CN1057256A - New benzimidizole derivatives, their method for making, new intermediate and they are as the application of medicine and contain their pharmaceutical composition - Google Patents
New benzimidizole derivatives, their method for making, new intermediate and they are as the application of medicine and contain their pharmaceutical composition Download PDFInfo
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- CN1057256A CN1057256A CN91103858A CN91103858A CN1057256A CN 1057256 A CN1057256 A CN 1057256A CN 91103858 A CN91103858 A CN 91103858A CN 91103858 A CN91103858 A CN 91103858A CN 1057256 A CN1057256 A CN 1057256A
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
- C07C233/15—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/40—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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- C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
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Abstract
The objective of the invention is formula (I
B) product and all possible isomer and formula (I
B) product and the additive salt of bronsted lowry acids and bases bronsted lowry formation and their preparation method.R, R in the formula
1B, R
2B, R
3B, R
4BAnd R
5BDefinition such as specification sheets described in.Described product has useful pharmacological properties, and these character have determined its application as medicine.
Description
The present invention relates to new benzimidizole derivatives, their preparation method, resulting new intermediate, they are as the application of medicine and contain their pharmaceutical composition.
The objective of the invention is formula (I
B) product:
In the formula:
The R representative contains the straight or branched alkyl or the alkenyl of 3 or 4 carbon atoms,
R
1B, R
2B, R
3BAnd R
5BBe defined as follows:
Perhaps R
1B, R
2B, R
3BAnd R
5BIt is mutually the same and represent hydrogen atom,
Perhaps R
2BAnd R
5BIn have one to represent hydrogen atom, and another represent hydrogen atom or-CH
2-O-R
10Group, wherein R
10Represent hydrogen atom or contain the straight or branched alkyl or the alkenyl of 5 carbon atoms at most, perhaps R
2BAnd R
5BOne of them representative
Group, wherein R
cAnd R
dBe same to each other or different to each other, and representative is hereinafter to R
aAnd R
bThe implication that is limited, R
1BAnd R
3BOne of them is a hydrogen atom, and another then is selected from-OR
6,-CO
2R
7With-R
11Group, wherein:
R
6And R
7Be same to each other or different to each other, represent hydrogen atom or contain the straight or branched alkyl or the alkenyl of 5 carbon atoms at the most,
R
11Be selected from:
A) contain the alkyl of 4 carbon atoms at the most, this alkyl can at random be selected from following group by one or more and replace:
-halogen atom,
-the hydroxyl of acidylate arbitrarily,
-contain the straight or branched alkoxyl group or the alkenyloxy of 5 carbon atoms at the most,
-can be by any aryl that replaces of one or more substituting groups, described substituting group is selected from: halogen atom, hydroxyl, trifluoromethyl, cyano group, nitro, amino, contain the alkoxyl group, phenyl, benzyl, free of 4 carbon atoms, the carboxyl and the tetrazyl of salifiable or esterification at the most
Carboxyl-free, esterification or salifiable,
-Shi
Group, R in the formula
aAnd R
bBe same to each other or different to each other, they are selected from hydrogen atom, contain the alkyl of 1 to 4 carbon atom or alkenyl and aryl, all these groups can at random be replaced by one or more substituting groups, described substituting group is selected from: halogen atom or hydroxyl, trifluoromethyl, cyano group, nitro or amino, contain alkoxyl group, phenyl or benzyl, the free of 4 carbon atoms, the carboxyl and the tetrazyl of salifiable or esterification at the most
B) contain the straight or branched alkenyl of 2 to 5 carbon atoms,
C) contain the acyl group and the formyl radical of 2 to 7 carbon atoms,
D) formula
Group, R in the formula
aAnd R
bDescribed as defined above, perhaps R
1B, R
2B, R
3BAnd R
5BIn have one to represent hydrogen atom at the most, other then is selected from-CH
2-O-R
10,-OR
6,-CO
2R
7, R
11And formula
Group, wherein R
6, R
7, R
10, R
11, R
cAnd R
dDescribed as defined above,
R
4BRepresent free, esterification or salifiable carboxyl or tetrazyl,
Or-(CH
2)
m-SO
2-X-R
12Group, in the formula m represent 0 to 4 integer and
Perhaps (X-R
12) represent NH
2
Perhaps X represents singly-bound, or-NH-,-NH-CO-NH-or-the NH-CO-group,
R
12Represent alkyl, alkenyl or aryl, these groups can at random be substituted,
Described formula (I
B) product comprises all possible racemize, mapping or diastereomer,
And described formula (I
B) product and inorganic or organic acid and additive salt inorganic or that organic bases forms.
Especially, the objective of the invention is the formula (I that preamble limits
B) product, in the formula:
R represents butyl or butene-1-Ji, R
2BAnd R
5BOne of them represents hydrogen atom, and another then represents formula
Group, R in the formula
cAnd R
dBe same to each other or different to each other, they are selected from: hydrogen atom, the alkyl that contains 1 to 4 carbon atom or alkenyl and phenyl, all these groups can be replaced arbitrarily by one or more substituting groups, described substituting group is selected from: halogen atom, hydroxyl, trifluoromethyl, cyano group, nitro or amino, the alkoxyl group, phenyl or the benzyl that contain 4 carbon atoms at the most, the carboxyl and the tetrazyl of free, salifiable or esterification, R
1BRepresentative contains the alkyl of 4 carbon atoms at the most, this alkyl can at random be replaced by one or more substituting groups, described substituting group is selected from: the carboxyl of halogen atom, hydroxyl, methoxyl group, oxyethyl group, free, salifiable or esterification, amino, one or dialkyl amido and phenyl, this phenyl itself can at random be replaced by one or more substituting groups again, described substituting group is selected from: the carboxyl and the tetrazyl of halogen atom, methoxyl group, trifluoromethyl, cyano group, free, salifiable or esterification, R
3BBe selected from OR
6And CO
2R
7Group, wherein R
6And R
7Represent hydrogen atom or contain the alkyl or the alkenyl of 5 carbon atoms at the most,
R
4BRepresent free, esterification or salifiable carboxyl or tetrazyl,
Perhaps R
4BRepresentative-(CH
2)
p-SO
2-X
d-R
12dGroup, P represents 0 and 1 in the formula, X
dRepresentative-NH-,-NH-CO-NH-,-NH-CO-group or singly-bound, R
12dRepresent methylidene, ethyl, propyl group, vinyl, allyl group, phenyl, benzyl, pyridyl, picolyl, pyridine ethyl, nitropyridine base, pyrimidyl, tetrazyl, di azoly, piperidyl, Alkylpiperidine base, thiazolyl, alkyl thiazolyl, THP trtrahydropyranyl, methyltetrahydrofuran base; Amino and carbamyl can be at random replaced by 1 or 2 substituting groups, described substituting group be selected from the preamble qualification-(CH
2)
p-SO
2-X
d-R
12dThe alkyl that can replace arbitrarily and the alkenyl that contain 4 carbon atoms at the most; All these groups can at random be replaced by one or more substituting groups, described substituting group is selected from halogen atom, hydroxyl, contains alkyl, alkenyl and alkoxyl group, trifluoromethyl, cyano group, the free of 4 carbon atoms, the carboxyl or the tetrazyl of salifiable or esterification, described formula (I at the most
B) product comprises all possible racemize, mapping and diastereomeric form, and described formula (I
B) product and inorganic or organic acid and additive salt inorganic or that organic bases forms.
More particularly, the objective of the invention is corresponding to formula (I
A) formula (I
B) compound:
In the formula:
The R representative contains the straight or branched alkyl or the alkenyl of 3 or 4 carbon atoms,
R
1A, R
2A, R
3AAnd R
5ABe defined as follows:
Perhaps R
1A, R
2A, R
3AAnd R
5AIt is mutually the same and represent hydrogen atom,
Perhaps R
2AAnd R
5ADefinition be: one of them represent hydrogen atom or-CH
2-O-R
10Group, R in the formula
10Represent hydrogen atom or contain the straight or branched alkyl or the alkenyl of 5 carbon atoms at the most, another then represents hydrogen atom, R
1AAnd R
3ADefinition be: one of them represents hydrogen atom, and another then is selected from-OR
6,-CO
2R
7With-R
11Group, wherein:
R
6And R
7Be same to each other or different to each other, represent hydrogen atom or contain the straight or branched alkyl or the alkenyl of 5 carbon atoms at the most,
R
11Be selected from following radicals:
A) contain the alkyl of 4 carbon atoms at the most, this alkyl can at random be replaced by one or more substituting groups, and described substituting group is selected from:
-halogen atom,
-the hydroxyl of acidylate arbitrarily,
-contain the straight or branched alkoxyl group or the alkenyloxy of 5 carbon atoms at the most,
Carboxyl-free, esterification or salifiable,
-Shi
Group, R in the formula
aAnd R
bBe same to each other or different to each other, alkyl or alkenyl that they are selected from hydrogen atom, contain 1 to 4 carbon atom and can be at random replaced by halogen atom or hydroxyl,
B) contain the straight or branched alkenyl of 2 to 5 carbon atoms,
C) contain the acyl group and the formyl radical of 2 to 7 carbon atoms,
R
4ARepresent free, esterification or salifiable carboxyl, cyano group or tetrazyl, this group is salify at random,
Described formula (I
A) product comprises all possible racemize, mapping or diastereomer,
And described formula (I
A) product and organic or inorganic is sour and inorganic or organic bases forms additive salt.
Therefore, the objective of the invention is the formula (I that preamble limits corresponding to formula I
B) and (I
A) compound:
In the formula
The R representative contains the straight or branched alkyl or the alkenyl of 3 or 4 carbon atoms,
R
1, R
2, R
3And R
5Be defined as follows:
Perhaps R
1, R
2, R
3And R
5Be same to each other or different to each other, and represent hydrogen atom,
Perhaps R
2And R
5One of them represent hydrogen atom or-CH
2-O-R
10, another then represents hydrogen atom, and R
1And R
3One of them represents hydrogen atom, and another then is selected from formula-OR
6,-CO
2R
7With-CH
2-O-R
8Group, wherein R
10, R
6, R
7And R
8Be same to each other or different to each other, represent hydrogen atom or contain the straight or branched alkyl or the alkenyl of 5 carbon atoms at the most,
R
4Represent free, esterification or salifiable carboxyl,
Described formula I product comprises all possible racemize, mapping or diastereomeric isomer, and described formula I product and inorganic or organic acid and additive salt inorganic or that organic bases forms.
In formula (I
B), (I
A) and (I) product in and during following the appearance, the implication of each group is as follows:
-term straight or branched alkyl preferably means methyl, ethyl, propyl group or sec.-propyl, butyl, isobutyl-, sec-butyl or the tertiary butyl but also can represent amyl group, particularly tert-pentyl.
-term straight or branched alkenyl preferably means vinyl, allyl group, 1-propenyl, 2-propenyl, 1-butylene base or crotyl, but also can represent 1-pentenyl, pentenyl or 3-pentenyl.
-term halogen atom preferably means bromine atoms, but also can represent fluorine, chlorine or iodine atom.
-OR
10With-OR
6The alkoxyl group or the alkenyloxy of representative for example can form it by alkyl or the alkenyl that preamble limits, the alkoxyl group of being worth mentioning is methoxy or ethoxy preferably, also can be propoxy-, isopropoxy, butoxy, sec-butoxy, tert.-butoxy or pentyloxy, the alkenyloxy of being worth mentioning is vinyloxy group or propenyloxy group preferably, the esterifying carboxyl group of being worth mentioning is (lower alkoxy or alkenyloxy) carbonyl preferably, for example, methoxycarbonyl or ethoxycarbonyl, but also can be the third oxygen carbonyl, butoxy carbonyl, butylene oxygen carbonyl, tertbutyloxycarbonyl or penta oxygen carbonyl.
-term acyl group preferably means the group that contains 7 carbon atoms at the most, for example, and formyl radical, ethanoyl, propionyl, butyryl radicals or benzoyl, but also can be pentanoyl, caproyl, acryl, crotonyl or carbamyl.
-term acyloxy preferably means acyl group that contains an aforementioned definitions and the group that links to each other with Sauerstoffatom, for example, and acetoxyl group or benzoyloxy,
The group that-term aryl means monocyclic groups or is made of condensed ring (carbocyclic ring or heterocycle), certainly, described heterocyclic group can contain one or more heteroatomss that are selected from oxygen, nitrogen or sulphur, and, if these heterocyclic radicals contain more than one heteroatoms, the heteroatoms in these heterocyclic groups can be identical or different so.
The term monocyclic groups preferably means the group that contains 5 or 6 links, with regard to the carbocyclic ring monocycle, what deserves to be mentioned is phenyl, with regard to monocyclic heterocycles, what deserves to be mentioned is for example following radicals: thienyl, furyl, pyranyl, pyrryl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, thiazolyl oxazolyl, the furazan base, pyrrolinyl is δ-2-pyrrolinyl for example, imidazolinyl is δ-2-imidazolinyl for example, pyrazolinyl is δ-3-pyrazolinyl for example, and the contained heteroatomic positional isomers of these groups, for example, isothiazolyl Huo isoxazolyl.
