CN1267281A - Glucagon antagonists/inverse agonists - Google Patents

Glucagon antagonists/inverse agonists Download PDF

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Publication number
CN1267281A
CN1267281A CN98808125A CN98808125A CN1267281A CN 1267281 A CN1267281 A CN 1267281A CN 98808125 A CN98808125 A CN 98808125A CN 98808125 A CN98808125 A CN 98808125A CN 1267281 A CN1267281 A CN 1267281A
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alkyl group
low alkyl
aromatic base
compound
hydrogen
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CN98808125A
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A·凌
V·格莱哥
J·冈萨雷斯
洪予丰
D·基尔
A·库吉
施盛华
L·内鲁姆
P·麦德森
C·撒姆斯
J·劳
M·B·普利弗
冯军
滕敏
M·D·约翰逊
K·A·泰斯顿
U·G·西黛尔曼
L·B·纳德森
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Novo Nordisk AS
Agouron Pharmaceuticals LLC
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Novo Nordisk AS
Agouron Pharmaceuticals LLC
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Publication of CN1267281A publication Critical patent/CN1267281A/en
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Abstract

Non-peptide compounds comprising a central hydrazide motif and methods for the synthesis thereof. The compounds act to antagonize the action of the glucagon peptide hormone.

Description

Glucagon antagonist/inverse agonist
Technical field that the present invention belongs to
The present invention relates to be used for the medicament of antagonism glucagon-like peptide functions of hormones.Specifically, the present invention relates to non-peptide glucagon antagonist or inverse agonist.Background of invention
Hyperglycemic-glycogenolytic factor is and the collaborative major hormone medicament that mediates the homeostasis adjusting of amount of glucose in the blood of Regular Insulin.Hyperglycemic-glycogenolytic factor mainly is to work by stimulating some cell (mainly being liver cell) to discharge glucose when blood glucose levels descends.Hyperglycemic-glycogenolytic factor act as Regular Insulin institute antagonism, wherein the effect of Regular Insulin is that irritation cell absorbs and storaging grape sugar when blood glucose levels raises.Hyperglycemic-glycogenolytic factor and Regular Insulin all belong to peptide hormone.
Hyperglycemic-glycogenolytic factor produces in the α of pancreas islet cells, and Regular Insulin then produces in the β of pancreas islet cells.Diabetes (being common glucose metabolism disorder) are feature with the hyperglycemia, and can be expressed as I type (insulin-dependent) or II type (a kind of form with non-insulin-dependent feature).The patient who suffers from type i diabetes has the feature of hyperglycemia and hyperinsulinism, and the conventional treatments of this form disease provides Regular Insulin.Yet, to suffer among the patient of I type or type ii diabetes at some, hyperglycemic-glycogenolytic factor level absolute or that improve relatively demonstrates and helps hyperglycemia state.In the animal model of healthy animal and I type and II type, remove (with selectivity and specific antibody) of circulation hyperglycemic-glycogenolytic factor causes glucose level to reduce (Brand etc., diabetology, 37,985 (1994); Diabetes, 43[supplementary issue 1], 172A (1994); U.S.'s physiology magazine, 269, E469-E477 (1995); Diabetes, 44[supplementary issue 1], 134A (1995); Diabetes, 45,1076 (1996)).These studies show that: hyperglycemic-glycogenolytic factor restraining effect or the antagonistic action of hyperglycemic-glycogenolytic factor is helped the conventional hyperglycemia treatment of diabetes.By the effect that antagonist or inverse agonist (suppressing or stop the material of hyperglycemic-glycogenolytic factor inductive reaction) can glucagon suppression is provided.Antagonist can be peptide or non-peptide in essence.Natural hyperglycemic-glycogenolytic factor is to comprise 29 amino acid whose peptides, and this peptide has sequence His-Ser-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-NH 2
Hyperglycemic-glycogenolytic factor is brought into play its effect by combination and its acceptor of activation, and said acceptor is hyperglycemic-glycogenolytic factor-secretin ramose part (Jelinek etc., science, 259,1614, (1993)) that 7-strides film G-protein coupled receptor family.Acceptor works by activating the adenylyl cyclase second messenger system, and the consequently increase of cAMP level.
Several publications disclose some peptide antagonists, and the antagonist that wherein obtains the most thorough evaluation may be DesHis 1[Glu 9]-hyperglycemic-glycogenolytic factor acid amides (Unson etc., peptide, 10,1171 (1989); Post etc., institute of American Academy of Sciences newspaper, 90,1662 (1993)).Other antagonist for example has DesHis 1, Phe 6[Glu 9]-hyperglycemic-glycogenolytic factor acid amides (Azizh etc., biological organic and medical chemistry communication, 16,1849 (1995)) or NLeu 9, Ala 11,16-hyperglycemic-glycogenolytic factor acid amides (Unson etc., journal of biological chemistry, 269 (17), 12548 (1994)).
The peptide antagonists of peptide hormone usually is very effective; Yet with regard to as medicine, they are defective, because the degraded of physiology enzyme and bad biology distribute.Therefore, the non-peptide antagonists of peptide hormone is preferred.In non-peptide glucagon antagonist, the measured value quinoxaline derivatives (2-styryl-3-[3-(dimethylamino) third methyl-amino]-6, the 7-dichloro-quinoxaline) from the rats'liver acceptor, displaces hyperglycemic-glycogenolytic factor (Collins, J.L. etc. (1992), biological organic and medical chemistry communication, 2 (9): 915-918).West, R.R. etc. (1994), WO94/14426 disclose skyrin (comprising 9 of a pair of connection, the natural product of 10-amerantrone group) and synthetic analogues thereof the purposes as glucagon antagonist.Anderson, P.L,, United States Patent (USP) 4,359,474 disclose the glucagon antagonist character of 1-phenylpyrazole derivatives.Barcza, S., United States Patent (USP) 4,374,130 disclose two silicon hexanaphthenes (disilacyclohexane) of the replacement that is used as glucagon antagonist.WO 98/04528 (Bayer company) discloses the pyridine and the biphenyl of the replacement that is used as glucagon antagonist.In addition, WO97/16442 (Merck ﹠amp; Co., the Pyridylpyrrole and WO 98/21957 (the Merck ﹠amp of the replacement that is used as glucagon antagonist Inc.) are disclosed; Co., Inc.) disclose and be used as 2 of glucagon antagonist, 4-diaryl-5-Pyridinylimidazoles.These glucagon antagonists structurally are different from The compounds of this invention.Definition is described in invention
Following is the specific definition that is used for describing the term of The compounds of this invention:
" halogen " means and is selected from by F, Cl, the atom in the group that Br or I form.
That the term of this paper " alkyl " means is in line style or branch or cyclic configuration, that have 1 to 10 carbon atom, saturated or unsaturated (comprising one or more pair or triple bond on suitable position) hydrocarbon chain or ring.Therefore, said alkyl comprises for example n-octyl, methyl, and ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, allyl group, propargyl, 2-hexin base, cyclopropyl is encircled third methyl, cyclopentyl, cyclohexyl, ring octyl group, 4-cyclohexyl butyl or the like.
The indefiniteness example of said alkyl also comprises sec-butyl, n-pentyl, isopentyl, neo-pentyl, tert-pentyl, n-hexyl, isohexyl, n-heptyl, n-nonyl, positive decyl, vinyl, 1-propenyl, the 1-butylene base, crotyl, 3-butenyl, 2-methyl isophthalic acid-propenyl, 1-pentenyl, pentenyl, the 3-pentenyl, 4-pentenyl, 3-methyl-2-butene base, the 1-hexenyl, 3-hexenyl, 2, the 4-hexadienyl, 5-hexenyl, 1-heptenyl, 2,4-heptadiene base, 1-octenyl, 2,4-octadienyl, ethynyl, the 1-proyl, ethyl acetylene base, 2-butyne base, the 3-butynyl, 1-pentynyl, valerylene base, the 3-pentynyl, 4-pentynyl, 1-hexin base, 3-hexin base, 2,4-hexadiyne base, 5-hexin base, 1-heptyne base, 1-octyne base, the 2-decynyl, cyclobutyl, cyclopentyl, the 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, the 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cyclopropyl ethyl, cyclobutylmethyl, 2-cyclobutyl ethyl, the cyclohexenyl methyl, 4-cyclohexyl-crotyl, 4-(1-cyclohexenyl)-vinyl or the like.
Term " low alkyl group " means hydrocarbon part above explanation, a 1-6 carbonatoms.
Term " aromatic base " means the aromatic nucleus part, for example: phenyl, naphthyl, furyl, thienyl, pyrryl, pyridyl, pyrimidyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl ， oxazolyl ， isoxazolyl, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,3,4-oxadiazole base, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, thiazolyl, isothiazolyl, tetrazyl, 1-H-tetrazolium-5-base, indyl, quinolyl, quinazolyl, benzofuryl, benzo thio-phenyl (thianaphthenyl) or the like.
More indefiniteness example is an xenyl, anthryl, phenanthryl, fluorenyl, indenyl, the 1,2,3,4-tetralin base, 2,3-dihydro benzofuryl, triazolyl, pyranyl, the thiadiazine base, pseudoindoyl, indazolyl, 1,2,5-oxadiazole base, 1,2, the 5-thiadiazolyl group, benzothienyl, benzimidazolyl-, benzothiazolyl, the benzisothiazole base, benzoxazolyl, benzoisoxazole base, purine radicals, quinolizinyl, isoquinolyl, quinoxalinyl, naphthyridinyl, pteridyl, carbazyl, acridyl, pyrrolinyl, pyrazolinyl, indolinyl, pyrrolidyl, piperidyl or the like.
The aromatic base part can optionally be replaced by one or more substituting group, for example is selected from the substituting group in the group of being made up of following groups: F, Cl, I and Br; Low alkyl group; Low-grade alkane acidyl, formyl radical for example, ethanoyl, propionyl, butyryl radicals, pentanoyl, caproyl or the like;-OH;-NO 2-CN;-CO 2H;-O-low alkyl group; Aromatic base; Aromatic base-low alkyl group;-CO 2CH 3-CONH 2-OCH 2CONH 2-NH 2-N (CH 3) 2-SO 2NH 2-OCHF 2-CF 3-OCF 3Or the like.Another indefiniteness example is-NH-(C=S)-NH 2
Such aromatic base part also can by two substituting groups that form bridge (for example-OCH 2O-) replace.
" aromatic base-low alkyl group " mean replace by aromatic base, low alkyl group as defined above, for example:
Figure A9880812500301
The description of this invention
Can be optionally method substituted aromatic base as described above.
The present invention is based on unexpected observations: have as described below, selected carry the center primitive of nitrogen and the generally effect of the compound antagonism hyperglycemic-glycogenolytic factor of constitutional features.
Therefore, the present invention relates to the compound of general formula I:
Figure A9880812500311
Wherein: R 1And R 2Be hydrogen or low alkyl group independently or form valence link together; R 3And R 4Be hydrogen or low alkyl group independently; N is 0,1,2 or 3; M is 0 or 1; X is＞C=O＞C=S,＞C=NR 5Or＞SO 2R wherein 5Be hydrogen, low alkyl group, aromatic base-low alkyl group or-OR 6R wherein 6Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group; A is
Figure A9880812500321
Wherein:
R 7Be hydrogen, halogen ,-CN ,-CF 3,-OCF 3,-OCH 2CF 3,-NO 2,-OR 11,-NR 11R 12, low alkyl group, aromatic base, aromatic base-low alkyl group ,-SCF 3,-SO 2NR 11R 12,-SR 11,-CHF 2,-OCHF 2,-OSO 2R 11,-CONR 11R 12,-OCH 2CONR 11R 12,-CH 2OR 11,-CH 2NR 11R 12,-OCOR 11,-CO 2R 13Or-OSO 2CF 3
R 8And R 9Be hydrogen independently, halogen ,-CN ,-CF 3,-OCF 3,-OCH 2CF 3,-NO 2,-OR 11,-NR 12R 12, low alkyl group, aromatic base ,-SCF 3,-SR 11,-CHF 2,-OCHF 2,-OSO 2R 11,-CONR 11R 12,-CH 2OR 11,-CH 2NR 11R 12,-OCOR 11,-CO 2R 13Or-OSO 2CF 3, or R 8And R 9Form bridge-OCH together 2O-or-OCH 2CH 2O-;
R wherein 11And R 12Be hydrogen independently ,-COR 13,-SO 2R 13, low alkyl group or aromatic base;
R wherein 13Be hydrogen, low alkyl group, aromatic base-low alkyl group or aromatic base; And
R 10Be hydrogen, low alkyl group, aromatic base-low alkyl group or aromatic base;
B is Or valence link.
Wherein:
R 14And R 15Be hydrogen independently, halogen ,-CN ,-CF 3,-OCF 3,-O (CH 2) 1CF 3,-NO 2,-OR 16,-NR 16R 17, low alkyl group, aromatic base, aromatic base-low alkyl group ,-SCF 3,-SR 16,-CHF 2,-OCHF 2,-OCF 2CHF 2,-OSO 2CF 3,-CONR 16R 17,-(CH 2) 1CONR 16R 17,-O (CH 2) 1CONR 16R 17,-(CH 2) 1COR 16,-(CH 2) 1COR 16,-(CH 2) 1OR 16,-O (CH 2) 1OR 16,-(CH 2) 1NR 16R 17,-O (CH 2) 1NR 16R 17,-OCOR 16,-CO 2R 18,-O (CH 2) 1CO 2R 18,-O (CH 2) 1CN ,-O (CH 2) 1Cl, or R 14And R 15Form bridge-O (CH together 2) 1O-or-(CH 2) 1-;
Wherein l is 1,2,3 or 4;
R 16And R 17Be hydrogen independently ,-COR 18,-SO 2R 18, low alkyl group, aromatic base, or R 16And R 17Form the cyclic alkyl bridge that comprises 2-7 carbon atom together;
R wherein 18Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
W is-N=or-CR 19=;
Y is-N=or-CR 20=;
Z is-N=or-CR 21=;
V is-N=or-CR 22=;
And Q is-NR 23-,-O-or-S-;
Wherein:
R 19, R 20, R 21And R 22Be hydrogen independently, halogen ,-CN ,-CF 3,-OCF 3,-OCH 2CF 3,-NO 2,-OR 24,-NR 24R 25, low alkyl group, aromatic base, aromatic base-low alkyl group ,-SCF 3,-SR 24,-CHF 2,-OCHF 2,-OCF 2CHF 2,-OSO 2CF 3,-CONR 24R 25,-CH 2CONR 24R 25,-OCH 2CONR 24R 25,-CH 2OR 24,-CH 2NR 24R 25,-OCOR 24Or-CO 2R 24, or R 19And R 20, R 20And R 21, or R 21And R 22Form bridge-OCH together 2O-;
R wherein 24And R 25Be hydrogen independently ,-COR 26,-SO 2R 26, low alkyl group, aromatic base or aromatic base-low alkyl group;
R wherein 26Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group; And
R 23Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
K is wherein:
Figure A9880812500341
R 3a, R 3b, R 4aAnd R 4bBe hydrogen independently, halogen ,-CN ,-CF 3,-OCF 3,-OCH 2CF 3,-NO 2,-OR 24a,-NR 24aR 25a, low alkyl group, aromatic base, aromatic base-low alkyl group ,-SCF 3,-SR 24a,-CHF 2,-OCHF 2,-OCF 2CHF 2,-OSO 2CF 3,-CONR 24aR 25a,-CH 2CONR 24aR 25a,-OCH 2CONR 24aR 25a,-CH 2OR 24a,-CH 2NR 24aR 25a,-OCOR 24aOr-CO 2R 24a
R wherein 24aAnd R 25aBe hydrogen independently ,-COR 26a,-SO 2R 26a, low alkyl group, aromatic base or aryl lower alkyl;
R wherein 26aBe hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group; Or
R 3aAnd R 3b, R 4aAnd R 4b, or R 3aAnd R 4bForm bridge-(CH together 2) i-;
Wherein i is 1,2,3 or 4;
A, b, c and d are 0,1,2,3 or 4 independently;
E, f and this are 0 or 1 independently;
Q is 0,1 or 2; And
L and M are-O--S-,-CH=CH-,-C ≡ C-,-NR independently 5a-,-CH 2NR 5a-,-CO-,-OCO-,-COO-,-CONR 5a-,-CONR 5b-,-NR 5aCO-,-SO-,-SO 2-,-OSO 2-,-SO 2NR 5a-,-NR 5aSO 2-,-NR 5aCONR 5b-,-CONR 5aNR 5b-,-NR 5aCSNR 5b-,-OCONR 5b-,-CH 2CONR 5b-,-OCH 2CONR 5b-,-P (O) (OR 5a) O-,-NR 5aC (O) O-or
-O-，-S-，-CH＝CH-，-NR 5a-，-CH 2NR 5a-，-CO-，-OCO-，-COO-，-CONR 5a，-CONR 5a-，
-NR 5aCO-，-SO-，-SO 2-，-OSO 2-，-SO 2NR 5a-，-NR 5aSO 2-，-NR 5aCONR 5b-，-CONR 5aNR 5b-，
-NR 5aCSNR 5b-，-OCONR 5b-，-CH 2CONR 5b-，-OCH 2CONR 5b-.
-P (O) (OR 5a) O-,-NR 5aC (O) O-or
R wherein 5aAnd R 5bBe hydrogen independently, low alkyl group ,-OH ,-(CH 2) k-OR 6a,-COR 6a,-(CH 2) k-CH (OR 6a) 2,-(CH 2) k-CN ,-(CH 2) k-NR 6aR 6b, aromatic base, aromatic base-low alkyl group ,-(CH 2) g-COOR 43Or-(CH 2) g-CF 3
Wherein k is 1,2,3 or 4;
R 6aAnd R 6bBe hydrogen independently, low alkyl group, aromatic base or aromatic base-low alkyl group;
G is 0,1,2,3 or 4;
R 43Be hydrogen or low alkyl group;
G " is-OCH 2CO-,-CH 2CO-,-CO-or valence link; And
E " is-CH 2-,-CH 2CH 2-,-CH=CH-,-CH 2NH-or-CH 2CH 2NH;
D is a hydrogen,
Figure A9880812500351
Figure A9880812500361
Wherein:
R is 0 or 1;
S is 0,1,2 or 3;
E, E ', F, G and G ' are-CHR independently 38-,＞C=O,＞NR 39,-O-or-S-;
F ' is＞CR 38-or＞N-;
Y ' is-N=or-CR 32=;
Z ' is-N=or-CR 33=;
V ' is-N=or-CR 34=;
W ' is-N=or-CR 35=; With
Q ' is-NR 36-,-O-or-S-;
Wherein:
R 27, R 28, R 32, R 33, R 34And R 35Be hydrogen independently, halogen ,-CN ,-CF 3,-O (CH 2) yCF 3,-(CH 2) yNHCOCF 3,-NO 2, low alkyl group, aromatic base, aromatic base-low alkyl group ,-SCF 3,-SR 29,-CHF 2,-OCHF 2,-OCF 2CHF 2,-OSO 2R 29,-OSO 2CF 3,-(CH 2) yCONR 29R 30,-O (CH 2) yCONR 29R 30,-(CH 2) yOR 29,-(CH 2) yNR 29R 30,-OCOR 29,-COR 29Or-CO 2R 29Perhaps
R 27And R 28, R 32And R 33, R 33And R 34, or R 34And R 35Form bridge-O (CH together 2) yO-;
Wherein y is 0,1,2,3 or 4; With
R 29And R 30Be hydrogen independently ,-COR 31,-CO 2R 31,-SO 2R 31, low alkyl group, aromatic base or aromatic base-low alkyl group;
R wherein 31Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
R 36And R 39Be hydrogen independently, low alkyl group, aromatic base or aromatic base-low alkyl group; With
R 38Be hydrogen ,-OR 40,-NR 40R 41, low alkyl group, aromatic base, aromatic base-low alkyl group ,-SCF 3,-SR 40,-CHF 2,-OCHF 2,-OCF 2CHF 2,-CONR 40R 41,-(CH 2) xCONR 40R 41,-O (CH 2) xCONR 40R 41,-(CH 2) xOR 40,-(CH 2) xNR 40R 41,-OCOR 40Or-CO 2R 40
Wherein x is 1,2,3 or 4;
R 40And R 41Be hydrogen independently ,-COR 42,-SO 2R 42, low alkyl group, aromatic base or aromatic base-low alkyl group;
R wherein 42Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
And arbitrary optical or geometric isomer or its tautomeric form, comprise their mixture or its pharmacy acceptable salt.
When B is described formula, R 19, R 20, R 21, R 22And R 23Can be respectively R alternatively 14Or R 15Replace.In such a case, for example W can be selected from-N=,-CR 19-and-CR 14-.
Similarly, when D is described formula, R 32, R 33, R 34, R 35, R 36, R 38And R 39Can be respectively R alternatively 27Or R 28Replace.In such a case, for example E can be selected from-CHR 38-,＞C=O,＞NR 39,-O-,-S-,-CHR 27-and＞NR 27
In preferred embodiments, the present invention relates to have the compound of following general formula I I:
A wherein, B, K, D, R 3, R 4, defined identical in n and m and the general formula I.
In another embodiment preferred, the present invention relates to have the compound of following general formula III:
Figure A9880812500372
A wherein, B, K, D, R 3, R 4, defined identical in n and m and the general formula I.
In another embodiment preferred, the present invention relates to have the compound of following general formula I V: A wherein, B, K, D, R 3, R 4, defined identical in n and m and the general formula I.
In the compound of following formula I to IV, following substituting group is preferred:
R 3Hydrogen preferably.
R 4Hydrogen preferably.
A is preferably selected from the group of being made up of following groups:
Figure A9880812500382
R wherein 7, R 8, R 9And R 10With defined identical in the general formula I.
A is preferred
R wherein 7, R 8And R 9With defined identical in the general formula I.
In the above-listed embodiment of A, R 7Halogen preferably, low alkyl group ,-OH ,-NO 2,-CN ,-CO 2H ,-O-low alkyl group, aromatic base, aromatic base-low alkyl group ,-CO 2CH 3,-CONH 2,-OCH 2CONH 2,-NH 2,-N (CH 3) 2,-SO 2NH 2,-OCHF 2,-CF 3Or-OCF 3
Preferably, R 8And R 9Be hydrogen independently, halogen ,-OH ,-NO 2,-NH 2,-CN ,-OCF 3,-SCF 3,-CF 3,-OCH 2CF 3,-O-low alkyl group (as methoxyl group and oxyethyl group), low alkyl group (as methyl and ethyl) or phenyl, and R 10Be hydrogen, low alkyl group or phenyl.
More preferably, R 8And R 9Be independently selected from hydrogen, halogen (as-F and-Cl) ,-O-low alkyl group (as methoxyl group and oxyethyl group) ,-NH 2,-CN or-NO 2, and R 10Be hydrogen.
In particularly preferred embodiments, A is
Figure A9880812500391
R wherein 8And R 9Be hydrogen independently, halogen ,-OH ,-NO 2,-NH 2,-CN ,-OCF 3,-SCF 3,-CF 3,-OCH 2CF 3,-O-low alkyl group (as methoxyl group and oxyethyl group), low alkyl group (as methyl and ethyl), or phenyl are preferably hydrogen, halogen (as-F and-Cl) ,-O-low alkyl group (as methoxyl group and oxyethyl group) ,-NH 2,-CN or-NO 2
In another particularly preferred embodiment, A is
Figure A9880812500392
R wherein 8Be hydrogen, halogen (as-F or-Cl) ,-O-low alkyl group is (as-OCH 3Or-OC 2H 5) ,-NH 2,-CN or-NO 2And R 9Be hydrogen or halogen (as-F or-Cl).
In preferred embodiments, R 8Be halogen, and R 9Be hydrogen.
In another embodiment preferred, the present invention relates to have the compound of following formula V:
Figure A9880812500393
R wherein 4, B, defined identical among the K, D and m and general formula I, be preferably in the above-listed preferred embodiment with A defined identical.
B is preferably:
Figure A9880812500402
V wherein, W is defined identical among the Z, Y and Q and general formula I; And
R 14And R 15Be hydrogen independently, halogen ,-CF 3,-OCF 3,-OR 16,-NR 16R 17, low alkyl group, aromatic base, aromatic base-low alkyl group ,-OSO 2CF 3,-CONR 16R 17,-CH 2OR 16,-CH 2NR 16R 17,-OCOR 16Or-CO 2R 18Or R 14And R 15Form bridge-OCH together 2O-or-(CH 2) 1-;
L wherein, R 16, R 17And R 18With defined identical in the general formula I.
Q preferably-O-or-NH-.
Particularly preferred compound be those wherein B be the compound of following groups:
Figure A9880812500403
V wherein, W is defined identical among the Z, Y and Q and general formula I; And
R 14And R 15Be hydrogen independently, halogen ,-CF 3,-OCF 3,-OR 16,-NR 16R 17, low alkyl group, aromatic base, aromatic base-low alkyl group ,-OSO 2CF 3,-CONR 16R 17,-CH 2OR 16,-CH 2NR 16R 17,-OCOR 16Or-CO 2R 18Or R 14And R 15Form bridge-OCH together 2O-or-(CH 2) 1-;
L wherein, R 16, R 17And R 18With defined identical in the general formula I.
Other more preferably has the compound of following formula VI: With the compound with following formula VII: And compound with general formula VIIIa or VIIIb:
Figure A9880812500413
R wherein 14And R 15Be hydrogen independently, halogen ,-CF 3,-OCF 3,-OR 16,-NR 16R 17, low alkyl group, aromatic base, aromatic base-low alkyl group ,-OSO 2CF 3,-CONR 16R 17,-CH 2OR 16,-CH 2NR 16R 17,-OCOR 16Or-CO 2R 18Or R 14And R 15Form bridge-OCH together 2O-or-(CH 2) 1-;
L wherein, R 16, R 17And R 18With defined identical in the general formula I;
Defined identical among the K, D and m and general formula I; With
R 8And R 9With defined identical in the general formula I, be preferably in the above-listed preferred embodiment with A defined identical.
At following formula VI, among VII and the VIII, R 14And R 15Preferably be hydrogen independently, halogen, low alkyl group, aromatic base (as phenyl) or-O-low alkyl group (as methoxyl group).
In following formula VI and VII, K is preferably with the contraposition combination, and in following formula VIIIa and VIIIb, the K preferred combination is on the nitrogen-atoms of indolyl radical.
K is preferably selected from the group of being made up of following groups:
Figure A9880812500421
Figure A9880812500441
R wherein 3a, R 3b, R 4a, R 4b, R 5a, R 5b, a, b, c is defined identical among the d, p and q and general formula I.
More preferably, K is selected from the group of being made up of following groups:
Figure A9880812500461
Figure A9880812500471
Figure A9880812500481
R wherein 3a, R 3b, R 4a, R 4b, R 5a, R 5b, a, b, c is defined identical among the d, p and q and general formula I.
In another preferred embodiment, K is selected from the group of being made up of following groups:
Figure A9880812500501
R wherein 3a, R 3b, R 4a, R 4b, R 5a, R 5b, b, c is defined identical among the d, p and q and general formula I.
In the above-listed embodiment of K, R 5aAnd R 5bPreferably be hydrogen independently, low alkyl group ,-OH ,-(CH 2) kOR 6a, aromatic base, aromatic base-low alkyl group ,-CH 2CF 3,-(CH 2) g-COOR 43,-COOR 43,-(CH 2) k-CN or-(CH 2) k-NR 6aR 6b, g wherein, k, R 43, R 6aAnd R 6bWith defined identical in the general formula I.
Preferably, g and k are 1,2 or 3 independently, and R 6aAnd R 6bBe hydrogen independently, low alkyl group (as methyl or ethyl), or aromatic base (as phenyl).
In the above-listed embodiment of K, R 3aAnd R 3bPreferably be hydrogen independently, halogen ,-OH ,-O-low alkyl group ,-COO-low alkyl group, low alkyl group or aromatic base-low alkyl group.
In the above-listed embodiment of K, R 4aAnd R 4bPreferably be hydrogen independently ,-CN ,-CONH 2,-(CH 2)-N (CH 3) 2,-O-low alkyl group ,-CH 2OH ,-CH 2The O-aromatic base ,-N (CH 3) 2,-OH ,-CO 2-low alkyl group or low alkyl group.
D is hydrogen preferably,
Figure A9880812500511
S wherein, r, R 27, R 28, V ', Y ', Q ', Z ', W ', E, E ', F is defined identical among the F ', G and G ' and general formula I.
In other embodiment preferred, D is a hydrogen,
Figure A9880812500522
S wherein, r, R 27, R 28, V ', Y ', Z ', Q ', Z ', W ', E, E ', F is defined identical among the F ', G and G ' and general formula I.
D is hydrogen more preferably,
Wherein E and E ' are＞CHR independently 38,＞NR 39Or-O-; F, G and G ' are＞CHR independently 38,＞C=O or＞NR 39F ' is＞CR 38-or＞N-; And s, r, R 27, R 28, R 38, R 39, V ', Y ' is defined identical among the Z ', Q ' and W ' and general formula I.
R 27And R 28Preferably be hydrogen independently; Halogen (as-Cl ,-Br or-F);-CF 3-OCF 3-OCHF 2-OCH 2CF 3-(CH 2) yNHCOCF 3-NHCOCF 3-CN;-NO 2-COR 29,-COOR 29,-(CH 2) yOR 29Or-OR 29(R wherein 29Be hydrogen, aromatic base or low alkyl group, and y is 1,2,3 or 4); Low alkyl group (as methyl, ethyl, 2-propenyl, sec.-propyl, the tertiary butyl or cyclohexyl); Lower alkylthio;-SCF 3Aromatic base (as phenyl);-(CH 2) yNR 29R 30Or-NR 29R 30(R wherein 29And R 30Be hydrogen independently ,-COO-low alkyl group or low alkyl group, and y is 1,2,3 or 4); Or-CONH 2Or R 27And R 28Form bridge-OCH together 2O-; R 38Be hydrogen;-OCHF 2-OR 40(R wherein 40Be hydrogen or low alkyl group); Low alkyl group (as methyl, the sec.-propyl or the tertiary butyl); Lower alkylthio;-SCF 3-CH 2OH;-COO-low alkyl group or-CONH 2And R 39Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group.
