.85(2H，m)，2.0-2.1(4H，m)，2.34(2H，t，J＝7.2Hz)，2.8-2.95(1H，m)，3.5-3.65(4H，m)，3.8-4.05(5H，m)，4.05-4.25(2H，m)，4.4-4.5(1H，m)，5.1-5.3(4H，m)，5.36(1H，t，J＝9.5Hz)，5.65(1H，d，J＝7.5Hz)，6.09(1H，brs)，6.29(1H，dd，J＝8.3Hz，2.2Hz)，6.4(1H，d，J＝2.2Hz)，6.83(1H，d，J＝8.3Hz)，7.25-7.4(5H，m)
The comparative example 69
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 48; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-[(4-{3-[1-benzyloxycarbonyl-1-(methyl) ethylamino formyl radical] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-benzyloxycarbonyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.05-1.15(6H，m)，1.55(3H，s)，1.56(3H，s)，1.79(3H，s)，1.98(3H，s)，2.0-2.2(8H，m)，2.26(3H，s)，2.4(2H，t，J＝6.9Hz)，2.7-2.85(1H，m)，3.49(1H，d，J＝16.6Hz)，3.59(1H，d，J＝16.6Hz)，3.98(2H，t，J＝6.1Hz)，4.0-4.2(2H，m)，4.22(1H，dd，J＝10.9Hz，5.7Hz)，5.0-5.1(1H，m)，5.3-5.45(3H，m)，6.24(1H，s)，6.59(1H，dd，J＝8.2Hz，2.7Hz)，6.69(1H，d，J＝2.7Hz)，6.75(1H，d，J＝8.2Hz)
The comparative example 70
4-{[4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propoxy-}-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2,3,4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles
The preparation method of title compound is similar to comparative example 48; wherein use 4-{[4-{3-[1-benzyloxycarbonyl-1-(methyl) ethylamino formyl radical] propoxy-}-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-1H-pyrazoles replacement 3-(2; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-benzyloxycarbonyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.0-1.2(42H，m)，1.54(6H，s)，1.7-1.9(2H，m)，1.95-2.15(4H，m)，2.35-2.45(2H，m)，2.8-2.95(1H，m)，3.45-3.65(4H，m)，3.8-3.9(1H，m)，3.9-4.05(4H，m)，4.05-4.25(2H，m)，4.4-4.55(1H，m)，5.15-5.3(2H，m)，5.36(1H，t，J＝9.4Hz)，5.56(1H，d，J＝8.4Hz)，6.17(1H，brs)，6.32(1H，d，J＝8.1Hz)，6.41(1H，s)，6.82(1H，d，J＝8.1Hz)
Embodiment 112
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 99; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-(benzyloxycarbonyl) piperazine; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-carboxyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-benzyl diethylenediamine.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.42(6H，s)，1.95-2.05(2H，m)，2.29(3H，s)，2.39(2H，t，J＝7.4Hz)，2.55-2.9(5H，m)，3.45-3.8(11H，m)，3.85(1H，d，J＝3.2Hz)，3.95(2H，t，J＝6.1Hz)，5.04(1H，d，J＝7.5Hz)，6.61(1H，dd，J＝8.2Hz，2.4Hz)，6.71(1H，d，J＝2.4Hz)，6.84(1H，d，J＝8.2Hz)
Embodiment 113
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-[(4-{3-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propoxy-}-the 2-aminomethyl phenyl) methyl]-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 78; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-(2-hydroxyethyl) piperazine; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-{[4-(2-carboxyl oxyethyl group)-2-aminomethyl phenyl] methyl }-5-sec.-propyl-1H-pyrazoles and 2-amino-2-methyl propionic acid amide.
1H-NMR(CD
3OD)δppm：
1.05-1.15(6H，m)，1.42(6H，s)，1.95-2.05(2H，m)，2.28(3H，s)，2.3-2.55(8H，m)，2.7-2.85(1H，m)，3.45-3.8(13H，m)，3.85(1H，d，J＝2.9Hz)，3.94(2H，t，J＝6.0Hz)，5.04(1H，d，J＝7.6Hz)，6.6(1H，d，J＝8.5Hz)，6.7(1H，s)，6.85(1H，d，J＝8.5Hz)
Embodiment 114
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propoxy-)-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-the 1H-pyrazoles
The preparation method of title compound is similar to embodiment 105; wherein use 4-{[4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propoxy-}-2-(tetrahydrochysene-4H-pyrans-4-base oxo) phenyl] methyl }-5-sec.-propyl-3-(2; 3; 4; 6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-and 1H-pyrazoles replacement 4-[(4-{3-[1-carboxyl-1-(methyl) ethylamino formyl radical] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-3-(2; 3; 4,6-four-O-pivaloyl group-β-D-pyranoglucose oxygen base)-the 1H-pyrazoles.