The group that term is made of fused rings preferably means the group that contains 8 to 14 links; With regard to the group that constitutes by carbocyclic fused ring, what deserves to be mentioned is for example naphthyl and phenanthryl; With regard to the group that constitutes by heterocyclic fused ring, what deserves to be mentioned is for example benzothienyl, naphtho-(2,3-b)-thienyl, thianthrenyl, isobenzofuran-base, benzopyranyl, xanthenyl, the phenoxathiin base, the indolizine base, pseudoindolyl, the 3H-indyl, indyl, indazolyl, purine radicals, quinolizinyl, isoquinolyl, quinolyl, 2, the 3-phthalazinyl, 1, the 5-phthalazinyl, imidazopyridyl, quinoxalinyl, quinazolyl, 1, the 2-phthalazinyl, pteridyl, carbazyl, the 2-carbolinyl, acridyl, phenazinyl, phenothiazinyl phenoxazinyl, indolinyl, isoindolinyl, the perhaps fused polycyclic system that constitutes by aforementioned monocyclic heterocycles, for example, furo (2,3-b) pyrroles or thieno-(2,3-b) furans.
The aryl of being worth mentioning is a following radicals: phenyl, naphthyl, thienyl are (for example, thiophene-2-base and thiene-3-yl-), furyl (for example, furans-2-yl), pyridyl (for example, pyridin-3-yl), pyrimidyl, pyrryl, thiazolyl, isothiazolyl, di azoly, triazolyl, tetrazyl, thiadiazolyl group, thiatriazole Ji, oxazolyl, oxadiazole base, 3-or 4-isoxazolyl; Contain the heteroatomic annelated heterocycles group that at least one is selected from sulphur, nitrogen and oxygen, for example, benzothienyl (for example, thionaphthene-3-yl), benzofuryl, benzopyrrole base, benzimidazolyl-, benzoxazolyl, thianaphthenyl, indyl or purine radicals.
These aryl can be to replace arbitrarily, for example, the pyrryl that N-replaces (as, N-methylpyrrole base), the 3-of replacement or 4-isoxazolyl, for example: 3-aryl-5-methyl-isoxazole-4-base, wherein aryl is for example phenyl or halogenophenyl;
-Shi
Group (amino that representative can be replaced arbitrarily by 1 or 2 group that is same to each other or different to each other) means for example monoalkyl and dialkyl amido, wherein alkyl can be the alkyl of preamble explanation, for example, be that methyl, ethyl, sec.-propyl, butyl, isobutyl-, these groups can at random be substituted, for example, in methylol, hydroxyethyl, methoxymethyl, methoxy ethyl or ethoxyethyl group, trifluoromethyl, pentafluoroethyl group; This amino also can be replaced by the alkenyl of 1 or 2 preamble qualification, for example, and vinyl, allyl group, 1-propenyl and 1-butylene base; In these amino substituting groups, the aryl and the aralkyl in addition of being worth mentioning, for example, following radicals: phenyl, benzyl, styroyl, naphthyl, indyl, indolinyl, thienyl, furyl, pyrryl, pyridyl, pyrrolidyl, piperidino-(1-position only), morpholino, piperazinyl, these groups also can be replaced by the group that one or more preambles limit, for example, in methylpiperazine base, methyl fluoride piperazinyl, ethyl piperazidine base, propyl group piperazinyl, Phenylpiperazinyl or benzyl diethylenediamine base.
--(CH
2)
m-SO
2-X-R
12Represent following radicals, wherein (CH
2)
mRepresent the alkylidene group of the alkyl that preamble mentions, for example, methylene radical, ethylidene, propylidene, isopropylidene, isobutylene or uncle's butylidene, R
12Representative is selected from the alkyl that preamble limits, or preamble is to the aryl that this group limited, for example, and phenyl, xenyl, naphthyl, tetrazyl, R
12The alkyl that can represent can at random be replaced by aryl, and described aryl is selected from the aryl that preamble limits, so as to forming aralkyl.
These alkyl, aryl and aralkyl itself can replace these groups are described like that by preamble.
What deserves to be mentioned is the group (being not whole) that exemplifies below :-SO
2-NH
2,-SO
2-NH-CH
3,-SO
2-NH-CF
3,-SO
2-NH-C
6H
5,-SO
2-NH-CH
2-C
6H
5
Radicals R is preferably represented propyl group, 1-propenyl, butyl or 1-butylene base, but also can be sec.-propyl, sec-butyl, the tertiary butyl and crotyl.
Formula (I
B), (I
A) and (I) product and inorganic or organic acid and additive salt inorganic or that organic bases generates can be for example following acid salt: hydrochloride, hydrobromate, hydriodate, nitrate, vitriol, phosphoric acid salt, propionic salt, acetate, formate, benzoate, maleate, fumarate, succinate, tartrate, Citrate trianion, oxalate, glyoxylate, aspartate, ascorbate salt, alkyl monosulfonate (as: mesylate, esilate, propanesulfonic acid salt), alkyl stilbene-4,4'-bis-(1-azo-3, 4-dihydroxy-benzene)-2,2'-disulfonate (as: methionate, 1, the 2-ethanedisulphonate), aryl monosulfonate (as: benzene sulfonate) and aryl disulfonic salt.
Preferred especially person is the salt that forms with hydrochloric acid.
The carboxyl of formula I product can with mineral alkali or organic bases salify, the example of described mineral alkali is the alkali that is formed by sodium, potassium, lithium, calcium, magnesium or ammonium, the example of described organic bases is methylamine, propylamine, Trimethylamine 99, diethylamine, triethylamine, N, N-dimethylethanolamine, three (methylol) aminomethane, thanomin, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, PROCAINE HCL, PHARMA GRADE, Methionin, arginine, Histidine, N-methylglucosamine.
Specifically, the objective of the invention is formula (I
B) product, wherein, R represents butyl or 1-butylene base and R
1BRepresent hydrogen atom or alkoxyl group, described formula (I
B) product comprises all possible racemize, mapping and diastereomer, and described formula (I
B) product and inorganic or organic acid and additive salt inorganic or that organic bases forms.
With regard to R in the formula
1BRepresent the product of hydrogen atom, preferred product is R in the formula
2B, R
3BAnd R
5BMutually the same and represent those products and the following product of hydrogen atom, R in the formula
2BOr R
5BRepresent hydrogen atom, hydroxyl or alkoxyl group, R
3BRepresentation hydroxy or alkoxyl group or be selected from-OR
6,-CO
2R
7With-R
11, wherein:
R
6And R
7Be same to each other or different to each other, represent hydrogen atom or contain the straight or branched alkyl or the alkenyl of 5 carbon atoms at the most, R
11Be selected from following radicals:
A) contain the alkyl of 4 carbon atoms at the most, this alkyl can at random be replaced by one or more substituting groups, and described substituting group is selected from:
-halogen atom,
-can be at random by the hydroxyl of acidylate,
-contain the straight or branched alkoxyl group or the alkenyloxy of 5 carbon atoms at the most,
Carboxyl-free, esterification or salifiable,
-group
, R in the formula
aAnd R
bBe same to each other or different to each other, be selected from hydrogen atom, contain the alkyl of 1 to 4 carbon atom or alkenyl, they can at random replace by halogen atom or hydroxyl,
B) contain the straight or branched alkenyl of 2 to 5 carbon atoms,
C) contain the acyl group and the formyl radical of 2 to 7 carbon atoms,
And R
4ARepresent tetrazyl or free, salifiable or by the carboxyl of alkyl esterification, aforesaid alkyl and alkoxyl group contain 1 to 5 carbon atom,
Described formula (I
A) product comprises all possible racemize, mapping or diastereomer,
And described formula (I
A) product and organic or inorganic is sour and inorganic or organic bases forms additive salt.
Therefore, the objective of the invention is the formula (I that preamble limits corresponding to formula I
B) and (I
A) compound:
With regard to R in the formula
1AThe product of representation alkoxy for example be what deserves to be mentioned is R in the formula
2A, R
3AAnd R
5ARepresent the product of hydrogen atom.
In aforesaid preferred product, described alkyl and alkoxyl group contain 1 to 5 carbon atom, preferably representative respectively:
-alkyl is ethyl and methyl,
-alkoxyl group is methoxyl group and oxyethyl group.
More particularly, the objective of the invention is the formula (I that preamble limits
A) compound, R represents butyl in the formula, and R
1A, R
2A, R
3AAnd R
5ARepresent hydrogen atom, described formula (I
A) product comprises all possible racemize, mapping and diastereomer, and said formula (I
A) product and inorganic or organic acid and additive salt inorganic or that organic bases forms.
More particularly, the objective of the invention is the formula (I that preamble limits
A) product, R represents butyl in the formula, R
1A, R
2AAnd R
5ARepresent hydrogen atom, R
3ABe selected from-OR
6,-CO
2R
7With-R
11Group, wherein:
R
6And R
7Be same to each other or different to each other, represent hydrogen atom or contain the straight or branched alkyl or the alkenyl of 5 carbon atoms at the most,
R
11Be selected from following radicals:
A) contain the alkyl of 4 carbon atoms at the most, they can at random be replaced by one or more substituting groups, and described substituting group is selected from:
-halogen atom,
-can be at random by the hydroxyl of acidylate,
-contain the straight or branched alkoxyl group or the alkenyloxy of 5 carbon atoms at the most,
Carboxyl-free, esterification or salifiable,
-Shi
Group, R in the formula
aAnd R
bBe same to each other or different to each other, be selected from halogen atom, contain the alkyl of 1 to 4 carbon atom or alkenyl, they can at random replace by halogen atom or hydroxyl,
B) contain the straight or branched alkenyl of 2 to 5 carbon atoms,
C) contain the acyl group and the formyl radical of 2 to 7 carbon atoms,
R
4ACivilian as defined above described, described formula (I
A) product comprises all possible racemize, mapping and diastereomer, and described formula (I
A) product and inorganic or organic acid and additive salt inorganic or that organic bases forms.
Especially, the objective of the invention is the formula (I that preamble limits
A) product, R represents butyl, R in the formula
1A, R
2AAnd R
5ARepresent hydrogen atom, R
3ARepresent hydrogen, free carboxy or by the carboxyl of the alkyl esterification that contains 4 carbon atoms at the most; Formyl radical; The alkyl or the alkenyl that contain 4 carbon atoms at the most; The amino that the alkyl that can at random be replaced by one or more substituting groups, described substituting group are selected from halogen atom, hydroxyl or acyloxy, can be at random replaced by 1 or 2 alkyl that contains 4 carbon atoms at the most; Described formula (I
A) product comprises all possible racemize, mapping and diastereomer, and described formula (I
A) product and inorganic or organic acid and additive salt inorganic or that organic bases forms.
In purpose product of the present invention, the what is worth mentioning particular compound is:
4 '-((2-butyl-1H-benzoglyoxaline-1-yl)-methyl)-diphenyl-2-carboxylic acid methyl esters and salt thereof,
4 '-((2-butyl-1H-benzoglyoxaline-1-yl) methyl)-diphenyl-2-carboxylic acid and salt thereof,
2-butyl-1-((2 '-carboxyl-biphenyl-4-yl)-methyl)-1H-benzoglyoxaline-7-carboxylic acid and salt thereof,
4 '-((2-butyl-7-(2-hydroxyethyl)-1H-benzoglyoxaline-1-yl)-methyl)-diphenyl-2-carboxylic acid and salt thereof,
4 '-((2-butyl-7-formyl radical-1H-benzoglyoxaline-1-yl)-methyl)-diphenyl-2-carboxylic acid and salt thereof,
2-butyl-1-((2 '-(1H-tetrazolium-5-yl)-(1,1 '-biphenyl)-the 4-yl)-methyl)-1H-benzoglyoxaline-7-carboxylic acid and salt thereof.
Another object of the present invention is the aforementioned formula (I of preparation
B) method of product, it is characterized in that:
Perhaps
By formula (IV
B) product and formula (V
B) the compound reaction, so as to making formula (IX
B) product,
In the formula R as defined above, R
1B', R
2B', R
3B' and R
5B' have preamble respectively to R
1B, R
2B, R
3BAnd R
5BThe definition of pointing out, wherein, the active function groups that can adopt the protecting group protection to exist as required,
Hal represents halogen atom in the formula, R
4B' have preamble to R
4BPointed definition, wherein, the active function groups that adopts the protecting group protection to exist as required,
R, R in the formula
1B', R
2B', R
3B', R
5B' and R
4B' implication the same,
Perhaps
A) by formula (VI
B) compound and the reaction of formula II compound, so as to making formula (X
B) product:
R in the formula
1B', R
2B', R
3B' and R
5B' as defined above,
R in the formula
9Representation hydroxy or alkoxy or halogen atom, R's is described as defined above,
R, R in the formula
1B', R
2B', R
3B' and R
5B' as defined above,
B) by formula (VI
B') the formula II compound reaction that limits of compound and preamble, so as to making formula (X
B') product,
R in the formula
1B', R
2B', R
3B' and R
5B' as defined above,
R in the formula
1B', R
2B', R
3B', R
5B' and R civilian as defined above described, with formula (X
B') product is nitrated, so as to making the formula (X of preamble definition
B) compound, make formula (X
B) formula (V that limits of product and preamble
B) the compound reaction, so as to making formula (XI
B) product,
R, R in the formula
1B', R
2B', R
3B', R
5B' and R
4B' civilian as defined above described, then with formula (XI
B) nitro functions of product carries out the selective reduction reaction, so as to making formula (XII
B) product:
R, R in the formula
1B', R
2B', R
3B', R
5B' and R
4B' civilian as defined above described, then with formula (XII
B) the product cyclisation, so as to making the formula (IX that preamble limits
B) product,
Perhaps
Make formula (VI
B) formula (V that limits of compound and preamble
B) the compound reaction, so as to making formula (VII
B) product:
R in the formula
1B', R
2B', R
3B', R
5B' and R
4B' civilian as defined above described, then with formula (VII
B) nitro of product carries out selective reduction, so as to making formula (VIII
B) product
R in the formula
1B', R
2B', R
3B', R
5B' and R
4B' civilian as defined above described, make it then to react with the formula III product
X represention oxygen atom or NH group in the formula, R
9With R as defined above, so as to after cyclization, making the formula (IX that preamble limits
B) product, reach necessity as requested, can make formula (IX
B) one step or the following reaction of multistep of product experience, its order is random:
-the protecting group that may exist remove reaction,
-with salt-forming reaction inorganic or organic acid or alkali, so as to making corresponding salt,
The esterification of-acid functional group or salt-forming reaction,
-make ester functional group be converted into the reaction of acid functional group by acid or basic hydrolysis,
-alkoxyl group is converted into the reaction of hydroxyl,
-haloalkyl is converted into the reaction of thiazolinyl,
The amino reaction that replaces halogen atom of-usefulness,
The reaction of-usefulness halogen atom substituted hydroxy,
-esterifying carboxyl group is changed into the reduction reaction of hydroxyalkyl,
-hydroxyalkyl is converted into the oxidizing reaction of esterifying carboxyl group,
-methylol is converted into the oxidizing reaction of formyl radical,
-racemic modification is converted into the resolution reaction of resolved product,
-free, carboxyl salifiable or esterification are changed into the reaction of tetrazyl,
Above-mentioned formula (the I of gained thus
B) product comprises all possible racemize, mapping and diastereomer.