In other embodiments, the present invention relates to have the compound of general formula I, wherein: R 1And R 2Be hydrogen or low alkyl group independently or form valence link together; R 3And R 4Be hydrogen or low alkyl group independently; X is＞C=O＞C=S,＞C=NR 5Or＞SO 2
N is 0,1,2 or 3;
M is 0 or 1;
R 5Be hydrogen, low alkyl group, aromatic base-low alkyl group, or-OR 6
R wherein 6Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
A is
Figure A9880812500541
Figure A9880812500551
R wherein 7Be hydrogen, halogen ,-CN ,-CF 3,-OCF 3,-OCH 2CF 3,-NO 2,-OR 11,-NR 11R 12, low alkyl group, aromatic base ,-SCF 3,-SR 11,-CHF 2,-OCHF 2,-OSO 2R 11,-CONR 11R 12,-CH 2OR 11,-CH 2NR 11R 12,-OCOR 11,-CO 2R 13,-OSO 2CF 3
R 8And R 9Be hydrogen independently, halogen ,-CN ,-CF 3,-OCF 3,-OCH 2CF 3,-NO 2,-OR 11,-NR 11R 12, low alkyl group, aromatic base ,-SCF 3,-SR 11,-CHF 2,-OCHF 2,-OSO 2R 11,-CONR 11R 12,-CH 2OR 11,-CH 2NR 11R 12,-OCOR 11,-CO 2R 13,-OSO 2CF 3, or R 8And R 9Form bridge-OCH together 2O-;
R 12And R 12Be hydrogen independently ,-COR 13,-SO 2R 13, low alkyl group or aromatic base;
R 13Be hydrogen, low alkyl group, aromatic base-low alkyl group or aromatic base;
R 10Be hydrogen, low alkyl group, aromatic base-low alkyl group or aromatic base;
B is Or valence link; Be preferably
Figure A9880812500561
R 14And R 15Be hydrogen independently, halogen ,-CN ,-CF 3,-OCF 3,-O (CH 2) 1CF 3,-NO 2,-OR 16,-NR 16R 17, low alkyl group, aromatic base ,-SCF 3,-SR 16,-CHF 2,-OCHF 2,-OCF 2CHF 2,-OSO 2CF 3,-CONR 16R 17,-(CH 2) 1CONR 16R 17,-O (CH 2) 1CONR 16R 17,-(CH 2) 1COR 16,-O (CH 2) 1COR 16,-(CH 2) 1OR 16,-O (CH 2) 1OR 16,-(CH 2) 1NR 16R 17,-O (CH 2) 1NR 16R 17,-OCOR 16,-CO 2R 18,-O (CH 2) 1CN ,-O (CH 2) 1Cl, or R 14And R 15Form bridge-O-CH together 2-O-;
R 14And R 15Preferably represent hydrogen, halogen ,-CF independently 3,-OCF 3,-OR 16,-NR 16R 17, low alkyl group, aromatic base, aromatic base-low alkyl group ,-OSO 2CF 3,-CONR 16R 17,-CH 2OR 16,-CH 2NR 16R 17,-OCOR 16Or-CO 2R 18Or form bridge-OCH together 2O-;
L is 1,2,3 or 4;
R 16And R 17Be hydrogen independently ,-COR 18,-SO 2R 18, low alkyl group, aromatic base, or R 16And R 17Form the cyclic alkyl bridge that comprises 2-7 carbon atom together;
R 18Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
W is-N=or-CR 19=;
Y is-N=or-CR 20=;
Z is-N=or-CR 21=;
V is-N=or-CR 22=;
Q is-NR 23-,-O-or-S-;
Wherein:
R 19, R 20, R 21And R 22Be hydrogen independently, halogen ,-CN ,-CF 3,-OCF 3,-OCH 2CF 3,-NO 2,-OR 24,-NR 24R 25, low alkyl group, aromatic base, aromatic base-low alkyl group, SCF 3,-SR 24,-CHF 2,-OCHF 2, OCF 2CHF 2,-OSO 2CF 3,-CONR 24R 25,-CH 2CONR 24R 25,-OCH 2CONR 24R 25,-CH 2OR 24, CH 2NR 24R 25,-OCOR 24Or-CO 2R 24, or R 19And R 20, R 20And R 21Or R 21And R 22Form bridge-OCH together 2O-;
R 24And R 25Be hydrogen independently ,-COR 26,-SO 2R 26, low alkyl group, aromatic base or aromatic base-low alkyl group;
R 26Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
R 23Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
K is
Figure A9880812500571
Wherein:
R 3a, R 3b, R 4aAnd R 4bBe hydrogen independently, halogen ,-CN ,-CF 3,-OCF 3,-OCH 2CF 3,-NO 2,-OR 24a,-NR 24aR 25a, low alkyl group, aromatic base, aromatic base-low alkyl group, SCF 3,-SR 24a,-CHF 2,-OCHF 2,-OCF 2CHF 2,-OSO 2CF 3,-CONR 24aR 25a,-CH 2CONR 24aR 25a,-OCH 2CONR 24aR 25a,-CH 2OR 24a,-CH 2NR 24aR 25a,-OCOR 24aOr-CO 2R 24a
R wherein 24aAnd R 25aBe hydrogen independently ,-COR 26a,-SO 2R 26a, low alkyl group, aromatic base or aromatic base-low alkyl group;
R 26aBe hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group; Or
R 3aAnd R 3b, R 4aAnd R 4bOr R 3aAnd R 4bForm bridge-(CH together 2) i-, wherein i is 1,2,3 or 4;
A, b, c and d are 0,1,2,3 or 4 independently;
E, f, p and q are 0 or 1 independently;
L and M are-O--S-,-CH=CH-,-C ≡ C-,-NR independently 5a-,-COO-,-CONR 5a-,-NR 5aCO-,-SO-,-SO 2-,-OSO 2-,-SO 2-NR 5a, ,-NR 5aSO 2-, NR 5aCONR 5b-,-NR 5aCSNR 5b-,-OCONR 5b-or-NR 5aC (O) O-, wherein R 5aAnd R 5bBe hydrogen independently, low alkyl group ,-(CH 2) k-OH ,-(CH 2) k-NR 6aR 6b, aromatic base or aromatic base-low alkyl group; Wherein k is 2,3 or 4;
R 6aAnd R 6bBe hydrogen independently, low alkyl group or aromatic base-low alkyl group;
K preferably represents
D be hydrogen or
Figure A9880812500582
Be preferably hydrogen,
Figure A9880812500592
Wherein:
Figure A9880812500593
R and s are 1 or 2 independently;
E, F and G are-CHR independently 38-,＞C=O,＞NR 39,-O-or-S-;
Y ' is-N=or-CR 32=;
Z ' is-N=or-CR 33=;
V ' is-N=or-CR 34=;
W ' is-N=or-CR 35=;
Q ' is-NR 36-,-O-or-S-;
R wherein 27, R 28, R 32, R 33, R 34And R 35Be hydrogen independently, halogen ,-CN ,-CF 3,-OCF 3,-O (CH 2) yCF 3,-NO 2,-OR 29,-NR 29R 30, low alkyl group, aromatic base, aromatic base-low alkyl group ,-SCF 3,-SR 29,-CHF 2,-OCHF 2,-OCF 2CHF 2,-OSO 2R 29,-OSO 2CF 3,-CONR 29R 30,-(CH 2) yCONR 29R 30,-O (CH 2) yCONR 29R 30,-(CH 2) yOR 29,-(CH 2) yNR 29R 30,-OCOR 29,-CO 2R 29, or R 27And R 28, R 32And R 33, R 33And R 34Or R 34And R 35Form bridge-OCH together 2O-;
R 27And R 28Preferably represent hydrogen, halogen ,-CF independently 3,-OCF 3,-OCH 2CF 3,-OR 29, low alkyl group, aromatic base or aromatic base-low alkyl group, or form bridge-OCH together 2O-;
Y is 1,2,3 or 4;
R 29And R 30Be hydrogen independently ,-COR 31,-SO 2R 31, low alkyl group, aromatic base or aromatic base-low alkyl group;
R 31Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
R 36And R 39Be hydrogen independently, low alkyl group, aromatic base or aromatic base-low alkyl group;
R 38Be hydrogen ,-OR 40,-NR 40R 41, low alkyl group, aromatic base, aromatic base-low alkyl group ,-SCF 3,-SR 40,-CHF 2,-OCHF 2,-OCF 2CHF 2,-CONR 40R 41,-(CH 2) xCONR 40R 41,-O (CH 2) xCONR 40R 41,-(CH 2) xOR 40,-(CH 2) xNR 40R 41,-OCOR 40Or-CO 2R 40X is 1,2,3 or 4;
R 40And R 41Be hydrogen independently ,-COR 42,-SO 2R 42, low alkyl group, aromatic base or aromatic base-low alkyl group; And
R 42Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group.
In other embodiment, the present invention relates to have the compound of general formula I, wherein:
R 1And R 2Be hydrogen or low alkyl group independently or form valence link together;
R 3And R 4Be hydrogen or low alkyl group independently;
N is 0,1,2 or 3;
M is 0 or 1;
X is＞C=O＞C=S,＞C=NR 5Or＞SO 2
R wherein 5Be hydrogen, low alkyl group, aromatic base-low alkyl group or-OR 6
R wherein 6Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
A is
Figure A9880812500611
Wherein:
R 7Be hydrogen, halogen ,-CN ,-CF 3,-OCF 3,-OCH 2CF 3,-NO 2,-OR 11,-NR 11R 12, low alkyl group, aromatic base ,-SCF 3,-SR 11,-CHF 2,-OCHF 2,-OSO 2R 11,-CONR 11R 12,-CH 2OR 11,-CH 2NR 11R 12,-OCOR 11,-CO 2R 13Or-OSO 2CF 3
R 8And R 9Be hydrogen independently, halogen ,-CN ,-CF 3,-OCF 3,-OCH 2CF 3,-NO 2,-OR 11,-NR 11R 12, low alkyl group, aromatic base ,-SCF 3,-SR 11,-CHF 2,-OCHF 2,-OSO 2R 11,-CONR 11R 12,-CH 2OR 11,-CH 2NR 11R 12,-OCOR 11,-CO 2R 13Or-OSO 2CF 3, or R 8And R 9Form bridge-OCH together 2O-or-OCH 2CH 2O-;
R wherein 11And R 12Be hydrogen independently ,-COR 13,-SO 2R 13, low alkyl group or aromatic base; R wherein 13Be hydrogen, low alkyl group, aromatic base-low alkyl group or aromatic base; And
R 10Be hydrogen, low alkyl group, aromatic base-low alkyl group or aromatic base;
B is
Figure A9880812500621
Or valence link; Be preferably
Figure A9880812500622
Wherein:
R 14And R 15Be hydrogen independently, halogen ,-CN ,-CF 3,-OCF 3,-O (CH 2) 1CF 3,-NO 2,-OR 16,-NR 16R 17, low alkyl group, aromatic base, aromatic base-low alkyl group ,-SCF 3,-SR 16,-CHF 2,-OCHF 2,-OCF 2CHF 2,-OSO 2CF 3,-CONR 16R 17,-(CH 2) 1CONR 16R 17,-O (CH 2) 1CONR 16R 17,-(CH 2) 1COR 16,-(CH 2) 1COR 16,-(CH 2) 1OR 16,-O (CH 2) 1OR 16,-(CH 2) 1NR 16R 17,-O (CH 2) 1NR 16R 17,-OCOR 16,-CO 2R 18,-O (CH 2) 1CO 2R 18,-O (CH 2) 1CN ,-O (CH 2) 1Cl, or R 14And R 15Form bridge-OCH together 2O-;
R 14And R 15Preferably represent hydrogen, halogen ,-CF independently 3,-OCF 3,-OR 16,-NR 16R 17, low alkyl group, aromatic base, aromatic base-low alkyl group ,-OSO 2CF 3,-CONR 16R 17,-CH 2OR 16,-CH 2NR 16R 17,-OCOR 16Or-CO 2R 18Or form bridge-OCH together 2O-;
Wherein l is 1,2,3 or 4;
R 16And R 17Be hydrogen independently ,-COR 18,-SO 2R 18, low alkyl group, aromatic base, or R 16And R 17Form the cyclic alkyl bridge that comprises 2-7 carbon atom together;
R wherein 18Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
W is-N=or-CR 19=:
Y is-N=or-CR 20=:
Z is-N=or-CR 21=;
V is-N=or-CR 22=; And
Q is-NR 23-,-O-or-S-;
Wherein:
R 19, R 20, R 21And R 22Be hydrogen independently, halogen ,-CN ,-CF 3,-OCF 3,-OCH 2CF 3,-NO 2,-OR 24,-NR 24R 25, low alkyl group, aromatic base, aromatic base-low alkyl group, SCF 3,-SR 24,-CHF 2,-OCHF 2,-OCF 2CHF 2,-OSO 2CF 3,-CONR 24R 25,-CH 2CONR 24R 25,-OCH 2CONR 24R 25,-CH 2OR 24,-CH 2NR 24R 25,-OCOR 24Or-CO 2R 24R 20And R 21Or R 21And R 22Form bridge-OCH together 2O-;
R wherein 24And R 25Be hydrogen independently ,-COR 26,-SO 2R 25, low alkyl group, aromatic base or aromatic base-low alkyl group;
R wherein 26Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group; And
R 23Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
K is
Figure A9880812500631
Wherein:
R 3a, R 3b, R 4aAnd R 4bBe hydrogen independently, halogen ,-CN ,-CF 3,-OCF 3,-OCH 2CF 3,-NO 2,-OR 24a,-NR 24aR 25a, low alkyl group, aromatic base, aromatic base-low alkyl group, SCF 3,-SR 24a,-CHF 2,-OCHF 2,-OCH 2CHF 2,-OSO 2CF 3,-CONR 24aR 25a,-CH 2CONR 24aR 25a,-OCH 2CONR 24aR 25a,-CH 2OR 24a,-CH 2NR 24aR 25a,-OCOR 24aOr-CO 2R 24a
R wherein 24aAnd R 25aBe hydrogen independently ,-COR 26a,-SO 2R 26a, low alkyl group, aromatic base or aromatic base-low alkyl group;
R wherein 26aBe hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
Or R 3aAnd R 3b, R 4aAnd R 4bOr R 3aAnd R 4bForm bridge-(CH together 2) i-; Wherein i is 1,2,3 or 4;
A, b, c and d are 0,1,2,3 or 4 independently;
E, f and p are 0 or 1 independently;
Q is 0,1 or 2; And
L and M are-O--S-,-CH=CH-,-C ≡ C-,-NR independently 5a-,-CO-,-OCO-;-COO-,-CONR 5a-,-NR 5aCO-,-SO-,-SO 2-,-OSO 2-,-SO 2-NR 5a-,-NR 5aSO 2-,-NR 5aCONR 5b-,-NR 5aCSNR 5b-,-OCONR 5b-or-NR 5aC (O) O-;
R wherein 5aAnd R 5bBe hydrogen independently, low alkyl group ,-(CH 2) k-OH ,-(CH 2) k-NR 6aR 6b, aromatic base or aromatic base-low alkyl group; Wherein k is 2,3 or 4; And
R 6aAnd R 6bBe hydrogen independently, low alkyl group or aromatic base-low alkyl group;
K preferably represents
Figure A9880812500651
D is a hydrogen,
Figure A9880812500652
Be preferably hydrogen,
Figure A9880812500661
Wherein:
R and s are 0,1 or 2 independently;
E, F and G are-CHR independently 38-,＞C=O,＞NR 39,-O-or-S-;
F ' is＞CR 38-or＞N-;
Y ' is-N=or-CR 32=;
Z ' is-N=or-CR 33=:
V ' is-N=or-CR 34=;
W ' is-N=or-CR 35=; And
Q ' is-NR 36-,-O-or-S-;
Wherein:
R 27, R 28, R 32, R 33, R 34And R 35Be hydrogen independently, halogen ,-CN ,-CF 3,-OCF 3,-O (CH 2) yCF 3,-NO 2,-OR 29,-NR 29R 30, low alkyl group, aromatic base, aromatic base-low alkyl group ,-SCF 3,-SR 29,-CHF 2,-OCHF 2,-OCH 2CHF 2,-OSO 2R 29,-OSO 2CF 3,-CONR 29R 30,-(CH 2) yCONR 29R 30Or-O (CH 2) yCONR 29R 30,-(CH 2) yOR 29,-(CH 2) yNR 29R 30,-OCOR 29Or-CO 2R 29
Or R 27And R 28, R 32And R 33, R 33And R 34Or R 34And R 35Form bridge-OCH together 2O-;
R 27And R 28Preferably represent hydrogen independently; Halogen (as-Cl or-F);-CF 3-OCF 3-OCHF 2-OCH 2CF 3-OR 29(R wherein 29Be hydrogen or low alkyl group); Low alkyl group (as methyl, the sec.-propyl or the tertiary butyl); Lower alkylthio;-SCF 3-CH 2OH;-COO-low alkyl group; Aromatic base or-CONH 2Or form bridge-OCH together 2O-;
Wherein y is 1,2,3 or 4; And
R 29And R 30Be hydrogen independently ,-COR 31,-SO 2R 31, low alkyl group, aromatic base or aromatic base-low alkyl group;
R wherein 31Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
R 36And R 39Be hydrogen independently, low alkyl group, aromatic base or aromatic base-low alkyl group; And
R 38Be hydrogen ,-OR 40,-NR 40OR 41, low alkyl group, aromatic base, aromatic base-low alkyl group ,-SCF 3,-SR 40,-CHF 2,-OCHF 2,-OCH 2CHF 2,-CONR 40R 41,-(CH 2) xCONR 40R 41,-O (CH 2) xCONR 40R 41,-(CH 2) xOR 40,-(CH 2) xNR 40R 41,-OCOR 40Or-CO 2R 40
Wherein x is 1,2,3 or 4;
R 40And R 41Be hydrogen independently ,-COR 42,-SO 2R 42, low alkyl group, aromatic base or aromatic base-low alkyl group; And
R wherein 42Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group.
The example of the particular compound of being represented by above-mentioned general formula V is as follows:
Figure A9880812500671
3-chloro-4-hydroxy-benzoic acid [5-chloro-2-methoxy 3-chloro-4-hydroxy-benzoic acid [3,5-two chloro-base-4-(4-isopropyl benzyloxy)-benzylidene] 4-(4-isopropyl benzyloxy) benzylidene] acyl hydrazides hydrazine 3-chloro-4-hydroxy-benzoic acid [2,3-dimethoxy 3-chloro-4-hydroxy-benzoic acid [2,3 two chloro-base-4-(4-isopropyl benzyloxy)-benzylidene] 4-(4-isopropyl benzyloxy) benzylidene] acyl hydrazides hydrazine
Figure A9880812500682
3-chloro-4-hydroxy-benzoic acid [2,3-dimethyl 3-chloro-4-hydroxy-benzoic acid [3-sec.-propyl--4-(4-isopropyl benzyloxy)-benzylidene] acyl 4-(4-isopropyl benzyloxy)-5-methoxyl group hydrazine benzylidene] hydrazides
Figure A9880812500683
3-chloro-4-hydroxy-benzoic acid [3-sec.-propyl-4-3-chloro-4-hydroxy-benzoic acid 3-[2-(1-pyrrole (4-isopropyl benzyloxy)-5-methyl benzal is coughed up alkane) oxyethyl group]-4-(the 4-isopropyl benzyloxy] hydrazide group)-5-methoxyl group benzylidene } hydrazides
Figure A9880812500684
3-chloro-4-hydroxy-benzoic acid [3-(2-diethylamino 3-chloro-4-hydroxy-benzoic acid [3-(2-diethyl oxyethyl group)-4-(4-sec.-propyl-benzyloxy amino-ethyl)-4-(4-isopropyl benzyloxy)-5-methoxyl group benzylidene] hydrazide group)-5-methoxyl group benzylidene] hydrazides
Figure A9880812500691
3-chloro-4-hydroxy-benzoic acid [3-diethylin 5-[(3-chloro-4-oxybenzene formyl radical) hydrazono-methyl-4-(4-isopropyl benzyloxy)-5-first-methyl]-3-methoxyl group-2-(4-sec.-propyl oxygen base benzylidene] the hydrazides benzyloxy)-phenylium
Figure A9880812500692
3-chloro-4-hydroxy-benzoic acid [3-(2-hydroxyl second 3-chloro-4-hydroxy-benzoic acid [3,5-pair-(2-oxygen base)-4-(4-sec.-propyl-benzyloxy)-5-hydroxyl-oxethyl)-4-(4-sec.-propyl benzyloxy methoxyl group benzylidene] hydrazide group) benzylidene] hydrazides
Figure A9880812500693
3-chloro-4-hydroxy-benzoic acid [2,3,5-three 3-chloro-4-hydroxy-benzoic acids [3,5-diformazan methoxyl group-4-(4-isopropyl benzyloxy-Ya benzyloxy-4-(4-just-propyl group benzyloxy)-subunit) hydrazides benzyl] hydrazides
Figure A9880812500701
3-chloro-4-hydroxy-benzoic acid [3,5-dimethoxy 3-fluoro-4-hydroxy-benzoic acid [3,5-dimethyl-4-(4-oxyethyl group benzyloxy base)-benzylidene] oxygen base-4-(4-isopropyl benzyloxy)-benzal hydrazide group] hydrazides
Figure A9880812500702
3-nitro-4-hydroxy-benzoic acid [3,5-diformazan 3-carboxyl-4-hydroxy-benzoic acid [3,5-dioxy base-4-(4-isopropyl benzyloxy)-benzal methoxyl group-4-(4-isopropyl benzyloxy)-subunit] hydrazides benzyl] hydrazides
Figure A9880812500703
3-formamyl-4-hydroxy-benzoic acid [3; 3-cyano group-4-hydroxy-benzoic acid [3,5-two 5-dimethoxy-4 's-(4-sec.-propyl benzyloxy methoxyl group-4-(4-isopropyl benzyloxy)-subunit)-benzylidene] hydrazides benzyl] hydrazides 3-chloro-4-hydroxy-benzoic acid { 3,5-dimethoxy 3-chloro-4-hydroxy-benzoic acid [3,5-dimethyl-4-[4-(2,2, the 2-trifluoro ethoxy)-oxygen base-4-[3-chloro-4-trifluoromethoxy benzyl benzyloxy]-benzylidene } hydrazides oxygen base] benzylidene] hydrazides 3-chloro-4-hydroxy-benzoic acid [3,5-dimethoxy 3-chloro-4-hydroxy-benzoic acid [3,5-dimethyl-4-(4-chlorophenoxy) benzylidene] hydrazides oxygen base-4-(4-sec.-propyl phenoxy group) benzal
Base] hydrazides
Figure A9880812500713
3-chloro-4-hydroxy-benzoic acid [3,5-dimethoxy 3-chloro-4-hydroxy-benzoic acid [3,5-dimethyl-4-(4-trifluoromethyl-2-pyridyl methoxy oxygen base-4-(6-methyl oxygen in heptan base) benzylidene] base)-benzylidene] the hydrazides hydrazides
Figure A9880812500721
3-chloro-4-hydroxy-benzoic acid [3, and 5-dimethoxy 3-chloro-4-hydroxy-benzoic acid [3,5-dimethyl-4-(5-hexene oxygen base) benzylidene] hydrazides oxygen base-4-(5,5-dimethyl-3-hexin oxygen
Base) benzylidene] hydrazides
Figure A9880812500722
3-chloro-4-hydroxy-benzoic acid [4-(4-fluoroform 3-chloro-4-hydroxy-benzoic acid [4-(4-isopropoxy phenoxy group)-1-naphthyl methylene radical] hydrazide group phenoxy group)-1-naphthyl methylene radical] hydrazides
Figure A9880812500723
3-chloro-4-hydroxy-benzoic acid { 3,5-dimethoxy 3-chloro-4-hydroxy-benzoic acid 3,5-dimethyl-4-[2-(4-E-fluoroform phenyl)-vinyloxy group-4-[(4-isopropyl phenyl)-ethynyl] benzylidene } hydrazide group] benzylidene } hydrazides
Figure A9880812500724
3-chloro-4-hydroxy-benzoic acid [3, and 5-dimethoxy 3-chloro-4-hydroxy-benzoic acid [3-(2-methoxyl group-4-(cyclohexyl-acetylene base) benzylidene] acyl group-4-tolyl) ethynyl-5-methoxyl group hydrazine benzylidene] hydrazides
Figure A9880812500731
3-chloro-4-hydroxy-benzoic acid (4-hydroxyl-1-naphthalene 3-chloro-4-hydroxy-benzoic acid [4-[3,5-double-basis methylene radical) hydrazides-trifluoromethyl benzyloxy)-1-naphthyl methylene
Base] hydrazides
Figure A9880812500732
3-chloro-4-hydroxy-benzoic acid [4-(2-chloroethene oxygen vanillic acid (2-naphthyl base)-1-naphthyl methylene radical] the hydrazides methylene radical) hydrazides Vanillic acid (4-methoxy vanillic acid (uncle 4--Ji-1-naphthyl methylene radical) hydrazides butyl benzylidene) hydrazides
Figure A9880812500741
Vanillic acid (different third vanillic acid of 4-(4-three fluorine-based benzylidenes) hydrazides methoxyl group benzylidene) hydrazides
Figure A9880812500742
Vanillic acid (1H-indoles vanillic acid (4-diformazan-3-methylene) hydrazides amino-1-naphthyl methylene radical) hydrazides
Figure A9880812500743
Vanillic acid (4-phenyl 4-hydroxy-benzoic acid (1-naphthyl methylene radical) acyl benzal) hydrazides hydrazine
Figure A9880812500744
4-hydroxy-benzoic acid (4-methoxyl group-1-naphthyl 3,4-resorcylic acid (1-naphthyl methylene methylene radical) hydrazide group) hydrazides Vanillic acid (1-naphthyl vanillic acid [3-(3-methylene radical) hydrazides 4-trifluoromethylphenopendant) benzylidene] hydrazides
Figure A9880812500752
Vanillic acid (4-quinoline 4-hydroxy-benzoic acid [3-(1,1,2, the 2-methylene radical) hydrazides tetrafluoro oxyethyl group) benzylidene] hydrazides The 4-hydroxy-benzoic acid [3-(4-tert-butyl benzene vanillic acid (4-hydroxyl base)-E-butenylidene] hydrazides-1-naphthyl methylene radical) hydrazides
Figure A9880812500754
4-hydroxy-benzoic acid (benzylidene) hydrazides 4-hydroxy-benzoic acid (1-naphthyl methylene radical) acyl
Hydrazine
Figure A9880812500761
3-amino-4-hydroxy phenylformic acid (1-naphthyl-Ya 3-amino-4-hydroxy phenylformic acid (4-hydroxyl-methyl) hydrazides 1-naphthyl methylene radical) hydrazides
Figure A9880812500762
The 4-hydroxy-benzoic acid [3-(3-three fluoro-methyl benzyl 3-chloro-4-hydroxy-benzoic acids (the inferior methoxyl group of 1-naphthyl) benzylidene] hydrazide group) hydrazides
Figure A9880812500763
3-chloro-4-hydroxy-benzoic acid (4-hydroxyl-1-naphthalene 4-hydroxy-benzoic acid (4-hydroxyl-1-naphthyl methylene) hydrazides methylene radical) hydrazides
Figure A9880812500771
The 4-hydroxy-benzoic acid [4-(3-trifluoromethylbenzene 4-hydroxy-benzoic acid (5-phenyl-3-pyrazolyl oxygen base) benzylidene] the hydrazides methylene radical) hydrazides 2,4-resorcylic acid (4-hydroxyl-1-naphthalene 4-hydroxyl-3-nitrobenzoic acid (1-naphthyl subunit methylene radical) hydrazides methyl) hydrazides
Figure A9880812500773
4-hydroxyl-3-nitrobenzoic acid (4-hydroxyl-1-3,4-resorcylic acid (4-hydroxyl-1-naphthyl methylene radical) hydrazides naphthyl methylene radical) hydrazides
Figure A9880812500774
4-hydroxy-benzoic acid (6-methoxyl group-2-naphthyl 3,5-two chloro-4-hydroxy-benzoic acid (4-hydroxy methylene) hydrazide group-1-naphthyl methylene radical) hydrazides
Figure A9880812500781
Vanillic acid (9-ethyl-vanillic acid [5-[3-9H-3-carbazyl methylene radical) the hydrazides chloro-phenyl-]-2-furyl methylene radical] hydrazides
Figure A9880812500782
3-chloro-4-hydroxy-benzoic acid (inferior 3-chloro-4-hydroxy-benzoic acid (4-allyloxy-2-propenyl) hydrazides of 3-phenyl-E--1-naphthyl methylene radical) hydrazides
Figure A9880812500783
3-chloro-4-hydroxy-benzoic acid (4-ethynyl first 3-chloro-4-hydroxy-benzoic acid (4-benzyloxy-Oxy-1-naphthyl methylene radical) hydrazides 1-naphthyl methylene radical) hydrazides
Figure A9880812500784
The inferior 3-chloro-4-hydroxy-benzoic acid of 2-(4-[(3-chloro-4-hydroxy benzoyl) (4-methyl isophthalic acid-diazanyl methyl] naphthalene-1-oxygen base) ethanamide naphthyl methylene radical) hydrazides
Figure A9880812500791
3-chloro-4-hydroxy-benzoic acid (2-hydroxyl-1-naphthalene 3-chloro-4-hydroxy-benzoic acid (4-methoxyl group-methylene) hydrazides 1-naphthyl methylene radical) hydrazides The inferior 3-chloro-4-hydroxy-benzoic acid of N-(2-[(3-chloro-4-hydroxy benzoyl) (1-hydroxyl-2-diazanyl] ethyl)-2,2-phenylbenzene ethanamide naphthyl methylene radical) hydrazides 3-chloro-4-hydroxy-benzoic acid (2,2-phenylbenzene 3-chloro-4-hydroxy-benzoic acid (4-benzyloxy-ethylidene) hydrazides 3,5-dimethoxybenzylidenegroup group) hydrazides 3-chloro-4-hydroxy-benzoic acid [3-(uncle 4--Ding 3-chloro-4-hydroxy-benzoic acid (4-methyl isophthalic acid-phenoxyl) benzylidene] hydrazides naphthyl methylene radical) hydrazides
Figure A9880812500801
3-chloro-4-hydroxy-benzoic acid [3-bromo-4-oxyacetic acid 4-[(3-chloro-4-oxybenzene formyl radical) Asia-1-naphthyl methylene radical] hydrazides diazanyl methyl]-1-naphthyl ester 3-chloro-4-hydroxy-benzoic acid (4-cyano group methoxy 3-chloro-4-hydroxy-benzoic acid (2-hydroxyl-1-base-1-naphthyl methylene radical) hydrazides naphthyl methylene radical) hydrazides 3-chloro-4-hydroxy-benzoic acid (2, and 3-methylene radical 3-chloro-4-hydroxy-benzoic acid [3-(4-methoxy dihydroxyl benzylidene) hydrazide group phenoxy group) benzylidene] hydrazides
Figure A9880812500804
3-chloro-4-hydroxy-benzoic acid (the inferior 3-chloro-of 9-phenanthrol base 4-hydroxy-benzoic acid [4-(2-hydroxymethyl) hydrazides oxyethyl group)-1-naphthyl methylene radical] hydrazides
Figure A9880812500811
3-bromo-4-hydroxy-benzoic acid (4-hydroxyl-1-naphthalene nicotinic acid 4-[(3-chloro-4-hydroxy benzoyl) methylene) hydrazides hydrazono-methyl]-1-naphthyl ester
Figure A9880812500812
[4-(1 for 3-chloro-4-hydroxy-benzoic acid, 3-two 3-chloro-4-hydroxy-benzoic acids [4-(cyclohexyl oxo-1,3-dihydro isoindole-2-base first methoxyl group)-1-naphthyl methylene radical] hydrazides oxygen base)-and 1-naphthyl-methylene radical] hydrazides 3-chloro-4-hydroxy-benzoic acid [4-(tetrahydrochysene-3-chloro-4-hydroxy-benzoic acid [4-[3-pyridine 2-pyranyl methoxyl group)-1-naphthyl-methylene radical methoxyl group)-1-naphthyl methylene radical] hydrazide group] hydrazides 4-[(3-chloro-4-oxybenzene formyl radical) hydrazides ethyl acetate base hydrazono-3-chloro-4-hydroxy-benzoic acid [3-nitro benzal methyl]-1-naphthyloxy))
Figure A9880812500822
3-chloro-4-hydroxy-benzoic acid (2, inferior 3-chloro-4-hydroxy-benzoic acid (4-fluoro-1-naphthalene benzyl) the hydrazide group methylene radical of 4-dichloro) hydrazides
Figure A9880812500823
3-fluoro-4-hydroxy-benzoic acid (4-hydroxyl-1-naphthalene 3-chloro-4-hydroxy-benzoic acid [4-(2,4-two methylenes) hydrazides fluorine benzyloxy)-1-naphthyl methylene radical] hydrazides
Figure A9880812500824
3-fluoro-4-hydroxy-benzoic acid (1-naphthyl methylene 3-chloro-4-hydroxy-benzoic acid [the 4-[3-methoxyl group) the hydrazide group benzyloxy)-1-naphthyl methylene radical] hydrazides
Figure A9880812500831
3-chloro-4-hydroxy-benzoic acid [4-(4-fluorine benzyloxy 3-chloro-4-hydroxy-benzoic acid [4-(2-tetrahydrochysene base)-1-naphthyl methylene radical] hydrazides furyl methoxyl group)-1-naphthyl methylene radical]
Hydrazides
Figure A9880812500832
3-chloro-4-hydroxy-benzoic acid [3-bromo-4-methoxy 3-chloro-4-hydroxy-benzoic acid [4-[3-tetrahydrochysene base-1-naphthyl methylene radical] hydrazides furyl methoxyl group)-1-naphthyl methylene radical]
Hydrazides
Figure A9880812500833
4-(4-[3-chloro-4-oxybenzene formyl radical] inferior hydrazine 3-chloro-4-hydroxy-benzoic acid [3,5-dimethyl methyl)-1-methanoyl methyl) phenylformic acid oxygen base-4-(4-trifluoromethoxy benzyloxy)-methyl esters benzylidene] hydrazides
Figure A9880812500841
3-chloro-4-hydroxy-benzoic acid [4-(4-fluoroform 3-chloro-4-hydroxy-benzoic acid [4-(2-methoxy oxygen base benzyloxy)-1-naphthyl methylene radical] hydrazide group benzyloxy)-1-naphthyl methylene radical] hydrazides 3-chloro-4-hydroxy-benzoic acid [4-(2-fluorine benzyloxy 3-chloro-4-hydroxy-benzoic acid [4-(2,6-two bases)-1-naphthyl methylene radical] hydrazides fluorine benzyloxy)-1-naphthyl methylene radical] hydrazides
Figure A9880812500843
Figure A9880812500851
Figure A9880812500861
The most preferred particular compound of being represented by above-mentioned general formula III is as follows: (p72, empty 10 row)
As follows by the most preferred particular compound that above-mentioned general formula I V represents:
Figure A9880812500871
As follows by the preferred particular compound that above-mentioned general formula VI and VII represent: (p73-83 ,+10 pages of empty 15 row)
Figure A9880812500872
Figure A9880812500891
Figure A9880812500911
Figure A9880812500921
Figure A9880812500931
Figure A9880812500961
The most preferred particular compound of general formula I (wherein A is heterocycle and/or dicyclo part) is as follows:
Figure A9880812500981
Indole-5-carboxylic acid [4-(4-trifluoromethyl benzyloxy indazole-5-carboxylic acid [4-(4-trifluoromethyl benzyl)-1-naphthyl methylene radical] hydrazides oxygen base)-1-naphthyl methylene radical] hydrazides Pyrazoles-3-carboxylic acid [4-(4-trifluoromethyl benzyloxy 3-hydoxyisoxazole-5-carboxylic acid [4-(4-three bases)-1-naphthyl methylene radical] hydrazides methyl fluoride benzyloxy)-1-naphthyl methylene radical]
Hydrazides
Figure A9880812500983
Figure A9880812500991
According to the present invention, especially preferred be demonstrate and human glucagon receptor between the following compounds of special high affinity:
Figure A9880812500992
Figure A9880812501011
Figure A9880812501021
Figure A9880812501031
Figure A9880812501041
Figure A9880812501091
Figure A9880812501121
Figure A9880812501131
Figure A9880812501141
Figure A9880812501151
Figure A9880812501161
Figure A9880812501171
Figure A9880812501181
Figure A9880812501191
Figure A9880812501201
Figure A9880812501211
Figure A9880812501231
Figure A9880812501241
Figure A9880812501251
Figure A9880812501261
Figure A9880812501281
Figure A9880812501291
Figure A9880812501301
Figure A9880812501311
Compound of the present invention can have one or more asymmetric center, and it means any optical isomer (as isolating, purifying or partially purified optical isomer or its racemic mixture) and all comprises within the scope of the present invention.
Secondly, one or more carbon-to-carbon or carbon-nitrogen two strands may reside in the compound, and this can produce geometrical isomer.It means any geometrical isomer (as isolating, purifying or partially purified geometrical isomer or its mixture) and all comprises within the scope of the present invention.
In addition, compound of the present invention can exist with different tautomeric forms, as following tautomeric form:
Figure A9880812501312
This means arbitrary tautomeric forms that compound can form and all comprises within the scope of the present invention.
