CN1030408A - Derivatives of cyclic amino acids, their salt, the medicine that contains it are formed and preparation method thereof - Google Patents
Derivatives of cyclic amino acids, their salt, the medicine that contains it are formed and preparation method thereof Download PDFInfo
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- CN1030408A CN1030408A CN88104162A CN88104162A CN1030408A CN 1030408 A CN1030408 A CN 1030408A CN 88104162 A CN88104162 A CN 88104162A CN 88104162 A CN88104162 A CN 88104162A CN 1030408 A CN1030408 A CN 1030408A
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- logical formula
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- acid
- oxo
- butenoic acid
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D277/06—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to general formula (I)
Compounds, wherein,
R represents hydrogen or halogen or a kind of C
1-4Alkyl or C
1-4Alkoxy base or contain a kind of acyl group group of 1 to 4 carbon atom at acyl moiety; X represents general formula (IV), (V) or (VI):
One of group, wherein a kind of straight chain of R ' expression hydrogen or E and/or Z configuration or branched C
1-4Alkyl group and their salt.
According to compound exhibits cytoprotective of the present invention and gastric acid secretion-retarding effect; Their toxicity is low.
Description
The present invention relates to logical formula I
The 4-oxo-4-(substituted-phenyl of novelty) the butenoic acid acid amides, wherein R represents hydrogen or halogen or a kind of C
1-4Alkyl or C
1-4Alkoxy base or contain a kind of amide group of 1 to 4 carbon atom at acyl moiety;
X represents logical formula IV, (V) or (VI)
One of group, R wherein
1A kind of straight chain or the branched C of expression hydrogen or E and/or Z configuration
1-4Alkyl group, the medicine of their salt and these compounds is formed.
The compound of logical formula I contains a two key, so they can exist with the form of E or Z geometrical isomer.
When a chiral centre when the amino acid moiety of the compound of logical formula I exists, logical formula I can be represented any enantiomorph or contain a kind of mixture of these enantiomorphs with any ratio.
The compound of logical formula I, wherein R
1Be hydrogen, can be converted into their acceptable salt on pharmacology.
The compound exhibits cytoprotective and the gastric acid secretion retarding effect of logical formula I.
Several active types and the proximate compound of chemical structure in british patent specification 2,096, are described in No. 999.
Think 4-oxo-4-(3 at one of compounds effective described in this patent specification, 4,5-trimethoxyphenyl) butenoic acid, by with Glyoxylic acid hydrate and 3,4,5-trimethoxy phenyl methyl ketone prepares through dewatering through the resulting product of aldol condensation again.The productive rate of aldehyde alcohol reaction equals 28%, and the productive rate of dehydration is 71%, means that so total productive rate only is 20%.
The objective of the invention is to find useful compound on novel, the pharmacology, it can from simple, with available initial substance and with produced in high yields.
According to a further aspect in the invention, provide a kind of method for preparing the new compound of logical formula I, wherein
R represents hydrogen or halogen or a kind of C
1-4Alkyl group or C
1-4Alkoxy base or contain a kind of amide group of 1 to 4 carbon atom at acyl moiety;
X represents in logical formula IV, (V) or (VI):
One of group, R wherein
1A kind of straight chain or the branched C of expression hydrogen or E and/or Z configuration
1-4Alkyl group with and salt, it comprises logical formula II;
A kind of compound, wherein X as above defines and R
1A kind of straight chain of expression or band side chain C in logical formula IV, (V) and (VI)
1-4Alkyl group, and logical formula III:
A kind of replacement butenoic acid; wherein R as above defines; or hydroxy-acid group a kind of-activatory derivatives reaction with it; and if need; with original known a kind of method remove any with choosing blocking group and/or, if need change the configuration that two key determined of compound of the logical formula I of gained with original known a kind of method.
Work as R
1During for hydrogen, the compound of logical formula I can be converted into their salt with acceptable organic or inorganic alkali on the pharmacology.
Starting material can maybe can pass through described in the literature method preparation in commercial acquisition.Therefore, the preparation of 4-oxo-4-phenyl-2(E)-butenoic acid such as 109 pages of (nineteen fifty-five) (Org.Synth.Coll.Vol.3 109(1955) of organic synthetic collection the 3rd volume) described in; The 4-(4-aminomethyl phenyl)-the 4-oxo-2(E)-[Bei Ruiqiete (Berichte) the 15th rolls up butenoic acid according to Pi Qieman (Pechman), 888 pages (nineteen eighty-two)] preparation, the 4-(4-p-methoxy-phenyl)-4-oxo-2(E)-butenoic acid is then according to sending amber [Journal of the American Chemical Society such as (Papa), the 70th phase, 3356 pages 1948) (J.am.Chem.Soc.70,3,356 1948)] synthetic.