With regard to implementing optimum condition of the present invention, can implement aforesaid method by following mode:
Halogen atom is preferably the formula (V of bromine in the formula
B) compound and formula (IV
B) reaction of the imidazole anion effect preparation of alkaline reagents (as: sodium hydride or potassium hydride KH, also can with the alkoxide such as the sodium methylate of sodium or potassium) (for example, by) can carry out in the organic solvent such as dimethyl formamide or tetrahydrofuran (THF).
For making formula (X
B) or (X
B') product and the formula III compound that carries out respectively with formula (VI
B) or (VI
B') addition reaction of the free amine group functional group of compound can be heated to above-mentioned reactant about 120 ℃ to 170 ℃ simply and carry out, the formula II compound can be a valeric acid, in this case, and with respect to formula (VI
B) or (VI
B') compound, preferably adopt excessive valeric acid.
Formula (X
B) product can pass through, for example, in the presence of nitric acid, making solvent such as acetic anhydride and acetate, between 0 to 10 ℃ with formula (X
B') product is nitrated prepares.
At normal temperature or be heated to 20 ℃ to 150 ℃, preferably in the presence of alkaline reagents such as triethylamine, soda, sodium methylate or sodium ethylate or sodium hydride,, can carry out formula (V to make solvent such as tetrahydrofuran (THF) or dimethyl formamide
B) compound and formula (X
B) addition reaction of amide functional group of compound, so as to making formula (XI
B) product.
According to ordinary method well known to those skilled in the art, can be with formula (XI
B) nitroreduction of product becomes amino, so as to obtaining formula (XII
B) product, preferable methods is in the presence of palladium hydroxide, carries out catalytic hydrogenation with for example ethanol as solvent, perhaps makes solvent with for example acetate in the presence of sodium acetate and adopts the zinc reduction, perhaps also can adopt sodium borohydride reduction.
By simple heating or in the presence of the catalyzer such as thionyl chloride, phosphorus pentachloride or phosphoric anhydride, make solvent with for example tetrahydrofuran (THF) or dimethyl formamide, with formula (XII
B) the product cyclization, so as to making formula (IX
B) product.
According to aforementioned formula (V
B) product is to formula (IV
B) the same terms of product addition, can perfect (V
B) product is to formula (VI
B) addition reaction of free amine group of compound, so as to making formula (VII
B) product.
According to method well known to those skilled in the art, preferably adopt with aforementioned with formula (XI
B) the identical reaction conditions of nitroreduction of product, can be with formula (VII
B) nitroreduction of product becomes amino, so as to making formula (VIII
B) product.
According to the whole bag of tricks well known to those skilled in the art, preferably in the organic solvent such as tetrahydrofuran (THF) or dimethyl formamide,, can finish formula III compound and formula (VIII in 20 ℃ to 200 ℃
B) addition reaction carried out of the free amine group of product, the product cyclization that will obtain thus then.
For example, this formula III compound can be: when X represents NH, be penta imido acid ethyl ester; When X represents o, then be valeric acid.
According to R
1B', R
2B', R
3B' and R
5B' definition, formula (IX
B) product can be, also can not be formula (I
B) product.
If necessary, can protect the carry-on various active function groups of aforesaid compound: for example, they are the free hydroxyl group or the carboxyls that can adopt the suitable protecting group protection of easily removing.
Hereinafter list the example that does not comprise whole protection active function groups:
-for example, can adopt TMS, methoxymethyl or THP trtrahydropyranyl protection hydroxyl,
-for example, by protecting carboxyl with the form of ester (as, the ester of known easy fracture in the chemistry of peptides, for example, the benzyl ester or the tert-butyl ester).
According to normal condition well known to those skilled in the art, particularly adopt the acid hydrolysis of all example hydrochloric acids, Phenylsulfonic acid, tosic acid, formic acid or trifluoroacetic acid and so on, can remove these protecting groups.
For example, at BF2, can find operable a series of different protecting group in 499,995.
As required, according to ordinary method well known to those skilled in the art, adopt inorganic or organic acid can be with aforementioned product salify.
As required, according to normal condition well known to those skilled in the art, particularly adopt sulfuric acid or hydrochloric acid to carry out acid hydrolysis, perhaps adopt soda or potash in alcohol medium (as: methyl alcohol), to carry out basic hydrolysis, the ester group functional group of product can be converted into acid functional group.
As required, according to normal condition well known to those skilled in the art, for example, make solvent with for example methylene dichloride and adopt boron tribromide, adopt hydrogen bromide pyridine or pyridine hydrochloride, perhaps in water or acetate, adopt Hydrogen bromide or hydrochloric acid reflux reaction, the alkoxy-functional (particularly methoxyl group) that may exist in the above-mentioned product can be changed into alcohol functional group.
As required,, for example, particularly in the presence of soda water solution, in the alcohol such as methyl alcohol, carry out saponification and dehydrohalogenation, the alkylhalide group of above-mentioned product can be converted into thiazolinyl according to condition well known to those skilled in the art.
As required, according to condition well known to those skilled in the art, particularly in the alcoholic solvent such as ethanol or methyl alcohol, make for example dimethylamine reaction of halogen compound and sulfonamide derivatives at ambient temperature, can finish of the substitution reaction of the amino of above-mentioned product halogen atom.
According to condition well known to those skilled in the art, for example, particularly adopt thionyl chloride to carry out chlorination, can use the halogen atom substituted hydroxy.
Continue it, as required, can adopt sulfonamide derivatives (for example dimethylamine) that above-mentioned chlorinated derivatives is carried out substitution reaction.
According to condition well known by persons skilled in the art, for example, particularly adopt lithium aluminum hydride, diisobutylaluminium hydride or other known reductive agents, esterifying carboxyl group can be reduced into hydroxyalkyl.
According to normal condition well known to those skilled in the art, for example, particularly use the mixed oxide such as BOWERS reagent to carry out oxidation, carry out esterification with for example diazomethane then, hydroxyalkyl can be oxidized to esterifying carboxyl group.
According to normal condition well known to those skilled in the art, for example, particularly in methylene dichloride, adopt activated manganese dioxide to carry out oxidation, methylol can be converted into formyl radical.
According to ordinary method resolution of racemates well known to those skilled in the art, can make formula (I
B) the optical activity form that may exist of product.For example, can adopt the salt that forms with optically active alkali.
Aforementioned formula (I
B) compound and their acid salt have useful pharmacological property.
Described product has antagonistic action to angiotensin-ii-receptor, therefore mainly as hypertensin, especially suppresses vasoconstriction, and to the nutritious effect of myocyte.
These character have determined their therepic use, and one of purpose of the present invention also is the preamble formula (I as medicine
B) product that limits, described formula (I
B) product comprises all possible racemize or optically active isomer, and described formula (I
B) product and pharmaceutically acceptable inorganic or organic acid and additive salt inorganic or that organic bases forms.
Specifically, one of purpose of the present invention is the following formula (I as the preamble qualification of medicine
B) product, in the formula, R represents butyl or 1-butylene base, R
1BRepresent hydrogen atom, preferred especially person is the following formula (I that preamble limits
B) product, R represents butyl in the formula, R
1B, R
2BAnd R
5BMutually the same and represent hydrogen atom, R separately
3BRepresent hydrogen atom, free carboxy or by the carboxyl of the alkyl esterification that contains 4 carbon atoms at the most; Formyl radical; The alkyl or the alkenyl that contain 4 carbon atoms at the most; By the alkyl that one or more groups replace, described group is selected from the carboxyl of halogen atom, hydroxyl, acyloxy, the amino that can be at random replaced by 1 or 2 alkyl that contains 4 carbon atoms at the most and free, salifiable or esterification, R
4BRepresent free, salifiable or esterification carboxyl, can any salifiable cyano group or tetrazyl, and described formula (I
B) product and pharmaceutically acceptable inorganic or organic acid and additive salt inorganic or that organic bases forms.
More particularly, one of purpose of the present invention is the following formula (I as medicine
B) product:
4 '-((2-butyl-1H-benzoglyoxaline-1-yl)-methyl)-diphenyl-2-carboxylic acid methyl esters,
4 '-((2-butyl-1H-benzoglyoxaline-1-yl)-methyl) diphenyl-2-carboxylic acid
2-butyl-1-((2 '-carboxyl biphenyl-4-yl)-methyl)-1H-benzoglyoxaline-7-carboxylic acid,
4 '-((2-butyl-7-(2-hydroxyethyl)-1H-benzoglyoxaline-1-yl)-methyl)-diphenyl-2-carboxylic acid,
4 '-((2-butyl-7-formyl radical-1H-benzoglyoxaline-1-yl)-methyl)-diphenyl-2-carboxylic acid,
2-butyl-1-((2 '-(1H-tetrazolium-5-yl)-(1,1 '-biphenyl)-the 4-yl)-methyl)-1H-benzoglyoxaline-7-carboxylic acid,
And they and pharmaceutically acceptable inorganic or organic acid and additive salt inorganic or that organic bases generates.Medicine as the object of the invention can be used for treating arterial hypertension, cardiac insufficiency, renal insufficiency, and can be used for preventing the angiostenosis recurrence of angioplasty postoperative.
Also they can be used for the treatment of some gi tract and gynaecopathia, particularly they have the effect in loose uterus.
The present invention includes and contain the pharmaceutical composition of at least a aforementioned medicine as active ingredient.
Can use these pharmaceutical compositions through cheek or rectum approach, perhaps pass through non-stomach and intestine approach or local approach (for example, being used for skin and mucous membrane outward) administration.
These compositions can be solid or liquid, and can adopt all habitual in human medication pharmaceutical dosage forms, for example, and common or sugar coated tablet, capsule, granule, suppository, injection formulations, ointment, creme, gel and aerosol; They can make by conventional process.Can be with active ingredient and mixed with excipients commonly used in these pharmaceutical preparations, described vehicle comprises, for example, lipid, paraffin derivative, glycol, various wetting agent, dispersion agent or the emulsifying agent and the sanitas of talcum powder, gum arabic, lactose, starch, Magnesium Stearate, theobroma oil, moisture or nonaqueous carrier, animal or plant.
According to the product that is adopted, controlled the difference of patient and illness, its common dose can change, for example, when adopting oral route, per day for adults can be 1 to 100 milligram.
Formula II, (III), (IV
B), (V
B), (VI
B) and (VI
B') initial compounds is that market can get, perhaps can make by conventional process well-known to those skilled in the art.
In＜J.Amer.Chem.Soc.(1937) 59,178 〉, some formula (IV have been introduced
B) preparation method of compound.
Formula III compound and the reaction of formula (X III) product by preamble limits can make other formula (IV
B) product,
R in the formula
1B', R
2B', R
3B' and R
5B' definition the same.
Formula III product and formula (VIII that this reaction conditions and preamble are described
B) reaction conditions of product is identical.
Some formulas (X III) compound is that market can get, for example, 3, the 4-diamino-methyl benzoate can obtain from LANCASTER.
Prepare these formulas (X III) examples for compounds referring to＜Journal of the Chemical Society, Chemical Communication, (1957) 2197-2201 〉.
In formula II and (III) compound, find, for example,, can make penta imido acid ethyl ester by hydrochloric acid gas in the acetate and valeronitrile (selling) reaction by LONZA.
Prepare these formula III examples for compounds referring to＜J.Amer.Chem.Soc.(1942), 64,1827 〉.
Formula (the V that preamble limits
B) preparation method of product is: for example, make iodobenzoic acid methyl esters (for example being sold by JANSSEN) and iodo toluene (for example being sold by FLUKA) reaction, for example, in the presence of copper powder, in 100 to 300 ℃ are carried out this reaction, so as to making formula (V
B') product:
If necessary, adopt conventional process well known to those skilled in the art or as mentioned before, adopt for example acid or basic hydrolysis, can make formula (V
B') esterifying carboxyl group in the compound removes alkyl, adopts conventional process well known to those skilled in the art, for example, makes it in tetracol phenixin and the N-bromosuccinimide reaction, can carry out bromination reaction on its methyl.