Because their effects aspect the antagonism glucagon receptor, The compounds of this invention can be suitable for treating and/or preventing symptom and the illness that any hyperglycemic-glycogenolytic factor mediates.
Therefore, The compounds of this invention can be used for treating relevant with the diabetes of arbitrary reason or relevant with symptom with other disease hyperglycemia, as the glucose tolerance that weakens, insulin resistance syndrome, syndrome X, type i diabetes, type ii diabetes, hyperlipemia, piarhemia obstacle, high sweet oily matter three ester mass formed by blood stasis, glucagonoma, acute pancreatitis, cardiovascular disorder, megalocardia, stomach disorder, diabetes (as the result of obesity) etc.In addition, they can be used as and be used for differentiating whether the patient has the diagnostic reagent of defective aspect glucagon receptor, as being used for the gastric acid secretion increasing thing, be used for reversing because the bowel movement that hyperglycemic-glycogenolytic factor is used weakens, be used for reversing katabolism and (comprise I type and type ii diabetes at the nitrogen loss and the protein depletion of negative nitrogen balance state, fasting, AIDS, cancer, apocleisis, all reasons of old and feeble and other illness) therapy is as being used for after operation or in the arbitrary above-mentioned symptom of perioperative therapy or treatment of diseases agent with as being used for reducing satiety and increasing the medicine of energy intake amount.Therefore, on the other hand, the present invention relates to pharmaceutical composition, it comprises and at least aly combines with one or more pharmaceutically acceptable carrier or vehicle according to compound of the present invention (as activeconstituents).
The invention still further relates to the method for treatment I type or type ii diabetes or hyperglycemia, this method comprise the curee to the needs treatment use significant quantity according to compound of the present invention.
In addition, the present invention relates to reduce the method for Mammals blood sugar, this method comprise to said administration significant quantity according to compound of the present invention.
The present invention also relates to be used for treating I type or type ii diabetes or hyperglycemia or be used for reducing purposes aspect the medicine of Mammals blood sugar in manufacturing according to compound of the present invention.
Pharmaceutical preparation and application process
For therapeutic purpose, can use with arbitrary suitable pathways according to compound of the present invention (also can be called as activeconstituents), these approach comprise oral, rectum, nose, lung, partial (comprise the oral cavity with hypogloeeis), through skin, vagina (comprise subcutaneous with parenteral, intramuscular, intravenous and intradermal), wherein oral route is preferred.People can recognize: preferred approach will change with curee's illness and age, the illness character that will treat and selected activeconstituents.
Compound of the present invention is effective in the dosage range of broadness.Typical dosage range is 0.05 to about 1000mg, is preferably about 0.1 to about 500mg, for example for use every day one or repeatedly (as every day 1 to 3 time) for about 0.5mg to about 250mg.This is construed as accurate dose will depend on frequency of administration and mode, curee's sex, age, body weight and general situation are subjected to sanatory character and severity and will treat any disease accompanied and are tangible other factors to those skilled in the art.
Preparation can be made unit dosage form by method known to those skilled in the art easily.
For parenteral approach, for example intravenous, in the sheath, intramuscular and similarly use, typical dosage is about 1/2 similar with Orally administered used dosage.
Compound of the present invention generally is used as free material or its pharmacy acceptable salt.An example is the acid salt with compound of free alkali function.When the compound of general formula I comprises free alkali, then can prepare such salt with ordinary method by solution or suspension with the free alkali of a stoichiometric pharmaceutically acceptable acid (as inorganic and organic acid) processing general formula I, said acid for example: maleic acid, fumaric acid, phenylformic acid, xitix is pounced on acid, succsinic acid, two-the methylene radical Whitfield's ointment, methylsulfonic acid, ethane disulfonic acid, acetate, oxalic acid, propionic acid, tartrate, Whitfield's ointment, citric acid, pyruvic acid, glyconic acid, lactic acid, oxysuccinic acid, tussol, styracin, citraconic acid, aspartic acid, stearic acid, palmitinic acid, EDTA, oxyacetic acid, para-amino benzoic acid, L-glutamic acid, Phenylsulfonic acid, tosic acid, hydrochloric acid; Hydrogen bromide, sulfuric acid, phosphoric acid or nitric acid.Have acceptable salt on the physiology of compound of hydroxyl and comprise negatively charged ion with suitable cation (as sodium or ammonium ion) the said compound of bonded.
The compounds of this invention can be used separately or combine with pharmaceutically acceptable carrier and use, and dosage is single or many multiple doses.
For parenteral administration, can use the solution of new compound in aseptic aqueous solution, aqueous propylene glycol or sesame oil or peanut oil of general formula I.Such aqueous solution should obtain suitable buffering (if necessary), and liquid diluent at first provides isotonicity with enough salt solution or glucose.The aqueous solution is particularly suited for intravenously, intramuscular, and subcutaneous and intraperitoneal is used.Employed sterile aqueous media all is easy to obtain by standard technique well known by persons skilled in the art.Suitable pharmaceutical carrier comprises inert solid diluent or weighting agent, aseptic aqueous solution and various organic solvent.The example of solid carrier is a lactose, carclazyte, sucrose, cyclodextrin, talcum powder, gelatin, agar, pectin, gum arabic, Magnesium Stearate, stearic acid or cellulosic lower alkyl ether.The example of liquid carrier is a soup compound, peanut oil, sweet oil, phosphatide, lipid acid, fatty acid amine, polyoxyethylene or water.Similarly, carrier or thinner can comprise any sustained-release material known in the art (individually or with wax blended), for example glyceryl monostearate or distearin.Then, the pharmaceutical composition that forms by new compound and pharmaceutically acceptable carrier in conjunction with general formula I just is easy to use with the various dosage forms that are suitable for disclosed route of administration.Preparation can be made unit dosage form by the known method of this pharmaceutical field easily.
Be suitable for Orally administered preparation of the present invention and can form the allocation unit form, as capsule or tablet, each form comprises the activeconstituents of predetermined amount, and each form can comprise suitable vehicle.These preparations can be pulvis or granula form, solution in moisture or anhydrous liq or suspension, or oil-in-water or water-in-oil emulsion.
If solid carrier be used in Orally administered in, preparation can be made tablet form, be placed in the hard-gelatin capsules with powder or piller form, or it can be lozenge or lozenge form.The quantitative change scope of solid carrier is very big, but is typically about 25mg to about 1g.
If utilize liquid carrier, then preparation can be soup compound, milk sap, Gelseal or aseptic parenteral solution (as a moisture or anhydrous liquid suspension or solution) form.
Can be comprised by the typical tablet of conventional tablet technology of preparing preparation: label: reactive compound (such as free compound or its salt) 100mg colloidal silica (Aerosil) 1.5mg cellulose, cellulose gum (Ac-Di-Sol) the 7.5mg dolomol dressing of crystallite (Avicel) 70mg modification: the about 0.9mg* of the about 9mg*Mywacett 9-40 of HPMC T utilizes single acid glycerol shape thing ester of acidylate as the film coating plasticizer.
For nasal administration, preparation can comprise dissolving or be suspended in the compound (being used as aerosol uses) of the general formula I in the liquid carrier (especially aqueous carrier).Carrier can comprise additive, as solubilizing agent (as propylene glycol), tensio-active agent, absorption enhancer (as Yelkin TTS (phosphatidylcholine) or cyclodextrin) or sanitas such as parabens.
Selectively, pharmaceutical composition of the present invention can comprise with one or more other pharmacologically active chemical compounds (as antidiabetic or other pharmacological active substance, comprise treat and/or prevent insulin resistance and wherein insulin resistance be the compound of the disease of physiopathology mechanism) compound of bonded general formula I.Suitable antidiabetic comprises Regular Insulin, GLP-1 derivative (being disclosed in GLP-1 derivative among the WO 98/08871 (Novo Nordisk A/S) with this paper reference in the lump) and Orally administered active Hypoylycemic agents (as sulfonylurea, for example Glyburide and Mitoneu) as those; Biguanides is as N1,N1-Dimethylbiguanide; Benzoic acid derivative is as repaglinide; And thiazolidinedione, as troglitazone and ciglitazone, and PPAR and rxr agonist.
Experiment
The hyperglycemic-glycogenolytic factor combination:
In following chapters and sections, described the drug effect that is used for estimating The compounds of this invention in conjunction with measuring and functional examination.
Hyperglycemic-glycogenolytic factor is in conjunction with measuring (I)
The human glucagon receptor that utilizes the clone in competition in conjunction with measuring combining of compound and glucagon receptor in measuring.
In screening scheme, when the 5nM hyperglycemic-glycogenolytic factor exists, suppress the ability of cAMP formation amount according to compound and determine antagonistic action.
For abundant evaluation, determine antagonistic action with functional examination, measure antagonistic action according to the move to right ability of hyperglycemic-glycogenolytic factor dose-response curve of compound.Utilize at least 3 different antagonist concentration, calculating K from the Schild figure iUtilize people's acceptor (Lok etc., gene, 140,203-209 (1994)) of clone to measure receptors bind.In immature hamster kidney cell line (A3 BHK570-25), expressed the acceptor that utilizes in EcoRI/Sstl restriction site (Lok etc.) insertion pLJ6 ' expression vector.When 0.5mg/ml G-418 exists, select the clone, show that its stability can keep more than 40 generations.Demonstrate K dBe 0.1nM.
By making cell grow to fusion, separate them from the surface and with the cell resuspending in refrigerative damping fluid (10mM tris/HCl, pH 7.4) in, utilize Polytron PT 10-35 homogenizer (Kinematica) to homogenize by breaking of twice 10 seconds, and on the 95.000*g of one deck 41W/V% sucrose, preparing plasma membrane in centrifugal 75 minutes, said damping fluid comprises 30mM NaCl, the 1mM dithiothreitol (DTT), 5mg/l leupeptin (Sigma), 5mg/l Pepstatin (Sigma), 100mg/l bacitracin (Sigma) and 15mg/l reorganization Trypsin inhibitor,Trasylol (NovoNordisk)).With the damping fluid dilution white ribbon between two-layer, and under 40.000*g centrifugal 45 minutes.Suspending in damping fluid comprises the throw out of plasma membrane, and-80 ℃ of storages during up to needs.
According to the method for chloramine-T (Hunter and Greenwood, nature, 194,495 (1962)) iodate hyperglycemic-glycogenolytic factor, and utilize anion-exchange chromatography (J  rgensen etc., hormone and metabolism research, 4,223-224 (1972)) purifying it.The specific activity on iodate same day is 460 μ Ci/ μ g.Tracer agent is stored under-18 ℃ with aliquots containig, and uses it immediately after melting.
(MADV N65 Millipore) upward carries out combination with three parts of samples and measures at the filter microtiter plate.The damping fluid that this mensuration is utilized is the 25mM HEPES pH7.4 that comprises 0.1% human serum albumin (Sigma, rank V).Hyperglycemic-glycogenolytic factor is dissolved among the 0.05M HCl, add the HSA of equivalent (w/w) and lyophilize it.In use, it is dissolved in the water, and is diluted to required concentration with damping fluid.
Every hole adds 175 μ l samples (hyperglycemic-glycogenolytic factor or test compound).Dilute tracer agent (50.000cpm) with damping fluid, and every hole adds 15 μ l damping fluids.Every hole adds the 0.5 μ g new plasmalemma protein matter of melting of 15 μ l with the damping fluid dilution.25 ℃ of following culture plates 2 hours.With 10 -6The M hyperglycemic-glycogenolytic factor is not measured to the specificity combination.Then by vacuum filtration (Millipore vacuum manifold) separation and combination with unconjugated tracer agent.With 150 μ l damping fluids/hole washing flat board once.Air-dry dull and stereotyped 3 two hours, utilize Millipore puncher separating filter and flat board subsequently.Count filter with gamma counter.
Functional examination (I)
(tissue culture plate Nunc) is carried out functional examination with 96 hole microtiter plates.The buffer concentration that is produced in the mensuration is 50mM tris/HCl, 1mM EGTA, 1.5mM MgSO 4, 1.7mM ATP, 20 μ M GTP, 2mM IBMX, 0.02% Tween-20 and 0.1% HSA.PH is 7.4.Add 35 μ l with the hyperglycemic-glycogenolytic factor of following material dilution and the antagonist of being advised: 50mM tris/HCl,, 1mM EGTA, 1.85mM MgSO 4, 0.0222% Tween-20 and 0.111% HSA, pH7.4.Add 20 μ l 50mM tris/HCl, 1mM EGTA, 1.5mM MgSO 4, 11.8mM ATP, 0.14mM GTP, 14mM isobutyl--methyl-xanthine (IBMX) and 0.1% HSA, pH7.4.Dissolve GTP before measuring immediately.
The 50 μ l solution that will comprise 5 μ g plasmalemma protein matter add tris/HCl, EGTA, MgSO 4, HSA damping fluid (actual concentrations depends on the proteinic concentration in the stored plasma membrane).
Total mensuration volume is 140 μ l.Cultivated working sample 2 hours 37 ℃ of following continuous oscillations.Come termination reaction by adding 25 μ l 0.5N HCl.Utilize scintillation proximity test kit (Amersham) to measure cAMP.
Hyperglycemic-glycogenolytic factor is in conjunction with measuring (II)
Utilize people's acceptor (Lok etc., gene, 140,203-209 (1994)) of clone to measure receptors bind.In immature hamster kidney cell line (A3 BHK 570-25), express the acceptor that utilizes in EcoRI/SSt1 restriction site (Lok etc.) insertion pLJ6 ' expression vector.When 0.5mg/ml G-418 exists, select the clone, and demonstrate its stability above 40 generations.Kd is shown as 0.1nM.
By making cell grow to fusion, go out them and cell is resuspended in refrigerative damping fluid (10mM tris/HCl from surface isolation, pH 7.4) in, utilize Polytron PT 10-35 homogenizer (Kinematica) to homogenize by breaking of twice 10 seconds, and the centrifugal plasma membrane for preparing, said damping fluid comprises 30mM NaCl, 1mM dithiothreitol (DTT), 5mg/l leupeptin (Sigma), 5mg/l Pepstatin (Sigma), 100mg/l bacitracin (Sigma) and 15mg/l reorganization Trypsin inhibitor,Trasylol (Novo Nordisk)).Resuspending and recentrifuge homogenate.Suspending in damping fluid comprises the final throw out of plasma membrane, and-80 ℃ of storages during up to needs.
Carrying out combination with two parts of samples in polypropylene tube or microtiter plate measures.The damping fluid that this mensuration is utilized is 25mM HEPES pH7.4, comprises 0.1% bovine serum albumin (Sigma, component V).Every pipe or every hole add sample (hyperglycemic-glycogenolytic factor (Bachem CA) or test compound).Dilute tracer agent (approximately 25000cpm) with damping fluid, and diluent is added in every pipe or the every hole.To new plasmalemma protein matter of melting be added in every pipe or the every hole with 0.5 μ g of damping fluid dilution in the aliquots containig mode then.37 ℃ of following culture tubes or dull and stereotyped 1 hour.Arrive the specificity combination with 10-7M hyperglycemic-glycogenolytic factor undetermined.By vacuum filtration (Brandel) separation and combination with unconjugated tracer agent.With twice in damping fluid sluicing pipe or hole.With gamma counter counting filter or flat board.
Functional examination (II)
Functional examination is used for determining the ability that compound antagonism hyperglycemic-glycogenolytic factor stimulates in full raji cell assay Raji cAMP forms.In borosilicate glass 12 * 75 pipes, measure.Buffer concentration in the mensuration is 10mM HEPES, 1mM EGTA, 1.4mM MgCl 2, 0.1mM IBMX, 30mMNaCl, 4.7mM KCl, 2.5mM NaH 2PO 2, 3mM glucose and 0.2%BSA.PH is 7.4.Following at 37 ℃ with the loose full cell of the compound pre-treatment of various concentration (0.5ml, 10 6/ ml) 10 minutes, attacked 20 minutes with hyperglycemic-glycogenolytic factor then.Handle some aliquots containigs (500 μ l) of cell with the check agonist activity with test compound (55 μ l) separately.By centrifugal termination reaction, make cytolysis by adding 500 μ l, 0.1% HCl subsequently.Make cell debris become pellets, and evaporation comprise the supernatant liquor of cAMP to doing.(NEN NEK-033) measures cAMP to utilize the RIA kit.The adenylate cyclase FlashPlate system that utilization derives from NEN carries out some mensuration.
Synthetic method
Intermediate compound and final product that following synthetic method relates in specification sheets and identifies in synthetic schemes.Utilize the following example to describe the preparation of The compounds of this invention in detail, but only the general applicability aspect that glucagon antagonist of the present invention prepares is disclosed described chemical reaction from them.Sometimes, described reaction may not be suitable for each compound that is included within the scope disclosed in this invention.Such compound is easy to be discerned by those skilled in the art.Under all such situations, can successfully carry out arbitrary reaction by conventional improvement the well known by persons skilled in the art (that is to say, interfere group, change into other conventional dose, or change reaction conditions routinely) by suitably protecting.In addition, other reaction disclosed herein or other ordinary method all will be applicable to the preparation of respective compound of the present invention.In ownership system Preparation Method, all raw materials all are known or are easy to by known feedstock production.All temperature are all degree centigrade to provide, except as otherwise noted, when relating to productive rate all umbers and percentage all by weight, all umbers by volume all when relating to solvent and eluent.
The general method of preparation alkylidene group hydrazides:
I is illustrated as scheme, the compound that can prepare general formula I according to embodiment of the present invention, it is the alkylidene group hydrazides of general formula I I, that is to say, be converted into hydrazide derivatives and further make the alkylidene group hydrazides of the aldehydes or ketones reaction of product compound and replacement with the generation replacement by ester with carboxylic acid (as aromatic acid).
Scheme I
Wherein A, B, K, D, m, n and R 4With defined identical in the general formula I, and R aBe low alkyl group.
Synthetic precursor hydrazides A-(C=O)-NHNH 2General method
Reaction be known (organic synthesis, Coll. rolls up II, A.H.Blatt edits, John Wiley and Sons, New York, 1943, p.85; Organic synthesis, Coll. roll up IV, N.Rabjohn edits, John Wiley and Sons, New York, 1963, p.819), and generally solvent (as the mixture of ethanol, methyl alcohol, Virahol or the trimethyl carbinol or tetrahydrofuran (THF), diox, DMSO, ethylene glycol, ethylene glycol bisthioglycolate methyl esters, benzene, toluene or above-mentioned solvent) when existing or when lacking solvent (at this moment excessive hydrazine plays solvent) react by stirring the corresponding esters (methyl, ethyl or other lower alkyl esters) and the hydrazine of 2-10 molar excess.React between 130 ℃ at 0 ℃, be preferably 20 ℃ to 100 ℃, most preferably be the reflux temperature of about solvent.The reaction preferably at inert atmosphere (as N 2Or Ar) carries out under.When (being judged according to the disappearance of starting ester by TLC or HPLC) finished in reaction, can under pressing or reduce pressure, atmosphere desolvate by concentrating to remove.
Can in solvent, be further purified product by recrystallization, said solvent such as ethanol, methyl alcohol, Virahol, toluene, dimethylbenzene, hexane, tetrahydrofuran (THF), diethyl ether, dibutyl ether, water or two or the mixture of multiple above-mentioned solvent.In addition, can utilize methylene chloride or chloroform/methanol or Virahol as eluent by the column chromatography purified product.Depress or under vacuum, concentrate respective components so that pure aroyl hydrazides to be provided in atmosphere.
Preparation aromatic acid hydrazides:
The methyl esters or the ethyl ester (as the benzoic ether that replaces) of corresponding aromatic acid are dissolved in the ethanol, and add hydrazine (5 equivalent).Reaction is refluxed a night.The hydrazide derivatives that replaces when cooling forms precipitation usually.After filtering product usually in hot methanol, ethanol or Virahol recrystallization come out.Do not form under the sedimentary situation at hydrazides, concentration response thing under vacuum, and utilize methylene chloride to compose in the enterprising circumstances in which people get things ready for a trip of silica gel as eluent.The specific embodiment of illustrating fragrant hydrazides preparation method below is provided.
Preparation 5-oxyindole-2-carboxylic acid hydrazides:
(4ml, (5g is in sample 24mmol) 121mmol) to be added to the 5-oxyindole-2-carbonyl acetoacetic ester that is dissolved in the ethanol (250ml) with hydrazine.Reaction is refluxed a night.When reactor vessel cooled, required product forms crystallization.By the filtering separation white solid.Recrystallization in hot ethanol produces the 5-oxyindole-3-carboxylic acid hydrazides of 85% productive rate.
Figure A9880812501401
Preparation 3-chloro-4-hydroxy-benzoic acid hydrazides:
Hydrazine (1.8ml) is added in the sample of the 3-chloro-4-methyl hydroxybenzoate (2g) that is dissolved in the ethanol (50ml).Reaction is refluxed a night.When reactor vessel cooled, required product crystallizes out from solution.By the filtering separation white solid.Recrystallization in hot ethanol produces the 3-chloro-4-hydroxy-benzoic acid hydrazides of 60% productive rate.
Figure A9880812501402
Utilize aforesaid method, can prepare other hydrazides that in the preparation of The compounds of this invention, can be used as intermediate, for example:
Figure A9880812501411
3-bromo-4-hydroxy-benzoic acid hydrazides 3-nitro-4-hydroxy-benzoic acid hydrazides
Figure A9880812501413
3-fluoro-4-hydroxy-benzoic acid hydrazides
1H NMR (DMSO-d 6): δ 9.45 (wide unimodal, 1H), 7.5 (d, 1H), 7.43 (d, 1H), 6.85 (t, 1H), 5.55 (wide unimodal, 3H).
Preparation 2-chloro-4-hydroxy-benzoic acid hydrazides, 2,3-two chloro-4-hydroxy-benzoic acid hydrazides and 2,5-two chloro-4-hydroxy-benzoic acid hydrazides.
Figure A9880812501421
Preparation 2-chloro-4-hydroxy-benzoic acid hydrazides:
Steps A: (10g 58mmol) is dissolved in H with 4-amino-2-chloro-benzoic acid by heating 2SO 4(12N, 120ml) in.After with the ice bath cooling solution, drip aqueous NaNO 2(2.5M, 25ml), so that internal temperature remains on 5 ℃.Urea is added in the mixture, and stirred 15 minutes, to destroy excessive N aNO 2(by the starch iodine test monitoring).Add CuSO 4(100-200mg), and heated mixt to 90 ℃ a effusion up to gas stop.After cooling, extract mixture with ether (3x).Extract the organic constituent that merges with 3N NaOH (3x).Also extract product with the waterbearing stratum that dense HCl acidifying merges with ether (3x).Water, salt water washing organic constituent, and at MgSO 4Last drying.With crude product introduce silicagel column and with ethyl acetate/hexane (1/1) wash-out so that 2-chloro-4-to be provided hydroxy-benzoic acid.
1H?NMR(DMSO-D6)：δ6.97(dd，1H)，7.05(d，1H)，7.95(d，1H)，10.90(brd?s，1H)。
Step B: thionyl chloride (1.5 equivalent) is added in the absolute methanol solution of 2-chloro-4-hydroxy-benzoic acid.At room temperature after the stirred solution 16 hours, evaporating solvent.Use the up in ethyl acetate resistates, and with saturated aqueous carbonic acid hydrogen sodium, water, salt water washing it, and at MgSO 4Last drying, and under vacuum, concentrate to produce 2-chloro-4-methyl hydroxybenzoate.
Step C: (9.8g, (13.6g is 73.1mmol) in the solution 73.7mmol) to be added to 2-chloro-4-methyl hydroxybenzoate in acetate (300ml) with N-chloro-succinimide.Make solution backflow 24h, and the vaporising under vacuum solvent.With chloroform absorption of residual excess, water, salt water washing, dry on sal epsom, filter and concentrate it.2,3-two chloro-4-methyl hydroxybenzoates are precipitated out in ethyl acetate.Utilize ethyl acetate/hexane (1/9 to 3/7) that resistates is carried out chromatogram and provide 2,5-two chloro-4-methyl hydroxybenzoates (1.4g, 60%) and a collection of additional 2,3-two chloro-4-methyl hydroxybenzoate isomer (gross weight 8.4g, 10%).
2,3-two chloro-4-methyl hydroxybenzoates:
1H?NMR(DMSO-D6)δ3.81(s，3H)，7.02(d，1H)，7.70(d?1H)，11.52(s，1H)；MS(APCl)：221，223。
2,5-two chloro-4-methyl hydroxybenzoates:
1H?NMR(CDCl 3)δ3.90(s，3H)，6.00(s，1H)，7.14(s，1H)，7.27(s，1H)，7.96(s，1H)；MS(APCl)：221.9。
Step D: according to synthetic precursor hydrazides A-(C=O)-NHNH 2General method prepare title compound.
1H?NMR(DMSO-D6)δ6.82(dd，1H)，6.90(d，1H)，7.79(d，1H)，10.68(brd?s，1H)。
Preparation 2,3-two chloro-4-hydroxy-benzoic acid hydrazides and 2,5-two chloro-4-hydroxy-benzoic acid hydrazides (step D):
According to synthetic precursor hydrazides A-(C=O)-NHNH 2General method (except that amylalcohol is that the solvent selected is), by above-mentioned 2,3-two chloro-4-methyl hydroxybenzoates prepare 2,3-two chloro-4-hydroxy-benzoic acid hydrazides.Utilize CH 2Cl 2/ MeOH (95/5 to 80/20) is by the silica gel column chromatography purified product, productive rate=50%.
From 2,5-two chloro-4-hydroxybenzoates are initial, use with quadrat method preparation 2,5-two chloro-4-hydroxy-benzoic acid hydrazides.
2,3-two chloro-4-hydroxy-benzoic acid hydrazides:
1H?NMR(DMSO-D6)δ4.41(brd?s，2H)，6.99(1，1H)，7.37(s，1H)，9.46(s，1H)，11.04(s，1H)。
2,5-two chloro-4-hydroxy-benzoic acid hydrazides:
1H?NMR(DMSO-D6)δ4.48(brd?s，3H)，6.92(d，2H)，7.18(d，2H)，9.45(brd?s，1H)。
Preparation 2,3-two fluoro-4-hydroxy-benzoic acid hydrazides:
Figure A9880812501431
Steps A: make at water (8ml), H 2SO 4(8ml) and 2 in the acetate (8ml), (1g, mixture 6.45mmol) refluxed 48 hours 3-two fluoro-4-cyano group phenol., except that desolvating these slurries are cast on ice by rotary evaporation to produce slurries.Product is precipitated out from solution and filters it.Wash with water solid and drying to produce 2,3-two fluoro-4-hydroxy-benzoic acids (800mg, 71%).
1H?NMR(DMSO-D 6)：δ6.87(t，1H)，7.60(t，1H)，11.28(s，1H)，12.53(brd?s，1H)。
Step B: with thionyl chloride (0.55ml 7.3mmol) is added to and is dissolved in 2 in the anhydrous methanol (50ml), 3-two fluoro-4-hydroxy-benzoic acids (800mg, 5.1mmol) in.At room temperature after the stirred solution 16 hours, evaporating solvent.With the up in ethyl acetate resistates and with saturated aqueous carbonic acid hydrogen sodium, water, salt water washing, and at MgSO 4Last dry to produce 2,3-two fluoro-4-methyl hydroxybenzoates (540mg, 62%).
1H?NMR(CDCl 3)：δ3.92(s，3H)，6.34(brd?s，1H)，6.82(dt，1H)，7.68(dt，1H)。
Step C: according to synthetic precursor hydrazides A-(C=O)-NHNH 2General method, by above-mentioned 2,3-two fluoro-4-methyl hydroxybenzoates preparation 2,3-two fluoro-4-hydroxy-benzoic acid hydrazides.Utilize CH 2Cl 2/ MeOH (95/5 to 80/20) by the silica gel column chromatography purified product so that title compound to be provided.
1H?NMR(DMSO-D 6)：δ4.48(s，2H)，6.80(m，1H)，7.22(m，1H)，9.36(s，1H)，10.89(s，1H)；MS(APCl)：189。
Preparation 3-cyano group-4-hydroxy-benzoic acid hydrazides, trifluoroacetate:
Figure A9880812501441
Steps A: (35.5g 0.233mol) is dissolved in warm (65 ℃) acetate of 200ml with methyl-4-hydroxybenzoate.Will the iodine monochloride in the 50ml acetate (37.8g, 0.233mol) solution slowly (40 minutes) be added in methyl-4-hydroxy-benzoic acid ester solution, keeping temperature simultaneously is 65 ℃ and vigorous stirring.When being cooled to room temperature and leave standstill a night, product crystallizes out from solution.On filter, collect crystal, wash with water, dry under vacuum then.Obtain the methyl-4-hydroxyl-3-benzene iodide manthanoate (28.6g, 44%) of white crystal form.
1H?NMR(DMSO-D 6)：δ3.79(s，3H)，6.95(d，J＝8.3，1H)，7.81(dd，J＝8.3，2.2，1H)，8.22(d，J＝2.2，1H)； 13C?NMR(DMSO-D 6)δ52.8，85.2，115.5，123.0，132.0，141.0，161.9，165.6；MS(APCl，neg)：277。
Step B: (2.00g 7.2mmol) is dissolved among the 5ml exsiccant DMF with methyl-4-hydroxyl-3-benzene iodide manthanoate.Add cupric cyanide (I) (0.72g, 8.0mmol) and the small-crystalline of sodium cyanide.Wash mixture with nitrogen, be placed in the oily matter heating bath (100-110 ℃), and stir a night.TLC shows that reaction is almost completely.Cooling mixture and by solids removed by filtration.Extract solid with DMF (3ml).With 100ml up in ethyl acetate filtrate and washings, then with 3 parts of saturated nacl aqueous solution washings.Combining solid and aqueous washings, and sway with 50ml ethyl acetate and ferric chloride Solution (iron(ic) chloride of the 4g hydration in the 7ml concentrated hydrochloric acid) mixture.The combined ethyl acetate layer, dry on sodium sulfate with the salt water washing that comprises Sodium Pyrosulfite, filter, and remove in a vacuum and desolvate.Go up by the solid that purified by flash chromatography produced, so that methyl-3-cyano group-4-hydroxybenzoate, 0.93g (73%) to be provided at silica gel (20% ethyl acetate/hexane).
1H?NMR(DMSO-D 6)：δ3.79(5，3H)，7.07(d，J＝8.7，1H)，8.02(dd，J＝8.7，1.9，1H)，8.10(d，J＝1.9，1H)。
Step C: (2.71g 15.3mmol) is dissolved among the 50ml THF with methyl-3-cyano group-4-hydroxybenzoate.Use the ice bath cooling solution, and dropping 2.0M potassium hydroxide (17ml, 34mmol).At room temperature stir one night of mixture that is produced.TLC shows that reaction is completely.Remove THF by rotary evaporation.With the aqueous resistates of aqueous trifluoroacetic acid acidifying, and by reversed-phase HPLC (C-18, the 0.1%TFA in water and acetonitrile) purifying it.Obtain the 3-cyano group-4-hydroxy-benzoic acid (2.1g, 84%) of white powder form after the lyophilize.
1H?NMR(DMSO-D 6)：δ7.09(d，J＝9.0，1H)，8.00(dd，J＝9.0，2.3，1H)，8.07(d，J＝2.3，1H)，12.50(br?s，2H)；MS(APCl，neg)：162。IR：2252cm -1，CN。
Step D: (1.88g 11.5mmol) is dissolved among 20ml methylene dichloride/DMF (1/1), and cools off with ice bath with 3-cyano group-4-hydroxy-benzoic acid.Add diisopropylethylamine (12ml, 69mmol), carbazic acid tert-butyl ester (1.76g, 13.3mmol) and PyBroP (bromo-three-tetramethyleneimine-Phosphonium hexafluorophosphates, 6g 12.9mmol), and stir the mixture with the formation settled solution.Solution leaves standstill a night in refrigerator.TLC show the reaction be incomplete, so add additional diisopropylethylamine (22ml, 127mmol), carbazic acid tert-butyl ester (0.85g, 6.4mmol) and PyBroP (3.0g, 6.4mmol).After leaving standstill under 0 ℃ more than 8 hour, it is as follows progressively to induce reaction.Reduce solution by rotary evaporation.Dilute remaining DMF solution with the 100ml ethyl acetate, and wash it (on litmus paper, keeping acid) up to washings with several parts of 0.1M HCl.Further wash ethyl acetate layer with 3 parts of salt solution, dry on sal epsom, filter, and under vacuum, become oily matter.At silica gel (6: 4 hexanes: ethyl acetate) go up by chromatography purification oily matter, with tertbutyloxycarbonyl (3-cyano group-4-hydroxyl) the phenylformic acid hydrazides (1.8g, 56%) that the white solid form is provided.
1H?NMR(DMSO-D 6)：δ1.42(s，9H)，7.09(d，J＝8.7，1H)，7.98(m，1H)，8.11(br?s，1H)，8.92(s，1H)，10.15(s，1H)，11.73(brs，1H)；MS(APCl，neg)：276；IR：2232cm -1，CN。
Step e: (1.8g 6.5mmol) is suspended in the 50ml chloroform, and cools off with ice bath to make the Boc-hydrazides.Follow to stir to add trifluoroacetic acid, and the solution that is produced was left standstill under 0 ℃ 4 hours.TLC shows that reaction is completely.Remove by rotary evaporation and to desolvate and excessive TFA.By anti-phase liquid chromatography method (Aquasil C-18 post, the oily matter that the purifying of water/acetonitrile/0.1%TFA) is remaining.Obtain the title compound (0.24g, 13%) of white solid form.
1H?NMR(DMSO-D 6)：δ7.16(d，J＝9.0，1H)，8.00(dd，J＝1.5，9.0，1H)，8.14(d，J＝1.5，1H)，10.47(br?s，5H)；MS(APCl，neg)：176。
Preparation 4-hydroxynaphthoic acid hydrazides:
Figure A9880812501471
Steps A: (17g 0.1mol) is dissolved in the water (10ml), and (300ml 0.3mol) handles it with 1NNaOH with Silver Nitrate.Stirred formed brown precipitate thing 30 minutes, and supernatant decanted liquid.Water (3x) with additional volume washs brown silver suboxide.