1H-NMR(CD
3OD)δppm：
1.05-1.2(6H，m)，1.42(6H，s)，1.7-1.85(2H，m)，1.95-2.1(4H，m)，2.38(2H，t，J＝7.4Hz)，2.6-2.8(4H，m)，2.8-2.95(1H，m)，3.25-3.45(4H，m)，3.5-3.75(9H，m)，3.83(1H，d，J＝12.1Hz)，3.9-4.0(4H，m)，4.5-4.65(1H，m)，5.07(1H，d，J＝7.1Hz)，6.4(1H，dd，J＝8.3Hz，2.5Hz)，6.54(1H，d，J＝2.5Hz)，6.89(1H，d，J＝8.3Hz)
The comparative example 71
4-[(4-bromo-2-fluorophenyl) methyl]-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone
The preparation method of title compound is similar to comparative example 2, wherein uses 4-bromo-2-fluoro benzyl bromide to replace the 4-bromo benzyl bromo.
1H-NMR(CDCl
3)δppm：
1.17(6H，d，J＝7.1Hz)，2.85-3.05(1H，m)，3.67(2H，s)，7.0-7.3(3H，m)
The comparative example 72
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-[(4-bromo-2-fluorophenyl) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 12, wherein use 4-[(4-bromo-2-fluorophenyl) methyl]-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and acetyl bromide-α-D-semi-lactosi, replace 4-{[4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl respectively] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone and acetyl bromide-α-D-glucose.
1H-NMR(CDCl
3)δppm：
1.15-1.25(6H，m)，1.92(3H，s)，1.99(3H，s)，2.02(3H，s)，2.18(3H，s)，2.9-3.0(1H，m)，3.59(1H，d，J＝16.1Hz)，3.67(1H，d，J＝16.1Hz)，4.05-4.25(3H，m)，5.1(1H，dd，J＝10.4Hz，3.4Hz)，5.35-5.45(2H，m)，5.58(1H，d，J＝8.1Hz)，6.95-7.05(1H，m)，7.1-7.2(2H，m)
The comparative example 73
3-(2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl]-the 2-fluorophenyl } methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 4; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-and 4-[(4-bromo-2-fluorophenyl) methyl]-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-the 4-[(4-bromophenyl) methyl]-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.89(3H，s)，1.99(3H，s)，2.01(3H，s)，2.17(3H，s)，2.85-3.0(1H，m)，3.27(2H，d，J＝6.9Hz)，3.59(1H，d，J＝16.2Hz)，3.7(1H，d，J＝16.2Hz)，4.05-4.3(3H，m)，5.1(1H，dd，J＝10.2Hz，3.5Hz)，5.3-5.5(3H，m)，6.2-6.35(1H，m)，6.43(1H，d，J＝16.2Hz)，6.9-7.15(3H，m)
The comparative example 74
1-(2-amino-2-methyl propionyl)-4-(benzyloxycarbonyl) piperazine
To 2-(tert-butoxycarbonyl the amino)-solution of 2 Methylpropionic acid (10g) in tetrahydrofuran (THF) (20mL), add 1-(benzyloxycarbonyl) piperazine (16.3g), I-hydroxybenzotriazole (8.02g) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (11.4g), mixture is in stirred overnight at room temperature then.Reaction mixture is poured in the water, and the mixture ethyl acetate extraction that forms.Anhydrous sodium sulfate drying is used in extract water and salt water washing then.Solvent is removed in decompression.Under 60 ℃ of heating, the mixed solvent (1/1) that residue is dissolved in normal hexane and ethyl acetate (40mL), solution at room temperature stirs and spends the night then.In this mixture, add same solvent (30mL), mixture stirs once more and spends the night then.Sedimentary crystal is collected by filtration, then with the same solvent washing, and drying under reduced pressure, obtain 4-benzyloxycarbonyl-1-[2-(tert-butoxycarbonyl amino)-2-methylpropionyl] piperazine (13.5g).To 4-benzyloxycarbonyl-1-[2-(tert-butoxycarbonyl the amino)-2-methylpropionyl that obtains] solution of piperazine (5g) in tetrahydrofuran (THF) (30mL), adding hydrochloric acid (4mol/L 1, the 4-dioxane solution, and 40mL), mixture is in stirred overnight at room temperature then.Sedimentary crystal is collected by filtration.The crystal that obtains is dissolved in ethyl acetate and the saturated sodium bicarbonate aqueous solution.Separate organic layer, anhydrous sodium sulfate drying is used in organic layer salt water washing then then.Solvent is removed in decompression, obtains title compound (3.65g).
1H-NMR(CDCl
3)δppm：
1.41(6H，s)，3.45-3.55(4H，m)，3.7-3.95(4H，br)，5.15(2H，s)，7.25-7.4(5H，m)
Embodiment 115
4-{[2-fluoro-4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 99; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-galactopyranose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl]-the 2-fluorophenyl } methyl)-5-sec.-propyl-1H-pyrazoles and 1-(2-amino-2-methyl propionyl)-4-(benzyloxycarbonyl) piperazine; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-carboxyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-benzyl diethylenediamine.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.42(6H，s)，1.8-1.95(2H，m)，2.17(2H，t，J＝7.6Hz)，2.6(2H，t，J＝7.6Hz)，2.7-2.85(4H，m)，2.85-3.0(1H，m)，3.45-3.85(11H，m)，3.85-3.9(1H，m)，5.09(1H，d，J＝7.8Hz)，6.8-6.9(2H，m)，7.0-7.15(1H，m)
The comparative example 75
4-bromo-2-chlorobenzyl alcohol
The preparation method of title compound is similar to comparative example 14, wherein uses 4-bromo-2-chloro-benzoic acid to replace 4-bromo-2-tolyl acid.