1,2,3, the ester of 4-tetrahydrochysene-β-Ka Lin-1-carboxylic acid can be as chemical abstracts, the 92nd phase (volume) 72769(Chem.abstr.92,72769) described in synthetic.
Found that in our research work the reaction of initial substance can be carried out with 45 to 70% productive rate.
In the method for the invention, a kind of replacement butenoic acid or its a kind of hydroxy-acid group-activatory derivative of logical formula III, it can have E or Z configuration based on the geometrical shape of two keys, in a kind of inert organic solvents, with a kind of amino acid derivative reaction of logical formula II.The reactive derivative of the compound of logical formula III is their ester, etheride or acid anhydrides or with the formed a kind of derivative of a kind of active agent.Carbodiimide such as dicyclohexylcarbodiimide preferably can be used as active agent.When adopting dicyclohexylcarbodiimide, reaction is preferably in anhydrous methylene chloride as in the inert organic solvents, carries out under a temperature of 0 ℃ and 20 ℃.Two phenenyl phosphinyl chlorine, under-10 ℃, also can be used as activator, be preferably in the ethyl acetate as inert organic solvents, as document (He Ben-Weir (Houben-weyl): " organic chemistry method (Mehtoden der organischen Chemie) ", the E5 volume, 949 pages (vol.E5 P949), G. Xi Mengfulaige (Thieme Verlag), Si Datejiate (Stuttgart), 1985) described in, by adding a kind of alkali of stoichiometric quantity, be preferably triethylamine or N-methylmorpholine to the reaction mixture with in conjunction with the hydrogenchloride that is generated.
If necessary, the isomer of compound with logical formula I of E or Z configuration can transform mutually, and for example, the product with E configuration is converted into the product with Z configuration by the utilization action of ultraviolet light in inert solvent.
Contain hydrogen as R
1The compound of logical formula I with the preparation of a kind of like this method, promptly any group, it is connected in the hydroxy-acid group and is different from hydrogen (being tertiary butyl groups suitably), with original known method, for example, removes by using trichoroacetic acid(TCA).
In our pharmaceutical research work, find, as low dose of (oral ED
50Value is 2 to 10 mg/kg) time, the compound exhibits cell protective effect of logical formula I; And by using heavy dose of (ED
50Value is 15 to 40 mg/kg) time, a kind of restraining effect of gastric acid secretion also can be induced.
The cell protective effect of the compound of logical formula I can be represented with following A. Robert's (Robert) method [gastroenterology the 77th volume, 761 pages (1979) (Gastroenterlogy 77 76(1979)].With the dehydrated alcohol administration that contains concentrated hydrochloric acid, it is partly induced vertically at the glandule of stomach in short duration and bleeds with the mouse of hunger.This deleterious effects can be prevented by the cytoprotective material.
The pylorus ligation method of gastric acid secretion-retarding effect by utilization Xie Ai etc. [gastroenterology the 5th volume, 43 pages (Gastroenterology 5,43(1945)] study.With the female Wei Sita rat that suffered from hunger in advance 20 hours before using pyloric ligation 30 minutes the time oral test substances volume be 0.5 milliliter/100 milligrams body weight.After this operation 4 hours, kill animals, and measure their hydrochloric acid in gastric juice content with phenolphthalein as 0.1 gram equivalent of the indicator/titration value that rises sodium hydroxide solution by (getting hydrochloric acid in gastric juice).And by measuring the pH value that stomach contains thing with this (Radelkis) OP-211/1 type equipment of a kind of auspicious Dare base.
By with one in the most active material, be called the N-[4-(4-p-methoxy-phenyl)-4-oxo-2(E)-crotonoyl]-4(R)-the resulting result of thiazolidine carboxylate methyl ester (referring to embodiment 3) describes in table 1." t " by Student measures.Numerical value accords with P＜0.05 value and is considered to effective.Mean value and ± the S.E. value also provides in table 1.
ED according to compound of the present invention
50Value proves 2 to 40 mg/kg; Simultaneously, because they do not cause any poisonous symptom under oral dosage 1000 mg/kg, their toxicity value is very good.
Table 1
The N-[4-(4-p-methoxy-phenyl)-the 4-oxo-2(E)-crotonoyl]
-4(R)-the thiazolidine carboxylate methyl ester
Oral ED
50Value is 67.76 mg/kg
N excretory hydrochloric acid in gastric juice suppresses acid
Acidity/u Eq/100 gram volume milliliter/100 gram secretion rate %
10 mg/kg 5 541.4 ± 98.7 5.0 ± 0.6 ψ
Contrast 4 531.6 ± 50.1 5.1 ± 0.4
25 mg/kg 5 331.0 ± 73.4 5.4 ± 0.9 26.6
Contrast 5 451.0 ± 108.7 4.3 ± 0.8
50 mg/kg 19 280.7 ± 29.3
X5.7 ± 0.3
X43.1
Contrast 14 493.2 ± 44.8 4.3 ± 0.3
100 mg/kg 5 222.3 ± 91.9
X6.3 ± 0.7 58.2
Contrast 4 531.6 ± 50.1 5.1 ± 0.4
X：P＜0.05
Describe the present invention in detail by following non-limiting examples.