In above-mentioned silver suboxide, and adding 1N NaOH (150ml) and 4-hydroxyl naphthalene aldehyde (1g, 6mmol).With mixture heating up to 70 ℃, kept this temperature 10 minutes, add thereafter in batches additional content the 4-hydroxyl naphthalene aldehyde (5.5g, 32mmol).Mixture was kept 16 hours down at 80 ℃.It is incomplete that the TLC analysis revealed transforms.Press the silver suboxide of additional part of as above method preparation, and it is added in the reaction mixture.After reheat mixture 6 hours, cooling mixture and with 1N HCl acidifying it.Extract the waterbearing stratum with ethyl acetate (3x), when concentrated, 4-hydroxynaphthoic acid (3.7g, 60%) is precipitated out in solution.
1H?NMR(DMSO-D 6)：δ6.69(d，1H)，7.28(t，1H)，7.39(t，1H)，7.93(d，1H)，8.03(d，1H)，8.82(d，1H)，10.82(s，1H)，12.29(s，1H)。
Step B: under 0 ℃, thionyl chloride (1.5 equivalent) is added in the 4-hydroxynaphthoic acid solution in anhydrous methanol.At room temperature after the stirred solution 16 hours, evaporating solvent.Use the up in ethyl acetate resistates, and with saturated aqueous carbonic acid hydrogen sodium, water, salt water washing, and at MgSO 4Last drying to produce 4-hydroxynaphthoic acid methyl esters.
1H?NMR(DMSO-D 6)：δ3.87(s，3H)，6.92(d，1H)，7.53(t，1H)，7.65(t，1H)，8.13(d，1H)，8.26(d，1H)，8.93(d，1H)，11.16(s，1H)。
Step C: according to synthetic precursor hydrazides A-(C=O)-NHNH 2Method, prepare title compound by 4-hydroxynaphthoic acid methyl esters.
1H?NMR(DMSO-D 6)：δ6.60(d，1H)，7.28(m，3H)，7.95(d，1H)，8.07(d，1H)，9.25(brd?s，1H)。
In addition, utilize aforesaid method, can prepare the following hydrazides that in the preparation method of The compounds of this invention, is used as intermediate:
Figure A9880812501481
Figure A9880812501491
The general method of the aromatic aldehyde that synthetic ether replaces:
Utilize various electrophilic alkylating agents (its often be called Williams ether synthetic (H.Feuer, J.Hooz, the ehter bond chemistry, S.Patai edit, Wiley, New York 1967, introducing is as defined above-(K) in the reaction p.446-460) m-D part), can prepare the aldehyde that ether connects by the alkylating corresponding phenolic compound of O-.
Scheme II
Figure A9880812501501
Wherein Lx be leavings group, as-Cl ,-Br ,-I ,-OSO 2CH 3,-OSO 2P-methylphenyl or-OSO 2CF 3And R 3a, R 3b, R 4a, R 4b, a, b, c, d, f, p, q, D, M, R 4And R 15With defined identical in the general formula I.
When existing 1-15 equivalent (being preferably the 1-5 equivalent) alkali (as sodium hydride, potassium hydride KH, methyl alcohol, ethanol or sodium tert-butoxide or potassium, yellow soda ash, potassium or caesium, Potassium monofluoride or caesium, sodium hydroxide or potassium) or organic bases (as diisopropylethylamine, 2,4,6-collidine or benzylidene dimethyl-methanol ammonium hydroxide or ammonium hydroxide) time, by stir organic solvent (as acetone, methyl ethyl ketone, dimethyl formamide diox, tetrahydrofuran (THF), toluene, ethylene glycol dimethyl ether, tetramethylene sulfone, diethyl ether, water two or the compatible blend of multiple above-mentioned solvent) in hydroxy benzaldehyde or the alkyl halide or the aromatic base-elementary alkyl halide of hydroxyl naphthalene aldehyde and equimolar amount, can prepare aromatic base-aldehyde that ether replaces according to scheme II.Reaction can be carried out under 0 ℃ to 150 ℃, is preferably 20 ℃-100 ℃, and preferably at inert atmosphere N 2Or carry out under the Ar.When reacting completely, filtering mixt concentrates it under vacuum, utilize ethyl acetate/hexane by column chromatography the product that is produced to be carried out the selectivity purifying as eluent on silica gel.Compound also can (suitably time) come purifying by the recrystallization in suitable solvent (as ethanol, ethyl acetate, Virahol, water, hexane, toluene or their compatible blend).The specific embodiment that the aromatic base-aldehyde for preparing ether-replacement is described is as follows.
Preparation 4-(2-tetrahydropyrans ylmethoxy)-1-naphthaldehyde:
60 ℃ stir down 4-hydroxyl naphthalene aldehyde in the dimethyl formamides (1g, 5.8mmol), 2-brooethyl tetrahydropyrans (1g, 5.8mmol) and powdered K 2CO 3(1.2g, one night of mixture 8.7mmol).Water and up in ethyl acetate mixture.Separate organic layer, and water, salt water washing, at MgSO 4Last dry, filter and concentrate it.Utilize ethyl acetate/hexane by the silica gel column chromatography purified product.
Figure A9880812501511
Preparation 4-[(3,5-pair-trifluoromethyl) benzyloxy]-the 1-naphthaldehyde:
In acetone (40ml), stir the 4-hydroxyl naphthalene aldehyde (1g, 5.8mmol), 3,5-is two-trifluoromethyl benzylidene bromide (1.8g, 5.8mmol) and powdered K 2CO 3(1.2g, one night of mixture 8.7mmol).Mixture is cast on the 200ml trash ice sheet, and stirs up to ice-out.Collect and dry yellow mercury oxide, i.e. 4-((3,5-pair-trifluoromethyl) benzyloxy)-1-naphthaldehyde.
Preparation 4-(2-chloroethoxy)-1-naphthaldehyde:
Be dissolved in N, the 4-hydroxyl-1-naphthaldehyde of dinethylformamide (DMF) in (40ml) (8.6g, 50mmol) and salt of wormwood (13.8g, in solution 100mmol), add 1-bromo-2-monochloroethane (7.4g, 50mmol).60 ℃ of one nights of following heated mixt.With ethyl acetate (500ml) diluting soln, water and saline water extraction.Dry organic layer and evaporating solvent are to obtain 12.1g product (52% productive rate) on sal epsom. Product is used for as further conversion.Use the aldehyde intermediate of the synthetic following replacement of aforesaid method:
Figure A9880812501522
M.p.:115-116 ℃ of 4-methoxycarbonyl methoxyl group-1-naphthaldehyde 4-benzyloxy-1-naphthaldehyde 4-(4-chlorine benzyloxy)-1-naphthaldehyde 4-allyloxy-1-naphthaldehyde
Figure A9880812501524
4-(4-trifluoromethoxy benzyloxy)-1-naphthaldehyde 4-alkynes propoxy--1-naphthaldehyde
Figure A9880812501531
4-(4-trifluoromethyl benzyloxy)-1-naphthaldehyde 2-[(4-carboxyl aldehyde)-and the 1-naphthyloxy] acetyl
Amine
M.p.174-175 ℃ 4-(3-trifluoromethyl benzyloxy)-1-naphthaldehyde 4-(2-(4-Trifluoromethoxyphen-l)-2-oxygen
Generation-oxyethyl group)-the 1-naphthaldehyde
M.p.112-114 ℃
Figure A9880812501533
4-(4-trifluoromethoxy benzyloxy)-3, m.p.142-143 ℃ of 5-two nicotinic acid 4-formyl radical-1-naphthyl ester methoxybenzaldehyde
Figure A9880812501534
4-(4-isopropyl benzyloxy)-3,5-dimethoxy 4-(1,3-dioxo-1, the different Yin benzaldehyde diindyl of 3-dihydro-2-ylmethoxy)-1-naphthaldehyde
M.p.191-192 ℃ 4-(4-isopropyl benzyloxy)-1-naphthaldehyde 4-(tetrahydrochysene-2-pyranyl methoxyl group)-1-naphthalene
Aldehyde M.p.100-101 ℃ of 4-(3,5-difluoro benzyloxy)-1-naphthaldehyde
Preparation 3-allyl group-4-hydroxy-5-methyl oxygen base-phenyl aldehyde
Figure A9880812501543
Vanillin in being dissolved in acetone (30ml) (1.0g, 6.57mmol) in the solution, add salt of wormwood (4.50g, 32.8mmol) and allyl bromide 98 (0.62ml, 7.3mmol).Under refluxad heated mixt is 6 hours.TLC shows: new spot occurs.By removing by filter sylvite, and with filtrate simmer down to soup compound.Utilize hexane/ethyl acetate 7: 3 as developping agent by preparation TLC purifying sample. 1H?NMR(CDCl 3)δ＝3.94(s，3H)，4.67-4.83(m，2H)，5.30-5.55(m，2H)，6.01-6.21(m，1H)，6.98(d，J＝9Hz，1H)，7.40-7.56(m，2H)，9.85(s，1H)；MS(APCl)：193.6。
Under 200 ℃, bathed the thick soup compound of even heating 6 hours with oily matter.With thick substance dissolves in chloroform, and by filtered through silica gel it.Crude product (productive rate 72%) is used for next step (being the O-alkylation).Utilize preparation TLC purifying aliquot product, to produce pure 3-allyl group-4-hydroxy-5-methyl oxygen base-phenyl aldehyde sample. 1H?NMR(CDCl 3)δ＝3.46(d，J＝6Hz，2H)，3.96(s，3H)，5.02-5.22(m，2H)，5.94-6.11(m，1H)，6.30(s，1H)，7.45(s，2H)，9.80(s，1H)；MS(APCl)：193.3。
Preparation 3-allyl group-4-(4-isopropyl benzyloxy)-5-methoxybenzaldehyde
With acetone 3-allyl group-4-hydroxy-5-methyl oxygen base-phenyl aldehyde crude product, and when having salt of wormwood, handle it, to produce required product with 4-isopropyl benzyl chlorine.
Figure A9880812501551
The general method of the compound of synthetic general formula I Xa and IXb:
Figure A9880812501552
In above-mentioned general formula, B, D, R 8And R 9Implication defined identical with general formula I.
Steps A: chloroacetyl chloride (1.2 equivalent) is dropped in aniline (or anils) (1 equivalent) solution in THF.At room temperature stir after the night, add 100ml water, and use the ethyl acetate extraction mixture.With dilute hydrochloric acid washing organic phase twice, wash twice with water, at MgSO 4Last dry, concentrate it then, to produce pure products.
Step B: salt of wormwood (1.5 equivalent) is added in chloroacetanilide (or derivatives thereof) (1.2 equivalent) in DMSO and 2-methoxyl group-4-hydroxy benzaldehyde (or another aromatic aldehyde that replaces with hydroxyl) (1 equivalent) solution.At room temperature stir after the night, add 100ml water.Use the ethyl acetate extraction mixture, wash organic extracting solution twice, wash twice with water with saturated sodium bicarbonate solution, and at MgSO 4Last drying.After under vacuum, concentrating, obtain product.
Embodiment as the compound that can utilize this method preparation has prepared two kinds of following aldehyde:
N-(4-chloro-phenyl-)-2-(4-formyl radical-3-methoxyl group phenoxy group) ethanamide:
N-(4-isopropyl phenyl)-2-(4-formyl radical-3-methoxyl group phenoxy group) ethanamide:
Utilize the described method of step D can make this class aldehyde and hydrazides coupling, thereby produce the compound of general formula I Xa.In addition, can be according to method as described below (step C), by reset these compounds with alkaline purification, subsequently with the compound of hydrazides coupling (step D) with generation general formula I Xb.
Step C: the mixture of aldehyde (1 equivalent) in the acetonitrile and salt of wormwood (1.5 equivalent) is refluxed.By TLC (hexane: ethyl acetate=2: 1) monitoring reaction.When the TLC demonstration transforms almost completely (about 48 hours), add 100ml water.Use the ethyl acetate extraction mixture, at MgSO 4Go up dry organic extracting solution, and concentrate it, producing required product, this product can be further by the column chromatography purifying or be directly used in next step.
Embodiment as the compound that can utilize this method preparation has prepared two kinds of following aldehyde:
4-(4-chlorobenzene amino)-2-methoxybenzaldehyde:
Utilize the method described in the above step C to prepare by N-(4-chloro-phenyl-)-2-(4-formyl radical-3-methoxyl group phenoxy group) ethanamide.
Figure A9880812501571
4-(4-isopropyl benzene amino)-2-methoxybenzaldehyde:
Utilize the method described in the above step C to prepare by N-(4-isopropyl phenyl)-2-(4-formyl radical-3-methoxyl group phenoxy group) ethanamide.
Figure A9880812501581
Step D: in solvent, handle the carbonyl compound that is produced with corresponding acyl group hydrazides.Solvent can be following a kind of: ethanol, methyl alcohol, Virahol, uncle-butanols, diox, tetrahydrofuran (THF), toluene, chlorobenzene, methyl-phenoxide, benzene, chloroform, methylene dichloride, DMSO, acetate, water or two or the compatible blend of multiple above-mentioned solvent.Can add catalyzer (as acetate).In reaction mixture, also can add dehydrated reagent (as triethyl orthoformate).Preferably at inert atmosphere N 2Or under the Ar, under 0 ℃ of-140 ℃ of temperature (being preferably 10 ℃-80 ℃), react by stirred reaction mixture.In many cases, product just crystallizes out simply when reaction is finished, and can be separated by suction filtration.If necessary, the reaction solvent that can also as above state from solvent of product recrystallization further.Also can utilize solvent systems (as chloroform/methanol or methylene chloride or chloroform/ethyl acetate) on silica gel, to come separated product subsequently, to produce the compound of general formula I Xb by concentrated reaction mixture under vacuum by column chromatography.
Embodiment as the compound that can utilize this method preparation prepares the following compounds according to general formula I Xa of the present invention or IXb:
Embodiment 1:3-chloro-4-hydroxy-benzoic acid [4-(4-chlorobenzene amino)-2-methoxyl group benzylidene] hydrazides
Figure A9880812501582
1H NMR (DMSO-D6): δ 3.81 (s, 3H), 6.72-6.67 (m, 2H), 7.04 (d, J=8.5Hz, 1H), 7.17 (d, J=8.7Hz, 2H) 7.31 (d, J=8.7Hz, 2H), 7.77-7.70 (m, 2H), 7.96 (d, J=1.6Hz, 1H), 8.65 (s, 1H), 8.70 (s, 1H), 10.87 (s, 1H), 11.51 (s, 1H); MS (APCl): 430.
Embodiment 2:3-chloro-4-hydroxy-benzoic acid [4-(4-isopropyl benzene amino)-2-methoxyl group benzylidene] hydrazides
Figure A9880812501591
1H NMR (DMSO-D 6): δ 1.18 (2s, 6H), 2.86 (m, 1H), 3.79 (s, 3H), 6.65 (m, 2H), 7.03 (d, 1H), 7.11 (d, 2H), 7.19 (d, 2H), 7.70 (d, 1H), 7.75 (dd, 1H), 7.97 (s, 1H), 8.49 (s, 1H), 8.64 (s, 1H), 10.88 (s, 1H), 11.48 (s, 1H); MS (FAB): 438.16.
Embodiment 3:2-{4-[(3-chloro-4-hydroxy benzoyl) hydrazono-methyl]-3-methoxyl group phenoxy group }-N-(4-chloro-phenyl-) ethanamide 1H NMR (DMSO-D 6): δ 3.66 (s, 3H), 4.57 (s, 2H), 6.48 (d, 1H), 6.55 (s, 1H), 6.83 (d, 1H), 7.20 (d, 2H), 7.48 (d, 2H), 7.56 (dd, 1H), 7.58 (d, 1H), 7.77 (d, 1H), 8.48 (s, 1H), 10.05 (s, 1H), 10.72 (brd s, 1H), 11.40 (s, 1H); MS (APCl): 487.8.
Embodiment 4:2-{4-[(3-chloro-4-hydroxy benzoyl) hydrazono-methyl]-3-methoxyl group phenoxy group }-N-(4-isopropyl phenyl) ethanamide 1H NMR (DMSO-D 6): δ 1.17 (2s, 6H), 2.85 (m, 1H), 3.87 (s, 3H), 4.76 (s, 2H), 6.70 (d, 1H), 6.76 (d, 1H), 7.05 (d, 1H), 7.20 (d, 2H), 7.55 (d, 2H), 7.77 (dd, 1H), 7.80 (d, 1H), 7.98 (s, 1H), 8.70 (s, 1H), 10.03 (s, 1H), 10.92 (s, 1H), 11.62 (s, 1H); MS (FAB): 496.16.
Embodiment 5:2-{4-[(3-chloro-4-hydroxy benzoyl) hydrazono-methyl]-3-methoxyl group phenoxy group }-N-(3, the 5-dichlorophenyl) ethanamide
Figure A9880812501601
1H NMR (DMSO-D 6): δ 4.06 (s, 3H), 4.94 (s, 2H), 6.8 (d, 1H), 6.88 (s, 1H), 7.20 (d, 1H), 7.45 (s, 1H), 7.90 (m, 3H), 8.10 (s, 1H), 8.82 (s, 1H), 10.62 (s, 1H), 11.07 (brd s, 1H), 11.75 (s, 1H); MS (APCl): 524.8.
Synthesize general method according to the alkylidene group hydrazides of general formula I I of the present invention:
In solvent, handle the acyl group hydrazides with corresponding carbonyl compound (as aldehydes or ketones).Solvent can be following a kind of: ethanol, methyl alcohol, Virahol, the trimethyl carbinol, diox, tetrahydrofuran (THF), toluene, chlorobenzene, methyl-phenoxide, benzene, chloroform, methylene dichloride, DMSO, acetate, water or two or the compatible blend of multiple above-mentioned solvent.Preferably at inert atmosphere N 2Or under the Ar, under 0 ℃ of-140 ℃ of temperature (being preferably 10 ℃-80 ℃), react by stirred reaction mixture.In many cases, product just crystallizes out simply when reaction is finished, and can be separated by suction filtration.If necessary, can be further in solvent (as above-mentioned reaction solvent) recrystallization go out product.Also can utilize solvent systems (as chloroform/methanol or methylene chloride or chloroform/ethyl acetate) on silica gel, to come separated product subsequently by concentrated reaction mixture under vacuum by column chromatography.By being carried out vacuum concentration, suitable component comes separated product.Illustrate that preparation is as follows according to the specific embodiment of the method for compound of the present invention.
Embodiment 6:3-chloro-4-hydroxy-benzoic acid (4-hydroxyl-1-naphthyl methylene radical) hydrazides
Figure A9880812501602
The glacial acetic acid (5) of 4-hydroxyl naphthalene aldehyde and catalytic amount is added to 3-chloro-4-hydroxy-benzoic acid hydrazides in DMSO (2ml), and (200mg is 1.1mmol) in the solution.One night of stirring reaction under nitrogen, and dilute it with ethyl acetate.With saturated sodium bicarbonate, water, salt solution washing soln, and at MgSO 4Last drying.Under vacuum, concentrate organic moiety, to produce crude product.Utilize CH 3Cl 2/ MeOH is as moving phase, by the silica gel column chromatography purified product.
1H?NMR(DMSO-D 6)：δ6.89(d，2H)，7.02(d，1H)，7.47(t，1H)，7.58(t，1H)，7.66(d，1H)，7.73(d，1H)，7.93(s，1H)，8.17(d，1H)，8.84(s，1H)，8.88(d，1H)，10.73(s，1H)，10.88(s，1H)，11.54(s，1H)；MS(ESI)；m/z?341.04(M+H) +。
Embodiment 7:3-chloro-4-hydroxy-benzoic acid [4-(3,5-couple-trifluoromethyl benzyloxy)-1-naphthyl methylene radical] hydrazides
With 4-(3,5-is two-trifluoromethyl benzyloxy)-1-naphthaldehyde (440mg, 1.1mmol) and the glacial acetic acid (5) of catalytic amount be added to 3-chloro-4-hydroxy-benzoic acid hydrazides in DMSO (2ml) (200mg be 1.1mmol) in the solution.One night of stirring reaction under nitrogen, and dilute it with ethyl acetate.With saturated sodium bicarbonate, water, salt solution washing soln, and at MgSO 4Last drying.Under vacuum, concentrate organic moiety, to produce crude product.Utilize CH 3Cl 2/ MeOH is as moving phase, by the silica gel column chromatography purified product.
1H NMR (DMSO-D 6): δ 3.77 (s, 6H), 4.91 (s, 2H), 6.95 (s, 2H), 6.99 (d, 1H), 7.30 (d, 2H), 7.52 (d, 2H), 7.68 (m, 1H), 7.89 (s, 1H), 8.29 (s, 1H), 10.90 (wide unimodal, 1H), 11.69 (s, 1H); MS (ESI): m/z 525.37 (M+H) +
Embodiment 8:3-chloro-4-hydroxy-benzoic acid [4-(2-chloroethoxy)-1-naphthyl methylene radical] hydrazides
At room temperature stir 1-(4-chloroethoxy) naphthaldehyde (2.35g, 10mmol), 3-chloro-4-hydroxy-benzoic acid hydrazides (1.87g, 10mmol), glacial acetic acid (0.2ml) and dimethyl sulfoxide (DMSO) (DMSO) (15ml) one night of solution.Add ethyl acetate (100ml).Water and saline water extraction solution, this process cause precipitation to produce.Obtain product (3.1g, 77% productive rate) by suction filtration.Come purified product by the recrystallization in ethyl acetate.
MS(Cl)：235。 1H?NMR(DMSO-D 6)：δ11.5(s，1H)，10.7(s，1H)，8.7(bs，2H)，8.1(m，1H)，7.8(s，1H)，7.6-7.3(m，2H)，7.0(m，2H)，4.3(t，2H)，3.7(t，2H)。
Use aforesaid method, use following general method to synthesize following compounds of the present invention:
1mmol carbonyl compound (aldehydes or ketones) is added in the 1mmol aromatic base carboxylic acid hydrazides solution in the anhydrous DMSO of 2ml, adds the glacial acetic acid of catalytic amount subsequently.One night of stirring reaction under nitrogen, and dilute it with ethyl acetate.With saturated sodium bicarbonate, water, salt water washing organic layer, and at MgSO 4Last dry.When at vacuum lower section concentrated solvent, the alkylidene group hydrazides precipitates usually.Be further purified the alkylidene group hydrazides by the recrystallization in hot ethanol or ethyl acetate, or utilize CH 2Cl 2/ MeOH carries out chromatogram as eluent.
Embodiment 9:4-hydroxy 3-methoxybenzene formic acid (2-naphthyl methylene radical) hydrazides 1H NMR (DMSO-d 6) δ 3.66 (s, 3H), 6.67 (d, J=8.2Hz, 1H), 7.32-7.47 (m, 5H), 7.74 (d, J=7.2Hz, 1H), 7.79 (d, J=8.2Hz, 2H), 8.60 (d, J=8.2Hz, 1H), 9.11 (s, 1H), 11.80 (s, 1H) .APCl m/z:321
Embodiment 10:4-hydroxy 3-methoxybenzene formic acid (4-methoxyl group-1-naphthyl methylene radical) hydrazides
Figure A9880812501631
1H NMR (CDCl 3): δ 4.80 (s, 3H), 3.86 (s, 3H), 6.00 (s, 1H), 6.59 (d, 1H), 6.83 (d, 1H), 7.39 (m, 3H), 7.52 (s, 1H), 7.73 (s, 1H), 8.18 (d, 1H), 8.58 (d, 1H), 8.88 (s, 1H), 9.95 (s, 1H) .MS (APCl): 351.
Embodiment 11:4-hydroxy 3-methoxybenzene formic acid (4-tertiary butyl benzylidene) hydrazides 1H NMR (CDCl 3): δ 1.30 (s, 9H), 3.91 (s, 3H), 6.16 (s, 1H), 6.88 (d, 1H), 7.23-7.78 (m, 6H), 8.28 (s, 1H), 9.58 (s, 1H) .MS (APCl): 327.
Embodiment 12:4-hydroxy 3-methoxybenzene formic acid (4-sec.-propyl benzylidene) hydrazides 1H NMR (CDCl 3) δ 1.29 (d, 6H), 2.94 (q, 1H), 3.98 (s, 3H), 6.13 (s, 1H), 6.97 (d, 1H), 7.20-7.80 (m, 6H), 8.29 (s, 1H), 9.38 (s, 1H) .MS (APCl): 313
Embodiment 13:4-hydroxy 3-methoxybenzene formic acid (4-trifluoromethoxy benzylidene) hydrazides
Figure A9880812501641
1H NMR (DMSO-d 6): δ 4.01 (s, 3H), 7.04 (d, J=8.1Hz, 1H), 7.60-7.65 (m, 4H), 8.01 (d, J=8.4Hz, 2H), 8.63 (s, 1H), 9.92 (s, 1H), 11.89 (s, 1H) .MS (APCl): 355,313,222,205.
Embodiment 14:4-hydroxy 3-methoxybenzene formic acid (1H-indol-3-yl methylene radical) hydrazides 1H NMR (DMSO-d 6) δ 3.79 (s, 3 H), 6.80 (d, J=8.2Hz, 1H), 7.11 (m, 2H), 7.38 (m, 3H), 7.73 (d, J=2.0Hz, 1H), 8.53 (d, J=7.5Hz, 1H), 8.53 (s, 1H), 9.58 (s, 1H), 11.23 (s, 1H), 11.49 (s, 1H) .MS (APCl): 310.
Embodiment 15:4-hydroxy 3-methoxybenzene formic acid (4-dimethylamino-1-naphthyl methylene radical) hydrazides 1H NMR (DMSO-d 6): δ 3.05 (s, 6H), 4.03 (s, 3H), 7.06 (d, J=8.1Hz, 1H), 7.33 (d, J=8.0Hz, 1H), 7.63-7.80 (m, 4H), 7.97 (d, J=8.0Hz, 1H), 8.38 (d, J=7.9Hz, 1H), 9.10 (d, J=8.4Hz, 1H), 9.15 (s, 1H), 9.90 (s, 1H), 11.73 (s, 1H) .MS (APCl): 364.
Embodiment 16:4-hydroxy 3-methoxybenzene formic acid (4-phenyl benzylidene) hydrazides
Figure A9880812501651
1H NMR (DMSO-d 6): δ 4.02 (s, 3H), 7.04 (d, J=8.2Hz, 1H), 7.63-7.68 (m, 5H), 7.88-7.96 (m, 6H), 8.64 (s, 1H), 9.91 (s, 1H), 11.83 (s, 1H) .MS (APCl): 347.
Embodiment 17:4-hydroxy-benzoic acid (1-naphthyl methylene radical) hydrazides
Figure A9880812501652
1H NMR (DMSO-d 6): δ 6.82 (d, J=8.2Hz, 2H), 7.48-7.68 (m, 3H), 7.72-7.88 (m, 3H), 7.95 (d, J=8.2Hz, 2H), 8.80 (d, 1H), 9.04 (s, 1H), 0.14 (s, 1H) .MS (APCl): 291.
Embodiment 18:4-hydroxy-benzoic acid (4-methoxyl group-1-naphthyl methylene radical) hydrazides
Figure A9880812501653
1H NMR (DMSO-d 6): δ 3.97 (s, 3H), 6.82 (d, J=8.6Hz, 2H), 7.04 (d, J=8.2Hz, 1H), 7.52 (dd, J=7.3,7.7Hz, 1H), 7.62 (dd, J=6.8,7.7Hz, 1H), 7.77 (d, J=8.5Hz, 3H), 8.19 (d, J=8.2Hz, 1H), 8.89 (m, 2H), 10.06 (s, 1H) .MS (APCl): 321.
Embodiment 19:3,4-resorcylic acid (1-naphthyl methylene radical) hydrazides 1H NMR (DMSO-d 6): δ 6.64 (d, J=8.6Hz, 1H), 7.13 (d, J=8.2Hz, 1H), 7.19 (d, J=2.0Hz, 1H), 7.36-7.42 (m, 3H), 7.68 (d, J=8.2Hz, 1H), 7.80 (d, J=8.2Hz, 2H), 8.65 (d, J=8.2Hz, 1H), 8.88 (s, 1H), 9.07 (s, 1H), 9.46 (s, 1H), 11.45 (s, 1H) .MS (APCl): 307.
Embodiment 20:4-hydroxy 3-methoxybenzene formic acid (1-naphthyl methylene radical) hydrazides
Figure A9880812501662
1H NMR (DMSO-d 6) δ 3.94 (s, 3H), 6.74 (d, 1H), 7.37-7.52 (m, 6H), 7.77 (d, 1H), 7.89 (d, 2H), 6.67 (d, 1H), 9.93 (s, 1H), 10.90 (s, 1H) .MS (APCl): 321.
Embodiment 21:4-hydroxy 3-methoxybenzene formic acid [3-(3-4-trifluoromethylphenopendant) benzylidene] hydrazides
Figure A9880812501663
(s, 3H), 6.85 (d, 1H), 7.16 (dd, 1H), 7.36 (m, 5H), 7.44 (m, 3H), 7.61 (t, 1H), 8.43 (s, 1H), 1.75 (s, 1H), 11.69 (s, 1H) .MS (APCl): 431.
Embodiment 22:4-hydroxy 3-methoxybenzene formic acid (4-quinolyl methylene radical) hydrazides 1H NMR (DMSO-d 6): δ 3.58 (s, 3H), 6.52 (d, J=8.0Hz, 1H), 7.28 (d, J=7.8Hz, 2H), 7.47 (dd, J=J '=8.1Hz, 1H), 7.59 (m, 2H), 7.86 (d, J=8.4Hz, 1H), 8.50 (d, J=8.4Hz, 1H), 8.73 (d, J=4.5Hz, 1H), 8.94 (s, 1H) .MS (APCl): 322.
Embodiment 23:4-hydroxy-benzoic acid [3-(1,1,2,2-tetrafluoro oxyethyl group) benzylidene] hydrazides
Figure A9880812501672
1H NMR (DMSO-d6) δ 6.49-6.78 (m, 3H), 7.10 (d, 1H), 7.32 (t, 1H), 7.41 (m, 2H), 7.57 (d, 2H), 8.23 (s, 1H), 10.01 (s, 1H), 11.59 (s, 1H) .MS (APCl): 357.
Embodiment 24:4-hydroxy-benzoic acid [3-(4-tert-butyl-phenyl)-2-butylidene] hydrazides
Figure A9880812501673
1H NMR (DMSO-d 6) δ 1.15 (s, 9H), 1.99 (s, 3H), 6.64 (s, 1H), 6.17 (d, 2H), 7.29 (s, 4H), 7.64 (d, 2H), 8.06 (s, 1H), 9.98 (s, 1H), 11.36 (s, 1H) .MS (APCl): 337.
Embodiment 25:4-hydroxy 3-methoxybenzene formic acid (4-hydroxyl-1-naphthyl methylene radical) hydrazides δ 3.90 (s, 3H), 6.89 (d, 1H), 6.99 (d, 1H), 7.19 (d, 1H), 7.45-7.80 (m, 5H), 8.22 (d, 1H), 8.90 (s, 2H), 9.62 (s, 1H), 10.68 (s, 1H) .MS (APCl): 337.
Embodiment 26:4-hydroxy-benzoic acid (benzylidene) hydrazides 1H NMR (DMSO-d 6): δ 6.86 (d, 2H), 7.41-7.52 (m, 3H), 7.72 (m, 2H), 7.82 (d, 2H), 8.41 (s, 1H), 10.14 (s, 1H) .MS (APCl): 241.
Embodiment 27:3-amino-4-hydroxy phenylformic acid (1-naphthyl methylene radical) hydrazides
Figure A9880812501683
1H NMR (DMSO-d 6): δ 4.71 (bs, 2H), 6.68 (d, J=8.1Hz, 1H), 7.01 (dd, J=2.0,8.2Hz, 1H), 7.17 (d, J=2.0Hz, 1H), 7.51-7.62 (m, 3H), 7.84 (d, J=7.2Hz, 1H), 7.94 (d, J=8.0Hz, 2H), 8.75 (d, J=7.6Hz, 1H), 9.01 (s, 1H), 9.70 (s, 1H), 11.54 (s, 1H) .MS (APCl): 306.
Embodiment 28:3-amino-4-hydroxy phenylformic acid (4-hydroxyl-1-naphthyl methylene radical) hydrazides
Figure A9880812501691
1H NMR (DMSO-d 6): δ 4.68 (bs, 2H), 6.67 (d, J=8.2Hz, 1H), 6.91 (d, J=7.3Hz, 1H), 7.03 (d, J=8.2Hz.1H), 7.15 (s, 1H), 7.43-7.65 (m, 3H), 8.16 (d, J=8.2Hz, 1H), 8.83 (m, 2H), 10.71 (s, 1H), 11.34 (s, 1H) .MS (APCl): 322.
Embodiment 29:4-hydroxy-benzoic acid [3-(3-trifluoromethyl benzyloxy) benzylidene] hydrazides
Figure A9880812501692
1H NMR (DMSO-d 6): δ 5.28 (s, 2H), 6.88 (d, 2H), 7.12 (m, 1H), 7.24-7.50 (m, 3H), 7.55-7.92 (m, 6H), 8.41 (s, 1H), 10.16 (s, 1H), 10.86 (s, 1H) .MS (APCl): 415.
Embodiment 30:3-chloro-4-hydroxy-benzoic acid (1-naphthyl methylene radical) hydrazides
Figure A9880812501693
1H NMR (DMSO-d 6): δ 7.03 (d, J=8.2Hz, 1H), 7.52-7.62 (m, 3H), 7.74 (d, J=8.2Hz, 1H), 7.86 (d, J=7.0Hz, 1H), 7.96 (m, 3H), 8.79 (d, J=8.2Hz, 1H), 9.01 (s, 1H), 10.94 (s, 1H), 11.76 (s, 1H) .MS (APCl): 325.