1H-NMR(CDCl
3)δppm：
1.9-2.0(1H，m)，4.73(2H，d，J＝5.5Hz)，7.3-7.45(2H，m)，7.45-7.55(1H，m)
The comparative example 76
4-[(4-bromo-2-chloro-phenyl-) methyl]-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone
The preparation method of title compound is similar to comparative example 15, wherein uses 4-bromo-2-chlorobenzyl alcohol to replace 4-bromo-2-methylbenzyl alcohol.
1H-NMR(DMSO-d
6)δppm：
1.07(6H，d，J＝6.9Hz)，2.7-2.85(1H，m)，3.61(2H，s)，6.97(1H，d，J＝8.5Hz)，7.46(1H，dd，J＝8.5Hz，2.0Hz)，7.66(1H，d，J＝2.0Hz)
The comparative example 77
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-bromo-2-chloro-phenyl-) methyl]-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 12, wherein use 4-[(4-bromo-2-chloro-phenyl-) methyl]-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone is replaced 4-{[4-(2-benzyloxycarbonyl-2-methyl propoxy-) phenyl] methyl }-1,2-dihydro-5-sec.-propyl-3H-pyrazoles-3-ketone.
1H-NMR(CDCl
3)δppm：
1.17(6H，d，J＝7.0Hz)，1.9(3H，s)，2.01(3H，s)，2.03(3H，s)，2.07(3H，s)，2.85-3.0(1H，m)，3.65(1H，d，J＝16.7Hz)，3.74(1H，d，J＝16.7Hz)，3.8-3.9(1H，m)，4.05-4.2(1H，m)，4.31(1H，dd，J＝12.8Hz，4.3Hz)，5.1-5.35(3H，m)，5.6(1H，d，J＝8.1Hz)，6.93(1H，d，J＝8.2Hz)，7.24(1H，dd，J＝8.2Hz，1.8Hz)，7.49(1H，d，J＝1.8Hz)
The comparative example 78
3-(2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl]-the 2-chloro-phenyl-} methyl)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to comparative example 4; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-and 4-[(4-bromo-2-chloro-phenyl-) methyl]-5-sec.-propyl-1H-pyrazoles replacement 3-(2; 3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-the 4-[(4-bromophenyl) methyl]-5-sec.-propyl-1H-pyrazoles.
1H-NMR(CDCl
3)δppm：
1.1-1.2(6H，m)，1.85(3H，s)，2.0(3H，s)，2.02(3H，s)，2.05(3H，s)，2.85-3.0(1H，m)，3.27(2H，d，J＝6.4Hz)，3.68(1H，d，J＝16.7Hz)，3.78(1H，d，J＝16.7Hz)，3.8-3.9(1H，m)，4.1-4.2(1H，m)，4.32(1H，dd，J＝12.6Hz，3.8Hz)，5.15-5.3(3H，m)，5.43(1H，d，J＝7.8Hz)，6.2-6.35(1H，m)，6.42(1H，d，J＝16.1Hz)，6.96(1H，d，J＝1.6Hz)，7.13(1H，dd，J＝8.2Hz，1.6Hz)，7.36(1H，d，J＝1.6Hz)
Embodiment 116
4-{[2-chloro-4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles
The preparation method of title compound is similar to embodiment 99; wherein use 3-(2; 3; 4; 6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-(4-[(1E)-3-carboxyl third-1-thiazolinyl]-the 2-chloro-phenyl-} methyl)-5-sec.-propyl-1H-pyrazoles and 1-(2-amino-2-methyl propionyl)-4-(benzyloxycarbonyl) piperazine; replace 3-(2 respectively; 3; 4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-carboxyl-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles and 1-benzyl diethylenediamine.
1H-NMR(CD
3OD)δppm：
1.1-1.2(6H，m)，1.43(6H，s)，1.8-1.95(2H，m)，2.17(2H，t，J＝7.7Hz)，2.59(2H，t，J＝7.6Hz)，2.65-2.95(5H，m)，3.25-3.45(4H，m)，3.5-3.9(8H，m)，5.09(1H，d，J＝7.1Hz)，6.95-7.1(2H，m)，7.2(1H，d，J＝1.3Hz)
Test implementation example 1
Test is to the active restraining effect of people SGLT1
1) carrier of clone and construction expression people SGLT1
As primer, be used for the cDNA library of pcr amplification with oligomerization dT by the reverse transcription preparation from the total RNA of people's small intestine (Ori gene).This cDNA library as template, is amplified the dna fragmentation (accession number: M24847 is by people such as Hediger report) of the 1-2005bp of coding people SGLT1 with the PCR method, be inserted into pcDNA3.1 (-) multiple clone site (Invitrogen) then.The dna sequence dna that inserts mates fully with the sequence of reporting in the past.