Embodiment 1
N-[4-oxo-4-phenyl-2(E)-crotonoyl]-4(R)-preparation of thiazolidine carboxylate methyl ester
With 1.83 gram (10.0 moles) 4(R)-after thiazolidine carboxylate methyl ester hydrochloride adds in a kind of solution that contains 1.85 gram (10.5 mmole) 4-oxo-4-phenyl-2(E)-butenoic acid in 30 milliliters of anhydrous methylene chlorides, this reaction mixture is cooled to 0 ℃, add 1.01 gram (10.0 moles) N-methylmorpholines, and be added in the gram of 2.06 in 10 milliliters of methylene dichloride (10.0 mmole) N, the solution of N-dicyclohexylcarbodiimide in a small amount of dropping mode then.Stir this mixture down after 2 hours, the N of filtering-depositing, N-cyclohexyl urea at 0 ℃, filtrate with each 15 milliliters 1 gram equivalent/rise the hcl as extraction agent secondary, then with the extraction of 15 ml waters, again with each 15 milliliters of saturated sodium bicarbonate solution extraction secondary, at last with 15 milliliters of saturated nacl aqueous solution extractions.Organic phase anhydrous magnesium sulfate drying, and evaporation.Resistates behind the recrystallization, is obtained the title compound of 2.34 gram (77%) productive rates from ether, fusing point: 110-112 ℃, [α]
25 D-130.2 ° (c=1, methylene dichloride).
Analyze:
Calculated value: C59.00%; N4.95%; N4.58%.
Experimental value: C59.52%; N5.33%; N4.49%.
Embodiment 2
N-[4-oxo-4-phenyl-2(E)-crotonoyl]-(S)-preparation of proline(Pro) (prolinate) methyl esters
With a kind of in 40 milliliters of anhydrous methylene chlorides, contain 3.52 gram (20 mmole) 4-oxo-4-phenyl-2(E)-butenoic acid and 3.14 grams (18.0 mmole) (S)-solution of proline methyl ester hydrochloride is cooled to 0 ℃, add then and be dissolved in gram (18.0 mmole) N-methylmorpholine of 1.92 in 10 milliliters of anhydrous methylene chlorides and then add 3.92 gram (18.0 mmole) N, N-dicyclohexylcarbodiimide.Stirred this mixture 2 hours down at 0 ℃, the dicyclohexylurea (DCU) of filtering-depositing then, filtrate each with 15 milliliters 1 gram equivalent/rise the hcl as extraction agent secondary, extract with 15 ml waters then, with each 15 milliliters of saturated sodium bicarbonate solution extraction secondary, and at last with 15 milliliters of saturated nacl aqueous solution extractions.(organic phase) with after anhydrous magnesium sulfate drying and the evaporating solns, with resistates recrystallization and provide 2.80 gram (52%) title compounds from the mixture of ether and sherwood oil, fusing point: 62-64 ℃, [α]
25 D-93.0 ° (c=1, methylene dichloride).
Analyze:
Calculated value: C66.88%; N5.96%; N4.87%.
Experimental value: C67.11%; N6.29%; N5.00%.
Embodiment 3
The N-[4-(4-p-methoxy-phenyl)-4-oxo-2(E)-crotonoyl]-4(R)-preparation of thiazolidine carboxylate methyl ester
With a kind of 2.16 gram (10.5 mmole) 4-(4-p-methoxy-phenyls that in 40 milliliters of anhydrous methylene chlorides, contain)-4-oxo-2(E)-butenoic acid and 1.83 gram (10.0 mmole) 4(R)-solution of thiazolidine carboxylate methyl ester hydrochloride is cooled to 0 ℃, add 1.01 gram (10.0 mmole) N-methylmorpholines that are dissolved in 10 milliliters of anhydrous methylene chlorides then and then add 2.06 gram (10.0 mmole) N, N-dicyclohexylcarbodiimide.After 0 ℃ of following this reaction mixture of stirring 2 hours, by removing by filter sedimentary dicyclohexylurea (DCU), and filtrate with each 10 milliliters 1 gram equivalent/rise the hcl as extraction agent secondary, extract with 15 ml waters then, with each 15 milliliters of sodium hydrogen carbonate solution extraction secondary, and at last with 15 milliliters of saturated nacl aqueous solution extractions.(organic phase) with anhydrous magnesium sulfate drying and the evaporation after, with resistates from a kind of mixture of ethyl acetate and ether recrystallization and provide 1.61 the gram (45%) title compounds, fusing point: 83-85 ℃, [α]
25 D-119.4 ° (c=1, methylene dichloride):
Analyze:
Calculated value: C57.30%, H5.10%, N4.17%.