Embodiment 31:3-chloro-4-hydroxy-benzoic acid (4-hydroxyl-1-naphthyl methylene radical) hydrazides
Figure A9880812501701
1H NMR (DMSO-d 6): δ 6.90 (d, J=8.0Hz, 1H), 7.02 (d, J=8.5Hz, 1H), 7.50 (dd, J=J '=7.8Hz, 1H), 7.58 (dd, J=7.1,8.0Hz, 1H), 7.65 (d, J=8.0Hz, 1H), 7.72 (d, J=8.5Hz, 1H), 7.93 (s, 1H), 8.17 (d, J=8.2Hz, 1H), 8.83 (s, 1H), 8.88 (d, J=8.5Hz, 1H), 10.73 (s, 1H), 10.88 (s, 1H), 11.54 (s, 1H) .MS (APCl): 343,341.
Embodiment 32:4-hydroxy-benzoic acid (4-hydroxyl-1-naphthyl methylene radical) hydrazides 1H NMR (DMSO-d 6): δ 6.88 (d, 2H), 6.98 (d, 1H), 7.55 (dd, 1H), 7.64 (dd, 1H), 7.71 (d, 1H), 7.82 (d, 2H), 8.22 (d, 1H), 8.94 (m, 2H), 10.11 (s, 1H), 10.77 (s, 1H) .MS (APCl): 307.
Embodiment 33:4-hydroxy-benzoic acid [4-(3-4-trifluoromethylphenopendant) benzylidene] hydrazides
Figure A9880812501703
1H NMR (DMSO-d 6): δ 6.81 (d, 2H), 6.98 (d, 1H), 7.13 (dd, 1H), 7.30-7.48 (m, 3H), 7.48-7.60 (m, 3H), 7.68 (dd, 1H), 7.81 (d, 2H), 8.41 (s, 1H) .MS (APCl): 401.
Embodiment 34:4-hydroxy-benzoic acid (5-phenyl-3-pyrazolyl methylene radical) hydrazides
Figure A9880812501711
1H NMR (DMSO-d 6): δ 6.81 (d, 2H), 7.40-7.62 (m, 5H), 7.78 (d, 2H), 8.09 (s, 1H), 8.50 (s, 1H) .MS (APCl): 307.
Embodiment 35:
2,4-resorcylic acid (4-hydroxyl-1-naphthyl methylene radical) hydrazides
Figure A9880812501712
1H NMR (DMSO-d 6): 6.35 (s, 1H), 6.39 (d, 1H), 6.99 (d, 1H), 7.51 (dd, 1H), 7.65 (dd, 1H), 7.73 (d, 1H), 7.82 (d, 1H), 8.26 (d, 1H), 8.88 (s, 1H), 8.98 (d, 1H), 10.0-11.0 (m, 4H) .MS (APCl): 323.
Embodiment 36:4-hydroxyl-3-nitrobenzoic acid (1-naphthyl methylene radical) hydrazides
Figure A9880812501713
1H NMR (DMSO-d 6): δ 6.15 (d, J=9.3Hz, 1H), 7.37-7.48 (m, 4H), 6.70 (d, J=7.1Hz, 1H), 7.78-7.82 (m, 2H), 8.29 (s, 1H), 8.43 (d, J=8.5Hz, 1H), 8.85 (s, 1H).
Embodiment 37:4-hydroxyl-3-nitrobenzoic acid (4-hydroxyl-1-naphthyl methylene radical) hydrazides
Figure A9880812501721
1H NMR (DMSO-d 6): δ 6.24 (d, J=9.3Hz, 1H), 6.83 (d, J=8.0Hz, 1H), 7.37-7.52 (m, 3H), 7.57 (d, J=8.0Hz, 1H), 8.10 (d, J=8.0Hz, 1H), 8.34 (s, 1H), 8.76 (s, 1H), 8.79 (s, 1H), 10.57 (s, 1H), 11.17 (m, 1H).
Embodiment 38:3,4-resorcylic acid (4-hydroxyl-1-naphthyl methylene radical) hydrazides 1H NMR (DMSO-d 6): δ 6.86 (d, 1H), 6.98 (d, 1H), 7.32 (d, 1H), 7.42 (s, 1H), 7.56 (dd, 1H), 7.63 (dd, 1H), 7.71 (d, 1H), 8.24 (d, 1H), 8.88 (s, 1H), 8.92 (m, 2H), 9.26 (s, 1H), 9.54 (s, 1H), 10.75 (s, 1H) .MS (APCl): 323.
Embodiment 39:4-hydroxy-benzoic acid (6-methoxyl group-2-naphthyl methylene radical) hydrazides 1H NMR (DMSO-d 6): δ 3.89 (s, 3H), 6.86 (d, J=8.6Hz, 2H), 7.22 (dd, J=2.3,8.9Hz, 1H), 7.37 (d, J=2.3Hz, 1H), 7.80-7.93 (m, 6H), 8.04 (s, 1H), 8.53 (s, 1H), 11.67 (s, 1H) .MS (APCl): 321.
Embodiment 40:3,5-two chloro-4-hydroxy-benzoic acids (4-hydroxyl-1-naphthyl methylene radical) hydrazides 1H NMR (DMSO-d 6): δ 6.98 (d, 1H), 7.58 (dd, 1H), 7.68 (dd, 1H), 7.78 (d, 1H), 8.02 (s, 2H), 8.27 (d, 1H), 8.90 (s, 1H), 8.96 (d, 1H), 10.81 (s, 1H), 10.98 (s, 1H), 11.67 (s, 1H) .MS (APCl): 375,377.
Embodiment 41:6-hydroxyl-2-naphthoic acid (4-hydroxyl-1-naphthyl methylene radical) hydrazides 1H NMR (DMSO-d 6): δ 6.04 (d, 2H), 6.33 (m, 1H), 6.62 (dd, 2H), 6.79 (dd, 2H), 7.06 (d, 2H), 7.44 (d, 2H), 8.27 (d, 2H), 8.39 (s, 2H).
Embodiment 42:4-hydroxy 3-methoxybenzene formic acid (9-ethyl-9H-3-carbazyl methylene radical) hydrazides
Figure A9880812501733
1H NMR (DMSO-d 6) δ 1.34 (t, J=7.0Hz, 3H), 3.88 (s, 3H), 4.47 (q, J=7.0Hz, 2H), 6.90 (d, J=8.0Hz, 1H), 7.25 (t, J=7.5Hz, 1H), 7.47-7.54 (m, 3H), 7.64 (d, J=8.2Hz, 1H), 7.69 (d, J=8.5Hz, 1H), 7.89 (d, J=8.5Hz, 1H), 8.24 (d, J=7.7Hz, 1H), 8.45 (s, 1H), 8.62 (s, and 1H) 9.62 (s, 1H), 11.51 (s, 1H) .MS (APCl): 388.
Embodiment 43:4-hydroxy 3-methoxybenzene formic acid [5-(3-chloro-phenyl-)-2-furyl methylene radical] hydrazides
Figure A9880812501741
1H NMR (DMSO-d 6): δ 3.93 (s, 3 H), 6.97 (d, J=8.2Hz, 1H), 7.14 (d, J=3.5Hz, 1H), 7.37 (d, J=3.5Hz, 1H), 7.48-7.63 (m, 4H), 7.84 (d, J=8.0Hz, 1H), 7.93 (s, 1H), 8.47 (s, 1H), 9.85 (s, 1H), 11.75 (s, 1H) .MS (APCl): 371.
Embodiment 44:3-chloro-4-hydroxy-benzoic acid (3-phenyl allylidene) hydrazides 1H NMR (DMSO-d 6): δ 7.00 (m, 3H), 7.22-7.40 (m, 3H), 7.57 (d, 2H), 7.69 (d, 1H), 7.89 (s, 1H), 8.12 (d, 1H), 11.0 (s, 1H), 12.0 (s, 1H) .MS (APCl): 301.
Embodiment 45:3-chloro-4-hydroxy-benzoic acid (4-allyloxy-1-naphthyl methylene radical) hydrazides 1H NMR (DMSO-d 6): δ 4.68 (m, 2H), 5.21 (d, 1H), 5.38 (d, 1H), 5.90-6.10 (m, 1H), 6.86 (dd, 2H), 7.42 (dd, 1H), 7.53 (dd, 1H), 7.67 (dd, 2H), 7.86 (s, 1H), 8.18 (d, 1H), 8.78 (s, 1H), 8.82 (d, 1H), 10.9 (s, 1H), 12.0 (s, 1H) .MS (APCl): 381.
Embodiment 46:3-chloro-4-hydroxy-benzoic acid (4-ethynyl methoxyl group-1-naphthyl methylene radical) hydrazides
Figure A9880812501751
1H NMR (DMSO-d 6): δ 3.60 (s, 1H), 5.06 (s, 2H), 6.99 (d, 1H), 7.12 (d, 1H), 7.55 (t, 1H), 7.66 (t, 1H), 7.73 (t, 1H), 7.93 (s, 1H), 8.02 (d, 1H), 8.16 (t, 1H), 8.86 (d, 1H), 9.27 (d, 1H), 10.90 (s, 1H), 11.62 (s, 1H) .MS (APCl): 378.
Embodiment 47:3-chloro-4-hydroxy-benzoic acid (4-benzyloxy-1-naphthyl methylene radical) hydrazides
Figure A9880812501752
1H NMR (DMSO-d 6): δ 5.40 (s, 2H), 7.08 (d, 1H), 7.08 (s, 1H), 7.39 (d, 1H), 7.43 (m, 3H), 7.70 (m, 5H), 8.00 (s, 1H), 8.01 (d, 1H), 8.33 (t, 1H), 8.94 (d, 1H), 9.35 (d, 1H), 10.98 (s, 1H), 11.69 (s, 1H) .MS (APCl): 431,433.
Embodiment 48:2-(4-[(3-chloro-4-hydroxy benzoyl) hydrazono-methyl]-the 1-naphthyloxy) ethanamide
Figure A9880812501753
1H NMR (DMSO-d 6): δ 4.68 (d, 2H), 6.94 (d, 1H), 6.98 (dd, 1H), 7.40-7.86 (m, 5H), 8.00 (m, 1H), 8.48 (dd, 1H), 8.93 (m, 1H), 9.38 (m, 1H) .MS (APCl): 398.
Embodiment 49:3-chloro-4-hydroxy-benzoic acid (4-methyl isophthalic acid-naphthyl methylene radical) hydrazides
Figure A9880812501761
1H NMR (DMSO-d 6): δ 2.70 (s, 3H), 7.10 (d, 1H), 7.49 (d, 1H), 7.67 (m, 2H), 7.81 (m, 2H), 8.00 (s, 1H), 8.11 (d, 1H), 8.88 (d, 1H), 9.07 (s, 1H), 11.0 (s, 1H) .MS (APCl): 339,341.
Embodiment 50:3-chloro-4-hydroxy-benzoic acid (2-hydroxyl-1-naphthyl methylene radical) hydrazides
Figure A9880812501762
1H NMR (DMSO-d 6): δ 6.98 (d, 1H), 7.98 (d, 1H), 7.29 (dd, 1H), 7.48 (dd, 1H), 7.69 (d, 1H), 7.78 (dd, 2H), 7.90 (s, 1H), 8.06 (d, 1H), 9.32 (s, 1H), 11.00 (s, 1H) .MS (APCl): 341.
Embodiment 51:3-chloro-4-hydroxy-benzoic acid (4-methoxyl group-1-naphthyl methylene radical) hydrazides
Figure A9880812501763
1H NMR (DMSO-d 6): δ 4.05 (s, 3H), 7.06 (m, 2H), 7.59 (dd, 1H), 7.70 (dd, 1H), 7.81 (d, 1H), 7.86 (d, 1H), 8.00 (s, 1H), 8.27 (d, 1H), 8.93 (s, 1H), 8.99 (d, 1H), 11.00 (s, 1H) .MS (APCl): 341,339.
Embodiment 52:N-(2-[(3-chloro-4-hydroxy benzoyl) hydrazono-] ethyl)-2,2-phenylbenzene ethanamide 1H NMR (DMSO-d 6) δ 3.85 (t, 2H), 4.93 (s, 2H), 7.16-7.25 (m, 10H), 7.26 (m, 1H), 7.62 (d, 1H), 7.82 (s, 1H), 8.69 (t, 1H), 10.85 (s, 1H), 11.39 (s, 1H) .MS (APCl): 422
Embodiment 53:3-chloro-4-hydroxy-benzoic acid (1-hydroxyl-2-naphthyl methylene radical) hydrazides
Figure A9880812501771
1H NMR (DMSO-d 6): δ 6.99 (d, 1H), 7.22 (d, 1H), 7.37-7.56 (m, 4H), 7.68 (dd, 1H), 7.77 (d, 1H), 7.90 (s, 1H), 8.19 (d, 1H), 8.58 (s, 1H), 11.00 (s, 1H) .MS (APCl): 341.
Embodiment 54:3-chloro-4-hydroxy-benzoic acid (2, the 2-diphenylethylene) hydrazides
Figure A9880812501772
1H NMR (DMSO-d 6): δ 4.94 (d, 1H), 6.98 (d, 1H), 7.11-7.22 (m, 5H), 7.22-7.34 (m, 4H), 7.68 (d, 1H), 7.82 (s, 1H), 8.19 (d, 1H), 11.00 (s, 1H) .MS (APCl): 365,367.
Embodiment 55:3-chloro-4-hydroxy-benzoic acid (4-benzyloxy-3,5-dimethoxybenzylidenegroup group) hydrazides 1H NMR (DMSO-d 6): δ 3.86 (s, 6H), 4.98 (s, 2H), 7.03 (s, 2H), 7.09 (d, 1H), 7.25-7.33 (m, 3H), 7.48 (m, 2H), 7.89 (dd, 1H), 7.99 (s, 1H), 8.32 (s, 1H), 11.00 (s, 1H) .MS (APCl): 441.
Embodiment 56:3-chloro-4-hydroxy-benzoic acid [3-(4-tert-butyl phenoxy group) benzylidene] hydrazides 1H NMR (DMSO-d 6): δ 1.05 (s, 9H), 6.90 (m, 3H), 7.09 (d, 1H), 7.30 (t, 1H), 7.40 (m, 3H), 7.69 (m, 2H), 7.88 (s, 1H), 8.44 (s, 1H), 10.60 (s, 1H), 11.55 (s, 1H) .MS (APCl): 423.
Embodiment 57:3-chloro-4-hydroxy-benzoic acid (4-methyl isophthalic acid-naphthyl methylene radical) hydrazides 1H NMR (DMSO-d 6): δ 2.64 (s, 3H), 7.03 (d, J=8.5Hz, 1H), 7.41 (d, J=7.4Hz, 1H), 7.58 (m, 2H), 7.78 (m, 2H), 7.95 (d, J=2.0Hz, 1H), 8.06 (dd, J=2.0,8.0Hz, 1H), 8.82 (d, J=8.0Hz, 1H), 9.07 (s, 1H), 10.93 (s, 1H), 11.71 (s, 1H) .MS (APCl): 337.339.
Embodiment 58:3-chloro-4-hydroxy-benzoic acid (3-bromo-4-hydroxyl-1-naphthyl methylene radical) hydrazides
Figure A9880812501783
1H NMR (CDCl 3): δ 7.02 (d, J=8.5Hz, 1H), 7.51-7.62 (m, 4H), 7.80 (dd, J=2.0,8.5Hz, 1H), 8.00 (d, J=2.0Hz, 1H), 8.21 (s, 1H), 8.59 (d, J=8.5Hz, 1H), 8.91 (s, 1H) .MS (APCl): 421,423.
Embodiment 59: hydrazono-methyl acetate 4-[(3-chloro-4-hydroxy benzoyl)]-1-naphthalene ester
Figure A9880812501791
1H NMR (DMSO-d 6): δ 2.63 (s, 3H), 7.03 (d, J=8.5Hz, 1H), 7.36 (d, J=8.0Hz, 1H), 7.60 (dd, J=7.0,7.5Hz, 1H), 7.68 (dd, J=7.0,8.0Hz, 1H), 7.75 (dd, J=1.4,8.0Hz, 1H), 7.89 (d, J=8.0Hz, 1H), 7.97 (d, J=8.0Hz, 2H), 8.85 (d, J=8.5Hz, 1H), 9.08 (s, 1H), 11.0 (s, 1H), 11.78 (s, 1H) .MS (APCl): 383.
Embodiment 60:3-chloro-4-hydroxy-benzoic acid (4-cyano group methoxyl group-1-naphthyl methylene radical) hydrazides
Figure A9880812501792
1H NMR (DMSO-d 6): δ 5.40 (s, 2H), 7.00 (d, 1H), 7.21 (d, 1H), 7.58-7.80 (m, 3H), 7.82 (d, 1H), 7.96 (s, 1H), 8.18 (d, 1H), 8.90 (s, 2H), 9.28 (s, 1H), 11.62 (s, 1H) .MS (APCl): 380,382.
Embodiment 61:3-chloro-4-hydroxy-benzoic acid (2-hydroxyl-1-naphthyl methylene radical] hydrazides
Figure A9880812501793
1H NMR (DMSO-d 6): δ 7.18 (d, 1H), 7.30 (d, 1H), 7.50 (dd, 1H), 7.68 (dd, 1H), 7.88 (d, 1H), 7.95 (m, 2H), 8.08 (s, 1H), 8.29 (d, 1H), 9.51 (s, 1H), 11.12 (s, 1H), 12.12 (s, 1H) .MS (APCl): 341,343.
Embodiment 62:3-chloro-4-hydroxy-benzoic acid (2,3-methylene radical dioxo benzylidene) hydrazides
Figure A9880812501801
1H NMR (DMSO-d 6): δ 6.06 (s, 2H), 6.86 (dd, 1H), 6.90 (dd, 1H), 7.01 (d, 1H), 7.25 (d, 1H), 7.71 (dd, 1H), 7.92 (s, 1H), 8.49 (s, 1H), 10.93 (s, 1H), 11.70 (s, 1H) .MS (APCl): 319,321.
Embodiment 63:3-chloro-4-hydroxy-benzoic acid [3-(4-methoxyl group phenoxy group) benzylidene] hydrazides
Figure A9880812501802
1H NMR (DMSO-d 6): δ 3.98 (s, 3H), 7.38 (m, 6H), 7.48 (s, 1H), 7.72 (m, 2H), 7.97 (d, 1H), 8.19 (s, 1H), 8.64 (s, 1H), 11.93 (s, 1H) .MS (APCl): 397,399.
Embodiment 64:3-chloro-4-hydroxy-benzoic acid (9-phenanthryl methylene radical) hydrazides
Figure A9880812501803
1H NMR (DMSO-d 6): δ 7.02 (d, 1H), 7.52-7.83 (m, 5H), 7.99 (d, 1H), 8.08 (d, 1H), 8.21 (s, 1H), 8.82 (d, 1H), 8.89 (dd, 1H), 8.96 (dd, 1H), 9.06 (s, 1H), 10.96 (s, 1H), 11.82 (s, 1H) .MS (APCl): 375,377.
Embodiment 65:3-chloro-4-hydroxy-benzoic acid [4-(2-hydroxyl-oxethyl)-1-naphthyl methylene radical] hydrazides
Figure A9880812501811
1H NMR (DMSO-d 6): δ 3.81 (t, J=4.8Hz, 2H), 4.16 (t, J=4.8Hz, 2H), 6.46 (d, J=8.5Hz, 1H), 7.01 (d, J=8.5Hz, 1H), and 7.51-7.61 (m, 3H), 7.72 (d, J=8.2Hz, 1H), 7.82 (d, J=2.1Hz, 1H), 8.30 (d, J=8.2Hz, 1H), 8.85 (s, 1H), 8.87 (d, J=8.5Hz, 1H), 11.38 (s, 1H) .MS (APCl): 385,387.
Embodiment 66:3-bromo-4-hydroxy-benzoic acid (4-hydroxyl-1-naphthyl methylene radical) hydrazides
Figure A9880812501812
1H NMR (DMSO-d 6): δ 6.90 (d, J=8.0Hz, 1H), 7.00 (d, J=8.0Hz, 1H), 7.47 (dd, J=J '=8.0Hz, 1H), 7.58 (dd, J=J "=8.0Hz, 1H); 7.66 (d, J=8.0Hz, 1H), 7.77 (dd, J=2.0,8.0Hz; 1H), 8.08 (d, J=2.0Hz, 1H), 8.17 (d, J=8.0Hz; 1H), 8.83 (s, 1H), 8.88 (d, J=8.0Hz, 1H); 10.73 (s, 1H), 11.53 (s, 1H) .MS (APCl): 385,387.
Embodiment 67: hydrazono-methyl nicotinic acid 4-[(3-chloro-4-hydroxy benzoyl)]-1-naphthalene ester 1H NMR (DMSO-d 6): δ 7.04 (d, J=8.5Hz, 1H), 7.58 (d, J=8.0Hz, 1H), and 7.64-7.69 (m, 4H), 7.74-8.02 (m, 3H), 8.56 (dd, J=2.0,8.0Hz, 1H), 8.91 (m, 2H), 9.05 (s, 1H), 8.35 (d, J=1.8Hz, 1H), 10.96 (s, 1H), 11.84 (s, 1H) .MS (APCl): 446,448.
Embodiment 68:3-chloro-4-hydroxy-benzoic acid [4-(1,3-dioxo-1,3-xylylenimine-2-ylmethoxy)-1-naphthyl-methylene radical] hydrazides
Figure A9880812501821
1H NMR (DMSO-d 6): δ 5.78 (s, 2H), 7.03 (d, J=8.5Hz, 1H), 7.37 (d, J=8.2Hz, 1H), 7.48 (m, 1H), 7.61 (m, 1H), 7.73-7.81 (m, 8H), 8.90 (m, 2H), 10.91 (s, 1H), 11.67 (s, 1H) .MS (APCl): 500,502.
Embodiment 69:3-chloro-4-hydroxy-benzoic acid [4-(cyclohexyl methoxyl group)-1-naphthyl methylene radical] hydrazides
Figure A9880812501822
1H NMR (DMSO-d 6): δ 1.08-1.19 (m, 4H), 1.66-1.72 (m, 3H), 1.83-1.92 (m, 3H), 3.21 (m, 1H), 3.95 (m, 2H), 6.99 (d, J=8.1Hz, 1H), 7.03 (d, J=8.5Hz, 1H), 7.53 (dd, J=J '=7.4Hz, 1H), 7.62 (dd, J=J '=7.5Hz, 1H), 7.72-7.93 (m, 2H), 7.94 (d, J=2.1Hz, 1H), 8.22 (d, J=8.0Hz, 1H), 8.87 (s, 1H), 8.90 (d, J=8.5Hz, 1H), 10.94 (s, 1H), 11.60 (s, 1H) .MS (APCl): 437,439.
Embodiment 70:3-chloro-4-hydroxy-benzoic acid [4-(tetrahydrochysene-2-pyranyl methoxyl group)-1-naphthyl methylene radical]-hydrazides 1H NMR (DMSO-d 6): δ 1.35 (m, 3H), 1.60-1.71 (m, 2H), 3.15-3.38 (m, 2H), 3.64 (m, 1H), 3.78 (m, 1H), 4.02 (m, 2H), 6.94 (d, J=8.5Hz, 2H), 7.46 (dd, J=J '=7.4Hz, 1H), 7.54 (dd, J=J '=8.2Hz, 1H), 7.66 (m, 2H), 7.86 (d, J=2.1Hz, 1H), 8.13 (d, J=8.0Hz, 1H), 8.78 (s, 1H), 8.83 (d, J=8.5Hz, 1H), 10.83 (s, 1H), 11.52 (s, 1H) .MS (APCl): 439,441.
Embodiment 71:3-chloro-4-hydroxy-benzoic acid [4-(3-pyridyl methoxyl group)-1-naphthyl methylene radical] hydrazides 1H NMR (DMSO-d 6): δ 5.28 (m, 2H), 6.94 (d, J=8.5Hz, 1H), 7.10 (d, J=8.5Hz, 1H), 7.34 (dd, J=4.8,7.8Hz, 1H), 7.45 (dd, J=J '=7.6Hz, 1H), 7.54 (dd, J=J '=7.5Hz, 1H), 7.66 (d, J=8.5Hz, 1H), 7.70 (d, J=8.2Hz, 1H), 7.86 (m, 2H), 8.15 (d, J=8.0Hz, 1H), 8.45 (dd, J=1.5,4.8Hz, 1H), 8.65 (s, 1H), 8.81 (m, 2H), 10.90 (s, 1H), 11.56 (s, 1H) .MS (APCl): 432,434.
Embodiment 72:4-[(3-chloro-4-hydroxy benzoyl) hydrazono-methyl]-the 1-naphthyloxy) ethyl acetate 1H NMR (DMSO-d 6): δ 1.25 (t, J=7.0Hz, 3H), 4.25 (q, J=7.0Hz, 2H), 5.11 (s, 2H), 7.06 (d, J=8.2Hz, 1H), 7.13 (d, J=8.5Hz, 1H), 7.64-7.70 (m, 2H), 7.76 (d, J=8.2Hz, 2H), 8.04 (d, J=2.1Hz, 1H), 8.36 (d, J=8.2Hz, 1H), 8.97 (s, 1H), 9.02 (d, J=8.5Hz, 1H), 11.01 (s, 1H), 11.74 (s, 1H) .MS (APCl): 427,429.
Embodiment 73:3-chloro-4-hydroxy-benzoic acid (3-nitro benzylidene) hydrazides
Figure A9880812501842
1H NMR (DMSO-d 6): δ 7.13 (d, J=8.5Hz, 1H), 7.79-7.86 (m, 2H), 8.03 (d, J=2.1Hz, 1H), 8.18 (d, J=7.5Hz, 1H), 8.30 (d, J=8.0Hz, 1H), 8.58 (s, 2H), 11.08 (s, 1H), 12.05 (s, 1H) .MS (APCl): 320,322.
Embodiment 74:3-chloro-4-hydroxy-benzoic acid (2, the 4-dichlorin benzylidene) hydrazides
Figure A9880812501843
1H NMR (DMSO-d 6): δ 7.02 (d, J=8.5Hz, 1H), 7.46 (d, J=8.2Hz, 1H), 7.66 (s, 1H), 7.73 (d, J=8.2Hz, 1H), 7.95 (m, 2H), 8.71 (s, 1H), 11.97 (s, 1H), 11.94 (s, 1H) .MS (APCl): 345.
Embodiment 75:3-chloro-4-hydroxy-benzoic acid (4-fluoro-1-naphthyl methylene radical) hydrazides
Figure A9880812501851
1H NMR (DMSO-d 6): δ 7.00 (d, J=8.5Hz, 1H), 7.33 (dd, J=8.2,10.3Hz, 1H), and 7.62-7.72 (m, 3H), 7.82 (m, 1H), 7.91 (d, J=1.9Hz, 1H), 8.04 (d, J=8.1Hz, 1H), 8.09 (m, 1H), 8.91 (s, 1H), 10.81 (s, 1H), 11.67 (s, 1H) .MS (APCl): 343.
Embodiment 76:3-fluoro-4-hydroxy-benzoic acid (4-hydroxyl-1-naphthyl methylene radical) hydrazides 1H NMR (DMSO-d 6): δ 6.90 (d, J=8.0Hz, 1H), 7.00 (t, J=8.6Hz, 1H), 7.44-7.72 (m, 6H), 8.17 (d, J=8.6Hz, 1H), 8.84 (s, 1H), 8.89 (d, J=8.5Hz, 1H), 10.60 (s, 1H), 11.50 (s, 1H) .MS (APCl): 325.
Embodiment 77:3-chloro-4-hydroxy-benzoic acid [4-(2,4-difluoro benzyloxy)-1-naphthyl methylene radical] hydrazides
Figure A9880812501853
1H NMR (DMSO-d 6): δ 5.33 (s, 2H), 7.03 (d, J=8.5Hz, 1H), 7.12 (m, 1H), 7.21 (d, J=8.2Hz, 1H), 7.31 (m, 1H), 7.52 (m, 1H), 7.54 (m, 1H), 7.69-7.80 (m, 3H), 7.94 (s, 1H), 8.16 (d, J=8.2Hz, 1H), 8.90 (m, 2H), 10.91 (s, 1H), 11.63 (s, 1H) .MS (APCl): 467,469.
Embodiment 78:3-fluoro-4-hydroxy-benzoic acid (1-naphthyl methylene radical) hydrazides MS (APCl): 309.
Embodiment 79:3-chloro-4-hydroxy-benzoic acid [4-(3-methoxyl group benzyloxy base)-1-naphthyl methylene radical] hydrazides
Figure A9880812501861
1H NMR (DMSO-d 6): δ 3.71 (s, 3H), 5.29 (s, 2H), 6.87 (d, J=8.5Hz, 1H), 7.00-7.14 (m, 4H), 7.29 (t, J=8.0Hz, 1H), 7.55 (m, 1H), 7.68 (m, 1H), 7.75 (m, 2H), 7.94 (d, J=2.0Hz, 1H), 8.25 (d, J=8.0Hz, 1H), 8.87 (s, 1H), 8.92 (d, J=8.5Hz, 1H), 11.00 (s, 1H), 11.62 (s, 1H) .MS (APCl): 461.
Embodiment 80:3-chloro-4-hydroxy-benzoic acid [4-(4-fluorine benzyloxy)-1-naphthyl methylene radical]
Figure A9880812501862
1H NMR (DMSO-d 6): δ 5.30 (s, 2H), 7.02 (d, J=8.5Hz, 1H), 7.13-7.25 (m, 3H), 7.53-7.60 (m, 4H), 7.79 (m, 2H), 7.94 (d, J=2.0Hz, 1H), 8.23 (d, J=8.0Hz, 1H), 8.88 (s, 1H), 8.92 (d, J=8.5Hz, 1H), 10.93 (s, 1H), 11.63 (s, 1H) .MS (APCl): 449,451.
Embodiment 81:3-chloro-4-hydroxy-benzoic acid [4-(2-tetrahydrofuran (THF) ylmethoxy)-1-naphthyl methylene radical] hydrazides
Figure A9880812501863
1H NMR (DMSO-d 6): δ 1.77-2.04 (m, 4H), 3.68 (m, 1H), 3.78 (m, 1H), 4.12-4.16 (m, 2H), 4.26 (m, 1H), 7.02 (d, J=8.5Hz, 1H), 7.04 (d, J=8.2Hz, 1H), 7.53 (m, 1H), 7.62 (m, 1H), 7.74 (m, 2H), 7.94 (d, J=2.0Hz, 1H), 8.20 (d, J=8.2Hz, 1H), 8.87 (s, 1H), 8.90 (d, J=8.5Hz, 1H), 10.93 (s, 1H), 11.61 (s, 1H) .MS (APCl): 425,427.
Embodiment 82:3-chloro-4-hydroxy-benzoic acid (3-bromo-4-methoxyl group-1-naphthyl methylene radical) hydrazides
Figure A9880812501871
1H NMR (DMSO-d 6): δ 3.91 (s, 3H), 7.03 (d, J=8.5Hz, 1H), 7.65-7.76 (m, 3H), 7.94 (d, J=2.0Hz, 1H), 8.02 (s, 1H), 8.12 (d, J=8.0Hz, 1H), 8.71 (d, J=8.0Hz, 1H), 8.95 (s, 1H), 10.96 (s, 1H), 11.85 (s, 1H) .MS (APCl): 433,435.
Embodiment 83:3-chloro-4-hydroxy-benzoic acid [4-(3-tetrahydrofuran (THF) ylmethoxy)-1-naphthalene naphthyl methylene radical] hydrazides
Figure A9880812501872
1H NMR (DMSO-d 6): δ 1.92 (m, 1H), 2.10 (m, 1H), 2.77 (m, 1H), 3.28-3.88 (m, 4H), 4.12 (m, 2H), 7.03 (d, J=8.5Hz, 1H), 7.04 (d, J=8.2Hz, 1H), 7.55 (m, 1H), 7.62 (m, 1H), 7.74 (d, J=8.5Hz, 1H), 7.76 (d, J=8.0Hz, 1H), 7.94 (d, J=2.0Hz, 1H), 8.20 (d, J=8.0Hz, 1H), 8.88 (s, 1H), 8.90 (d, J=8.5Hz, 1H), 10.91 (s, 1H), 11.63 (s, 1H) .MS (APCl): 425,427.
Embodiment 84:4-[4-[3-chloro-4-hydroxy benzoyl) hydrazono-methyl]-1-naphthyloxy methyl) methyl benzoate
Figure A9880812501881
1H NMR (DMSO-d 6): δ 3.80 (s, 3H), 5.43 (s, 2H), 7.03 (d, J=8.5Hz, 1H), 7.12 (d, J=8.2Hz, 1H), 7.54 (m, 1H), 7.57 (d, J=8.0Hz, 4H), 7.93-7.99 (m, 3H), 8.30 (d, J=8.0Hz, 1H), 8.87 (s, 1H), 8.93 (d, J=8.5Hz, 1H), 10.91 (s, 1H), 11.63 (s, 1H) .MS (APCl): 489,491.
Embodiment 85:3-chloro-4-hydroxy-benzoic acid [3,5-dimethoxy-4 '-(4-trifluoromethoxy benzyloxy) benzylidene] hydrazides 1H NMR (DMSO-d 6): δ 3.76 (s, 6H), 4.91 (s, 2H), 6.95-7.00 (m, 3H), 7.30 (d, J=8.2Hz, 2H), 7.52 (d, J=8.5Hz, 2H), 7.68 (d, J=2.0,8.5Hz, 1H), 7.88 (s, 1H), 8.29 (s, 1H), 10.91 (s, 1H), 11.69 (s, 1H) .MS (APCl): 525,527.