2) set up the clone of stably express people SGLT1
Expression vector with ScaI digestion people SGLT1 forms linear DNA.By lipofection (Effectene transfection reagent: QIAGEN), change this linear DNA over to the CHO-K1 cell.By in the substratum that contains G418 (1mg/mL, LIFE TECHNOLOGIES), cultivating, select neomycin resistance clone.Then, measure the activity of antagonism methyl-α-D-Glucopyranose picked-up with following method.Select and have the active clone of maximum ingestion, called after CS1-5-11D.In the presence of 200 μ g/mL G418, cultivate the CS1-5-11D cell.
3) measure methyl-α-D-Glucopyranose (inhibition activity of picked-up of α-MG)
(density is 3 * 10 in the 96-well culture plate with the CS1-5-11D cell inoculation
4Cells/well) and cultivated 2 days, be used for the picked-up test then.With cold (Sigma) and
14The mixture of the α-MG of C-mark (AmershamPharmcia Biotec) adds to (pH7.4 in the picked-up damping fluid; Contain 140mM sodium-chlor, 2mM Repone K, 1mM calcium chloride, 1mM magnesium chloride, 10mM 2-[4-(2-hydroxyethyl)-1-piperazinyl] ethyl sulfonic acid and 5mM three (methylol) aminomethane), make that final concentration is 1mM.Test compounds is dissolved in methyl-sulphoxide, suitably dilutes then with distilled water.Test compounds solution is added the picked-up damping fluid (being called assay buffer) that contains 1mM α-MG.For control group, preparation does not contain the assay buffer of test compounds.For the Fundamentals of Measurement picked-up, preparation basis picked-up assay buffer (it contains 140mM choline chloride 60 (chorine chloride) to replace sodium-chlor).After the substratum of having removed the CS1-5-11D cell, 180 μ L pretreatment buffer liquids (the basis picked-up damping fluid that does not contain α-MG) are added each hole, hatched 10 minutes at 37 ℃ then.After repeating same processing, remove pretreatment buffer liquid.In each hole, add 75 μ L assay buffer or add basis picked-up damping fluid, hatched 1 hour at 37 ℃ then.After removing assay buffer, with 180 μ L/ hole lavation buffer solutions (damping fluid is absorbed on the basis that contains the unmarked α-MG of 10mM) washed cell 2 times.0.2mol/L sodium hydroxide with 75 μ L/ holes makes lysis.Cell lysate is changed over to Pico plate (Packard), adds 150 μ L MicroScint-40 (Packard) and mixing then.Measure radioactivity with micro-scintillation detector TopCount (Packard).Difference between control group and the basis picked-up is made as 100%, calculates the picked-up of methyl α-D-Glucopyranose under each drug level then.Calculate drug level (IC when suppressing 50% methyl α-D-Glucopyranose picked-up with logarithmic curve
50Value).These the results are shown in table 1.
[table 1]
| Test compounds | IC 50Value (nM) |
| Embodiment 15 | 113 |
| Embodiment 18 | 181 |
| Embodiment 21 | 12 |
| Embodiment 24 | 24 |
| Embodiment 27 | 237 |
| Embodiment 28 | 267 |
| Embodiment 29 | 431 |
| Embodiment 30 | 52 |
| Embodiment 31 | 96 |
| Embodiment 32 | 220 |
| Embodiment 33 | 174 |
| Embodiment 34 | 245 |
| Embodiment 35 | 115 |
| Embodiment 48 | 31 |
| Embodiment 57 | 39 |
| Embodiment 61 | 18 |
Test implementation example 2
The restraining effect that test raises to blood glucose level in the rat
1) preparation diabetes rat model
Male Wistar rat (Japan Charles River) peritoneal injection niacinamide (230mg/kg) to 8 ages in week.Injected back 15 minutes, under etherization, from the tail vein by intravenous injection U-9889 (85mg/kg).After one week, the rat overnight fasting carries out glucose tolerance test (2g/kg) then.Select after giving glucose 1 hour plasma glucose concentration rat, be used for the test of liquid food tolerance greater than 300mg/dL.
2) liquid food tolerance test
After overnight fasting, give the oral test compounds of diabetes rat (1mg/kg) (being dissolved in distilled water, medication therapy groups) or only give distilled water (control group).After giving compound, per os gives the 17.25kcal/kg liquid food (No.038 is furnished with the control food of dextrin and maltose at once; Oriental YeastCo., Ltd.).Just the fixed time before giving and after giving, collect blood, handle with heparin at once then from caudal artery.Centrifugal blood is collected blood plasma then, so that with the quantitative plasma glucose concentration of glucose oxidase method.(0 hour), the plasma glucose concentration that gives behind the medicine 0.5 hour and 1 hour are shown in table 2 before processing.Numeric representation is mean value ± S.E in the table.
[table 2]
| Test compounds | Plasma glucose concentration (mg/dL) | ||
| 0h | 0.5h | 1h | |
| Contrast | 117±8 | 326±46 | 297±35 |
| Embodiment 21 | 118±9 | 156±15 | 178±19 |
| Contrast | 121±7 | 313±33 | 303±63 |
| Embodiment 30 | 121±6 | 163±8 | 187±9 |
| Contrast | 140±11 | 280±22 | 287±23 |
| Embodiment 32 | 125±8 | 223±20 | 278±32 |
| Embodiment 33 | 127±11 | 207±8 | 251±21 |
| Contrast | 116±11 | 241±15 | 237±10 |
| Embodiment 48 | 112±5 | 139±4 | 132±4 |
| Contrast | 133±9 | 236±9 | 210±11 |
| Embodiment 57 | 126±6 | 149±7 | 158±10 |
| Contrast | 122±6 | 277±16 | 272±21 |
| Embodiment 61 | 116±6 | 136±6 | 172±37 |
Test implementation example 3
Acute toxic test
With 6 the week age male ICR mouse (CLEA Japan, Inc.; 32-37g, n=5) fasting is 4 hours.To be dissolved in the test compounds of distilled water, give, observe mouse then 24 hours with the oral dose of 1g/kg.The results are shown in following table 3.