Some formula (V
B) or (V
B') preparation or formula (IX
B) some formula R in the product
4BThe conversion of group can referring to: for example,＜United States Patent (USP) 4,880,804 or European patent 0,253,310 〉.
Formula (VI
B) compound can be o-Nitraniline (for example by UCB sell) for example.
Formula (VI
B) product also can be with reference to＜Canadian journal of Chemistry(1977), 55(10), pp.1653-1657〉described method preparation.
Formula (the VI that belongs to anils
B') product is that market can get, for example by ALDRICH sell 2,4-dimethoxyaniline or the method preparation that also can introduce by following document:
-BEILSTEIN, the 7th the volume, third edition supplementary copy P.1662,
-BEILSTEIN, the 8th volume, third edition supplementary copy is P.2128.
Last purpose of the present invention is as new industrial product, particularly is used for preparation formula (I as intermediate
B) formula (IV of product
B), (VII
B), (VIII
B), (X
B) and (X
B') compound.
Except being used for the product that explanation (rather than restriction) embodiments of the invention introduce, following product belongs to the product that can make within the scope of the present invention; In these formula (I
A) in the product, R represents butyl, R
4ARepresentation carboxy, R
1A, R
2A, R
3AAnd R
5ADefinition be listed in the table below:
Following embodiment explanation (but not limiting) the present invention.
Embodiment 1
4 '-((2-butyl-1H-benzoglyoxaline-1-yl)-methyl)-diphenyl-2-carboxylic acid methyl ester hydrochloride
2g 2-butyl-1H-benzoglyoxaline (is pressed＜W.O.Pool, HJ HARWOOD and AW RALSTON-J.Amer.Chem.Soc., (1937) 59,178〉preparation) be dissolved in the 3ml dimethyl formamide, be cooled to below 0 ℃, this solution be added in the 5ml dimethyl formamide suspension of 650mg sodium methylate.This mixture was stirred 15 minutes, make it to normal temperature simultaneously.With the 5ml dimethyl formamide solution that added 3.6g 4 '-(brooethyl)-diphenyl-2-carboxylic acid methyl esters (pressing European patent 0,253,310 preparations) in 15 minutes.
In 40 ℃ of stirrings 4 hours, steam dimethyl formamide, add the 50ml sodium bicarbonate aqueous solution, after 100ml ethyl acetate extraction 3 times, wash extract with water, drying is filtered evaporate to dryness.Residue (4.6g) is through silica gel column chromatography purifying (eluent: ethyl acetate-hexanaphthene (1-1)), obtain the free alkali of 1.8g institute phase product.
Salify:
The hydrogenchloride ethyl acetate solution is added in the aqueous isopropanol that contains the aforementioned gained free alkali of 500mg, till pH is acidity.Steam ethyl acetate, product separates through the Virahol crystallization, uses washed with isopropyl alcohol, in 100 ℃ of drying under reduced pressure, obtains the 350mg hydrochloride, M.p.=155 ℃, with Virahol recrystallization twice, obtains the hydrochloride of 230mg institute phase product, M.p.=155-160 ℃.
Ultimate analysis: C
26H
27N
2O
2Cl=435.01
C H Cl N
Calculated value %:71.79 6.25 8.15 6.44
Measured value %:72.00 6.2 8.3 6.3
Infrared spectra: (CHCl
3)
Embodiment 2
4 '-((2-butyl-1H-benzoglyoxaline-1-yl)-methyl)-diphenyl-2-carboxylic acid
500mg embodiment 1 gained ester (free alkali) is dissolved in the 8ml methyl alcohol, adds 0.8ml 2N soda.Stirring and refluxing 4 hours steams methyl alcohol, and the gained mixture is cooled to 10 ℃, with the 2N hcl acidifying to pH 5-6, stirred 30 minutes at 10 ℃ then, separate, wash with water, decompression is down in 80 ℃ of dryings, obtain the 400mg product, M.p.=190 ℃, the latter uses twice in Virahol recrystallization, obtain 125mg institute phase product, M.p.=234 ℃.
Ultimate analysis: C
25H
24N
2O
2=384.48
C H N
Calculated value %:78.10 6.29 7.28
Measured value %:78.00 6.3 7.2
Infrared spectra (whiteruss)
Preparation example 1:
4 '-(N-(2-(methoxycarbonyl)-6-nitrophenyl)-N-(pentanoyl)-amino methyl)-the diphenyl-2-carboxylic acid methyl esters
Steps A: 2-amino-3-nitrobenzoic acid
A) acetylize:
The suspension of 12g 2-amino-3-nitrotoluene and 14.4ml acetic anhydride is cooled to 10 ℃, add the 0.65ml vitriol oil, this mixture was stirred 1 hour at normal temperatures, add 50ml water, stirred then 15 minutes, separate, elder generation's water, with the ether washing, decompression is down in 100 ℃ of dryings again, obtain 13.6g institute phase product, M.p.=156 ℃.
B) oxidation:
The aforementioned gained compound of 13.4g is added in 29.48g potassium permanganate and the suspended matter of 21.44g sal epsom in 1470ml water, this mixture in 100 ℃ of stirrings 3 hours, is made it to be cooled to normal temperature, be cooled to 0 ℃-5 ℃ then.The insoluble part of filtering adds 10ml concentrated hydrochloric acid (pH 2-3) in being cooled to 0 ℃-5 ℃ filtrate in advance, with 500ml ethyl acetate extraction 4 times, wash extracting solution with water, drying is filtered reduction vaporization, obtain the 16.1g product, recrystallization in ether obtains 12.1g institute phase product.M.p.＝192℃。
C) hydrolysis:
Contain in the water of 5% concentrated hydrochloric acid at 75ml,, the aforementioned products therefrom of 12g was stirred 4 hours, this mixture is cooled to normal temperature in 120 ℃, be cooled to 0 ℃-5 ℃ again, under this temperature, stirred 1 hour, separate, elder generation's water, again with ether washing, at 100 ℃ of drying under reduced pressure, obtain 8.8g institute phase product.M.p.＝210℃。
Step B:2-amino-3-nitrobenzoic acid methyl esters
With the suspension stirring and refluxing of 1g steps A gained acid and 15ml methyl alcohol and 1.4ml 95-97% sulfuric acid composition 48 hours, steam and remove methyl alcohol, add 100ml water, add sodium bicarbonate and alkalize, use the 200ml dichloromethane extraction then 3 times, wash extracting solution with water, drying is filtered reduction vaporization, obtain 1g institute phase product, M.p.=96 ℃.
Step C:3-nitro-2-valeryl Methyl anthranilate
With 850mg above-mentioned steps B products therefrom and 5ml valeryl chloride stirring and refluxing 1 hour, behind the evaporate to dryness, residue is dissolved in the 80ml ether, use activated carbon treatment, filter reduction vaporization, obtain the 1.3g product, the latter obtains 1.0g institute phase product through the mixture recrystallization of isopropyl ether and pentane.M.p.＝58℃。
Prepare analytic sample as follows: be dissolved in the 20ml isopropyl ether and reflux, filter, be concentrated into 5ml, placed at normal temperatures 18 hours, separate,, obtain the 710mg sample, M.p.=60 ℃ with the isopropyl ether washing.
This 710mg sample is dissolved in the hot isopropyl ether of 25ml, uses activated carbon treatment, filter, be concentrated into 10ml, placed at normal temperatures 1 hour, separate,, obtain 380mg institute phase product with the isopropyl ether washing.M.p.＝60℃。
Ultimate analysis C
13H
16N
2O
5=280.27
C H N
Calculated value % 55.71 5.75 10.00
Measured value % 55.8 5.38 9.9
Infrared spectra (CHCl
3)
Step D:4 '-(N-(2-(methoxycarbonyl)-6-nitrophenyl)-N-(pentanoyl)-amino methyl)-the diphenyl-2-carboxylic acid methyl esters
1g abovementioned steps B products therefrom is dissolved in the 5ml dimethyl formamide, sodium hydride-the oil dispersion that adds 170mg concentration 50%, stop the back and stirred 5 minutes putting hydrogen, add 1.09g 4 '-(brooethyl)-diphenyl-2-carboxylic acid methyl esters then and (press European patent 0,253,310 preparations), stirred 1 hour down in normal temperature, steaming desolventizes, residue 250ml ethyl acetate extraction three times are used the 50ml water washing 3 times, drying then, filter, underpressure distillation obtains the 2g product, and the latter is through the silica gel column chromatography purifying, with methylene chloride-methanol (99-1) wash-out, obtain 1.6g institute phase product.
Infrared spectra (CHCl
3)
C=O compound 1726 and 1670cm
-1
NO
21538 and 1352cm
-1
Fragrance absorption 1600 and 1576cm
-1
Embodiment 3
2-butyl-1-(2 '-(methoxycarbonyl)-biphenyl-4-yl)-methyl)-1H-benzoglyoxaline-7-carboxylate methyl ester hydrochloride
A) hydrogenation:
Gained 730mg compound dissolution among the preparation example 1 step D in the 15ml tetrahydrofuran (THF), is added 365mg 18% palladium-charcoal, under nitrogen atmosphere, stir 1.5 hours (absorbing 109ml hydrogen), filtration catalizer, use the dichloromethane residue, be evaporated to driedly under the decompression, obtain the 730mg product.
B) cyclization:
The aforementioned product of 730mg is dissolved in 5ml ethyl acetate and the 5ml Virahol, add excessive greatly hydrogenchloride ethyl acetate solution, with this mixture heating up to 50 ℃ reaction 5 minutes, placed at normal temperatures 30 minutes, steaming desolventizes, and residue 3ml ethyl acetate extraction 3 times are through separation and after with the ether washing, obtain 640mg institute phase product, M.p.=160 ℃.
With the aforementioned product of 190mg Virahol recrystallization, obtain 163mg institute phase product, M.p.=160 ℃.
Ultimate analysis C
28H
28N
2O
4, HCl=492.99
C H Cl N
Calculated value % 68.21 5.93 7.19 5.68
Measured value % 67.8 5.8 7.3 5.5
Infrared spectra
Embodiment 4:
2-butyl-1-((2 '-carboxyl biphenyl-4-yl)-methyl)-1H-benzoglyoxaline-7-carboxylic acid
440mg embodiment 3 products therefroms are dissolved in the 10ml ethanol, add 1ml water and 1ml caustic soda alkali lye, stirring and refluxing 1 hour is steamed and is removed ethanol, in residue water-soluble (10ml), is acidified with acetic acid to pH 3-4.Obtain the 360mg product after the separation, M.p.=160 ℃, with the above-mentioned products therefrom of 450mg with 15ml methyl alcohol, 5 acetate and 5ml water recrystallization, obtain the 370mg product, M.p.=255 ℃, the latter is dissolved in 20ml methyl alcohol and the 10ml methylene dichloride refluxes, this solution is filtered, steam methylene dichloride, add 1 acetate and 5ml water, spend the night at normal temperatures, separate, obtain the 330mg product, M.p.=255 ℃.
Ultimate analysis C
26H
24N
2O
4=428.47
C H N
Calculated value % 72.88 5.65 6.54
Measured value % 73.0 5.6 6.5
Infrared spectra (whiteruss)
Common OH/NH absorption band
C＝O 1704cm
-1
NMR composes (DMSO)
CH
30.88（t）
CH
21.39（m）
CH
21.76（m）
CH
2-C＝ 2.87（m）
N-CH
2- 5.90（s）
C
6H
46.88（d，l） 7.23（d，l）
7 other fragrant H 7.20 to 7.90(m)
Removable H is about 12.95(m)
Preparation example 2
4 '-(N-((2-nitro-6-((penta acyloxy) methyl) phenyl)-N-pentanoyl)-aminomethyl)-diphenyl-2-carboxylic acid methyl esters
Steps A: 2-amino-3-nitrobenzyl alcohol
Between 7 ℃ to 8 ℃, with 1 hour 30 minutes, 50ml diisobutylaluminium hydride (hexane solution of 1.0M) is added in the solution of 3.54g preparation example 1 step B products therefrom in the 90ml tetrahydrofuran (THF), the gained mixture was stirred 30 minutes, then with adding the tetrahydrofuran (THF) that 40ml contains 10% water in 15 minutes, continue to stir, add 10ml water then, continue at normal temperatures to stir 30 minutes, add the methylene dichloride that 350ml contains 10% methyl alcohol, stirred 15 minutes, filter, with the filtrate decompression evaporate to dryness, 3.3g gained residue with the crystallization of 10ml isopropyl ether, is obtained 2.22g institute phase product.M.p.＝110℃。
Adopt cold and hot method to carry out recrystallization with isopropyl ether to the above-mentioned product of 170mg, the preparation analytic sample obtains the 80mg pure products, M.p.=112 ℃.
Ultimate analysis C
7H
8N
2O
3=168.15
C H N
Calculated value % 50.00 4.80 16.66
Measured value % 49.8 4.8 16.5
Infrared spectra (CHCl
3)
OH 3604cm
-1
＝C-NH
23498-3390cm
-1
NH
2def 1624cm
-1（F）
NO
21520-1345cm
-1Compound
Fragrance absorbs 1580cm
-1
Step B:3-nitro-2-valeryl aminobenzyl valerate
1.5g steps A products therefrom and 15ml valeryl chloride were stirred 6 hours at normal temperatures, add G(B.p.40-70 ℃ of 80ml essential oil), separate, obtain 2.55g institute phase product, M.p.=82 ℃, get the aforementioned product of 118mg isopropyl ether recrystallization, obtain the 72mg product, M.p.=84 ℃.