Embodiment 86:3-chloro-4-hydroxy-benzoic acid [4-(4-trifluoromethoxy benzyloxy)-1-naphthyl methylene radical]-hydrazides
Figure A9880812501883
1H NMR (DMSO-d 6): δ 5.36 (s, 2H), 7.02 (d, J=8.4Hz, 1H), 7.14 (d, J=8.2Hz, 1H), 7.39 (d, J=8.2Hz, 2H), 7.56 (m, 1H), 7.62 (m, 3H), 7.76 (m, 2H), 7.94 (d, J=2.0Hz, 1H), 8.26 (d, J=8.3Hz, 1H), 8.88 (s, 1H), 8.93 (d, J=8.5Hz, 1H), 10.91 (s, 1H), 11.63 (s, 1H) .MS (APCl): 515,517.
Embodiment 87:3-chloro-4-hydroxy-benzoic acid [4-(2-methoxyl group benzyloxy base)-1-naphthyl methylene radical] hydrazides 1H NMR (DMSO-d 6): δ 3.79 (s, 3H), 5.27 (s, 2H), 6.95 (m, 1H), 7.03 (d, J=8.5Hz, 1H), 7.04 (d, J=8.2Hz, 1H), 7.13 (d, J=8.5Hz, 1H), 7.31 (m, 1H), 7.46-7.53 (m, 2H), 7.61 (m, 1H), 7.76 (m, 2H), 7.94 (d, J=2.0Hz, 1H), 8.22 (d, J=8.3Hz, 1H), 8.88 (s, 1H), 8.92 (d, J=8.5Hz, 1H), 10.90 (s, 1H), 11.62 (s, 1H) .MS (APCl): 461,463.
Embodiment 88:3-chloro-4-hydroxy-benzoic acid [4-(2-fluorine benzyloxy)-1-naphthyl methylene radical] hydrazides 1H NMR (DMSO-d 6): δ 5.36 (s, 2H), 7.03 (d, J=8.5Hz, 1H), 7.19-7.28 (m, 3H), 7.39 (m, 1H), 7.53 (m, 1H), 7.63 (m, 2H), 7.72-7.80 (m, 2H), 7.94 (d, J=2.1Hz, 1H), 8.19 (d, J=8.3Hz, 1H), 8.88 (s, 1H), 8.92 (d, J=8.5Hz, 1H), 10.90 (s, 1H), 11.64 (s, 1H) .MS (APCl): 449,451.
Embodiment 89:3-chloro-4-hydroxy-benzoic acid [4-(2,6-difluoro benzyloxy)-1-naphthyl methylene radical] hydrazides
Figure A9880812501893
1H NMR (DMSO-d 6): δ 5.34 (s, 2H), 7.03 (d, J=8.5Hz, 1H), 7.16 (d, J=8.2Hz, 1H), 7.18 (d, J=8.0Hz, 1H), 7.27 (d, J=8.2Hz, 1H), 7.51 (m, 2H), 7.72 (m, 1H), 7.74 (d, J=8.0Hz, 1H), 7.78 (d, J=8.0Hz, 1H), 7.94 (d, J=2.1Hz, 1H), 8.03 (d, J=8.3Hz, 1H), 8.89 (s, 1H), 8.91 (d, J=8.5Hz, 1H), 10.97 (s, 1H), 11.65 (s, 1H) .MS (APCl): 467,469.
Embodiment 90:4-hydroxy 3-methoxybenzene formic acid [3,5-dimethoxy-4 '-(5,5,8,8-tetramethyl--5,6,7,8-naphthane-1-ylmethoxy) benzylidene] hydrazides 1H NMR (DMSO-d 6): δ 1.2 (s, 12H), 1.63 (s, 4H), 3.82 (s, 6H), 3.85 (s, 3H), 4.90 (s, 2H), 6.88 (d, 1H), 7.01 (s, 2H), 7.18 (d, 1H), 7.29 (d, 1H), 7.38 (s, 1H), 7.44 (d, 1H), 7.48 (s, 1H), 8.40 (brd s, 1H), 11.62 (s 1H); MS (APCl): 547.1.
Embodiment 91:3-fluoro-4-hydroxy-benzoic acid [4-(4-isopropyl benzyloxy)-3,5-dimethoxybenzylidenegroup group] hydrazides
Figure A9880812501902
1H NMR (DMSO-d 6): δ 1.05 (d, 6H), 2.67 (m, 1H), 3.61 (s, 6H), 4.69 (s, 2H), 6.79 (s, 2H), 6.86 (t, 1H), 7.01 (d, 2H), 7.24 (d, 1H), 7.44 (dd, 1H), 7.51 (d, 1H), 8.10 (brd s, 1H), 10.32 (s, 1H), 11.41 (s, 1H); MS (APCl): 467.19.
Embodiment 92:3-chloro-4-hydroxy-benzoic acid [4-(4-tertiary butyl benzyloxy)-3,5-dimethyl benzylidene] hydrazides
Figure A9880812501903
1H NMR (DMSO-d 6): δ 1.06 (s, 9H), 1.99 (s, 6H), 4.55 (s, 2H), 6.83 (d, 1H), 7.19 (s, 6H), 7.52 (d, 1H), 7.73 (s, 1H), 8.09 (s, 1H), 10.74 (brd s, 1H), 11.44 (s, 1H); MS (FAB): 465.6.
Embodiment 93:3-chloro-4-hydroxy-benzoic acid [3-bromo-5-methoxyl group-4-(4-trifluoromethoxy benzyloxy) benzylidene] hydrazides
Figure A9880812501911
1H NMR (DMSO-d 6): δ 3.92 (s, 3H), 5.07 (s, 2H), 7.07 (d, 1H), 7.40 (m, 3H), 7.52 (s, 1H), 7.63 (d, 2H), 7.77 (dd, 1H), 7.97 (d, 1H), 8.35 (s, 1H), 11.00 (brd s, 1H), 11.86 (s, 1H); MS (FAB): 575.0
Embodiment 94:4-hydroxy-benzoic acid [4-(4-isopropyl benzyloxy)-3,5-dimethoxybenzylidenegroup group] hydrazides
Figure A9880812501912
1H NMR (DMSO-d 6): δ 1.05 (d, 6H), 2.71 (m, 1H), 3.67 (s, 6H), 4.75 (s, 2H), 6.70 (d, 2H), 6.85 (s, 2H), 7.14 (d, 2H), 7.21 (d, 2H), 7.64 (d, 2H), 8.21 (brd s, 1H), 9.97 (brd s, 1H), 11.47 (s, 1H); MS (APCl): 448.9.
Embodiment 95:2-chloro-4-hydroxy-benzoic acid [4-(4-isopropyl benzyloxy)-3,5-dimethoxybenzylidenegroup group] hydrazides 1H NMR (DMSO-D 6): d 1.18 (d, 6H), 2.87 (septet, 1H), [3.68 (s, 1H)+3.81 (s, 5H), 6H], [4.83 (s, and 0.5H)+4.90 (s, 1.5H), 2H], [6.76 (s, and 0.5H)+7.01 (s, 1.5H), 2H], [6.80 (dd, 1H)+6.88 (d, 1H), 2H], 7.23 (d, 2H), 7.35 (d, 2H), 7.38 (m, 1H), [7.91 (s, and 0.3H)+8.18 (s, 0.7H), 2H], 10.17 (s, and 0.7H)+11.73 (s, 0.3H), 1H]; MS (APCl): 483.0.
Embodiment 96:3-chloro-4-hydroxy-benzoic acid [3-(4-isopropyl benzyloxy)-4,5-dimethoxybenzylidenegroup group] hydrazides
Figure A9880812501922
1H NMR (DMSO-d 6): δ 1.05 (d, 6H), 2.70 (m, 1H), 3.54 (s, 3H), 3.66 (s, 3H), 4.94 (s, 2H), 6.87 (m, 3H), 7.08 (d, 2H), 7.20 (d, 2H), 7.56 (dd, 1H), 7.77 (s, 1H), 8.15 (s, 1H), 10.76 (s, 1H), 11.52 (s, 1H); MS (APCl): 483.7.
Embodiment 97:3-chloro-4-hydroxy-benzoic acid [3-(4-isopropyl benzyloxy)-2,4-dimethoxybenzylidenegroup group] hydrazides
Figure A9880812501923
1H NMR (DMSO-d 6): δ 1.20 (d, 6H), 2.89 (m, 1H), 3.85 (s, 6H), 4.95 (s, 2H), 6.95 (d, 1H), 7.07 (d, 1H), 7.22 (d, 2H), 7.40 (d, 2H), 7.64 (d, 1H), 7.78 (dd, 1H), 7.97 (d, 1H), 8.62 (s, 1H), 11.68 (s, 1H); MS (APCl): 483.8.
Embodiment 98:3-chloro-4-hydroxy-benzoic acid [4-(3-Trifluoromethyl phenyl ether oxygen base) naphthalene-1-methylene] hydrazides
Figure A9880812501931
1H NMR (DMSO-d 6): δ 5.46 (s, 2H), 7.10 (d, 1H), 7.20 (d, 1H), 7.37 (d, 1H), 7.65 (m, 5H), 7.82 (m, 2H), 8.01 (s, 1H), 8.32 (d, 1H), 8.97 (m, 2H), 11.70 (s, 1H); MS (APCl): 514.8
Embodiment 99:3-chloro-4-hydroxy-benzoic acid [4-(4-isopropyl benzyloxy)-8-methoxynaphthalene-1-methylene]-hydrazides
Figure A9880812501932
(2g 9.9mmol) is dissolved among the DMF (25ml) with 4-hydroxyl-8-methoxynaphthalene-1-kappa aldehyde.In this mixture, add salt of wormwood (6.8g, 50mmol) and 4-isopropyl benzyl chlorine (1.8g 10.4mmol), and at room temperature stirred the mixture that produced 16 hours.Add entry (100ml), and (3 * 100ml) extract the mixture that is produced with diethyl ether.With organic extracting solution that saturated sodium-chloride (100ml) washing merges, dry (MgSO 4) and vaporising under vacuum so that 3.0g to be provided crude product.On the silica gel (300ml) of the mixture wash-out of using ethyl acetate and heptane (1: 4), utilize this product of column chromatography purifying.This provides 2.57g (81%) 4-isopropyl benzyloxy-8-methoxynaphthalene-1-kappa aldehyde.
C 22H 22O 3Calculated value: C, 79.02%; H, 6.63%.Measured value: C, 79.10%, H, 6.69%; C, 79.17%, H, 6.69%.
With 3-chloro-4-hydroxy-benzoic acid hydrazides (205mg, 1.1mmol) be dissolved among the DMSO (2ml), and (365mg 1.1mmol) and glacial acetic acid (5), at room temperature stirred the mixture that produced 20 minutes to add above-mentioned 4-isopropyl benzyloxy-8-methoxynaphthalene-kappa aldehyde.Add more DMSO (2ml), and at room temperature stirred the mixture 16 hours.By solid collected by filtration, and in succession with DMSO and ethyl acetate washing, so that 330mg to be provided the title compound of (66%).
m.p.：＞250℃。
Embodiment 100:
Figure A9880812501941
1H NMR (DMSO-d 6) δ 1.13 (d, 6H), 2.82 (sept, 1H), 3.77 (s, 6H), 4.8 (s, 2H), 7.15 (s, 1H), 7.18 (s, 2H), 7.30 (d, 2H), 8.00 (dd, 1H), 8.30 (s, 1H), 8.44 (s, 1H), 11.84 (s, 1H); .MS (APCl): 494.0
Embodiment 101:
Figure A9880812501942
1H NMR (DMSO-d 6) δ 5.38 (s, 2H), 6.95 (d, 1H), 7.06 (d, 1H), 7.49 (t, 1H), 7.56 (t, 1H), 7.65-7.71 (m, 6H), 7.87 (d, 1H), 8.22 (d, 1H), 8.80 (s, 1H), 8.86 (d, 1H), 10.82 (s, 1H), 11.55 (s, 1H); MS (FAB): 499
Embodiment 102:
Figure A9880812501943
1H NMR (DMSO-d 6) δ 5.85 (s, 2H), 7.05 (t, 2H), 7.52-7.63 (m, 4H), 7.73 (m, 2H), 7.95 (s, 1H), 8.16 (d, 2H), 8.33 (d, 1H), 8.90 (s, 1H), 893 (s, 1H), 10.90 (brd s, 1H), 11.63 (s, 1H); MS (FAB): 543
Embodiment 103:3-chloro-4-hydroxy-benzoic acid 4-[2-(4-bromine phenoxy group)-oxyethyl group]-3,
The 5-dimethoxybenzylidenegroup group } hydrazides
Figure A9880812501951
1H NMR (DMSO-d 6): δ 3.78 (s, 6H), 4.21 (m, 4H), 6.87 (d, 2H), 7.00 (s, 2H), 7.05 (d, 1H), 7.44 (d, 2H), 7.75 (dd, 1H), 7.96 (s, 1H), 8.36 (s, 1H), 10.95 (brd s, 1H), 11.66 (s, 1H); MS (APCl): 548.8.
Embodiment 104:3-chloro-4-hydroxy-benzoic acid [4-(3-methoxyl group-3-(4-aminomethyl phenyl)-propoxy-) naphthalene-1-methylene] hydrazides
Figure A9880812501952
MS(APCl)：502.9
Embodiment 105:(2-ethylphenyl) hydrazono-methyl carboxylamine 2-{4-[(3-chloro-4-hydroxy benzoyl)]-naphthalene-1-base oxygen base) ethyl ester
Figure A9880812501953
1H NMR (CDCl 3): δ 1.12 (t, 3H), 2.50 (qt, 2H), 3.69 (t, 2H), 4.39 (t, 2H), 5.20 (t, 1H), 6.57 (t, 1H), 6.74 (d, 1H), 6.97 (d, 1H), 7.08 (m, 3H), 7.57 (t, 1H), 7.67 (t, 1H), 7.81 (t, 2H), 8.01 (s, 1H), 8.35 (d, 1H), 8.95 (m, 2H), 11.67 (s, 1H).
Embodiment 106:3-chloro-4-hydroxy-benzoic acid [3-allyl group-4-(4-isopropyl benzyloxy)-5-methoxyl group benzylidene] hydrazides
Figure A9880812501961
1H NMR (DMSO-d 6): δ 1.13 (d, 8H), 2.80 (m, 1H), 3.20 (m, 2H), 3.85 (s, 3H), 4.82 (s, 2H), 5.00 (d, 2H), 5.70 (m, 1H), 6.96 (s, 1H), 7.05 (s, 1H), 7.20 (d, 2H), 7.30 (d, 2H), 7.70 (d, 1H), 7.89 (s, 1H), 8.28 (s, 1H), 10.80 (brd s, 1H), 11.61 (s, 1H); MS (APCl): 493.1.
Similarly, make following compounds:
Embodiment 107: 1H NMR (DMSO-D 6): δ 0.99 (d, 6H), 2.68 (septet, 1H), 4.89 (s, 2H), 6.84 (d, 2H), 7.06 (m, 2H), 7.16 (m, 3H), 7.55 (d, 1H), 7.75 (s, 1H), 8.18 (s, 1H), 10.75 (s, 1H), 11.52 (s, 1H); MS (APCl): 423.7,425.6.
Embodiment 108: 1H NMR (DMSO-D 6): δ 1.18 (d, 1H), 2.88 (septet, 1H), 5.20 (s, 2H), 7.04 (d, 1H), 7.28 (t, 2H), 7.30 (s, 1H), 7.38 (d, 2H), 7.62 (d, 1H), 7.73 (dd, 1H), 7.79 (s, 1H), 7.94 (d, 1H), 8.32 (s, 1H), 11.94 (s, 1H), 11.72 (s, 1H); MS (APCl): 457.4,459.1.
Embodiment 109: 1H NMR (DMSO-D 6): δ 1.1 (d, 6H), 2.2 (s, 6H), 2.8 (septet, 1H), 4.7 (s, 2H), 7.0 (d, 1H), 7.2 (d, 2H), 7.4 (d, 4H), 7.7 (d, 1H), 7.9 (s, 1H), 8.2 (s, 1H), 10.9 (s, 1H), 11.6 (s, 1H); MS (APCl): 451.6,453.3.
Embodiment 110:
Figure A9880812501972
1H NMR (DMSO-D 6): δ 1.1 (d, 6H), 2.8 (septet, 1H), 3.3 (d, 1H), 5.0 (d, 1H), 5.1 (d, 1H), 5.2 (s, 2H), 5.9 (m, 1H), 7.0 (d, 1H), 7.1 (d, 1H), 7.2 (d, 2H), 7.3 (d, 2H), 7.4 (d, 1H), 7.5 (s, 1H), 7.7 (dd, 1H), 7.9 (d, 1H), 8.3 (s, 1H), 10.9 (brd s, 1H), 11.5 (s, 1H); MS (APCl): 463.5,465.1.
Embodiment 111:
Figure A9880812501973
1H NMR (DMSO-D 6): δ 4.47 (t, 2H), 4.54 (t, 2H), 7.01 (d, 2H), 7.07 (d, 1H), 7.14 (d, 1H), 7.45 (d, 2H), 7.53 (t, 1H), 7.27 (d, 1H), 7.79 (m, 2H), 7.96 (d, 1H), 8.17 (d, 1H), 8.91 (s, 1H), 8.94 (d, 1H), 10.92 (s, 1H), 11.64 (s, 1H), MS (APCl): 539.3,541.1,543.1.
Embodiment 112:
Figure A9880812501981
1H NMR (DMSO-D 6): δ 1.18 (d, 6H), 2.87 (septet, 1H), [3.67 (s, 1.5H)+3.81 (s, 4.5H), 6H], [4.83 (s, and 0.5H)+4.90 (s, 1.5H), 2H], 6.73 (s, 0.5H)+[7.02 (m, 2.5H) ,+7.27 (m, 2.5H)+7.37 (m, 2.5H), 8H], [7.92 (s, 0.3H)+8.17 (s, 0.7H), 1H], [10.96 (s, and 0.3H)+11.12 (s, 0.7H), 1H], [11.82 (s, and 0.7H)+11.95 (s, 0.3H), 1H]; MS (APCl): 517.6,519.2.
Embodiment 113:
Figure A9880812501982
1H NMR (DMSO-D 6): δ 1.19 (d, 6H), 2.89 (septet, 1H), [3.68 (s, 1.5H)+3.82 (s, 4.5H), 6H], [4.84 (s, and 0.5H)+4.89 (s, 1.5H), 2H], [6.76 (s, 0.5H)+7.02 (m, 2.5H), 3H], 7.20 (m, 2H), 7.34 (m, 2H), [7.50 (s, and 0.3H)+7.62 (s, 0.7H), 1H], 7.92 (s, and 0.3H)+8.18 (s, 0.7H), 1H], 11.17 (brds, 1H), 11.81 (s, and 0.7H)+11.96 (s, 0.3H), 1H]; MS (APCl): 517.7,519.2.
Embodiment 114:
Figure A9880812501983
1H NMR (DMSO-D 6): δ 1.20 (d, 6H), 2.87 (septet, 1H), 3.82 (s, 6H), 4.89 (s, 2H), 6.69 (d, 1H), 6.98 (m, 3H), 7.21 (m, 3H), 7.36 (d, 2H), 8.32 (s, 1H), 9.8 (brd s, 1H), 11.50 (s, 1H); MS (APCl): 464.7.
Embodiment 115:
Figure A9880812501991
1H NMR (DMSO-D 6): δ 1.19 (d, 6H), 2.30 (septet, 1H), [3.71 (s)+3.82 (s), 6H], 4.90 (s, 2H), [6.81 (m, and 1.5H)+6.88 (s, 1.5H), 3H], [7.24 (s, and 0.2H)+8.24 (s, 0.8H), 1H], 11.05 (brd, 1H), 11.69 (s, 0.75H)+11.94 (s, 0.25H), 1H]; MS (APCl): 485.5,486.3.
Embodiment 116: 1H NMR (DMSO-D 6): δ 1.19 (d, 6H), 2.88 (septet, 1H), 3.83 (s, 6H), 4.90 (s, 2H), 6.87 (d, 1H), 7.03 (s, 2H), 7.23 (d, 2H), 7.36 (d, 2H), 7.53 (m, 3h), 8.26 (m, 3H), 10.73 (s, 1H), 11.82 (s, 1H); MS (APCl): 499.8.
Embodiment 117:
Figure A9880812501993
1H NMR (DMSO-D 6): δ 1.20 (d, J=6.9,6H), 2.89 (sept, J=6.9,1H), 3.84 (s, 6H), 4.91 (s, 2H), 7.03 (br s, 2H), 7.12 (d, J=8.8,1H), 7.23 (d, J=8.0,2H), 7.37 (d, J=8.0,2H), 8.04 (dd, J=2.2,8.8,1H), 8.21 (br s, 1H), 8.35 (br s, 1H), 11.78 (s, 1H), 11.89 (br s, 1H); MS (APCl, neg): 472.
Acyl group-the hydrazone of preparation 4-(2-hydroxyethyl)-1-naphthaldehyde:
Be used for the general method of compound of synthetic general formula X:
Figure A9880812501994
Wherein b is 1,2,3 or 4.
Preparation 4-(2-hydroxyethyl)-1-naphthaldehyde:
Figure A9880812502001
1-bromo-4-(2-hydroxyethyl) naphthalene:
Under 0 ℃, (2.0g is 7.16mmol) in the solution will to drop to 4-bromonaphthalene methyl acetate in anhydrous THF (15ml) at the 1M lithium aluminum hydride among the THF (4ml).At room temperature stirred the mixture 16 hours, the concentrated hydrochloric acid acidifying is used in water (5ml) dilution, and (3 * 20ml) extract with ethyl acetate.Dry (MgSO 4) organic extracting solution of merging, and concentrate it, so that 1.71g (95%) colorless oil (1.71g, 95%) to be provided.Similar synthetic is with reference to being described in the following document: A.A.Kiprianov, A.A.Shulezhko.Zh.Org.Khim.2 (1966), 1852, English translation: organic chemistry magazine (USSR) 2 (1966) 1820.
1H?NMR(CDCl 3)δ＝2.36(s，1H)，3.33(t，J＝6.7Hz，2H)，3.99(t，J＝6.7Hz，2H)，7.24(d，J＝7.3Hz，1H)，7.58-7.63(m，2H)，7.73(d，J＝7.6Hz，1H)，7.61(m，1H)，8.31(dd，J＝1.1，8.0Hz，1H)。GCMS(pos.)250，252。
1-bromo-4-(2-tetrahydro-pyran oxy ethyl) naphthalene:
With 3,4-dihydro-2H-pyrans (1ml, 0.92g, 11.0mmol) and tosic acid (80mg) be added to 1-bromo-4-(2-hydroxyethyl) naphthalene in methylene dichloride (20ml) (1.71g be 6.8mmol) in the solution.At room temperature stirred the mixture 90 minutes, and, used saturated NaHCO with methylene dichloride (20ml) dilution 2Solution (20ml) washing, dry (MgSO 4), and concentrate it.Utilize hexane/ethyl acetate (9: 1) that the colorless oil of 1.69g (75%) is provided as the flash chromatography of eluent.
1H?NMR(CDCl 3)δ＝1.51-1.60m(6H)，3.37(t，J＝7.2Hz，2H)，3.39-3.47(m，1H)，3.74(t，J＝7.2Hz，2H)，4.08(dd，J＝2.4，7.5Hz，1H)，4.60(m，1H)，7.25(d，J＝7.3Hz，1H)，7.56-7.61(m，2H)，7.72(d，J＝7.6Hz，1H)，8.09-8.12(m，1H)，8.29(dd，J＝2.5，7.1Hz，1H)。GCMS(pos)，334，336。
1-formyl radical-4-(2-tetrahydro-pyran oxy ethyl) naphthalene:
Under nitrogen, will be cooled to-78 ℃ at the 1-bromo-4-among the anhydrous THF (15ml) (2-tetrahydro-pyran oxy ethyl) naphthalene solution.Add n-Butyl Lithium (the 1.4ml 2.5M solution in hexane) via syringe, and under same temperature, stirred the mixture 30 minutes.Add DMF (1.1ml), make the temperature of mixture reach room temperature.Use saturated NH 4Cl solution (10ml) diluted mixture thing, (3 * 10ml) extract, dry (MgSO with ether 4) and concentrate it.Utilize hexane/ethyl acetate (5: 1) that the colorless oil of 408mg (54%) is provided as the flash chromatography of eluent.
1H?NMR(CDCl 3)δ＝1.48-1.69m(6H)，3.45-3.50(m，3H)，3.69-3.85(m，2H)，4.07-4.17(m，1H)，4.61(m，1H)，7.58(d，J＝7.3Hz，1H)，7.62，-7.73(m，2H)，7.92(d，J＝7.3Hz，1H)，8.20(d，J＝1.0，8.1Hz，1H)，10.36(s，1H)。GCMS：284。
1-formyl radical-4-(2-hydroxyethyl) naphthalene:
((400mg 1.40mmol) is dissolved in the methyl alcohol (15ml) 2-tetrahydro-pyran oxy ethyl, and adds tosic acid (45mg) with 1-formyl radical-4-.At room temperature stirred the mixture 16 hours, and concentrate it.Resistates is dissolved in ethyl acetate (in 3 * 10ml), uses saturated NaHCO 3(20ml) washing, dry (MgSO 4) and concentrate it.Provide 182mg the colorless oil of (65%) by the purifying that utilizes hexane/ethyl acetate (3: 1) as the flash chromatography of eluent.
1H?NMR(CDCl 3)δ＝2.09(s，1H)，3.40(t，J＝6.6Hz，2H)，4.02(t，J＝6.6Hz，2H)，7.54(d，J＝7.3Hz，1H)，7.61-7.71(m，2H)，7.88(d，J＝7.3Hz，1H)，8.13(dd，J＝1.3，8.0Hz，1H)，9.29(dd，J＝1.3，8.0Hz，1H)，10.28(s，1H)。GCMS：200。
According to the general method of synthetic alkylidene group hydrazone, prepare following compounds by the condensation of 1-formyl radical-4-(2-hydroxyethyl) naphthalene (deriving from step D) and 4-hydroxy-benzoic acid hydrazides.
Embodiment 118:
Figure A9880812502021
1H NMR (DMSO-D 6) δ=3.25 (t, J=6.5Hz, 2H), 3.73 (dt, J=J '=6.5Hz, 2H), 4.84 (t, J=6.5Hz, 1H), 7.08 (d, J=8.5Hz, 1H), 7.49 (d, J=7.4Hz, 1H), 7.60-7.68 (m, 2H), 7.80 (dd, J=1.8,7.4Hz, 1H), 7.84 (d, J=7.3Hz, 1H), 8.00 (d, J=1.8Hz, 1H), 9.19 (d, J=6.7Hz, 1H), 8.85 (d, J=7.7Hz, 1H), 9.05 (s, 1H), 10.98 (s, 1H), 11.76 (s, 1H); MS (APCl, pos.): 369.4,371.2.
Embodiment 119: 1H NMR (DMSO-D6) δ=3.18 (t, J=7.0Hz, 1H), 3.25 (t, J=7.0Hz, 1H), 3.65 (dd, J=7.0Hz, 1H), 3.74 (dd, J=5.3,7.0Hz, 1H), 4.74 (t, J=5.3Hz, 0.5H), 4.79 (t, J=5.3Hz, 0.5H), 7.04 (d, J=8.3Hz, 0.5H), 7.05 (d, J=8.3Hz, 0.5H), 7.25 (d, J=8.3Hz, 0.5H), 7.28 (d, J=8.3Hz, 0.5H), 7.38 (d, J=7.4Hz, 0.5H), 7.43 (d, J=8.4Hz, 0.5H), 7.47-7.57 (m, 1.5H), 7.61-7.72 (m, 1H), 7.82 (d, J=7.2Hz, 0.5H), 8.10 (d, J=8.6Hz, 0.5H), 8.19 (dd, J=2.2,7.2Hz, 0.5H), 8.45 (d, J=8.6Hz, 0.5H), 8.48 (s, 0.5H), 8.85 (s, 0.5H), 8.87 (dd, J=2.2,6.5Hz, 0.5H), 11.00 (s, 0.5H), 11.15 (s, 0.5H), 11.86 (s, 0.5H), 11.92 (s, 0.5H); MS (APCl, pos.): 403.4,405.2,406.1.
The acyl group hydrazone of preparation 4-methylol naphthaldehyde:
Figure A9880812502023
Steps A: with 1, (25g, (15g 395mmol) in the mixture, and makes it to reflux two days to the 4-naphthalene dicarboxylic acids 116mmol) to drip to lithium aluminum hydride in the anhydrous THF of 600ml.Use the ice bath cooling mixture, and by slow adding methyl alcohol and subsequently rubble ice excessive LAH is decomposed.Under vacuum, remove THF, and with 1N HCl acidifying resistates.Extract product with ethyl acetate (3x), with aqueous carbonic acid hydrogen sodium (3x), water, salt water washing, and dry on sal epsom.After solvent evaporation, obtain 1 of solid form, the two methylol naphthalenes (70%) of 4-, and product can be used for oxidation step then and need not to be further purified.In order to identify this product, utilize hexane/ethyl acetate (80/20-75/25) by 1 part of product of column chromatography purifying.
1H?NMR(DMSO-D 6)：δ5.19(s，4H)，7.77(m，4H)，8.32(m，2H)。
Step B: with Manganse Dioxide (28g, 325mmol) be added in ethyl acetate (300ml) 1, (12g is 65mmol) in the solution for the two methylol naphthalenes of 4-.After stirring 45 minutes, most raw materials disappear, and observe two new spots (single aldehyde and dialdehyde) on TLC.The top spot is corresponding to dialdehyde.Make mixture pass through bed of diatomaceous earth, and with the eluent ethyl acetate of additional content.Evaporating solvent, and utilize hexane/ethyl acetate (80/20-75/25) by column chromatography purifying 4-methylol naphthaldehyde (productive rate 50%).
H?NMR(DMSO-D 6)：δ5.19(s，2H)，5.71(brd?s，1H)，7.73(t，1H)，7.78(t，1H)，7.95(d，1H)，8.26(m，2H)，9.34(d，1H)，10.46(s，1H)。
Use the embodiment of the product of above-mentioned aldehyde generation:
Embodiment 120:
Figure A9880812502031
General method according to synthetic alkylidene group hydrazone prepares above-claimed cpd by the above-mentioned aldehyde of condensation and 3-cyano group-4-hydroxy-benzoic acid hydrazides.
1H?NMR(DMSO-D 6)：δ5.02(s，2H)，5.44(s，1H)，7.14(d，1H)，7.69(m，3H)，7.91(d，1H)，8.10(d，1H)，8.14(d，1H)，8.27(s，1H)，8.87(d，1H)，9.06(s，1H)，11.84(brd?s，2H)；MS(ACPI)：346.3，347.2。
Embodiment 121:
Figure A9880812502041
General method according to synthetic alkylidene group hydrazone prepares above-claimed cpd by above-mentioned aldehyde of condensation and 3-chloro-4-hydroxy-benzoic acid hydrazides.
1H?NMR(DMSO-D 6)：δ5.02(s，2H)，5.43(t，1H)，7.10(d，1H)，7.66(m，3H)，7.80(d，1H)，7.90(d，1H)，8.02(s，1H)，8.15(d，1H)，8.87(d，1H)，9.08(s，1H)，10.98(s，1H)，11.79(s，1H)；MS(APCl)：355.5。
Embodiment 122:
Figure A9880812502042
General method according to synthetic alkylidene group hydrazone prepares above-claimed cpd by above-mentioned aldehyde of condensation and 3-fluoro-4-hydroxy-benzoic acid hydrazides.
1H?NMR(DMSO-D 6)：d4.84(s，2H)，6.91(t，1H)，7.43-7.53(m，4H)，7.62(d，1H)，7.72(d，1H)，7.96(d，1H)，8.68(d，1H)，8.98(s，1H)，11.71(brds，1H)；MS(APCl)：339.4，340.3.
Also can utilize aforesaid method with the parallel compound for preparing general formula I I that synthesizes of array mode.The compound that therefore, can prepare thousands of kinds of general formula I I by this semi-automatic or full automatic array mode.Use automatic synthesis device, utilize the combined chemistry of solution,, can realize the automatization of this method with as 96 aperture apparatus.In the synthetic the first step,,, can prepare aldehydes or ketones by in conjunction with the aldehydes or ketones of selected quantity and the alkylation medicament of selected quantity according to scheme II.In second step, formed aldehyde/ketone is combined with the hydrazides (it can be synthetic according to scheme I) of selected quantity, thereby produce predetermined a large amount of compounds as single entities.
Institute's synthetic above-claimed cpd is the embodiment that can utilize this compounds of this combined method preparation.
Use aforesaid method, also can synthesize following compounds:
Embodiment 123:
Figure A9880812502051
Embodiment 124:
Figure A9880812502052
Embodiment 125:
Figure A9880812502053
Embodiment 126: Embodiment 127: Embodiment 128: Embodiment 129:
Figure A9880812502064
Embodiment 130:
Figure A9880812502065
Embodiment 131:
Figure A9880812502071
Embodiment 132: Embodiment 133:
Figure A9880812502073
Embodiment 134:
Figure A9880812502074
Embodiment 135:
Figure A9880812502075
Embodiment 136: Embodiment 137: Embodiment 138:
Figure A9880812502083
Embodiment 139:
Figure A9880812502084
Embodiment 140:
Figure A9880812502091
Embodiment 141:
Embodiment 142:
Figure A9880812502093
The general method of the further deutero-hydrazides of synthetic general formula I I:
The compound that can prepare general formula I according to one embodiment of the invention, it is the alkylidene group hydrazides of general formula I I, III is illustrated as scheme, that is to say, by being converted into further deutero-alkylidene group hydrazides, alkylidene group hydrazides (according to the preparation of the shown general method of scheme I, more specifically can referring to embodiment 8) prepares.Therefore, by making amine and the alkylidene group hydrazides reaction (scheme III) that comprises leavings group XL, can be formed on the new alkylidene group hydrazides that comprises amine among the group K of general formula I I.