[table 3]
| Test compounds | Mortality |
| Embodiment 57 | 0/5 |
Industrial applicability
Pyrazoles derivative, its pharmaceutically acceptable salt and the prodrug of following formula of the present invention (I) expression; people SGLT1 there is the activity of inhibition; and can suppress the rising of blood glucose levels in the absorption of small intestine by suppressing carbohydrate such as glucose, especially make postprandial hyperglycemia normalization based on this mechanism by the absorption that postpones carbohydrate. Therefore, the invention provides the outstanding medicine of prevention or treatment hyperglycaemia relevant disease (such as diabetes, impaired glucose tolerance, diabetic complication, obesity etc.). In addition, because the pyrazoles derivative of following formula of the present invention (II) expression and salt thereof are the main intermediates of pyrazoles derivative of production following formula of the present invention (I) expression, so the compound of following formula of the present invention (I) expression can be prepared by these compounds easily.
Claims (28)
1. the pyrazole derivatives that general formula is represented below a kind:
In the formula
R
1Be hydrogen atom, hydroxyl C
2-6Alkyl;
One among Q and the T is β-D-galactopyranose oxygen base or β-D-pyranoglucose oxygen base; And another group is C
1-6Alkyl;
R
2Be hydrogen atom, halogen atom, C
1-6Group shown in alkyl or the following general formula:
-A-R
8, A is a Sauerstoffatom in the formula, R
8Be C
2-6Heterocyclylalkyl;
X is singly-bound or Sauerstoffatom;
Y is C
1-6Alkylidene group or C
2-6Alkylene group;
Z is carbonyl or alkylsulfonyl;
R
4And R
5Identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have identical or different 1-3 substituting group that is selected from following substituting group group (i);
R
3, R
6And R
7Each is hydrogen atom naturally;
Substituting group group (i) is made of following: hydroxyl, amino, list or two (C
1-6Alkyl) amino, single or two [hydroxyl (C
1-6Alkyl)] amino, sulfoamido, C
2-7Group shown in acyl amino, the following general formula:
-CON (R
9) R
10, R wherein
9And R
10Identical or different, and each hydrogen atom, C naturally
1-6Alkyl, they can have identical or different 1-3 substituting group that is selected from down group: hydroxyl, amino, list or two (C
1-6Alkyl) amino, formamyl, or they constitute C with adjacent nitrogen-atoms combination
2-6Ring is amino, and this ring is amino can to have the substituting group of group: C down
1-6Alkyl and hydroxyl C
1-6Alkyl can have identical or different 1-3 substituent aryl, and described substituting group is selected from hydroxyl, heteroaryl, and C
2-6Ring is amino,
Or its pharmacy acceptable salt.
2. pyrazole derivatives as claimed in claim 1 is characterized in that, Y is C
1-6Alkylidene group or C
2-6Alkylene group; R
4And R
5In one be C
1-6Alkyl, it can have identical or different 1-3 substituting group that is selected from following substituting group group (i), and another is hydrogen atom or C
1-6Alkyl, it can have identical or different 1-3 substituting group that is selected from following substituting group group (i); And substituting group group (i) is made of following: hydroxyl, amino, list or two (C
1-6Alkyl) amino, single or two [hydroxyl (C
1-6Alkyl)] amino, sulfoamido, C
2-7Group shown in acyl amino, the following general formula:
-CON(R
9)R
10，
R wherein
9And R
10Identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have identical or different 1-3 substituting group that is selected from down group: hydroxyl, amino, list or two (C
1-6Alkyl) amino, formamyl, or they constitute C with adjacent nitrogen-atoms combination
2-6Ring is amino, and this ring is amino can to have the substituting group of group: C down
1-6Alkyl and hydroxyl C
1-6Alkyl can have identical or different 1-3 substituent aryl, and described substituting group is selected from hydroxyl, heteroaryl, and C
2-6Ring is amino, or its pharmacy acceptable salt.
3. pyrazole derivatives as claimed in claim 2 is characterized in that R
4And R
5In one be C
1-6Alkyl, this alkyl have the group that is selected from following (iA) substituting group group, and another is a hydrogen atom; And substituting group group (iA) is the group shown in the following general formula :-CON (R
9A) R
10A, R wherein
9AAnd R
10ABe combined together to form the substituent C that can have the group of being selected from down with adjacent nitrogen atom
2-6Ring is amino: C
1-6Alkyl and hydroxyl C
1-6Alkyl, or its pharmacy acceptable salt.
4. as arbitrary described pyrazole derivatives among the claim 1-3, it is characterized in that X is a singly-bound; And Y is trimethylene or propenylene, or its pharmacy acceptable salt.