Ultimate analysis C
17H
24N
2O
5=336.38
C H N
Calculated value % 60.70 7.19 8.33
Measured value % 60.7 7.3 8.4
Infrared spectra (CHCl
3)
Step C:4 '-(N-((2-nitro-6-((penta acyloxy) methyl) phenyl)-N-pentanoyl) aminomethyl)-diphenyl-2-carboxylic acid methyl esters
1.35g abovementioned steps B products therefrom is dissolved in the 13.5ml dimethyl formamide, add 240mg 50% sodium hydride oil dispersion then, this mixture was stirred 15 minutes, add 1.35g 4 '-(brooethyl)-diphenyl-2-carboxylic acid methyl esters then and (press European patent 0,253,310 make); Stirred at normal temperatures 30 minutes, use the 50ml dichloromethane extraction then 3 times, wash extracting solution with water, drying is filtered, and is evaporated to dried under the decompression, residue (2.7g) is through the silica gel column chromatography purifying, with hexanaphthene-ethyl acetate (8-2) wash-out, obtain 2.05g institute phase product, Rf 0.20(hexanaphthene-ethyl acetate 8-2).It is used for same as before following synthetic.
Embodiment 5
4 ' ((2-butyl-7-((penta acyloxy) methyl)-1H-benzoglyoxaline-1-yl) methyl)-diphenyl-2-carboxylic acid methyl ester hydrochloride
With preparation example 2 step C products therefroms (2.05g) is raw material, adopts 1.025g palladium-charcoal, uses the 20ml ethyl acetate of the saturated mistake of hydrogen chloride gas then, presses embodiment 3 operations, obtains 1.8g institute phase product, about 145 ℃ of M.p.=.
Get the above-mentioned product of 300mg Virahol recrystallization, obtain the 180mg product, M.p.=145 ℃.
Ultimate analysis C
32H
36N
2O
4, HCl=549.124
C H Cl N
Calculated value % 69.99 6.79 8.33 5.10
Measured value % 69.9 6.9 6.5 5.2
Infrared spectra (CHCl
3)
Embodiment 6
4 '-((2-butyl-7-(methylol)-1H-benzoglyoxaline-1-yl) methyl)-diphenyl-2-carboxylic acid
With 400mg embodiment 5 products therefroms is raw material, presses embodiment 4 operation, has made 290mg institute phase product (M.p.=250 ℃), earlier with the aqueous ethanolic solution that contains small amount of acetic acid, again with ethanol with its recrystallization, obtain 207mg institute phase product, M.p.=250 ℃.
Ultimate analysis C
26H
26N
2O
3=414.51
C H N
Calculated value % 75.34 6.32 6.76
Measured value % 75.2 6.3 6.8
Infrared spectra (CHCl
3)
Embodiment 7
4 '-((2-butyl-7-(methylol)-1H-benzoglyoxaline-1-yl)-diphenyl-2-carboxylic acid methyl esters
823mg embodiment 5 products therefroms are dissolved in 8.2ml ethanol and the 1.6ml 2N soda, and stirring reaction 30 minutes adds 10ml water then, separate then, drying obtains 600mg institute phase product (M.p.=138 ℃), earlier use ethyl acetate, use the Virahol recrystallization again, M.p.=140 ℃.
Ultimate analysis C
27H
28N
2O
3=428.51
C H N
Calculated value % 75.67 6.59 6.54
Measured value % 75.8 6.5 6.5
Infrared spectra (CHCl
3)
OH 3600cm
-1
C＝O 1722cm
-1
Embodiment 8
4 '-((2-butyl-7-(chloromethyl)-1H-benzoglyoxaline-1-yl) methyl)-the diphenyl-2-carboxylic acid methyl ester hydrochloride
250mg embodiment 7 products therefroms are dissolved in the 25ml methylene dichloride, add the 1ml thionyl chloride that is dissolved in the 5ml methylene dichloride, stirring reaction 15 minutes, behind the evaporate to dryness, residue obtains 250mg institute phase product with the crystalline mixture of ethyl acetate and ether.M.p.＝150℃。
Ultimate analysis C
27H
28Cl
2N
2O
2=483.43
C H Cl N
Calculated value % 67.08 5.84 14.66 5.80
Measured value % 67.0 5.9 14.4 5.9
Infrared spectra (CHCl
3)
C＝O 1724cm
-1
Embodiment 9
4 '-((2-butyl-7-(chloromethyl)-1H-benzoglyoxaline-1-yl) methyl) diphenyl-2-carboxylic acid
350mg embodiment 6 products therefroms were stirred in the 5ml thionyl chloride 2 hours at normal temperatures, after the evaporation, add about 5g ice earlier, add 20ml water then, stir at normal temperatures and spend the night, the water outlet of inclining is dissolved in residue in the 30ml methylene dichloride, drying is filtered evaporated under reduced pressure.Obtain 360mg oily institute phase product, CCM Rf=0.40, (methylene chloride-methanol (9: 1)).
Preparation example 3
4 '-(N-(2-nitro-6-((2-penta acyloxy) ethyl) phenyl)-N-pentanoyl) aminomethyl) the diphenyl-2-carboxylic acid methyl esters
Steps A: ethyl valerate 2-(2-valeryl aminophenyl)
With 5ml 2-amino-benzene ethanol is raw material, by preparation example 2 step B operation, has made 10.06g institute phase product, M.p.=59 ℃, and get the 1.1g product and carry out continuous recrystallization 2 times with essential oil G, made analytic sample, get pure products 610mg, M.M.p.=62 ℃.
Ultimate analysis C
18H
27NO
3=305.42
C H N
Calculated value % 70.79 8.91 4.59
Measured value % 70.9 9.2 4.6
Infrared spectra (CHCl
3)
Step B:2-(3-nitro-2-valeryl aminophenyl)-the ethyl valerate
9.1g abovementioned steps A products therefrom is dissolved in the 50ml acetic anhydride, between 0 ℃ to 10 ℃, adds 7.1ml acetate.0 ℃ to 10 ℃ stirring reaction 2 hours, add 150ml water, separate then, wash with water, obtain the 9.9g product, through the silica gel column chromatography purifying,, obtain 5.89g institute phase product, M.p.=117 ℃ with ethyl acetate-hexanaphthene (30-70) wash-out.
Get the above-mentioned product of 859mg,, obtain 494mg institute phase product, M.p.=120 ℃ earlier with isopropyl ether, use the ether recrystallization again.
Ultimate analysis C
18H
26N
2O
5=350.42
C H N
Calculated value % 61.7 7.48 7.99
Measured value % 61.5 7.5 7.9
Infrared spectra
Step C:4 '-(N-((2-nitro-6-((2-penta acyloxy) ethyl) phenyl)-N-pentanoyl) aminomethyl) diphenyl-2-carboxylic acid methyl esters
By preparation example 2 step C operation, with 3.5g abovementioned steps B product is raw material, adopt 480mg 50% sodium hydride oil dispersion and 3.05g 4 '-(brooethyl)-diphenyl-2-carboxylic acid methyl esters (to press European patent 0,253,310 preparations), through silica gel column chromatography purifying (eluent: ethyl acetate: hexanaphthene (3-7)), obtain 5.19g institute phase product.
Embodiment 10:
4 '-((2-butyl-7-(2-(penta acyloxy) ethyl)-1H-benzoglyoxaline-1-yl) methyl)-the diphenyl-2-carboxylic acid methyl esters
Pressing embodiment 3 operations, is raw material with 3.38g preparation example 3 step C products therefroms, adopts the 1.03g catalyzer, through silica gel column chromatography purifying (eluent: ethyl acetate/hexanaphthene (3: 7)), obtain 2.42g institute phase product.
Infrared spectra (CHCl
3)
Embodiment 11
4 '-((2-butyl-7-(2-hydroxyethyl)-1H-benzoglyoxaline-1-yl) methyl) the diphenyl-2-carboxylic acid methyl esters
2.42g embodiment 10 products therefroms were stirred 30 minutes at normal temperatures with 20ml methyl alcohol and 5.5ml 1N soda, steam methyl alcohol, use dichloromethane extraction, wash extracting solution with water, be evaporated to dried under the decompression, residue is through the ethyl acetate crystallization, obtain 1.59g institute phase product, M.p.=139 ℃, get the above-mentioned product re-crystallizing in ethyl acetate of 110mg, make the 79mg analytic sample, M.p.=139 ℃.
Ultimate analysis C
23H
30N
2O
3=442.56
C H N
Calculated value % 75.99 6.83 6.33
Measured value % 75.8 6.8 6.2
Infrared spectra (CHCl
3)
Implement 12:
4 '-((2-butyl-7-(2-hydroxyethyl)-1H-benzoglyoxaline-1-yl) methyl) diphenyl-2-carboxylic acid
Operating by embodiment 4, is raw material with 400mg embodiment 11 products therefroms, has made 371mg institute phase product, M.p.=174 ℃.This product is through ethyl alcohol recrystallization 2 times, 96mg institute phase product, M.p.=175 ℃.
Ultimate analysis C
27H
28N
2O
3, 1/2 C
2H
5OH=451.574
C H N
Calculated value % 74.48 6.92 6.20
Measured value % 74.15 7.0 6.2
Infrared spectra
Embodiment 13
4 '-((2-butyl-7-(2-chloroethyl)-1H-benzoglyoxaline-1-yl) methyl) the diphenyl-2-carboxylic acid methyl ester hydrochloride
The mixture of 714mg embodiment 11 products therefroms and 14ml thionyl chloride was stirred 45 minutes at 80 ℃, steam and remove thionyl chloride, and with 20ml dichloromethane extraction 3 times of this mixture, each evaporate to dryness, the ethyl acetate crystallization of last dry extract, obtain 733mg institute phase product, M.p.=151 ℃,, make the trace analysis sample by ether-ethyl acetate (1: 1) mixture continuous recrystallization twice, pure products, M.p.=160 ℃.
Ultimate analysis C
28H
30N
2O
2Cl
2=497.47
C H N Cl
Calculated value % 67.50 6.08 5.63 14.25
Measured value % 67.5 6.08 5.6 14.2
Infrared spectra CHCl
3
Embodiment 14:
4 '-((2-butyl-7-(2-chloroethyl)-1H-benzoglyoxaline-1-yl) methyl) diphenyl-2-carboxylic acid
Under normal temperature, stirring, 500mg embodiment 13 products therefroms are poured in the hydrochloric acid of 35ml 36%, this mixture was refluxed 30 minutes, then evaporation.
(eluent: ethanol/methylene (1: 9)), obtain the 479mg product, the latter is dissolved in the mixture of 60ml 50/50 water and formic acid, it is about 10 to transfer to pH with soda, is neutralized to about pH 5 with acetate then through the silica gel column chromatography purifying.Steam and remove methyl alcohol, separate then,,, obtain 310mg institute phase product, M.p.=226 ℃ at about 100 ℃ of following drying under reduced pressure with the ether washing.
Through three recrystallizations, obtain 112mg institute phase product, M.p.=233 ℃ with methyl alcohol.
Embodiment 15
4 '-((2-butyl-7-formyl radical-1H-benzoglyoxaline-1-yl) methyl) diphenyl-2-carboxylic acid methyl ester hydrochloride
600mg embodiment 7 products therefroms are dissolved in the 60ml methylene dichloride, add the 1.2g activated manganese dioxide, this mixture was stirred 24 hours at normal temperatures, filter, evaporated under reduced pressure obtains the free alkali of 600mg institute phase product.
The preparation hydrochloride
The aforementioned products therefrom of 600mg is dissolved in the 3ml ethyl acetate, adds excessive ethyl acetate and hydrogen chloride mixture, separate, with the ether washing,, obtain 610mg institute phase hydrochloride, M.p.=145 ℃ then in 80 ℃ of drying under reduced pressure.
Infrared spectra (CHCl
3)
1723-1706cm
-1
Fragrance absorbs 1618-1599-1563-1520cm
-1
Heterocycle 1498cm
-1
Embodiment 16:
4 '-((2-butyl-7-formyl radical-1H-benzoglyoxaline-1-yl) methyl) diphenyl-2-carboxylic acid
600mg embodiment 15 products therefroms are dissolved in 6ml ethanol, 0.8ml water and the 0.8ml caustic soda alkali lye,,, add 30ml water, add acetate till pH is 4-5 this mixture cooling in 50 ℃ of stirrings 2.5 hours.
Stirred 30 minutes down in normal temperature, separate then, wash with water, in 90 ℃ of drying under reduced pressure, obtain the 470mg product, M.p.=225 ℃.
Under refluxing, the preamble products therefrom is dissolved in the 30ml formic acid, filters then, concentrate, place, crystallization at normal temperatures, the fractional crystallization thing is used methanol wash, in 90 ℃ of drying under reduced pressure, obtains 360mg institute phase product, M.p.=230 ℃.
Ultimate analysis C
26H
24N
2O
3=412.47
C H N
Calculated value % 75.7 5.87 6.79
Measured value % 75.5 5.8 6.7
Infrared (whiteruss)
C＝O 1690cm
-1
Fragrance absorbs 1600-1580cm
-1
Heterocycle 1516cm
-1
Embodiment 17:
4 '-((2-butyl-7-((dimethylamino) methyl)-1H-benzoglyoxaline-1-yl) methyl) diphenyl-2-carboxylic acid dihydrochloride
360mg embodiment 9 products therefroms are dissolved in the 10ml 33% decil acid solution, stirred at normal temperatures 19 hours, with this mixture evaporation, use 20ml dichloromethane extraction 3 times, with 15ml salt water washing 2 times, drying is filtered reduction vaporization.Obtain the free alkali of 300mg institute phase product.