Scheme III
A wherein, B, D, n, R 4, R 3a, a, b is defined identical with general formula I with d, R 5aIt is low alkyl group.
The specific embodiment of illustrating the further deutero-hydrazides for preparing general formula I I is as follows:
Embodiment 143:3-chloro-4-hydroxy-benzoic acid 4-[2-[N '-(2-N, N-diethylamino ethyl)-N '-(4-trifluoromethoxy-benzyl amino)]] oxyethyl group-1-naphthyl methylene radical hydrazides
Figure A9880812502102
N, N-diethyl-N '-(4-trifluoro-methoxybenzyl) quadrol
Figure A9880812502103
At room temperature, in exsiccant 100ml round-bottomed flask, be stirred in (4-trifluoromethoxy) phenyl aldehyde (1.9g in the methyl alcohol (10ml), 10mmol), N, N-diethyl ethylenediamine (1.16g, 10mmol), zinc chloride (1.36g, 10mmol) and sodium cyanoborohydride (1.26g, solution 20mmol) 8 hours.Add entry (20ml) then, under vacuum, remove most methyl alcohol.Resistates is allocated between ethyl acetate and the 1N HCl.With the excessive sodium hydroxide acidic aqueous phase that alkalizes.Obtain crude product N, N-diethyl-N '-(4-trifluoro-methoxybenzyl) quadrol.This crude product uses in following reaction, and need not to be further purified.
MS(Cl)：291。 1H?NMR(CDCl 3)：δ7.4(m，2H)，7.2(m，2H)，3.9(bs，2H)，3.1-2.6(m，9H)，1.4-1.1(t，6H)。
Comprising the N that is dissolved among the DMF (5ml), N-diethyl-N '-(0.29g is in flask 1mmol) for (4-trifluoro-methoxybenzyl) quadrol, add [1-(4-chloroethoxy) naphthyl] (3-chloro-4-hydroxyl) phenylformic acid hydrazides (0.41g,, mmol) and triethylamine (0.1g, 1mmol).Heat one night of solution that is produced down at 80 ℃.Under vacuum, remove and desolvate, on silica gel, carry out flash chromatography (10: 1 CHCl subsequently 3/ MeOH), the result has produced the title compound of brown solid form.
1H?NMR(DMSO-D 6)：δ11.7(1H)，9.0bs，2H)，8.4-7.0(m，12H)，4.75(bs，1H)，4.65(bs，1H)，4.55(t，1H)，4.35(t，1H)，4.15(t，1H)，3.9(bs，1H)，3.5(q，4H)，3.05(t，1H)，1.3(t，3H)，0.95(t，3H)。m.p.：134-136℃。MS(Cl)：657，659。
Embodiment 144:3-chloro-4-hydroxy-benzoic acid 4-[2-(4-trifluoromethoxy) benzyl amino ethoxy]-the naphthyl methylene radical) hydrazides
Figure A9880812502111
Comprise the 4-trifluoromethoxy benzylamine that is dissolved among the DMF (5ml) (0.29g, in flask 1mmol), add 3-chloro-4-hydroxy-benzoic acid [4-(2-chloroethoxy)-1-naphthyl methylene radical] hydrazides (0.403g, 1mmol) and triethylamine (0.1g, 1mmol).The solution that heating is produced under 80 ℃ 16 hours.Under vacuum, remove most solvents, on silica gel, carry out flash chromatography (10: 1CHCl subsequently 3/ MeOH), the result produces the title compound of brown solid form.
1H?NMR(DMSO-D 6)：δ11.6(s，1H)，9.0(m，2H)，8.3(m?1H)，8.0(m，1H)，7.8(s，2H)，7.7(m，1H)，7.6(m，1H)，7.5(m，3H)，7.3(m，2H)，7.1(m，2H)，4.3(t，2H)，3.9(s，2H)，3.0(t，2H)。MS(Cl)：557，559。
Use aforesaid method, synthesized following compounds of the present invention:
Embodiment 145:3-chloro-4-hydroxy-benzoic acid { 3,5-dimethoxy-4 '-[2-(4-trifluoromethoxy benzyl amino)-oxyethyl group] benzylidene } hydrazides 1H NMR (CD 3OD): δ 2.90 (brd t, 2H), 3.75 (s, 6H), 3.89 (s, 2H), 4.08 (brd t, 2H), 6.87 (d, 1H), 7.10 (s, 2H), 7.20 (d, 2H), 7.43 (d, 2H), 7.65 (m, 1H), 7.82 (m, 1H), 8.11 (brd s, 1H); MS (APCl): 567.9.
Embodiment 146:3-chloro-4-hydroxy-benzoic acid 4 one [2-(2-piperidines-1-base ethylamino) oxyethyl group] naphthalene 1-methylene) hydrazides
Figure A9880812502122
1H NMR (DMSO-d 6): δ 1.53 (m, 2H), 1.74 (m, 4H), 3.12 (m, 2H), 3.40 (m, 2H), 3.54 (m, 2H), 3.63 (m, 4H), 4.52 (s, 2H), 7.10 (d, 1H), 7.14 (d, 1H), 7.60 (t, 1H), 7.71 (m, 1H), 7.80 (dd, 1H), 7.83 (d, 1H), 8.00 (d, 1H), 8.51 (d, 1H), 8.95 (d, 1H), 8.98 (s, 1H), 11.69 (s, 1H); MS (APCl): 495.0
Embodiment 147:3-chloro-4-hydroxy-benzoic acid 4-[2-(3-diethylin third amino) oxyethyl group] and naphthalene-1-methylene } hydrazides
Figure A9880812502123
1H NMR (DMSO-d 6): δ 1.21 (t, 6H), 2.10 (m, 2H), 3.14 (m, 10H), 4.52 (t, 2H), 7.10 (d, 1H), 7.14 (d, 1H), 7.63 (t, 1H), 7.73 (m, 1H), 7.80 (dd, 1H), 7.84 (d, 1H), 8.00 (d, 1H), 8.46 (d, 1H), 8.93 (s, 1H), 8.98 (m, 1H), 9.20 (m, 2H), 9.69 (m, 1H), 11.00 (s, 1H), 11.69 (s, 1H); MS (APCl): 497.0.
Embodiment 148:1-(2-{4-[(3-chloro-4-hydroxy benzoyl) hydrazono-methyl] naphthalene-1-base oxygen base } ethyl)-4-phenylamino piperidines-4-carboxylic acid amide
Figure A9880812502131
1H NMR (DMSO-d 6): δ 1.16 (m, 2H), 1.88 (m, 2H), 2.03 (m, 2H), 2.80 (m, 2H), 2.92 (m, 2H), 4.37 (m, 2H), 4.40 (brd s, 2H), 4.44 (s, 1H), 6.55-6.62 (m, 3H), 6.96 (s, 1H), 7.03-7.16 (m, 5H), 7.61 (dd, 1H), 7.68 (dd, 1H), 8.00 (d, 1H), 8.27 (d, 1H), 8.94 (s, 1H), 8.97 (s, 1H), 11.63 (s, 1H); MS (APCl): 586.4
Embodiment 149:4-(2-{4-[(3-chloro-4-hydroxy benzoyl) hydrazono-methyl] naphthalene-1- 1H NMR (DMSO-d 6): δ 1,10 (t, 3H), 1.15-1.23 (m, 2H), 1.86 (m, 2H), 2.79 (m, 3H), 3.30 (m, 2H), 3.87 (m, 2H), 3.94 (q, 2H), 4.28 (m, 2H), 7.03 (d, 1H), 7.05 (m, 1H), 7.51-7.63 (m, 3H), 7.13 (d, 1H), 7.75 (m, 1H), 7.93 (d, 1H), 8.29 (d, 1H), 8.87 (m, 2H), 11.55 (s, 1H); MS (APCl): 539.1,541.0.
Embodiment 150:3-chloro-4-hydroxy-benzoic acid 4-[2-(1,2,3,4-naphthane-1-base is amino) oxyethyl group]-naphthalene-1-methylene } hydrazides
Figure A9880812502141
1H NMR (DMSO-d 6): δ 1.76 (m, 1H), 2.04 (m, 1H), 2.17 (m, 2H), 2.75-2.94 (m, 2H), 3.61 (m, 2H), 4.55 (m, 2H), 4.71 (s, 1H), 7.11 (d, 1H), 7.13 (d, 1H), 7.23-7.35 (m, 3H), 7.61 (d, 1H), 7.67 (d, 1H), 7.71 (dd, 1H), 7.81 (dd, 1H), 7.86 (d, 1H), 8.01 (d, 1H), 8.48 (d, 1H), 8.94 (m, 1H), 8.99 (m, 1H), 9.22 (m, 2H), 11.00 (s, 1H), 11.64 (s, 1H); MS (APCl): 514.0,516.0
Embodiment 151:1-(2-{4-[(3-chloro-4-hydroxy benzoyl) hydrazono-methyl] naphthalene-1-base oxygen base } ethyl) piperidines-4-carboxylic acid amide
Figure A9880812502142
MS (APCl): 495.0
Embodiment 152:3-chloro-4-hydroxy-benzoic acid 4-[2-(2-trifluoromethoxy benzyl amino)-oxyethyl group]-1-naphthyl methylene radical } hydrazides
Figure A9880812502143
Embodiment 153:3-chloro-4-hydroxy-benzoic acid 4-[2-(4-morpholinyl ethylamino) oxyethyl group]-1-naphthyl methylene radical) hydrazides
Also can use synthetic following compounds: the embodiment 154 of aforesaid method: Embodiment 155:
Figure A9880812502152
Embodiment 157: Embodiment 158:
Figure A9880812502161
Embodiment 159:
Figure A9880812502162
Embodiment 160:
Figure A9880812502163
The general method for preparing alkylidene aryl sulphonyl hydrazides according to the present invention
The compound for preparing general formula I according to one embodiment of the invention, it is the alkylidene aryl sulphonyl hydrazides of the III of general formula, that is to say, by aromatic base-sulfonic acid halide (as chlorine or bromine) is converted into corresponding hydrazide derivatives, and the aldehydes or ketones of product arylsulfonyl hydrazide compound and replacement is further reacted, thereby produce alkylidene aryl sulphonyl hydrazide derivatives, this process illustrates in scheme IV.
Scheme IV
Figure A9880812502164
Wherein A, B, K, D, m, n and R 4With defined identical in the general formula I.
Under-20 ℃-100 ℃ (being preferably 0 ℃-60 ℃), use general method (Friedman for example, L.; Litle, R.L; Reichle, W.R.Org.Synth.Coll.Vol.V, 1973, the described method of 1055-1057), be dissolved in inert solvent (as tetrahydrofuran (THF) by the purified aryl sulfonyl chloride of slow adding or its, dimethyl ether, diox or diethyl ether) in solution to excessive purified hydrazine or its solution (being dissolved in a kind of of above-mentioned solvent or their mixture), come synthesizing aryl sulphonyl hydrazides precursor.When judging reaction when finishing, depress or under vacuum, remove excessive solvent and volatile medicine by distillation in atmosphere.By from solvent (as methyl alcohol, ethanol, Virahol, water, toluene, acetate, diox, tetrahydrofuran (THF) two or the compatible blend of multiple above-mentioned solvent) in recrystallization, can be further purified residual product.
In addition, can utilize methylene chloride or chloroform/methanol or Virahol as eluent by the column chromatography purified product.Depress or under vacuum, concentrate respective components in atmosphere, to produce pure arylsulfonyl hydrazides.
Can utilize the method for preparing following compounds:
Embodiment 161:
3-chloro-4-hydroxy benzenesulfonic acid (benzylidene) hydrazides
Figure A9880812502171
3-chloro-4-hydroxybenzene sulphonyl hydrazides:
In 3.4ml 50% hydrazine hydrate (54.4mmol, 2.5 equivalents), be lower than 10 ℃ speed to keep temperature, follow 4.82g (21.2mmol) the 3-chloro-4-hydroxyl-benzene sulfonyl chloride of agitation and dropping in 15ml THF (according to Popoff, I.C.; Frank, J.R.; Whitaker R.L.; Miller H.J., Demaree K.D. agricultural food product The Chemicals, 1969,17, the 810 method preparations of describing) solution.After being added dropwise to complete, throw out forms.Restir mixture 30 minutes, and it is cooled to 0 ℃.Collect solid with B ü chner funnel, with distilled water wash for several times, and air-dry it.Recrystallization in methyl alcohol provides the 3-chloro-4-hydroxybenzene sulphonyl hydrazides of 1.20g white solid form.
1H?NMR(DMSO-D 6)：δ4.78(bs，4H)，6.72(d，J＝8.6Hz，1H)，7.35(dd，J＝2.3，8.6Hz，1H)，5.55(J＝2.2Hz，1H)；MS(Cl)：m/z?223，221。
In the above-mentioned 3-chloro-4-hydroxybenzene sulphonyl hydrazides solution of 105mg in 5ml methyl alcohol (0.48mmol), add 0.05ml (52mg, 0.49mmol) phenyl aldehyde and an acetate.Enriched mixture after 30 minutes.Flash chromatography (silica gel, 2: 1 hexane/ethyl acetate) provides the title compound of 67mg (45%) solid form.
1H(DMSO-D 6)：δ7.10(d，J＝8.6Hz，1H)，7.38(m，3H)，7.55(dd，J＝2，3，6.0Hz，2H)，7.66(d，J＝2.2，8.6Hz，1H)，7.76(d，J＝2.2Hz，1H)，7.90(s，1H)，11.3(m，2H)。MS(Cl)：m/z?311。
Embodiment 162:3-chloro-4-hydroxyl-Phenylsulfonic acid [4-(4-trifluoromethoxy benzyloxy)-1-naphthyl methylene radical] hydrazides
Figure A9880812502181
3-chloro-4-hydroxyl-benzene sulfonyl hydrazides in 5ml methyl alcohol (105mg, 0.48mmol) in the solution, add 4-trifluoromethoxy benzyloxy-1-naphthaldehyde (163mg, 0.49mmol) and the glacial acetic acid (5) of catalytic amount.One night of stirred reaction mixture is also filtered it.Concentrated filtrate is to produce crude product under vacuum.Flash chromatography (silica gel, 1: 1 hexane/ethyl acetate) provides the title compound of 145mg (56%) solid form.
1H?NMR(DMSO-D 6)δ5.27(s，2H)，6.06(s，1H)，6.83(d，J＝8.1，Hz，1H)，7.10(d，J＝8.1Hz，1H)，7.26(d，J＝7.3Hz，2H)，7.50-7.60(m，5H)，7.80(s，1H)，7.85(dd，J＝3.0，8.2Hz，1H)，8.08(d，J＝2.1Hz，1H)，8.26(s，1H)，8.36(d，J＝7.76Hz，1H)，8.67(d，J＝8.5Hz，1H)。ClMS?m/z：551，553。
Can utilize the method for preparing following compounds:
Embodiment 163:
Figure A9880812502191
Embodiment 164:
Figure A9880812502192
Embodiment 165:
Figure A9880812502193
Embodiment 166:
Figure A9880812502194
According to synthesis of alkyl hydrazides of the present invention:
More than the alkylidene group hydrazide derivatives of Chan Shenging can be reduced to dihydro derivative by the method that plan V provides:
Plan V
Figure A9880812502201
A wherein, R 4, B, K is defined identical among the D, m and n and general formula I.
Can utilize metal hydride (as sodium borohydride or sodium cyanoborohydride), (be Lane, C.F. (1975) synthesizes, and p135) corresponding alkylidene group hydrazides prepares the alkyl hydrazide derivatives by reduction.Solvent (as methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF) ， diox, water or two or the compatible blend of multiple solvent) in, handle the alkylidene group hydrazide derivatives with the sodium cyanoborohydride of 1-10 equivalent (being preferably the 1-3 equivalent).Selectively, use small amount of acid as catalyzer, example hydrochloric acid, trifluoroacetic acid, acetate or sulfuric acid.Under 0 ℃-60 ℃ (being preferably 10 ℃-30 ℃), react.When judging that by HPLC or TLC (silica gel, 1% methyl alcohol in methylene dichloride is as eluent) reaction is finished, remove and desolvate, utilize 1% methyl alcohol in methylene dichloride or chloroform as eluent, and on silicagel column, resistates is carried out chromatogram.Concentrate respective components to produce required product.Illustrate that preparation is as follows according to the specific embodiment of alkyl hydrazides of the present invention.
Embodiment 167:4-hydroxy-benzoic acid (1-menaphthyl) hydrazides
Figure A9880812502202
(100mg 0.34mmol) is dissolved in the methyl alcohol (10ml), and (236mg, 4.1mmol) two trifluoroacetic acids that reach are subsequently handled it with sodium cyanoborohydride with 4-hydroxy-benzoic acid (1-naphthyl methylene radical) hydrazides.At room temperature after the stirring reaction solution 3 hours, the vaporising under vacuum solvent.Resistates is introduced silicagel column, and with methylene chloride (99/1) wash-out.It is 30% title compound that the evaporation of respective components under vacuum produced productive rate.MS(ESI)m/z293(M+H) +。
Utilize and as above describe identical method and prepared following compounds:
Embodiment 168:3-chloro-4-hydroxy-benzoic acid N-[4-(4-isopropyl benzyloxy)-3, the 5-dimethoxy-benzyl] hydrazides 1H NMR (DMSO-d 6): δ 1.18 (d, 6H), 2.87 (m, 1H), 3.75 (s, 6H), 3.90 (m, 2H), 4.80 (s, 2H), 5.43 (brd s, 1H), 6.68 (s, 2H), 6.98 (d, 1H), 7.20 (d, 2H), 7.34 (d, 2H), 7.64 (dd, 1H), 7.87 (d, 1H), 9.89 (brd s, 1H), 10.80 (s, 1H); MS (APCl): 485.2.
In addition, also can prepare following compounds:
Embodiment 169:
Figure A9880812502212
Embodiment 170:
Embodiment 171:
Figure A9880812502221
Embodiment 172:
Embodiment 173:
Figure A9880812502223
The general method of the compound of synthetic general formula X I:
Figure A9880812502224
A and B such as general formula I define, and-NR 5cR 5dBe R wherein 6a, R 4a, R 4b, c, q, d and D such as general formula I define or are-D ', wherein-D ' be defined as comprise the uncle that can play the nucleophilic reagent effect or secondary amine-subclass of D.
Steps A: reaction is known, and generally under the situation of the alkali the Quilonum Retard, sodium, potassium or the caesium that exist in the mixture that is dissolved in solvent such as acetone, 2-methyl-propione, tetrahydrofuran (THF), diox, DMSO, DMF, ethylene glycol, benzene, toluene or above-mentioned solvent, react by stirring hydroxy benzaldehyde, hydroxyl naphthalene aldehyde or the like and bromacetate (methyl, ethyl or other lower alkyl esters).Be reflected at 0 ℃-130 ℃ and preferably carry out, most preferably at or about carrying out under the reflux temperature of solvent at 20 ℃-100 ℃.Reaction is preferably at rare gas element such as N 2Or Ar) carries out under.When the starting ester of being analyzed by TLC or HPLC disappears when judging reaction and finishing, can by under the pressure of pressing in atmosphere or reducing concentrate to remove desolvate.Can by from solvent such as ethanol, methyl alcohol, Virahol, toluene, dimethylbenzene, hexane, tetrahydrofuran (THF), diethyl ether, dibutyl ether, water two or the mixture of multiple above-mentioned solvent in recrystallization be further purified product.In addition, can utilize methylene chloride or chloroform/methanol or Virahol as eluent, by the column chromatography purified product.
Step B: utilize method known to those skilled in the art then, for example at dissolved compound in the appropriate solvent of lower alcohol (as methyl alcohol, ethanol or Virahol), DMF, diox or DMSO with add as the aqueous bases lithium hydroxide, sodium or the potassium, the acetic ester derivative that comes saponification to produce.At 0 ℃-130 ℃, preferably react at 20 ℃-100 ℃.When the disappearance of the starting ester of being analyzed by TLC or HPLC is judged reaction and is finished, can by under the pressure of pressing in atmosphere or reducing concentrate to remove desolvate.Can come separated product by resistates is injected water or cold water and utilizes the mineral acid example hydrochloric acid or the sulfuric acid acidation mixture then.Can utilize solvent such as ethyl acetate, toluene, methylene dichloride or diethyl ether then,, can desolvate by next the removing that concentrate under the pressure of pressing in atmosphere or reducing then by filtering or the extraction separation product.Product can by from solvent such as ethanol, methyl alcohol, Virahol, toluene, dimethylbenzene, hexane, tetrahydrofuran (THF), diethyl ether, dibutyl ether, water two or the mixture of multiple above-mentioned solvent in recrystallization be further purified.In addition, can utilize methylene chloride or chloroform/methanol or Virahol as eluent, by the column chromatography purified product.
Step C: the acyl group hydrazides that is used in the solvent is handled the carbonyl compound that is produced.Solvent can be following a kind of: ethanol, methyl alcohol, Virahol, the trimethyl carbinol, diox, tetrahydrofuran (THF), toluene, chlorobenzene, methyl-phenoxide, benzene, chloroform, methylene dichloride, DMSO, acetate, water or two or the compatible blend of multiple above-mentioned solvent.Can add catalyzer such as acetate.Dewatering agent such as triethyl ortho-formiate also can add in the reaction mixture.At 0 ℃-140 ℃, preferably at 10 ℃-80 ℃, preferably at N 2Or under the rare gas element of Ar, react by stirred reaction mixture.In many cases, product just crystallizes out simply when reaction is finished, and can be separated by suction filtration.If necessary, it can further as above state recrystallization in the reaction solvent from solvent.Also can be by concentrated reaction mixture under vacuum, on silica gel, carry out column chromatography with solvent systems such as chloroform/methanol or methylene chloride or chloroform/ethyl acetate again and come separated product.
Step D: the acid that utilizes method known to those skilled in the art to make then to be produced and uncle or secondary amine coupling.Can utilize the acid amides or the peptide synthetic method of standard, for example, realize this coupling by producing active ester, acid anhydrides or the acyl halide that can produce the compound of general formula X I then with the amine reaction.Step D also can finish by combining with the amine of selected quantity.Can utilize solvent such as ethyl acetate, toluene, methylene dichloride or diethyl ether then, by filtering or extract separated product, and can by under the pressure of pressing in atmosphere or reducing concentrate to remove desolvate.Product can by from solvent such as ethanol, methyl alcohol, Virahol, toluene, dimethylbenzene, hexane, tetrahydrofuran (THF), diethyl ether, dibutyl ether, water two or the mixture of multiple above-mentioned solvent in recrystallization be further purified.In addition, can be with methylene chloride or chloroform/methanol or Virahol as eluent, by the column chromatography purified product to produce the compound of general formula X I.
Explanation is as follows according to the object lesson of the compound of the general formula X I of the present invention's preparation.
Embodiment 174:2-{4-[(3-chloro-4-hydroxyl-benzoyl) hydrazono-methyl] naphthalene-1-base oxygen base }-N-(4-chloro-phenyl-) ethanamide
Figure A9880812502241
Steps A: make hydroxyl naphthalene aldehyde (10g, 58mmol), salt of wormwood (16g, 110mmol) and the monobromomethane acetate (16g 100mmol) refluxes in acetone (120ml) and spends the night.Reaction mixture is injected the Erlenmeyer flask that comprises about 500ml ice fragment.Stir the mixture up to all ice-outs.(13g's methyl acetate 50mmol) spends the night for filtration and dry (4-formyl radical naphthalene-1-base oxygen base) under vacuum.
1H?NMR(CDCl 3)：δ3.86(s，3H)，4.93(s，2H)，6.80(d，1H)，7.61(t，1H)，7.72(t，1H)，7.90(d，1H)，8.42(d，1H)，9.29(d，1H)，10.22(s，1H)。
Step B: (13g 50mmol) is dissolved in the methyl alcohol (100ml) and adds 2M NaOH (40ml) with above-mentioned ester.The reaction soln stirring is spent the night and the about 100ml of simmer down under vacuum.Resistates is injected on the ice fragment of about 500ml and add 3N HCl acidifying (judging) mixture by the pH test paper.Stir the mixture up to all ice-outs.Filtration (4-formyl radical naphthalene-1-base oxygen base) acetate also washes with water.
Step C: the 3-chloro-4-hydroxy-benzoic acid hydrazides in being dissolved in DMSO (20ml) (2g, 10.7mmol) in the solution, add above-mentioned (4-formyl radical naphthalene-1-base oxygen base) acetate (3g, 13mmol) and the acetate (10) of catalytic amount.Stirred solution spends the night and dilutes with ethyl acetate.Water (3x), salt solution washing soln, and at MgSO 4Last dry.Volume is reduced to about 100ml, and is placed in the ice bath.Filter the solid produced, and with the cold ethyl acetate washing so that { 4-[(3-chloro-4-hydroxyl-benzoyl) hydrazono-methyl] naphthalene-1-base oxygen base } acetate to be provided.
1H?NMR(DMSO-d 6)：δ4.91(s，2H)，6.95(d，1H)，7.02(d，1H)，7.55(t，1H)，7.64(t，1H)，7.74(d，1H)，7.92(d，1H)，8.27(d，1H)，8.90(m，2H)，10.92(brd?s，1H)，11.63(s，1H)，13.14(brd?s，1H)。
Step D: in being dissolved in hydrazone-carboxylic acid of anhydrous DMSO (50mmol) solution, add carbonyl dimidazoles (55mmol) solution that is dissolved in anhydrous DMSO.Stop (approximately 3-4 minute) at gaseous volatilization and afterwards, added amine and stirred reaction mixture 3 hours.With ethyl acetate diluted mixture thing and water, salt water washing, and dry on sal epsom.The evaporation of solvent provides crude product, and this product can produce title compound by the reversed-phase HPLC chromatography purifying.
1H?NMR(DMSO-d 6)：δ4.99(s，2H)，7.04(m，2H)，7.36(d，2H)，7.65(m，4H)，7.79(t，2H)，7.99(s，1H)，8.40(d，1H)，8.72(s，1H)，8.92(d，1H)，10.42(s，1H)，10.96(s，1H)，11.69(s，1H)；MS(APCl)：507.9.
The profit preparation following compounds that uses the same method:
Embodiment 175:N-(1-benzyl-3-pyrrolidyl)-2-{4-[(3-chloro-4-hydroxyl-benzoyl) hydrazono-methyl] naphthalene-1-base oxygen base } ethanamide
Figure A9880812502261
1H NMR (DMSO-d 6): δ 1.96 (m, 2H), 2.32 (m, 5H), 4.58 (s, 2H), 6.78 (d, 1H), 6.92 (d, 1H), 7.15 (m, 5H), 7.47 (t, 1H), 7.52 (t, 1H), 7.62 (d, 2H), 7.82 (d, 1H), 8.18 (m, 2H), 8.78 (d, 2H), 10.75 (brd s, 1H), 11.52 (s, 1H); MS (APCl): 556.9.
Embodiment 176:2-{4-[(3-chloro-4-hydroxy benzoyl) hydrazono-methyl] naphthalene-1-base oxygen base }-N-indane-1-base-ethanamide
Figure A9880812502262
1H NMR (DMSO-d 6): δ 1.94 (m, 1H), 2.40 (m, 1H), 2.80-3.07 (m, 3H), 4.87 (s, 2H), 7.04 (d, 1H), 7.10 (d, 1H), 7.21 (m, 4H), 7.61 (t, 1H), 7.69 (t, 1H), 7.80 (t, 2H), 8.10 (s, 1H), 8.42 (d, 1H), 8.64 (d, 1H), 8.98 (m, 2H), 11.00 (brd s, 1H), 11.68 (s, 1H); MS (APCl): 514,516.
Embodiment 177:2-(4-[(3-chloro-4-hydroxy benzoyl) hydrazono-methyl] naphthalene-1-base oxygen base }-N-(1,2,, 3,4-naphthane-1-yl) ethanamide 1H NMR (DMSO-d 6): δ 1.75 (m, 2H), 1.92 (m, 2H), 2.74 (m, 2H), 4.87 (m, 2H), 5.12 (m, 1H), 7.12 (m, 6H), 7.61 (t, 1H), 7.74 (t, 1H), 7.84 (m, 2H), 8.01 (s, 1H), 8.40 (d, 1H), 8.62 (d, 1H), 8.97 (m, 2H), 11.72 (s, 1H); MS (APCl): 528,530.
Embodiment 178:2-{4-[(3-chloro-4-hydroxy benzoyl) hydrazono-methyl] naphthalene-1-base oxygen base }-N-[2-(4-chloro-phenyl-) ethyl] ethanamide 1H NMR (DMSO-d 6): δ 2.40 (t, 2H), 2.79 (t, 2H), 4.74 (s, 2H), 6.96 (d, 1H), 7.10 (d, 1H), 7.63 (t, 1H), 7.69 (t, 1H), 7.72 (m, 2H), 7.81 (s, 1H), 8.01 (m, 2H), 8.23 (t, 1H), 8.40 (d, 1H), 8.95 (s, 1H), 9.01 (d, 1H), 10.98 (brd s, 1H), 11.70 (s, 1H); MS (APCl) 538.8,537.8.
Embodiment 179:2-{4-[(3-chloro-4-hydroxy benzoyl) hydrazono-methyl] naphthalene-1-base oxygen base }-N-[3-(4-methylpiperazine-1-yl) propyl group] ethanamide
Figure A9880812502273
1H NMR (DMSO-d 6): δ 1.50 (m, 2H), 2.26 (m, 2H), 2.48 (m, 5H), 3.01 (m, 8H), 4.53 (s, 2H), 6.78 (d, 1H), 6.89 (d, 1H), 7.38 (t, 1H), 7.47 (t, 1H), 7.5 (t, 2H), 7.76 (d, 1H), 8.01 (t, 1H), 8.22 (d, 1H), 8.68 (d, 1H), 8.74 (s, 1H), 10.74 (brd s, 1H), 11.45 (s, 1H); MS (APCl): 538.0.
Embodiment 180:3-chloro-4-hydroxy-benzoic acid 4-[2-(1,2,3,4-tetrahydroisoquinoline-2-yl)-2-oxo oxyethyl group] and naphthalene-1-methylene } hydrazides
Figure A9880812502281
1H NMR (DMSO-d 6): δ 2.90 (d, 2H), 2.75 (m, 2H), 4.70 (d, 2H), 5.24 (s, 2H), 6.90 (t, 2H), 7.10 (m, 4H), 7.66 (m, 4H), 8.01 (s, 1H), 8.34 (t, 1H), 8.95 (m, 2H), 10.97 (brd s, 1H), 11.68 (brd s, 1H); MS (APCl): 514.2.
Embodiment 181:2-{4-[(3-chloro-4-hydroxyl-benzoyl) hydrazono-methyl] naphthalene-1-base oxygen base }-N-(3-trifluoro-methoxybenzyl) ethanamide
Figure A9880812502282
1H NMR (DMSO-d 6): δ 4.49 (d, 2H), 4.90 (s, 2H), 7.13 (m, 2H), 7.42 (m, 4H), 7.59 (dd, 1H), 7.68 (dd, 1H), 7.78 (m, 2H), 8.03 (s, 1H), 8.51 (d, 1H), 8.79 (t, 1H), 9.0 (m, 2H), 10.85 (brd s, 1H), 11.72 (s, 1H); MS (APCl): 572.1.
Embodiment 182:3-chloro-4-hydroxy-benzoic acid (4-{2-[4-(4-bromophenyl)-4-hydroxy piperidine-1-yl]-2-oxo oxyethyl group } naphthalene-1-methylene) hydrazides
Figure A9880812502283
MS(APCl)：636，638.
Embodiment 183:2-{4-[(3-chloro-4-hydroxy benzoyl) hydrazono-methyl] naphthalene-1-base oxygen base }-N-(4-trifluoromethyl sulfanilyl-benzyl) ethanamide
Figure A9880812502291
1H NMR (DMSO-d 6): δ 4.48 (d, 2H), 4.88 (s, 2H), 7.08 (m, 2H), 7.45 (d, 2H), 7.68 (m, 4H), 7.82 (m, 2H), 8.01 (d, 1H), 8.52 (d, 1H), 8.87 (t, 1H), 8.96 (s, 1H), 9.01 (d, 1H), 10.98 (brd s, 1H), 11.72 (s, 1H); MS (APCl): 588.2
Embodiment 184:2-{4-[(3-chloro-4-hydroxy benzoyl) hydrazono-methyl] naphthalene-1-base oxygen base }-N-(3, the 4-dichloro benzyl) ethanamide 1H NMR (DMSO-d 6): δ 4.42 (d, 2H), 4.91 (s, 2H), 7.08 (d, 1H), 7.11 (d, 1H), 7.22 (d, 1H), 7.48-7.76 (m, 4H), 7.82 (d, 2H), 8.04 (d, 1H), 8.51 (dd, 1H), 8.83 (m, 1H), 8.91 (s, 1H), 10.02 (d, 1H), 11.00 (brd s, 1H), 11.73 (s, 1H); MS (APCl): 556.0
Embodiment 185: 1H NMR (DMSO-D 6): δ 0.97 (d, 6H), 2.42 (m, 2H), 2.50 (m, 2H), 2.68 (septet, 1H), 3.49 (m, 4H), 5.12 (s, 2H), 7.03 (d, 1H), 7.08 (d, 1H), 7.60 (t, 1H), 7.68 (t, 1H), 7.80 (d, 2H), 8.01 (d, 1H), 8.33 (d, 1H), 8.94 (s, 1H), 9.00 (d, 1H), 11.68 (s, 1H); MS (APCl, neg.): 507.1,509.1.