5. as arbitrary described pyrazole derivatives among the claim 1-3, it is characterized in that X is a Sauerstoffatom; And Y is ethylene or trimethylene, or its pharmacy acceptable salt.
6. pyrazole derivatives as claimed in claim 1 is characterized in that, X is a singly-bound; R
4And R
5In one be to have the C that identical or different 1-3 is selected from the group of following substituting group group (iB)
1-6Alkyl, another is hydrogen or has identical or different 1-3 C that is selected from the group of following substituting group group (iB)
1-6Alkyl; And substituting group group (iB) is made of following group: the group shown in sulfoamido, the following general formula :-CON (R
9B) R
10B, R wherein
9BAnd R
10BIn one be C
1-6Alkyl, described alkyl have identical or different 1-3 substituting group that is selected from down group: hydroxyl, amino, list or two (C
1-6Alkyl) amino, formamyl, and another is hydrogen atom, C
1-6Alkyl, this alkyl can have identical or different 1-3 substituting group that is selected from down group: hydroxyl, amino, list or two (C
1-6Alkyl) amino, formamyl, or they constitute C with adjacent nitrogen-atoms combination
2-6Ring is amino, and this ring is amino can to have the substituting group of group: C down
1-6Alkyl and hydroxyl C
1-6Alkyl can have identical or different 1-3 substituent aryl, and described substituting group is selected from hydroxyl, heteroaryl, and C
2-6Ring is amino;
Or its pharmacy acceptable salt.
7. as arbitrary described pyrazole derivatives among the claim 1-3, it is characterized in that R
1Be hydrogen atom; T represents β-D-galactopyranose oxygen base or β-D-pyranoglucose oxygen base,
Q is C
1-6Alkyl; And R
3, R
6And R
7Be hydrogen atom,
Or its pharmacy acceptable salt.
8. as arbitrary described pyrazole derivatives among the claim 1-3, it is characterized in that one among Q and the T is β-D-galactopyranose oxygen base or β-D-pyranoglucose oxygen base,
Another is C
1-6Alkyl,
Or its pharmacy acceptable salt.
9. pyrazole derivatives as claimed in claim 7 is characterized in that, T is β-D-galactopyranose oxygen base or β-D-pyranoglucose oxygen base,
Or its pharmacy acceptable salt.
10. pyrazole derivatives as claimed in claim 8 is characterized in that, T is β-D-galactopyranose oxygen base or β-D-pyranoglucose oxygen base,
Or its pharmacy acceptable salt.
11., it is characterized in that Q is a sec.-propyl, or its pharmacy acceptable salt as claim 7 or 9 described pyrazole derivatives.
12. as the prodrug of arbitrary described pyrazole derivatives among the claim 1-10, or the pharmacy acceptable salt of this described prodrug, wherein, T is β-D-galactopyranose oxygen base or β-D-pyranoglucose oxygen base.
13. pyrazole derivatives as claimed in claim 1, it is the compound that is selected from down group:
4-[(4-{3-[1-formamyl-1-(methyl) ethylamino formyl radical] propyl group }-the 2-aminomethyl phenyl) methyl]-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-4-[(4-{3-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[2-(dimethylamino) ethylamino formyl radical]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles;
4-[(4-{3-[1-(2-aminoethylamino formyl radical)-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(4-methylpiperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(4-sec.-propyl piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[(S)-2-hydroxyl-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-4-[(4-{ (1E)-3-[(S)-2-hydroxyl-1-(methyl) ethylamino formyl radical] propylene-1-yl } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(2-{1-[(4-methylpiperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } oxyethyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[2-hydroxyl-1,1-two-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(2-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } oxyethyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propoxy-}-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(4-methylpiperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-1-(3-hydroxypropyl)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
4-{[2-fluoro-4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-1H-pyrazoles;
4-{[2-chloro-4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-1H-pyrazoles, or
Its pharmacy acceptable salt.
14. pyrazole derivatives as claimed in claim 13 is characterized in that, it is the compound that is selected from down group:
3-(β-D-galactopyranose oxygen base)-4-[(4-{3-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propyl group } phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-4-[(4-{3-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] propyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(4-methylpiperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(2-{1-[(4-methylpiperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } oxyethyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-4-[(4-{2-[1-{[4-(2-hydroxyethyl) piperazine-1-yl] carbonyl }-1-(methyl) ethylamino formyl radical] oxyethyl group }-the 2-aminomethyl phenyl) methyl]-5-sec.-propyl-1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(2-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } oxyethyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-pyranoglucose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-4-{[4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propoxy-)-the 2-aminomethyl phenyl] methyl }-the 1H-pyrazoles;
4-{[2-fluoro-4-(3-{1-[(piperazine-1-yl) carbonyl]-1-(methyl) ethylamino formyl radical } propyl group) phenyl] methyl }-3-(β-D-galactopyranose oxygen base)-5-sec.-propyl-1H-pyrazoles, or
Its pharmacy acceptable salt.
15. a pharmaceutical composition is characterized in that, it contains among the claim 1-14 arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug as activeconstituents.
16. arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug are used for suppressing the purposes of the preparation of people SGLT1 among the claim 1-14 in preparation.
17. arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug are used for suppressing the purposes of the preparation of postprandial hyperglycemia among the claim 1-14 in preparation.
18. arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug are used for preventing or treating the purposes of the preparation of hyperglycemia relative disease among the claim 1-14 in preparation.
19. purposes as claimed in claim 18, it is characterized in that this hyperglycemia relative disease is the disease that is selected from down group: diabetes, impaired glucose tolerance, diabetic complication, obesity, hyperinsulinemia, hyperlipidaemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism imbalance, atherosclerosis, hypertension, congestive heart failure, oedema, hyperuricemia and gout.
20. arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug are used for being suppressed at purposes individuality develops into diabetes from impaired glucose tolerance or the too much obstacle of fasting plasma glucose the preparation in preparation among the claim 1-14.
21. arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug are used for preventing or the raise purposes of preparation of relevant disease of treatment and blood semi-lactosi level in preparation among the claim 1-14.
22. purposes as claimed in claim 21 is characterized in that, the disease relevant with the rising of blood semi-lactosi level is galactosemia.
23. pharmaceutical composition as claimed in claim 15 is characterized in that, described formulation is a sustained release preparation.
24., it is characterized in that described formulation is a sustained release preparation as arbitrary described purposes among the claim 16-22.
25. the purposes of arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug is characterized in that among the claim 1-14, is used to prepare the pharmaceutical composition of prevention or treatment hyperglycemia relative disease.
26. the purposes of arbitrary described pyrazole derivatives, its pharmacy acceptable salt or its prodrug is characterized in that among the claim 1-14, is used for preparing being suppressed at individuality develops into diabetes from impaired glucose tolerance pharmaceutical composition.
27. pharmaceutical composition; it is characterized in that; it contains arbitrary described pyrazole derivatives among (A) claim 1-14; its pharmacy acceptable salt or its prodrug, and (B) at least a be selected from down the group member's material: insulin sensitivity enhancer; glucose absorption inhibitor; biguanides; insulin secretion enhancers; the SGLT2 inhibitor; Regular Insulin or insulin analog; glucagon receptor antagonist; the insulin receptor kinase stimulant; three peptidyl peptase II inhibitor; inhibitors of dipeptidyl IV; Protein Tyrosine Phosphatases-1B inhibitor; glycogen phosphorylase inhibitors; the Robison ester enzyme inhibitors; the fructose diphosphate enzyme inhibitors; pyruvate dehydrogenase inhibitor; liver starch heteroplasia inhibitor; the D-chiro-inositol; glycogen synthase kinase-3 inhibitor; glucagon-like-peptide-1; the glucagon-like-peptide-1 analogue; the glucagon-like-peptide-1 agonist; islet amyloid polypeptide; the islet amyloid polypeptide analogue; the islet amyloid polypeptide agonist; aldose reductase inhibitor; senior glycan end product synthetic inhibitor; inhibitors of protein kinase C; the gamma aminobutyric acid receptor antagonist; the sodium channel antagonist; the transcription factor NF-KB inhibitor; the lipid peroxidation enzyme inhibitors; acid-the Dipeptidase inhibitor of N-acetylize-α-connection; insulin like growth factor-1; Thr6 PDGF BB; the Thr6 PDGF BB analogue; Urogastron; nerve growth factor; carnitine derivative; uridine; 5-hydroxyl-1-methyl glycolylurea; EGB-761; than the More; sulosemide; Y-128; anti-diarrhea agents; cathartic; the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; fiber acid derivative; β
3-adrenoceptor agonist; the acetyl-CoA chole-sterol acyltransferase inhibitor; probucol; the Thyroid Hormone Receptors agonist; cholesterol absorption inhibitor; esterase inhibitor; the microsomal triglyceride transfer protein inhibitor; lipoxygenase inhibitors; the carnitine palmitoyl transferase inhibitors; inhibitor for squalene synthetic enzyme; the low density lipoprotein receptor toughener; nicotinic acid derivates; the bile acide intercalating agent; sodium/biliary salts cotransporter inhibitor; cholestery ester transfer protein inhibitors; appetite-inhibiting agent; angiotensin converting enzyme inhibitor; the neutral endopeptidase inhibitor; angiotensin II receptor antagonists; the endothelin converting enzyme inhibitor; endothelin-receptor antagonists; diuretic(s); calcium antagonist; the vasorelaxation hypotensive agent; sympathetic blocker; the hypotensive agent of central action; α
2-adrenoceptor agonist, anti-platelet agents, uric acid synthetic inhibitor, uricosuric agent and urine basifier.