The preparation dihydrochloride
Press embodiment 15 described method operations, that is, 300mg preamble products therefrom is dissolved in the 5ml isopropyl acid that contains excessive acetic acid ethyl ester hydrogenchloride.
Obtain 110mg institute phase product, M.p.=260 ℃.
Ultimate analysis C
28H
31N
3O
2, 2HCl=514.47
C H Cl N
Calculated value % 65.36 6.46 13.78 8.17
Measured value % 65.3 6.5 13.8 8.0
Infrared (whiteruss)
C＝O 1770-1680cm
-1
Fragrance absorbs 1623-1597cm
-1
Heterocycle 1514-1495cm
-1
NMR spectrum (DMSO) 300MHz
Embodiment 18
(2-butyl-1-(2 '-(methoxycarbonyl) biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-methyl acetate hydrochloride
A) preparation (2-butyl-1-(2 '-(methoxycarbonyl) biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylic acid
1g embodiment 11 products therefroms are added in 10ml acetone and the 1.5ml BOWERS reagent, this mixture was stirred 1 hour at normal temperatures, filter, use dichloromethane filtrate, evaporation is dissolved in residue in 50ml water and the 50ml methyl alcohol, transfers to pH12 with 1N soda, be acidified with acetic acid to pH4-5 then, 100ml dichloromethane extraction 3 times of evaporation back use 40ml water with extracting solution washed twice, drying, filter evaporate to dryness.Obtain 1.07g institute phase product.
B) preparation (2-butyl-1-(2-(methoxycarbonyl) biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-methyl acetate
Aforementioned product is dissolved in the 10ml methylene dichloride, carries out esterification with about 10ml diazomethane then in methylene dichloride, evaporate to dryness obtains the 968mg product, through silica gel column chromatography purifying (eluent: ethyl acetate-flugene(7-3)).Obtain 745mg institute phase product (free alkali).
C) preparation hydrochloride
Operating by embodiment 15, is raw material with the aforementioned products therefrom of 303mg, handles it with ethyl acetate-hydrogen chloride mixture, obtains 280mg institute phase hydrochloride, M.p.=128 ℃.
Infrared (CHCl
3)
Embodiment 19
2-butyl-1-((2 '-carboxyl-biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylic acid
At normal temperatures, 745mg embodiment 8 products therefroms are added in the soda of 8ml ethanol and 1.6ml 32%, under the alcoholic acid reflux temperature, stirred 1 hour, with this mixture evaporation, residue is dissolved in the 10ml water, is acidified with acetic acid to pH5, separate, wash with water, decompression is down in 80 ℃ of dryings, obtain 516mg institute phase product, M.p.=161 ℃, use Virahol earlier, use the methylethylketone recrystallization again, obtain 184mg institute phase product, M.p.=220 ℃.
Ultimate analysis C
27H
26N
2O
4=442.52
C H N
Calculated value % 73.29 5.92 6.33
Measured value % 73.3 5.9 6.3
Infrared (whiteruss)
Very typical OH/NH association absorption band
Embodiment 20
4 '-((2-butyl-7-vinyl-1H-benzoglyoxaline-1-yl) methyl)-diphenyl-2-carboxylic acid
At normal temperatures, 300mg embodiment 13 products are added in the soda of 3ml methyl alcohol, 0.6ml water and 0.6ml 32%.
With this mixture stirring and refluxing 1 hour, steam and remove methyl alcohol, add 5ml water, be neutralized to pH 5-6 with acetate then, separate, wash with water, decompression obtains 228mg institute phase product, M.p.=228 ℃ down in 100 ℃ of dryings.
The aforementioned products therefrom of 474mg earlier with methylethylketone, use the Virahol recrystallization again, is obtained 278mg institute phase product, M.p.=238 ℃.
Ultimate analysis C
27H
26N
2O
2=410.52
C H N
Calculated value % 79.00 6.38 6.82
Measured value % 79.2 6.5 6.9
Infrared (whiteruss)
Very typical OH/NH association absorption band
Embodiment 21:
4 ' (2-butyl-7-(2-dimethylamino) ethyls)-the diphenyl-2-carboxylic acid methyl esters
Under normal temperature, stirring, 1.05g embodiment 13 products therefroms are added to 25ml contain in the ethanol of 33% dimethylamine.
Make this mixture keep reaction 16 hours at 80 ℃, then at 60 ℃ of reduction vaporizations, use 60ml dichloromethane extraction 3 times, with extracting solution washing 3 times, drying is evaporated to dried with 20ml water.Through the silica gel column chromatography purifying,, obtain 789mg institute phase product with methyl alcohol-methylene dichloride (1-9) wash-out.CCM:Rf 0.37(developping agent: methylene chloride-methanol (9-1)).
Embodiment 22
4 '-((2-butyl-7-(2-(dimethylamino) ethyl)-1H-benzoglyoxaline-1-yl) methyl) the diphenyl-2-carboxylic acid dihydrochloride
At normal temperatures, 789mg embodiment 21 products therefroms are added in the soda of 15ml ethanol and 1.3ml 32%.
This mixture was stirred 1 hour at 85 ℃, and evaporation is dissolved in residue in the 10ml water, is acidified with acetic acid to pH 5, uses 60ml dichloromethane extraction 3 times; With extracting solution washing 2 times, drying is filtered evaporate to dryness with 10ml water.
Products therefrom is dissolved in the 5ml methylethylketone, adds the mixture of 5ml ethyl acetate and hydrogenchloride, the entire reaction thing is placed crystallization at normal temperatures, tell crystallisate then, with the methylethylketone washing, decompression is down in 60 ℃ of dryings, behind the acetonitrile recrystallization, obtain 429mg institute phase product, M.p.=218 ℃.
Ultimate analysis C
29H
33N
3O
2, 2HCl
C H Cl N
Calculated value % 65.9 6.67 13.42 7.95
Measured value % 65.7 6.6 13.1 8.2
Infrared (whiteruss)
Very typical OH/NH association absorption band
Embodiment 23:
2-butyl-1-(2 '-cyano group-(1,1 '-biphenyl)-the 4-yl) methyl)-1H-benzoglyoxaline-7-carboxylate methyl ester
Steps A: 3-amino-2-valeryl Methyl anthranilate
Products therefrom among the 560mg preparation example 1 step C is dissolved in the 12ml tetrahydrofuran (THF), palladium-the charcoal that adds 280mg 18% is with this reaction medium hydrogenation 30 minutes (absorbing 160ml hydrogen), restir 10 minutes, filter then, decompression is steamed down and is desolventized, and residue is dissolved in the isopropyl ether, separates, in 80 ℃ of drying under reduced pressure, obtain the 450mg crude product, the latter is through the isopropyl ether recrystallization, M.p.=90 ℃.
Ultimate analysis C
13H
18N
2O
3, 250.29
C H N
Calculated value % 62.38 7.25 11.19
Measured value % 62.4 7.4 11.1
Step B:4 '-(N-((2-(methoxycarbonyl)-6-aminophenyl)-positive pentanoyl) amino methyl-diphenyl-2-carboxylic acid methyl esters
250mg abovementioned steps A products therefrom is dissolved in the 2ml dimethyl formamide, the sodium hydride oil dispersion that adds 52mg 50%, this mixture was stirred 15 minutes, add 300mg 4 '-(brooethyl)-biphenyl-2-nitrile then, stirred at normal temperatures 15 minutes, steaming desolventizes, and adds 60ml water, uses dichloromethane extraction; Wash extracting solution with water, dry, decompression is evaporate to dryness down, obtain the crude product of 600mg institute phase product, this crude product is earlier through silica gel column chromatography purifying (eluent: flugene-ethyl acetate (7-3)), use the isopropyl ether recrystallization then, that continues uses the ether recrystallization, obtain 125mg institute phase product, M.p.=80 ℃, 145 ℃ then.
Ultimate analysis C
27H
27N
3O
3, 441.51
C H N
Calculated value % 73.45 6.16 9.52
Measured value % 73.4 6.2 9.2
Infrared spectra (CHCl
3)
Step C:
2-butyl-1-(2 '-cyano group-(1,1 '-biphenyl)-the 4-yl) methyl)-1H-benzoglyoxaline-7-carboxylate methyl ester hydrochloride
730mg abovementioned steps B products therefrom is dissolved in the 10ml hydrogenchloride ethyl acetate solution, and in 50 ℃ of stirrings 10 minutes, steaming desolventized, and residue was dissolved in the mixture of methylethylketone and ether, separated then, in 80 ℃ of drying under reduced pressure.Gained 715mg crude product is used ethyl acetate earlier, use the mixture recrystallization of methylethylketone and ether again, obtain 270mg institute phase product, M.p.=140 ℃.
Ultimate analysis C
27H
25N
3O
2, HCl 459.96
C H N Cl
Calculated value % 70.50 5.70 9.14 7.71
Measured value % 70.6 5.8 9.2 7.8
Infrared spectra (CHCl
3)
-CO
2CH
31723cm
-11436cm
-1
-C≡N 2226cm
-1
≡ N
+The maximum composite absorption of-H is about 2450cm
-1
Embodiment 24
2-butyl-1-(2 '-(1H-tetrazolium-5-yl)-(1,1 '-biphenyl)-the 4-yl) methyl)-1H-benzoglyoxaline-7-carboxylate methyl ester
A) the 10ml saturated sodium bicarbonate aqueous solution is added in the suspension of hydrochloride in 50ml water that contains 650mg embodiment 23 preparations, this mixture was stirred 10 minutes, with the dichloromethane extraction that contains 2% methyl alcohol, wash extracting solution with water, drying, decompression are removed down and are desolvated, and obtain the 600mg free alkali.
B) the above-mentioned product of 600mg is dissolved in the 6ml dimethylbenzene, adds 511mg nitrine tin trimethyl.After 23 hours, add the 205mg trinitride 115-120 ℃ of stirring again, reheat 24 hours steams and removes dimethylbenzene, adds 30ml water, stirs 15 minutes, adds 10ml methyl alcohol, uses dichloromethane extraction then, dry extraction liquid, evaporated under reduced pressure.Obtain the 1g crude product, through silica gel column chromatography purifying (eluent: methylene chloride-methanol (9-1)), make residue then, obtain 470mg institute phase product through the ether crystallization.M.p.＝165℃。
Embodiment 25:
2-butyl-1-((2 '-(1H-tetrazolium-5-yl)-(1,1 '-biphenyl)-the 4-yl) methyl)-1H-benzoglyoxaline-7-carboxylic acid
The solution of 470mg embodiment 24 products therefroms in 12ml ethanol refluxed in the presence of 3ml soda stirred 2 hours, steam ethanol, add 10ml water, drip 0.8ml acetate then.Stirred at normal temperatures 2 hours, and separated then, wash with water, in 80 ℃ of drying under reduced pressure, obtain the 420mg crude product, the latter is dissolved in 10ml methyl alcohol-methylethylketone mixture (1-1), filter this solution, be concentrated into 5ml, add 1 acetate earlier, add 5ml water again, the beginning crystallization was placed 16 hours at+4 ℃, the fractional crystallization thing washes with water, in 90 ℃ of drying under reduced pressure, through re-crystallizing in ethyl acetate, obtain 310mg institute phase product.The about 210-220 of M.p.=℃.
Ultimate analysis C
26H
24N
6O
2, 452.50
C H N
Calculated value % 69.01 5.35 18.57
Measured value % 68.7 5.3 18.3
Infrared spectra
OH/NH composite absorption band
C＝O 1700cm
-1
Fragrance absorbs 1609cm
-11598cm
-1
Assorted virtue absorbs 1515cm
-11488cm
-1
Embodiment 26: pharmaceutical composition
Press following formulation tablet:
Embodiment 2 products ... 10mg
Tablet excipient adds to ... 100mg
(concrete vehicle is: lactose, talcum powder, starch, Magnesium Stearate).
Embodiment 27: pharmaceutical composition
Press following formulation tablet:
Embodiment 25 products ... 10mg
Tablet excipient adds to ... 100mg
(concrete vehicle is: lactose, talcum powder, starch, Magnesium Stearate).
Pharmacology result
1-tests with angiotensin-ii-receptor
The fresh membrane prepare thing that employing is made by rat liver.Will this tissue polytron(homogenizer) in the 50mM of pH 7.4 Tris damping fluid, grind, then with trituration 30, under the 000g centrifugal 3 times, each 15 minutes, the settling that each interval is obtained all moved in the Tris damping fluid of pH 7.4.
Last settling is suspended in insulation damping fluid (Tris 20mM, NaCl 135mM, KCl 10mM, glucose 5mM, MgCl
210mM, phenylmethylsulfonyl fluoride 0.3mM, bacitracin 0.1mM, two (TMS) ethanamide 0.2%) in.
Each equal portions that will be divided into 2ml are added in each haemolysis pipe, add I
125Angiotensin (every pipe 25,000DPM) and test-manufactured thing.(this product is earlier 3 * 10
-5M test 3 times).Replaced with receptor-specific bonded radioactive 50% when above when test-manufacturing thing, tested once more, so as to determining to suppress 50% required concentration during with receptor-specific bonded radioactivity by 7 concentration ranges.Record 50% inhibition concentration by this way.
By adding object of reference, promptly European patent 0,253, and (concentration is 10 to the product of embodiment 94 in 310
-5M determines non-specific binding in triplicate).This medium 25 ℃ of insulations 150 minutes, is put into 0 ℃ of water-bath 5 minutes, and filtration under diminished pressure with the Tris damping fluid rinsing of pH 7.4, writes down radioactivity in the presence of the Triton that has added scintillator.