Embodiment 186:
Figure A9880812502301
1H NMR (DMSO-D 6): δ 1.75 (m, 2H), 2.25 (m, 2H), 2.24 (d, 3H), 2.39 (quintet, 1H), 3.26 (m, 2H), [2.84 (s, 1.5H)+3.04 (s, 1.5H), 3H], 5.16 (d, 2H), 6.72 (t, 1H), 7.07 (d, 1H), 7.62 (t, 1H), 7.68 (t, 1H), 7.78 (dd, 2H), 8.00 (d, 1H), 8.34 (m, 1H), 8.94 (s, 1H), 9.00 (d, 1H), 11.65 (brds, 1H); MS (APCl): 495.2,497.2.
Embodiment 187:
Figure A9880812502302
1H NMR (DMSO-D 6): δ 0.86 (s, 3H), 1.48 (m, 4H), 2.38 (t, 1H), 2.72 (m, 1H), 3.09 (t, 1H), 3.84 (t, 1H), 4.18 (t, 1H), 5.09 (m, 2H), 7.03 (d, 1H), 7.11 (d, 1H), 7.59 (t, 1H), 7.64 (t, 1H), 7.82 (d, 2H), 8.01 (s, 1H), 8.33 (d, 1H), 8.94 (s, 1H), 9.00 (d, 1H), 11.0 (brd, 1H), 11.69 (brds, 1H); MS (APCl): 480.1,482.1.
Embodiment 188:
Figure A9880812502303
1H NMR (DMSO-D 6): δ 2.88 (s, 1.5H)+(s, 1.5H), 3H], 2.95 (t, 1H), 3.01 (s, 1.5H), 3.10 (s, 1.5H), 3.10 (t, 1H), 3.69 (t, 1H), 3.81 (t, 1H), 5.05 (d, 2H), [6.66+6.95 (d), 1H], 7.10 (d, 1H), [7.20+7.38 (d), 1H], 7.29 (d, 1H), 7.67 (m, 5H), 8.01 (s, 1H), 8.30 (t, 1H), 8.53 (dd, 1H), 8.97 (m, 2H), 11.67 (brd s, 1H); MS (APCl): 517.3,519.2.
Embodiment 189:
Figure A9880812502311
1H NMR (DMSO-D 6): δ 3.88 (s, 6H), 4.75 (s, 2H), 6.93 (d, 1H), 7.08 (m, 3H), 7.34 (dd, 1H), 7.74 (dd, 1H), 7.79 (d, 1H), 7.95 (s, 1H), 8.37 (s, 1H), 9.74 (s, 1H), 10.03 (m, 1H), 10.96 (brds, 1H), 11.76 (brd s, 1H); MS (APCl): 534.4,536.2.
Embodiment 190:
Figure A9880812502312
1H NMR (DMSO-D 6): δ 1.18 (d, 6H), 2.85 (m, 1H), 3.87 (s, 3H), 4.76 (s, 2H), 6.71 (d, 1H), 6.78 (d, 1H), 7.06 (d, 1H), 7.20 (d, 2H), 7.58 (d, 2H), 7.78 (dd, 1H), 7.82 (d, 1H), 7.99 (d, 1H), 8.70 (s, 1H), 10.04 (s, 1H), 10.92 (brd s, 1H), 11.62 (brd s, 1H); MS (APCl): 496.5,498.2.
Embodiment 191:
Figure A9880812502313
1H NMR (DMSO-D 6): δ 4.88 (s, 2H), 6.93 (t, 2H), 7.23 (d, 2H), 7.47-7.70 (m, 6H), 7.86 (d, 1H), 8.30 (d, 1H), 8.80 (s, 1H), 8.87 (d, 1H), 10.34 (s, 1H), 10.82 (brd s, 1H), 11.55 (brd s, 1H); MS (APCl): 558.5,560.0.
Embodiment 192:
Figure A9880812502314
1H NMR (DMSO-D 6): δ 4.06 (s, 3H), 4.94 (s, 2H), 6.81 (d, 1H), 6.89 (s, 1H), 7.19 (d, 1H), 7.45 (s, 1H), 7.90 (m, 3H), 8.10 (s, 1H), 8.82 (s, 1H), 10.62 (s, 1H), 11.07 (brd s, 1H), 11.75 (s, 1H); MS (APCl): 523.3,524.8,526.6.
Embodiment 193: 1H NMR (DMSO-D 6): δ 1.68 (m, 2H), 2.01 (m, 2H), 3.05 (m, 2H), 3.35 (m, 2H), 3.86 (m, 1H), 4.26 (s, 2h), 4.81 (s, 2H), 6.95 (d, 1H), 7.09 (d, 1H), 7.46 (s, 5H), 7.59 (m, 1H), 7.66 (t, 1H), 7.77 (d, 1H), 7.98 (d, 1H), 8.34 (d, 1H), 8.41 (d, 1H), 8.92 (m, 2H), 9.65 (brds, 1H), 11.02 (brd s, 1H), 11.80 (brd s, 1H); MS (APCl): 571.3,572.3,573.3.
Embodiment 194: 1H NMR (DMSO-D 6): δ 2.79 (t, 2H), 3.43 (qt, 2H), 4.71 (s, 2H), 6.95 (d, 1H), 7.08 (d, 1H), 7.17 (m, 1H), 7.26-7.30 (m, 3H), 7.61 (t, 1H), 7.67 (t, 1H), 7.76 (m, 2H), 7.99 (d, 1H), 8.24 (t, 1H), 8.38 (d, 1H), 8.91 (s, 1H), 8.98 (d, 1H), 10.94 (s, 1H), 11.67 (s, 1H); MS (APCl): 536.3,538.2,539.1.
Embodiment 195:
Figure A9880812502323
1H NMR (DMSO-D 6): δ 4.42 (d, 2H), 4.87 (s, 2H), 7.06 (m, 2H), 7.38 (d, 2H), 7.60 (t, 1H), 7.63 (m, 1H), 7.80 (t, 1H), 7.99 (d, 1H), 8.49 (d, 1H), 8.79 (t, 1HJ), 8.93 (s, 1H), 8.98 (d, 1H), 10.95 (s, 1H), 11.68 (s, 1H); MS (APCl): 558.2,560.1.
Embodiment 196:4-(4-bromophenyl-3,4-dihydroxyl piperidines acetic oxide amine) naphthalene-1-methylene-3-chloro-4-hydroxy-benzoic acid hydrazone
Figure A9880812502331
Reaction scheme:
4-(4-bromophenyl)-4-piperidines alcohol chlor(o)acetamide (steps A): at the 4-that is dissolved in DMF (30ml) (4-bromophenyl)-4-piperidines alcohol (5g, 19.5mmol) and diisopropylethylamine (2.8g, 21.5mmol) drip in the solution chloroacetyl chloride (2.2g, 21.5mmol).After stirring the mixture 1 hour, with ethyl acetate diluted mixture thing, with aqueous carbonic acid hydrogen sodium (2x), 1N HCl (3x), water, salt water washing, and at MgSO 4Last dry.Concentrated solution also utilizes ethyl acetate to carry out chromatogram on silica gel, thereby produces the product (4g, 62%) of brown solid form.
1H?NMR(DMSO-D 6)：δ1.21(d，2H)，1.71(t，1H)，1.96(t，1H)，2.71(t，1H)，3.37(t，1H)，3.70(d，1H)，4.27(d，1H)，4.54(s，2H)，5.26(s，1H)，7.42(d，2H)，7.51(d，2H)。
4-(4-bromophenyl)-3,4-dihydroxyl piperidines chlor(o)acetamide (step B): be dissolved in the usefulness ice bath refrigerative 4-(4-bromophenyl) of THF (40ml)-4-piperidines alcohol chlor(o)acetamide (4g, 12mmol) and diisopropylethylamine (4.6ml, 26mmol) in the solution, add methane sulfonyl chloride (2ml, 26mmol) and mixture was refluxed 16 hours under nitrogen blanket.Also use 1N HCl (2x), aqueous NaHCO with the ethyl acetate diluted reaction mixture 3(2x), salt solution (2x) washing, and at MgSO 4Last dry.Evaporating solvent also utilizes ethyl acetate/hexane (4/6) in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel.Obtain the product (1.5g, 32%) of yellow solid form.
1H?NMR(DMSO-D 6)：δ2.44(t，2H)，3.62(m，2H)，4.14(dd，2H)，4.42(d，2H)，6.21(s，1H)，7.36(m，2H)，7.51(d，2H)。
4 (4-bromophenyls-3,4-dihydroxyl piperidines acetic oxide amine) naphthaldehyde (step C): make the 4-(4-bromophenyl)-3 that is dissolved in the acetonitrile (50ml), 4-dihydro piperidines chlor(o)acetamide (1.5g, 4.8mmol), 4-hydroxyl naphthalene aldehyde (1.2g, 7mmol) and potassium carbonate powder (1g, 7.2mmol) mixture refluxed 16 hours.With ethyl acetate diluted mixture thing and with salt solution (3x) washing, at MgSO 4Last dry, and make it concentrated.Utilize the silica gel chromatography of ethyl acetate/hexane (1/1) that product (1.4g, 65%) is provided.
1H?NMR(DMSO-D 6)：δ2.27-2.32(m，2H)，3.49-3.55(m，2H)，3.94(brds，1H)，4.06(brd?s，1H)，5.08(s，1H)，5.13(s，1H)，6.05(s，1H)，6.97(t，1H)，7.20(t，1H)，7.34(d，2H)，7.42-7.47(m，1H)，7.52-7.57(m，1H)，7.92(d，1H)，8.16(d，1H)，9.01(d，1H)，9.97(s，1H)。
4 (4-bromophenyls-3,4-dihydro piperidines acetic oxide amine) naphthalene-1-methylene-3-chloro-4-hydroxy-benzoic acid hydrazone (step D): according to the general method of synthetic alkylidene group hydrazides, by condensation 3-chloro-4-hydroxy-benzoic acid hydrazides and 4-(4-bromophenyl-3,4-dihydro piperidines acetic oxide amine) naphthaldehyde prepares title compound:
1H?NMR(DMSO-D 6)：δ2.47-2.58(m，2H)，3.72(br?s，2H)，4.13(s，1H)，4.26(s，1H)，5.14(s，1H)，5.18(s，1H)，6.23(s，1H)，6.50-6.53(m，1H)，7.03-7.06(m，1H)，7.35-7.38(m，2H)，7.52(d，2H)，7.58(d，2H)，7.59-7.67(m，1H)，7.75(d，1H)，7.84(s，1H)，8.32(d，1H)，8.89(s，1H)，8.92(s，1H)，11.41(s，1H)；MS(APCl)：618.1，620.1，621.1，622.1。
Embodiment 197: embodiment 202:
Embodiment 199:
Embodiment 204:
Figure A9880812502353
Embodiment 201: embodiment 206:
Figure A9880812502354
Embodiment 207:15 embodiment 212:
Embodiment 208: embodiment 213:
Figure A9880812502362
Embodiment 209: embodiment 214:
Figure A9880812502363
Embodiment 210: embodiment 215:
Embodiment 217: embodiment 222:
Embodiment 218: embodiment 223:
Figure A9880812502372
Embodiment 219: embodiment 224:
Figure A9880812502373
Embodiment 220: embodiment 225:
Figure A9880812502374
Embodiment 221: embodiment 226:
Embodiment 227: embodiment 232:
Figure A9880812502381
Figure A9880812502382
Figure A9880812502383
Embodiment 230: embodiment 235:
Embodiment 231: embodiment 236:
Embodiment 237: embodiment 242:
Figure A9880812502391
Embodiment 238:20 embodiment 243:
Figure A9880812502392
Embodiment 239: embodiment 244:
Figure A9880812502394
Embodiment 247:15 embodiment 252:
Figure A9880812502401
Embodiment 248: embodiment 253:
Figure A9880812502402
Embodiment 249: embodiment 254:
Figure A9880812502404
Embodiment 251: embodiment 256:
Figure A9880812502405
Embodiment 257:15 embodiment 262:
Figure A9880812502411
Embodiment 258: embodiment 263:
Figure A9880812502412
Embodiment 259: embodiment 264:
Figure A9880812502413
Embodiment 260: embodiment 265:
Figure A9880812502414
Embodiment 261: embodiment: 266
Embodiment 267: embodiment 272:
Figure A9880812502421
Embodiment 268:20 embodiment 273:
Figure A9880812502422
Embodiment 269: embodiment 274:
Figure A9880812502423
Embodiment 270: embodiment 275:
Figure A9880812502424
Embodiment 271: embodiment 276:
Figure A9880812502425
Embodiment 277: embodiment 282:
Figure A9880812502431
Embodiment 278: embodiment 283:
Figure A9880812502432
Embodiment 279: embodiment 284:
Figure A9880812502433
Embodiment 285:
Embodiment 280:
Figure A9880812502434
Embodiment 287: embodiment 291:
Figure A9880812502441
Embodiment 288:15 embodiment 292:
Embodiment 289: embodiment 293:
Figure A9880812502443
Embodiment 290: embodiment 294:
Figure A9880812502444
Embodiment 295: embodiment 299:
Embodiment 296: embodiment 300:
Figure A9880812502452
Embodiment 297: embodiment 301:
Figure A9880812502453
Embodiment 298:
Embodiment 302:15 embodiment 307:
Figure A9880812502461
Embodiment 303: embodiment 308:
Figure A9880812502462
Embodiment 304: embodiment 309:
Figure A9880812502463
Embodiment 305: embodiment 310:
Embodiment 306: embodiment 311:
Figure A9880812502465
Embodiment 312:15 embodiment 317:
Embodiment 313: embodiment 318:
Embodiment 314: embodiment 319:
Figure A9880812502473
10 embodiment 315: embodiment 320:
Figure A9880812502481
Embodiment 316: embodiment 321:
Figure A9880812502482
Embodiment 322:15 embodiment 327:
Figure A9880812502491
Embodiment 323: embodiment 328:
Figure A9880812502492
Embodiment 324: embodiment 329:
Figure A9880812502493

Claims (43)

1. compound with general formula I:
Figure A9880812500021
R wherein 1And R 2Be respectively hydrogen or low alkyl group or their common valence links that forms; R 3And R 4Be respectively hydrogen or low alkyl group; N is 0,1,2 or 3; M is 0 or 1; X is＞C=O,＞C=S,＞C=NR5 or＞SO 2R wherein 5Be hydrogen, low alkyl group, aromatic base-low alkyl group or-OR 6R wherein 6Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
A is:
R wherein 7Be hydrogen, halogen ,-CN ,-CF 3,-OCF 3,-OCH 2CF 3,-NO 2,-OR 11,-NR 11R 12, low alkyl group, aromatic base, aromatic base-low alkyl group ,-SCF 3,-SO 2NR 11R 12,-SR 11,-CHF 2,-CHF 2,-OCHF 2,-OSO 2R 11,-CONR 11R 12,-OCH 2CONR 11R 12,-CH 2OR 11,-CH 2NR 11R 12,-OCOR 11,-CO 2R 13Or-OSO 2CF 3
R 8And R 9Be respectively hydrogen, halogen ,-CN ,-CF 3,-OCF 3,-OCF 3,-OCH 2CF 3,-NO 2,-OR 11,-NR 11R 12, low alkyl group, aromatic base ,-SCF 3,-SR 11,-CHF 2,-OCHF 2,-OSO 2R 11,-CONR 11R 12,-CH 2OR 11,-CH 2NR 11R 12,-OCOR 11,-CO 2R 13Or-OSO 2CF 3, or R 8And R 9Common bridge-the OCH that forms 2O-or-OCH 2CH 2O;
R wherein 11And R 12Be respectively hydrogen ,-COR 13,-SO 2R 13, low alkyl group or aromatic base;
R wherein 13Be hydrogen, low alkyl group, aromatic base-low alkyl group or aromatic base; And
R wherein 10Be hydrogen, low alkyl group, aromatic base-low alkyl group or aromatic base;
B is Or valence link;
Wherein: R 14And R 15Be respectively hydrogen, halogen ,-CN ,-CF 3,-OCF 3,-O (CH 2) 1CF 2,-NO 2,-OR 16,-NR 16R 17, low alkyl group, aromatic base, aromatic base-low alkyl group ,-SCF 3,-SR 16,-CHF 2,-OCHF 2,-OCF 2CHF 2,-OSO 2CF 3,-CONR 16R 17,-(CH 2) 1CONR 16R 17, O (CH 2) 1CONR 16R 17,-(CH 2) 1COR 16,-(CH 2) 1COR 16,-(CH 2) 1OR 16,-O (CH 2) 1OR 16,-(CH 2) 1NR 16R 17,-O (CH 2) 1NR 16R 17,-OCOR 16,-CO 2R 18,-O (CH 2) 1CO 2R 18,-O (CH 2) 1CN ,-O (CH 2) 1Cl, or R 14And R 15Form bridge-O (CH together 2) 1O-or-(CH 2) 1-;
Wherein l is 1,2,3 or 4;
R 16And R 17Be respectively hydrogen ,-COR 18,-SO 2R 18, low alkyl group, aromatic base, or R 16And R 17The common cyclic alkyl bridge that includes 2 to 7 carbon atoms that forms;
R wherein 18Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
W is-N=or-CR 19=;
Y is-N=or-CR 20=;
Z is-N=or-CR 21=;
V is-N=or-CR 22=; And
Q is-NR 23-,-O-or-S-;
Wherein:
R 19, R 20, R 21And R 22Be respectively hydrogen, halogen ,-CN ,-CF 3,-OCF 3,-OCH 2CF 3,-NO 2,-OR 24,-NR 24R 25, low alkyl group, aromatic base, aromatic base-low alkyl group ,-SCF 3,-SR 24,-CHF 2,-OCHF 2,-OCF 2CHF 2,-OSO 2CF 3,-CONR 24R 25,-CH 2CONR 24R 25,-OCH 2CONR 24R 25,-CH 2OR 24,-CH 2NR 24R 25,-OCOR 24Or-CO 2R 24, or R 19And R 20, R 20And R 21, perhaps R 21And R 22Common bridge-the OCH that forms 2O-;
R wherein 24And R 25Be respectively hydrogen ,-COR 26,-SO 2R 26, low alkyl group, aromatic base or aromatic base low alkyl group;
R wherein 26Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group; And
R 23Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
K is
Figure A9880812500051
Wherein:
R 3a, R 3b, R 4aAnd R 4bBe respectively hydrogen, halogen ,-CN ,-CF 3,-OCF 3,-OCH 2CF 3,-NO 2,-OR 24a,-NR 24aR 25a, low alkyl group, aromatic base, aromatic base-low alkyl group ,-SCF 3,-SR 24a,-CHF 2,-OCHF 2,-OCF 2CHF 2,-OSO 2CF 3,-CONR 24aR 25a,-CH 2CONR 24aR 25a,-OCH 2CONR 24aR 25a,-CH 2OR 24a,-CH 2NR 24aR 25a,-OCOR 24aOr-CO 2R 24a
R wherein 24aAnd R 25aBe respectively hydrogen ,-COR 26a,-SO 2R 26a, low alkyl group, aromatic base or aromatic base-low alkyl group;
R wherein 26aBe hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group; Perhaps
R 3aAnd R 3b, R 4aAnd R 4b, or R 3aAnd R 4bThe common bridge-(CH that forms 2) i-;
Wherein i is 1,2,3 or 4;
A, b, c and d are respectively 0,1,2,3 or 4;
E, f and p are respectively 0 or 1;
Q is 0,1 or 2; And
L and M are-O--S-,-CH=CH-,-C ≡ C-,-NR respectively 5a-,-CH 2NR 5a-,-CO-,-OCO-,-COO-,-CONR 5a-,-CONRU ,-NR 5aCO-,-SO-,-SO 2-,-OSO 2-,-SO 2NR 5a-,-NR 5aSO 2,-NR 5aCONR 5b,-CONR 5aNR 5b-,-NR 5aCSNR 5b-,-OCONR 5b-,-CH 2CONR 5b-,-OCH 2CONR 5b-,-P (O) (OR 5a) O-,-NR 5aC (O) O-or
Figure A9880812500061
R wherein 5aAnd R 5bBe respectively hydrogen, low alkyl group ,-OH ,-(CH 2) k-OR 6a,-COR 6a,-(CH 2) k-CH (OR 6a) ,-(CH 2) k-CN ,-(CH 2) k-NR 6aR 6b, aromatic base, aromatic base-low alkyl group ,-(CH 2) g-COOR 43Or-(CH 2) g-CF 3
Wherein k is 1,2,3 or 4;
R 6aAnd R 6bBe respectively hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
G is 0,1,2,3 or 4;
R 43Be hydrogen or low alkyl group;
G " is-OCH 2CO-,-CH 2CO-,-CO-or valence link; And E " is-CH 2-,-CH 2CH 2-,-CH=CH-,-CH 2NH-or-CH 2CH 2NH-; D is a hydrogen,
Figure A9880812500071
Wherein:
R is 0 or 1;
S is 0,1,2 or 3;
E, E ', F, G and G ' are respectively-CHR 38-,＞C=O,＞NR 39,-O-or-S-;
F ' is＞CR 38-or＞N-;
Y ' is-N=or-CR 32=;
Z ' is-N=or-CR 33=;
V ' is-N=or-CR 34=;
W ' is-N=or-CR 35=; And
Q ' is-NR 36-,-O-or-S-;
Wherein:
R 27, R 28, R 32, R 33, R 34And R 35Be respectively hydrogen, halogen ,-CN ,-CF 3,-O (CH 2) yCF 3,-(CH 2) yNHCOCF 3,-NO 2, low alkyl group, aromatic base, aromatic base-low alkyl group ,-SCF 3,-SR 29,-CHF 2,-OCHF 2,-OCF 2CHF 2,-OSO 2R 29,-OSO 2CF 3,-(CH 2) yCONR 29R 30,-O (CH 2) yCONR 29R 30,-(CH 2) yOR 29,-(CH 2) yNR 29R 30,-OCOR 29,-COR 29Or-CO 2R 29Perhaps
R 27And R 28, R 32And R 33, R 33And R 34, or R 34And R 35Common bridge-O (CH that forms 2) yO-;
Wherein y is 0,1,2,3 or 4; And
R 29And R 30Be respectively hydrogen ,-COR 31,-CO 2R 31,-SO 2R 31, low alkyl group, aromatic base or aromatic base-low alkyl group;
R wherein 31Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
R 36And R 39Be respectively hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group; And
R 38Be hydrogen ,-OR 40,-NR 40R 41, low alkyl group, aromatic base, aromatic base-low alkyl group ,-SCF 3,-SR 40,-CHF 2,-OCHF 2,-OCF 2CHF 2,-CONR 40R 41,-(CH 2) xCONR 40R 41,-O (CH 2) xCONR 40R 41,-(CH 2) xOR 40,-(CH 2) xNR 40R 41,-OCOR 40Or ,-CO 2R 40
Wherein x is 1,2,3 or 4;
R 40And R 41Be respectively hydrogen ,-COR 42,-SO 2R 42, low alkyl group, aromatic base or aromatic base-low alkyl group;
R wherein 42Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group;
Also can be its optics or geometry isomer or tautomer, wherein include mixture or a kind of pharmacy acceptable salt of these materials.
2. according to the compound of claim 1, this compound has Formula Il:
Figure A9880812500091
A wherein, B, K, D, R 3, R 4, the definition in n and m such as the claim 1.
3. according to the compound of claim 1, this compound has Formula Il I:
Figure A9880812500092
A wherein, B, K, D, R 3, R 4, the definition in n and m such as the claim 1.
4. according to the compound of claim 1, this compound has following formula I V:
Figure A9880812500093
A wherein, B, K, D, R 3, R 4, the definition in n and m such as the claim 1.
5. according to the compound of the arbitrary claim in front, R wherein 3Be hydrogen.
6. according to the compound of the arbitrary claim in front, R wherein 4Be hydrogen.
7. according to the compound of the arbitrary claim in front, wherein A is selected from the group of following formula:
Figure A9880812500094
Figure A9880812500101
R wherein 7, R 8, R 9And R 10As the definition in the claim 1.
8. according to the compound of claim 7, wherein A is
Figure A9880812500102
R wherein 7, R 8And R 9As the definition in the claim 1.
9. according to the compound of claim 7 or 8, R wherein 7Be halogen, low alkyl group ,-OH ,-NO 2,-CN ,-CO 2H ,-O-low alkyl group, aromatic base, aromatic base-low alkyl group ,-CO 2CH 3,-CONH 2,-OCH 2CONH 2,-NH 2,-N (CH 3) 2,-SO 2NH 2,-OCHF 2,-CF 3Or-OCF 3
10. according to arbitrary compound of claim 7 to 9, R wherein 8And R 9Be respectively hydrogen, halogen ,-OH ,-NO 2,-NH 2,-CN ,-OCF 3,-SCF 3,-CF 3,-OCH 2CF 3,-O-low alkyl group, low alkyl group or phenyl, and R 10Be hydrogen, low alkyl group or phenyl.
11. according to the compound of claim 10, wherein R 8And R 9Be respectively hydrogen, halogen ,-O-low alkyl group ,-NH 2,-CN or-NO 2, and R 10Be hydrogen.
12. according to the compound of claim 8, wherein A is
Figure A9880812500103
R wherein 8And R 9Respectively as the definition in claim 10 or 11.
13. according to the compound of claim 12, wherein A is
Figure A9880812500111
R wherein 8Be hydrogen, halogen ,-O-low alkyl group ,-NH 2,-CN or-NO 2And R 9It is hydrogen or halogen.
14. according to arbitrary compound of claim 7 to 13, this compound has following formula V:
Figure A9880812500112
R wherein 8And R 9As claim 1, arbitrary definition of 10,11 or 13, and R 4, B, K, the definition in D and m such as the claim 1.
15. according to the compound in the arbitrary claim in front, wherein B is
Figure A9880812500113
V wherein, W, Z, the definition in Y and Q such as the claim 1, and R 14And R 15Be respectively hydrogen, halogen ,-CF 3,-OCF 3,-OR 16,-NR 16R 17, low alkyl group, aromatic base, aromatic base-low alkyl group ,-OSO 2CF 3,-CONR 16R 17,-CH 2OR 16,-CH 2NR 16R 17,-OCOR 16Or-CO 2R 18Or R 14And R 15Common bridge-the OCH that forms 2O-or-(CH 2) 1-; L wherein, R 16, R 17And R 18As the definition in the claim 1.
16. according to the compound in the claim 15, wherein Q be-O-or-NH-.
17. according to the compound in the claim 15, wherein B is
Figure A9880812500121
R wherein 14And R 15As the definition in the claim 15, and V, W, the definition in Z and Y such as the claim 1.
18. according to the compound in the claim 17, this compound has following formula VI:
Figure A9880812500122
R wherein 14And R 15As the definition in the claim 15, R 8And R 9As claim 1,10,11 or 13 arbitrary in definition, and K, the definition in D and m such as the claim 1.
19. according to the compound of claim 17, this compound has following formula VII:
R wherein 14And R 15As the definition in the claim 15, R 8And R 9As claim 1,10,11 or 13 arbitrary in definition, and K, 1 definition in D and m such as the claim.
20. according to the compound of claim 17, this compound has following formula VIIIa or VIIIb:
R wherein 14And R 15As the definition in the claim 15, R 8And R 9As claim 1,10,11 or 13 arbitrary in definition, and K, the definition in D and m such as the claim 1.
21. according to arbitrary compound of claim 15 to 20, wherein R 14And R 15Be respectively hydrogen, halogen, low alkyl group ,-O-low alkyl group or aromatic base.
22. according to the compound of the arbitrary claim in front, wherein K is selected from the group that following formula is formed:
Figure A9880812500141
Figure A9880812500151
Figure A9880812500161
R wherein 3a, R 3b, R 4a, R 4b, R 5a, R 5b, a, b, c, d, the definition in p and q such as the claim 1.
23. according to the compound of claim 22, wherein K is selected from the group that following formula is formed:
Figure A9880812500181
Figure A9880812500191
R wherein 3a, R 3b, R 4a, R 4b, R 5a, R 5b, a, b, c, d, the definition in p and q such as the claim 1.
24. according to the compound of claim 23, wherein K is selected from the group that following formula is formed:
Figure A9880812500201
Figure A9880812500211
Figure A9880812500221
R wherein 3a, R 3b, R 4a, R 4b, R 5a, R 5b, b, c, d, the definition in p and q such as the claim 1.
25. according to the arbitrary compound of claim 22 to 24, wherein R 5aAnd R 5bBe respectively hydrogen, low alkyl group ,-OH ,-(CH 2) kOR 6a, aromatic base, aromatic base-low alkyl group ,-CH 2CF 3,-(CH 2) g-COOR 43,-COOR 43,-(CH 2) kCN or-(CH 2) k-NR 6aR 6b, g wherein, k, R 43, R 6aAnd R 6bAs the definition in the claim 1.
26. according to the compound of claim 25, wherein g and k are respectively 1,2 or 3, R 6aAnd R 6bBe respectively hydrogen, low alkyl group such as methyl or ethyl, perhaps aromatic base such as phenyl.
27. according to the arbitrary compound of claim 22 to 26, wherein R 3aAnd R 3bBe respectively hydrogen, halogen ,-OH ,-O-low alkyl group ,-COO-low alkyl group, low alkyl group or aromatic base-low alkyl group.
28. according to the arbitrary compound of claim 22 to 27, wherein R 4bAnd R 4bBe respectively hydrogen ,-CN ,-CONH 2,-(CH 2)-N (CH 3) 2,-O-low alkyl group ,-CH 2OH ,-CH 2The O-aromatic base ,-N (CH 3) 2,-OH ,-CO 2-low alkyl group or low alkyl group.
29. according to the compound of the arbitrary claim in front, wherein D is a hydrogen,
Figure A9880812500231
S wherein, r, R 27, R 28, V ', Y ', Q ', Z ', W ', E, E ', F, F ', G and G ' are as the definition in the claim 1.
30. according to the compound of claim 29, wherein D is a hydrogen,
Figure A9880812500232
S wherein, r, R 27, R 28, V ', Y ', Z ', Q ', Z ', W ', E, E ', F, F ', G and G ' are as the definition in the claim 1.
31. according to the compound of claim 29, wherein D is a hydrogen,
Figure A9880812500242
Figure A9880812500251
Wherein E and E ' are respectively＞CHR 38,＞NR 39Or-O-; F, G and G ' are respectively＞CHR 38,＞C=O or＞NR 39F ' is＞CR 38-or＞N-; And s, r, Ru, R 28, R 38, R 39, V ', Y ', Z ', Q ' and W ' are as the definition in the claim 1.
32. according to compound arbitrary in the claim 29 to 31, wherein R 27And R 28Be respectively hydrogen; Halogen is as-Cl ,-Br or-F;-CF 3,-OCF 3-OCHF 2-OCH 2CF 3-(CH 2) yNHCOCF 3-NHCOCF 3-CN;-NO 2-COR 29,-COOR 29,-(CH 2) yOR 29Or-OR 29, R wherein 29Be hydrogen, aromatic base or low alkyl group and y are 1,2,3 or 4; Low alkyl group such as methyl, ethyl, 2-propenyl, sec.-propyl, the tertiary butyl or cyclohexyl; Lower alkylthio;-SCF 3Aromatic base such as phenyl;-(CH 2) yNR 29R 30Or-NR 29R 30, R wherein 29And R 30Be respectively hydrogen ,-COO-low alkyl group or low alkyl group and y are 1,2,3 or 4; Or-CONH 2Perhaps R 27And R 28Common bridge-the OCH that forms 2O-; R 38Be hydrogen;-OCHF 2-OR 40, R wherein 40Be hydrogen or low alkyl group; Low alkyl group such as methyl, the sec.-propyl or the tertiary butyl; Lower alkylthio;-SCF 3-CH 2OH;-COO-low alkyl group or-CONH 2And R 39Be hydrogen, low alkyl group, aromatic base or aromatic base-low alkyl group.
33. the arbitrary compound according to claim 1 to 32 is used as a kind of medicine.
34. a pharmaceutical composition, said composition comprise the compound as the arbitrary description at least a claim 1 to 32 of activeconstituents, and one or more pharmaceutically acceptable carrier or vehicle.
35. pharmaceutical composition according to claim 34, it is on unit dosage form, comprise from about 0.05mg to about 1000mg, be preferably from about 0.1mg to about 500mg, as the compound of describing arbitrary from about 0.5mg to about 250mg claim 1 to 32.
36. a method for the treatment of I type or type ii diabetes is included in the arbitrary middle compound of describing of claim 1 to 32 of using effective dose when needing to the patient.
37. a method for the treatment of hyperglycemia is included in the arbitrary middle compound of describing of claim 1 to 32 of using effective dose when needing to the patient.
38. a method that reduces Mammals blood sugar is included in the arbitrary middle compound of describing of claim 1 to 32 of using effective dose when needing to the patient.
39. arbitrary method according to claim 36 to 38, comprise when needed and use a certain amount of compound that defines as in the claim 1 to 33 to the patient, amount ranges is to about 1000mg from about 0.05mg, be preferably from about 0.1mg to about 500mg, as from about 0.5mg to about 250mg, once a day or repeatedly, as every day 1 to 3 time.
40. use the purposes of the medicine of arbitrary middle compound manufacturing treatment I type of describing of claim 1 to 32 and type ii diabetes.
41. use the purposes of the medicine of the arbitrary middle compound manufacturing treatment hyperglycemia of describing of claim 1 to 32.
42. use the arbitrary middle compound manufacturing of describing of claim 1 to 32 to reduce the purposes of the medicine of Mammals blood sugar.
43. according to arbitrary compound of claim 1 to 32, be feature to have the hyperglycemic-glycogenolytic factor antagonistic activity, as the hyperglycemic-glycogenolytic factor here in conjunction with measuring I and hyperglycemic-glycogenolytic factor in conjunction with measuring as shown in the II corresponding IC 50Value is preferably less than 500nM less than 1 μ M, even more preferably less than 100nM.
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