28. the pyrazole derivatives shown in the general formula below a kind:
In the formula
R
11Be hydrogen atom, the hydroxyl (C that can have protecting group
2-6Alkyl) group;
Q
2And T
2In one be 2,3,4,6-four-O-ethanoyl-β-D-pyranoglucose oxygen base group or 2,3,4,6-four-O-ethanoyl-β-D-galactopyranose oxygen base group, and another group is C
1-6Alkyl;
R
12Be hydrogen atom, halogen atom, C
1-6Group shown in alkyl or the following general formula :-A-R
18, A is a Sauerstoffatom in the formula; And R
18Be C
2-6Heterocyclylalkyl;
X is singly-bound or Sauerstoffatom;
Y is C
1-6Alkylidene group or C
2-6Alkylene group;
Z is carbonyl or alkylsulfonyl;
R
14And R
15Identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have identical or different 1-3 and be selected from following substituting group group group (ii);
R
3, R
6And R
7Each is hydrogen atom naturally; And
The substituting group group (ii) is made of following: can have the hydroxyl of protecting group, the amino that can have protecting group, the list that can have protecting group or two (C
1-6Alkyl) amino, list or the two [hydroxyl (C that can have protecting group
1-6Alkyl)] amino, sulfoamido, C
2-7Group shown in acyl amino, the following general formula:
-CON (R
19) R
20, R wherein
19And R
20Identical or different, and each hydrogen atom or C naturally
1-6Alkyl, they can have identical or different 1-3 and be selected from down the substituting group of organizing: can have the hydroxyl of protecting group, the amino that can have protecting group, the list that can have protecting group or two (C
1-6Alkyl) amino, formamyl, or they constitute C with adjacent nitrogen-atoms combination
2-6Ring is amino, and this ring is amino can to have the substituting group of group: C down
1-6Alkyl and the hydroxyl C that can have protecting group
1-6Alkyl can have identical or different 1-3 substituent aryl, and described substituting group is selected from the hydroxyl that can have protecting group, heteroaryl, and C
2-6Ring is amino,
Or its salt.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP232074/2002 | 2002-08-08 | ||
| JP2002232074 | 2002-08-08 | ||
| JP321729/2002 | 2002-11-05 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1688596A CN1688596A (en) | 2005-10-26 |
| CN100351263C true CN100351263C (en) | 2007-11-28 |
Family
ID=35306305
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB038239299A Expired - Fee Related CN100351263C (en) | 2002-08-08 | 2003-08-07 | Pyrazole derivative, medicinal composition containing the same, medicinal use thereof, and intermediate for production thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN100351263C (en) |
| ZA (1) | ZA200501094B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105705509A (en) * | 2013-11-08 | 2016-06-22 | 伊莱利利公司 | 4-{4-[(1 e)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-1 -en-1 -yl]-2-methylbenzyl}-5-(propan-2-yl)-1 h-pyrazol-3-yl beta-d- glucopyranoside acetate |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2298782A1 (en) * | 2009-08-26 | 2011-03-23 | Sanofi-Aventis | Method for producing pyrazole glycoside derivatives |
| IN2012DN02711A (en) * | 2009-09-15 | 2015-09-11 | Janssen Pharmaceutica Nv | |
| JP5656092B2 (en) * | 2010-08-20 | 2015-01-21 | 大正製薬株式会社 | Crystal form of 4-isopropylphenylglucitol compound and process for producing the same |
| JO3298B1 (en) * | 2013-11-01 | 2018-09-16 | Lilly Co Eli | Glucopyranosyl-substituted indole-urea derivatives and their use as sglt inhibitors |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5274111A (en) * | 1992-04-07 | 1993-12-28 | American Home Products Corporation | Trifluoromethyl substituted 1H-pyrazoles and derivatives thereof |
| WO2000059889A1 (en) * | 1999-04-06 | 2000-10-12 | Sankyo Company, Limited | α-SUBSTITUTED CARBOXYLIC ACID DERIVATIVES |
| WO2001016147A1 (en) * | 1999-08-31 | 2001-03-08 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof |
| WO2002036602A1 (en) * | 2000-11-02 | 2002-05-10 | Ajinomoto Co., Inc. | Novel pyrazole derivatives and diabetes remedies containing the same |
| WO2002053573A1 (en) * | 2000-12-28 | 2002-07-11 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxypyrazole derivatives and use thereof in medicines |
-
2003
- 2003-08-07 ZA ZA200501094A patent/ZA200501094B/en unknown
- 2003-08-07 CN CNB038239299A patent/CN100351263C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5274111A (en) * | 1992-04-07 | 1993-12-28 | American Home Products Corporation | Trifluoromethyl substituted 1H-pyrazoles and derivatives thereof |
| WO2000059889A1 (en) * | 1999-04-06 | 2000-10-12 | Sankyo Company, Limited | α-SUBSTITUTED CARBOXYLIC ACID DERIVATIVES |
| WO2001016147A1 (en) * | 1999-08-31 | 2001-03-08 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof |
| WO2002036602A1 (en) * | 2000-11-02 | 2002-05-10 | Ajinomoto Co., Inc. | Novel pyrazole derivatives and diabetes remedies containing the same |
| WO2002053573A1 (en) * | 2000-12-28 | 2002-07-11 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxypyrazole derivatives and use thereof in medicines |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105705509A (en) * | 2013-11-08 | 2016-06-22 | 伊莱利利公司 | 4-{4-[(1 e)-4-(2,9-diazaspiro[5.5]undec-2-yl)but-1 -en-1 -yl]-2-methylbenzyl}-5-(propan-2-yl)-1 h-pyrazol-3-yl beta-d- glucopyranoside acetate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1688596A (en) | 2005-10-26 |
| ZA200501094B (en) | 2006-10-25 |
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