Direct representation as a result is 50% inhibition concentration (IC
50), that is, displacement 50% is tried the required concentration of being test-manufactured thing of receptor-specific bonded radioactivity, and (nM) represents it with nanomole.
The result:
| The embodiment product | IC 50(nM) |
| 2 4 12 16 19 6 | 911 52 105 99 207 270 |
2-utilizes the antagonistic action of portal vein announcement to angiotensin that exsomatize
Extracting male Wistar rat (about 350g) (IFFA Credo France), neck dislocation are put to death back excision portal vein, and existing side by side soon, portal vein places normal temperature physiological solution (seeing below).The ring of about 1mm diameter is fixed in the bathing pool, and (mM forms: NaCl 118.3, and KCl 4.7, MgSO to contain described prepared ex vivo thing and following physiological solution in the bathing pool
41.2, KH
2PO
41.2, NaHCO
325, glucose 11.1, CaCl
22.5), this medium is maintained 37 ℃, and feed O
2(95%) and CO
2(5%) mixture.Begin load for 1g, above-mentioned ring was left standstill 60-90 minute.For fear of spontaneous contraction, in cultivating bath, add isoptin (1 * 10
-6M).
When finish storage period, in bathing, insulation adds angiotensin (Ciba Ipertensinu) 3 * 10
-8M, make it to contact 1 minute with prepared product, per 30 minutes repeat this operation once, between stimulating, twice Angiotensin will organize washing 3 or 4 times, newly stimulating by Angiotensin preceding 15 minutes, in bathing pool, add test-compound, can calculate IC from the concentration of the test-compound of continuous increase
50Value (Angiotensin is produced 50% concentration that suppresses), (nM) represents it with nanomole.
The result:
| The embodiment product | IC 50(nM) |
| 4 16 2 | 9.5 45 1000 |
The angiotensin II and antagonisti activity test that 3-carries out in removing the spinal rat body
Make male Sprague-Dawley rat (250 to 350g) anesthesia by peritoneal injection vetanarcol (50mg/kg).Left neck artery animal inserts the conduit (PE50) that has added heparin, and by the Gould pressure transmitter itself and calculation of pressure instrument (Gould, Pressure Processor) is linked to each other, and presses so as to the record auterial diastole.
Right jugular vein animal inserts a conduit, so as to the injection test-compound.
Animal is placed under the condition of assisted respiartion, lung stomogastric nerve bilateral is cut, remove the spinal cord of rat then.
After stablizing the sufficiently long time, in the following manner research test-manufactured thing to angiotensin (Ipertensinu, antagonistic action CIBA):
1. continuous 3 injection angiotensins (0.75 μ g/kg) (15 minutes at interval) impel generation blood pressure that reappear, stable.
2. in the 15 minute interim that gives angiotensin, giving angiotensin preceding 5 minutes, injection test-compound (0.01 to 10mg/kg).
The boosting of the angiotensin in the presence of antagonist is expressed as the percentage ratio that gives the boosting of angiotensin own.Determine to suppress the dosage (ID of this boosting 50% thus
50).
Each animal with itself in contrast.
The result:
| The embodiment product | ID 50（mg/kg) |
| 4 12 16 | 0.3 1.77 1.97 |
Claims (14)
1, preparation formula (I
B) method of product:
In the formula:
The R representative contains the straight or branched alkyl or the alkenyl of 3 or 4 carbon atoms,
R
1B, R
2B, R
3BAnd R
5BBe defined as follows:
Perhaps R
1B, R
2B, R
3BAnd R
5BIt is mutually the same and represent hydrogen atom,
Perhaps R
2BAnd R
5BIn have one to represent hydrogen atom, and another represent hydrogen atom or-CH
2-O-R
10Group, wherein R
10Represent hydrogen atom or contain the straight or branched alkyl or the alkenyl of 5 carbon atoms at most, perhaps R
2BAnd R
5BOne of them representative
Group, wherein R
cAnd R
dBe same to each other or different to each other, and representative is hereinafter to R
aAnd R
bThe implication that is limited, R
1BAnd R
3BOne of them is a hydrogen atom, and another then is selected from-OR
6,-CO
2R
7With-R
11Group, wherein:
R
6And R
7Be same to each other or different to each other, represent hydrogen atom or contain the straight or branched alkyl or the alkenyl of 5 carbon atoms at the most,
R
11Be selected from:
A) contain the alkyl of 4 carbon atoms at the most, this alkyl can at random be selected from following group by one or more and replace:
-halogen atom,
--the hydroxyl of acidylate arbitrarily,
--contain the straight or branched alkoxyl group or the alkenyloxy of 5 carbon atoms at the most,
--can be by any aryl that replaces of one or more substituting groups, described substituting group is selected from: halogen atom, hydroxyl, trifluoromethyl, cyano group, nitro, amino, contain the alkoxyl group, phenyl, benzyl, free of 4 carbon atoms, the carboxyl and the tetrazyl of salifiable or esterification at the most
--carboxyl free, esterification or salifiable,
--formula
Group, R in the formula
aAnd R
bBe same to each other or different to each other, they are selected from hydrogen atom, contain alkyl or the alkenyl and the aryl of 1 to 4 carbon atom, all these groups can at random be replaced by one or more substituting groups, described substituting group is selected from: halogen atom or hydroxyl, trifluoromethyl, cyano group, nitro or amino, contain alkoxyl group, phenyl or benzyl, the free of 4 carbon atoms, the carboxyl and the tetrazyl of salifiable or esterification at the most
B) contain the straight or branched alkenyl of 2 to 5 carbon atoms,
C) contain the acyl group and the formyl radical of 2 to 7 carbon atoms,
D) formula
Group, R in the formula
aAnd R
bDescribed as defined above, perhaps R
1B, R
2B, R
3BAnd R
5BIn have two to represent hydrogen atom at the most, other then is selected from-CH
2-O-R
10,-OR
6,-CO
2R
7,-R
11And formula
Group, wherein R
6, R
7, R
10, R
11, R
cAnd R
dDescribed as defined above,
R
4BRepresent free, esterification or salifiable carboxyl, cyano group or tetrazyl,
Or-(CH
2)
m-SO
2-X-R
12Group, in the formula m represent 0 to 4 integer and
Perhaps (X-R
12) represent NH
2
Perhaps X represents singly-bound, or-NH-,-NH-CO-NH-or-the NH-CO-group,
R
12Represent alkyl, alkenyl or aryl, these groups can at random be substituted,
Described formula (IB) product comprises all possible racemize, mapping or diastereomer, and described formula (IB) product and inorganic or organic acid and additive salt inorganic or that organic bases generates,
The method is characterized in that:
Perhaps
By formula (IV
B) product and formula (V
B) the compound reaction, so as to making formula (IX
B) product,
In the formula described in the definition such as claim 1 of R, R
1B', R
2B', R
3B' and R
5B' mean respectively in the claim 1 R
1B, R
2B, R
3BAnd R
5BPointed meaning, wherein, the active function groups that can adopt the protecting group protection to exist as required,
Hal represents halogen atom in the formula, R
4B' mean in the claim 1 R
4BPointed meaning, wherein, the active function groups that adopts the protecting group protection to exist as required,
R, R in the formula
1B', R
2B', R
3B', R
5B' and R
4B' implication the same, perhaps
A) by formula (IV
B) compound and the reaction of formula II compound, so as to making formula (X
B), product:
R in the formula
1B', R
2B', R
3B' and R
5B' as defined above,
R in the formula
9Representation hydroxy or alkoxy or halogen atom, R's is described as defined above,
R, R in the formula
1B', R
2B', R
3B' and R
5B' as defined above,
B) by formula (VI
B') the formula II compound reaction that limits of compound and preamble, so as to making formula (X
B') product,
R in the formula
1B', R
2B', R
3B' and R
5B' as defined above,
R in the formula
1B', R
2B', R
3B', R
5B' and R civilian as defined above described, with formula (X
B') product is nitrated, so as to making the formula (X of preamble definition
B) compound, make formula (X
B) formula (V that limits of product and preamble
B) the compound reaction, so as to making formula (XI
B) product,
R, R in the formula
1B', R
2B', R
3B', R
5B' and R
4B' civilian as defined above described, make formula (XI then
B) nitro functions of product carries out the selective reduction reaction, so as to making formula (XII
B) product:
R, R in the formula
1B', R
2B', R
3B', R
5B' and R
4B' civilian as defined above described, make formula (XII then
B) the product cyclisation, so as to making the formula (IX that preamble limits
B) product,
Perhaps
Make formula (VI
B) formula (V that limits of compound and preamble
B) the compound reaction, so as to making formula (VII
B) product:
R in the formula
1B', R
2B', R
3B', R
5B' and R
4B' civilian as defined above described, then nitroreduction is become amino, so as to making formula (VIII
B) product
R in the formula
1B', R
2B', R
3B', R
5B' and R
4B' civilian as defined above described, make it then to react with the formula III product
X represention oxygen atom or NH group in the formula, R
9With R as defined above, so as to after cyclization, making the formula (IX that preamble limits
B) product, reach necessity as requested, can make formula (IX
B) one step or the following reaction of multistep of product experience, its order is random:
-remove the reaction of being protected the protecting group that active function groups has,
-with salt-forming reaction inorganic or organic acid or alkali, so as to making corresponding salt,
The esterification of-acid functional group or salt-forming reaction,
-make ester functional group be converted into the reaction of acid functional group by acid or basic hydrolysis,
-alkoxyl group is converted into the reaction of hydroxyl,
-halogenated alkyl is converted into the reaction of thiazolinyl,
The amino reaction that replaces halogen atom of-usefulness,
The reaction of-usefulness halogen atom substituted hydroxy,
-esterifying carboxyl group is changed into the reduction reaction of hydroxyalkyl,
-hydroxyalkyl is converted into the oxidizing reaction of esterifying carboxyl group,
-methylol is converted into the oxidizing reaction of formyl radical,
-racemic modification is converted into the resolution reaction of resolved product,
-free, carboxyl salifiable or esterification are changed into the reaction of tetrazyl,
Above-mentioned formula (the I of gained thus
B) product comprises all possible racemize, mapping and diastereomer.
2, be used for preparing the formula (I that claim 1 limits according to claim 1
B) method of compound, the method is characterized in that: adopt following compound as starting raw material: formula (IV
B), (VI
B) or (VI '
B) compound, in formula (IV
B), (VI
B) or (VI '
B) in, R
2B' and R
5B' be defined as follows: R
2B' and R
5B' one of them represents hydrogen atom, and another then represents formula
Group,
R in the formula
cAnd R
dBe same to each other or different to each other, be selected from hydrogen atom, the alkyl or alkenyl and the phenyl that contain 1 to 4 carbon atom, all these groups can at random be replaced by one or more substituting groups, described substituting group is selected from: halogen atom, hydroxyl, trifluoromethyl, cyano group, nitro or amino, contain alkoxyl group, phenyl or the benzyl of 4 carbon atoms at the most, the carboxyl and the tetrazyl of free, salifiable or esterification
R
1B' representative contains the alkyl of 4 carbon atoms at the most; this alkyl can at random be replaced by one or more substituting groups; described substituting group is selected from: the carboxyl of halogen atom, hydroxyl, methoxyl group, oxyethyl group, free, salifiable or esterification, amino, one or dialkyl amido and phenyl; this phenyl itself can at random be replaced by one or more following radicals again; described group is selected from: the carboxyl and the tetrazyl of halogen atom, methoxyl group, trifluoromethyl, cyano group, free, salifiable or esterification; wherein; can protect R as required to active function groups
3B' be selected from formula OR
6And CO
2R
7Group, in the formula, R
6And R
7Represent hydrogen atom or contain the alkyl or the alkenyl of 5 carbon atoms at the most, wherein, can protect active function groups as required; Formula (V
B) compound, in the formula
R
4B' represent free, esterification or salifiable carboxyl or tetrazyl, or formula-(CH
2)
p-SO
2-X
d-R
12dGroup, in the formula, p represents 0 and 1, X
dRepresent Shi-NH-,-NH-CO-NH-,-NH-CO-or singly-bound, R
12dRepresent methylidene, ethyl, propyl group, vinyl, allyl group, phenyl, benzyl, pyridyl, picolyl, pyridine ethyl, nitropyridine base, pyrimidyl, tetrazyl, di azoly, piperidyl, Alkylpiperidine base, thiazolyl, alkyl thiazolyl, THP trtrahydropyranyl, methyltetrahydrofuran base; Amino and carbamyl can be at random replaced by 1 or 2 substituting groups, described substituting group be selected from the preamble qualification-(CH
2)
p-SO
2-X
d-R
12dWith the alkyl that contains 4 carbon atoms at the most and the alkenyl that can replace arbitrarily; All these groups can be at random replaced by one or more substituting groups, and described substituting group is selected from halogen atom, hydroxyl, contains alkyl, alkenyl and alkoxyl group, trifluoromethyl, cyano group, the free of 4 carbon atoms, the carboxyl or the tetrazyl of salifiable or esterification at the most; And R represents formula II, (III) or (IV of butyl or butene-1-Ji in the formula
B) compound.
3, be used for preparing the formula (I that claim 1 limits according to claim 1 or 2
B) method of product, the method is characterized in that: adopt following formula (V
B) compound is as starting raw material, in the formula, R
4B' represent free, esterification or salifiable carboxyl or tetrazyl or formula-(CH
2)
p-SO
2-X
d-R
12dGroup, in the formula, p represents 0 and 1, X
dRepresentative-NH-,-NH-CO-NH-,-NH-CO-group or singly-bound, and, R
12dRepresent methylidene, vinyl, allyl group, phenyl, benzyl, picolyl or pyridine ethyl wherein, can at random protect active function groups.
4, be used for preparation corresponding to formula (I according to claim 1
A) formula (I
B) method of compound:
In the formula
The R representative contains the straight or branched alkyl or the alkenyl of 3 or 4 carbon atoms,
R
1A, R
2A, R
3AAnd R
5ABe defined as follows:
Perhaps R
1A, R
2A, R
3AAnd R
5AIt is mutually the same and represent hydrogen atom,
Perhaps R
2AAnd R
5ADefinition be: one of them represent hydrogen atom or-CH
2-O-R
10Group, R in the formula
10Represent hydrogen atom or contain the straight or branched alkyl or the alkenyl of 5 carbon atoms at the most, another then represents hydrogen atom, R
1AAnd R
3AOne of them represents hydrogen atom, and another then is selected from-OR
6,-CO
2R
7And R
11Group, wherein:
R
6And R
7Be same to each other or different to each other, represent hydrogen atom or contain the straight or branched alkyl or the alkenyl of 5 carbon atoms at the most,
R
11Be selected from following radicals:
A) contain the alkyl of 4 carbon atoms at the most, this alkyl can be replaced arbitrarily by one or more substituting groups, and described substituting group is selected from:
-halogen atom,
-the hydroxyl of acidylate arbitrarily,
-contain the straight or branched alkoxyl group or the alkenyloxy of 5 carbon atoms at the most,
Carboxyl-free, esterification or salifiable,
-Shi
Group, R in the formula
aAnd R
bBe same to each other or different to each other, they are selected from hydrogen atom, the alkyl or the alkenyl that contain 1 to 4 carbon atom, can at random replace by halogen atom or hydroxyl,
B) contain the straight or branched alkenyl of 2 to 5 carbon atoms,
C) contain the acyl group and the formyl radical of 2 to 7 carbon atoms,
R
4ARepresent free, esterification or salifiable carboxyl, cyano group or tetrazyl, this group is salify at random,
Said formula (I
A) product comprises all possible racemize, mapping or diastereomer, and said formula (I
A) product and organic or inorganic is sour and inorganic or organic bases generates additive salt,
The method is characterized in that: employing formula (IV
B), (VI
B) or (VI '
B) compound and formula (V
B) compound is as starting raw material, in formula (IV
B), (VI
B) or (VI '
B) in, R
1B', R
2B', R
3B' and R
5B' respectively with aforementioned R
1A, R
2A, R
3AAnd R
5ADefinition identical, wherein can at random protect active function groups; In formula (V
B) in, R
4B' definition and aforementioned R
4AIdentical, active function groups wherein can at random be protected.
5, be used to prepare formula (I according to claim 1 corresponding to formula I
B) method of compound,
In the formula:
The R representative contains the straight or branched alkyl or the alkenyl of 3 or 4 carbon atoms,
R
1, R
2, R
3And R
5Definition be:
Perhaps R
1, R
2, R
3And R
5Be same to each other or different to each other, and represent hydrogen atom,
Perhaps R
2And R
5One of them represent hydrogen atom or-CH
2-O-R
10, another then represents hydrogen atom, R
1And R
3One of them represents hydrogen atom, and another then is selected from-OR
6,-CO
2R
7With-CH
2-O-R
8Group, wherein R
10, R
6, R
7And R
8Be same to each other or different to each other, represent hydrogen atom or contain the straight or branched alkyl or the alkenyl of 5 carbon atoms at the most,
R
4Represent free, esterification or salifiable carboxyl,
Said formula I product comprises all possible racemize, mapping or diastereomer, and said formula I product and inorganic or organic acid and additive salt inorganic or that organic bases generates,
The method is characterized in that: employing formula (IV
B), (VI
B) or (VI '
B) compound and formula (V
B) product is as starting raw material, in formula (IV
B), (VI
B) or (VI '
B) in, R
1B', R
2B', R
3B' and R
5B' definition respectively with aforementioned R
1, R
2, R
3And R
5Identical, active function groups wherein can at random be protected, in formula (V
B) in, R
4B' definition and aforementioned R
4Identical, active function groups wherein can at random be protected.
6, according to the method for claim 4, it is characterized in that: R represents R in formula II, (III) or (IV) compound and the formula of butyl or butene-1-Ji in the employing formula
1B' represent the formula (IV of hydrogen atom or alkoxyl group
B), (VI
B) or (VI '
B) compound is as starting raw material.
7, according to the method for claim 4, it is characterized in that: R represents R in formula II, (III) or (IV) compound and the formula of butyl in the employing formula
1B' represent the formula (IV of hydrogen atom
B), (VI
B) or (VI '
B) compound is as starting raw material.
8, according to the method for claim 4, it is characterized in that: R represents formula II, (III) or (IV) compound and the formula (IV of butyl in the employing formula
B), (VI
B) or (VI '
B) compound is as starting raw material, in formula (IV
B), (VI
B) or (VI '
B) middle R
1B', R
2B' and R
5B' represent hydrogen atom, R
3B' be selected from formula-OR
6,-CO
2R
7With-R
11, R wherein
6And R
7Be same to each other or different to each other, represent hydrogen atom or contain the straight or branched alkyl or the alkenyl of 5 carbon atoms at the most,
R
11Be selected from:
A) contain the alkyl of 4 carbon atoms at the most, this alkyl can at random be replaced by one or more groups, and described group is selected from:
-halogen atom,
-the hydroxyl of acidylate arbitrarily,
-contain straight chain or the straight chain alkoxyl group or the alkenyloxy of 5 carbon atoms at the most,
-free, ester or the salifiable carboxyl of one-tenth,
-Shi
Group, R in the formula
aAnd R
bBe same to each other or different to each other, be selected from hydrogen atom, contain the alkyl or the alkenyl that can be at random replace by halogen atom or hydroxyl of 1 to 4 carbon atom,
B) contain the straight or branched alkenyl of 2 to 5 carbon atoms,
C) contain the acyl group and the formyl radical of 2 to 7 carbon atoms, active function groups wherein can at random be protected.
9, according to the method for claim 4, it is characterized in that: R represents formula II, (III) or (IV) compound and the formula (IV of butyl in the employing formula
B), (VI
B) or (VI '
B) compound is as starting raw material, in formula (IV
B), (VI
B) or (IV '
B) in, R
1B', R
2B' and R
5B' represent hydrogen atom, R
3B' represent hydrogen atom, R
3ARepresent hydrogen atom; Free carboxyl or contained the carboxyl of the alkyl esterification of 4 carbon atoms at the most; Formyl radical; The alkyl or the alkenyl that contain 4 carbon atoms at most; The alkyl that can at random replace by one or more following radicals; described group is selected from: the carboxyl of halogen atom, hydroxyl, acyloxy, the amino that can be replaced arbitrarily by 1 or 2 alkyl that contains 4 carbon atoms at the most and free, salifiable or esterification, active function groups wherein can at random be protected.
10, according to the method for claim 1, it is characterized in that: selected initial compounds should make:
4 '-((2-butyl-1H-benzoglyoxaline-1-yl) methyl) diphenyl-2-carboxylic acid methyl esters and salt thereof,
4 '-((2-butyl-1H-benzoglyoxaline-1-yl) methyl) diphenyl-2-carboxylic acid and salt thereof.
11, according to the method for claim 1, it is characterized in that: selected initial compounds should make:
2-butyl-1-((2 '-carboxyl-biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylic acid and salt thereof,
4 '-((2-butyl-7-(2-hydroxyethyl)-1H-benzoglyoxaline-1-yl) methyl) diphenyl-2-carboxylic acid and salt thereof,
4 '-((2-butyl-7-formyl radical-1H-benzoglyoxaline-1-yl) methyl) diphenyl-2-carboxylic acid and salt thereof,
2-butyl-1-((2 '-(1H-tetrazolium-5-yl)-(1,1 '-biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylic acid and salt thereof.
12, the method for pharmaceutical compositions is characterized in that: at least a their the pharmaceutically useful additive salt that adopts at least a claim 1 the formula I compound that limits or meet this application requiring is as active ingredient.
13, the method for pharmaceutical compositions is characterized in that: at least a their the pharmaceutically useful additive salt that adopts the formula I compound that at least a claim 2 limits or meet this application requiring is as active ingredient.
14, the method for pharmaceutical compositions is characterized in that: at least a their the pharmaceutically useful additive salt that adopts the formula I compound that at least a claim 3 limits or meet this service requirements is as active ingredient.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9007135 | 1990-06-08 | ||
| FR909007135A FR2663028B1 (en) | 1990-06-08 | 1990-06-08 | NOVEL BENZIMIDAZOLE DERIVATIVES, THEIR PREPARATION PROCESS, THE NEW INTERMEDIATES OBTAINED, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| FR9015811 | 1990-12-18 | ||
| FR9103778 | 1991-03-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1057256A true CN1057256A (en) | 1991-12-25 |
| CN1045771C CN1045771C (en) | 1999-10-20 |
Family
ID=9397404
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN91103858A Expired - Fee Related CN1045771C (en) | 1990-06-08 | 1991-06-08 | Benzimidazole derivatives, their preparation process, intermediates obtained, their use as medicaments and pharmaceutical compositions containing them |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN1045771C (en) |
| FR (1) | FR2663028B1 (en) |
| ZA (1) | ZA914376B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1056140C (en) * | 1992-12-17 | 2000-09-06 | 三共株式会社 | Biphenyl derivatives, their preparation and their use for the treatment of hypertension and cardiac disease |
| CN102276585A (en) * | 2010-06-09 | 2011-12-14 | 中国药科大学 | Preparation method for and medicinal usage of 4-substituted-phenyl-aryl-carboxylate derivatives |
| CN111057011A (en) * | 2019-12-24 | 2020-04-24 | 山西大学 | Preparation method of 5, 6-bis (4-aminobenzyl) -1-methyl-2-phenylbenzimidazole |
| CN111116485A (en) * | 2019-12-24 | 2020-05-08 | 山西大学 | Preparation method of 5, 6-bis (4-aminobenzyl) -2-trifluoromethyl-1H-benzimidazole |
| CN111116484A (en) * | 2019-12-24 | 2020-05-08 | 山西大学 | Preparation method of 5, 6-bis (4-aminobenzyl) -1,2 dimethyl-benzimidazole |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61151176A (en) * | 1984-12-24 | 1986-07-09 | Sumitomo Chem Co Ltd | Benzimidazole derivative, production thereof, insecticide and acaricide comprising same as active ingredient |
| CA1334092C (en) * | 1986-07-11 | 1995-01-24 | David John Carini | Angiotensin ii receptor blocking imidazoles |
| NZ221729A (en) * | 1986-09-15 | 1989-07-27 | Janssen Pharmaceutica Nv | Imidazolyl methyl-substituted benzimidazole derivatives and pharmaceutical compositions |
| CA1338238C (en) * | 1988-01-07 | 1996-04-09 | David John Carini | Angiotensin ii receptor blocking imidazoles and combinations thereof with diuretics and nsaids |
| US4880804A (en) * | 1988-01-07 | 1989-11-14 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking benzimidazoles |
-
1990
- 1990-06-08 FR FR909007135A patent/FR2663028B1/en not_active Expired - Fee Related
-
1991
- 1991-06-07 ZA ZA914376A patent/ZA914376B/en unknown
- 1991-06-08 CN CN91103858A patent/CN1045771C/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1056140C (en) * | 1992-12-17 | 2000-09-06 | 三共株式会社 | Biphenyl derivatives, their preparation and their use for the treatment of hypertension and cardiac disease |
| CN102276585A (en) * | 2010-06-09 | 2011-12-14 | 中国药科大学 | Preparation method for and medicinal usage of 4-substituted-phenyl-aryl-carboxylate derivatives |
| CN102276585B (en) * | 2010-06-09 | 2013-06-19 | 中国药科大学 | Preparation method for and medicinal usage of 4-substituted-phenyl-aryl-carboxylate derivatives |
| CN111057011A (en) * | 2019-12-24 | 2020-04-24 | 山西大学 | Preparation method of 5, 6-bis (4-aminobenzyl) -1-methyl-2-phenylbenzimidazole |
| CN111116485A (en) * | 2019-12-24 | 2020-05-08 | 山西大学 | Preparation method of 5, 6-bis (4-aminobenzyl) -2-trifluoromethyl-1H-benzimidazole |
| CN111116484A (en) * | 2019-12-24 | 2020-05-08 | 山西大学 | Preparation method of 5, 6-bis (4-aminobenzyl) -1,2 dimethyl-benzimidazole |
| CN111057011B (en) * | 2019-12-24 | 2022-11-11 | 山西大学 | Preparation method of 5, 6-bis (4-aminobenzyl) -1-methyl-2-phenylbenzimidazole |
| CN111116484B (en) * | 2019-12-24 | 2022-11-11 | 山西大学 | Preparation method of 5,6-bis (4-aminobenzyl) -1,2 dimethyl-benzimidazole |
| CN111116485B (en) * | 2019-12-24 | 2022-11-11 | 山西大学 | Preparation method of 5, 6-bis (4-aminobenzyl) -2-trifluoromethyl-1H-benzimidazole |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2663028B1 (en) | 1994-10-14 |
| CN1045771C (en) | 1999-10-20 |
| ZA914376B (en) | 1992-08-26 |
| FR2663028A1 (en) | 1991-12-13 |
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