Experimental value: C56.91%; H5.15%; N4.32%.
Embodiment 4
N-[4-oxo-4-phenyl-2(E)-crotonoyl]-1,2,3,4-tetrahydrochysene-β-Ka Lin-1(R, S)-preparation of carboxylic acid, ethyl ester
With a kind of 2.88 gram (16.3 mmole) 4-oxo-4-phenyl-2(E)-butenoic acid and 4.0 gram (16.3 mmoles) 1 in 40 milliliters of anhydrous methylene chlorides, 2,3,4-tetrahydrochysene-β-Ka Lin-1(R, S)-solution of carboxylic acid, ethyl ester is cooled to 0 ℃, and add and be dissolved in the gram of 3.37 in 15 milliliters of anhydrous methylene chlorides (16.3 mmole) N, N-dicyclohexylcarbodiimide.After 0 ℃ of following this reaction mixture of stirring 2 hours, by removing by filter sedimentary dicyclohexylurea (DCU).Filtrate with each 20 milliliters 1 gram equivalent/rise the hcl as extraction agent secondary, extract with 20 ml waters then, with each 20 milliliters of saturated sodium bicarbonate solution extraction secondary, and after using anhydrous magnesium sulfate drying and evaporate with 20 milliliters of saturated nacl aqueous solution extractions (organic phase) at last, resistates is by providing 3.95 gram (61%) title compounds, fusing point: 183-186 ℃ with the ether crystallization.
Analyze:
Calculated value: C71.63%; H5.51%; N6.95%.
Experimental value: C71.20%; H5.61%; N6.86%.
Claims (7)
1, logical formula I
4-oxo-4-(substituted-phenyl) butenoic acid acid amides, wherein
R represents hydrogen or halogen or a kind of C
1-4Alkyl or C
1-4Alkoxy base or contain a kind of amide group of 1 to 4 carbon atom at acyl moiety;
X represents logical formula IV, (V) or (VI):
One of group, wherein a kind of straight chain of R ' expression hydrogen or E and/or Z configuration or branched C
1-4Alkyl group and their salt.
2, a kind of medicine is formed, and it comprises the logical formula I as active ingredient:
A kind of 4-oxo-4-(substituted-phenyl) the butenoic acid acid amides, wherein
R represents hydrogen or halogen or a kind of C
1-4Alkyl or C
1-4Alkoxy base or contain a kind of amide group of 1 to 4 carbon atom at acyl moiety;
X represents logical formula IV, (V) or (VI):
One of group, wherein
R represents a kind of straight chain or the branched C of hydrogen or E and/or Z configuration
1-4Acceptable salt on alkyl group or its a kind of pharmacology mixes with carrier that is generally used for pharmaceutical industries and/or additive.
3, the logical formula I of a kind of preparation:
4-oxo-4-(substituted-phenyl) method of butenoic acid acid amides, wherein
R represents hydrogen or halogen or a kind of C
1-4Alkyl or C
1-4Alkoxy base or contain a kind of amide group of 1 to 4 carbon atom at acyl moiety;
X represents logical formula IV, (V) or (VI):
One of group, R wherein
1A kind of straight chain or the branched C of expression hydrogen or E and/or Z configuration
1-4Alkyl group and their salt, it comprises logical formula II
A kind of compound, wherein X as above defines, and the R in logical formula IV, (V) and (VI) represents a kind of straight chain or branched C
1-4Alkyl group, and logical formula III:
A kind of replacement butenoic acid; wherein R as above defines; or hydroxy-acid group a kind of-activatory derivatives reaction with it and; if need; with original known a kind of method remove any blocking group that exists with choosing and/or; if need, change with original known a kind of method resulting logical formula I compound by configuration that two key determined.
4, a kind of method according to claim 3, it comprises a kind of replacement butenoic acid of utilization structure formula III, wherein R such as claim 3 definition, to be activated by a kind of carbodiimide, preferably dicyclohexylcarbodiimide activatory form exists.
5, a kind of method according to claim 3, it comprises a kind of replacement butenoic acid of utilization structure formula III, wherein R as above defines, and exists with its ester, etheride or the acid anhydrides form as the activatory derivative that forms with original known method.
6, according to any one the described a kind of method in the claim 3 to 5, it comprises by adopting UV-light, change by in logical formula I, as in claim 3 definition by the R of two keys decisions and the configuration of X.
7, a kind of method for preparing a kind of medicine composition, it comprises the logical formula I of mixing as active ingredient, R and X a kind of 4-oxo as claimed in claim 3-4-(substituted-phenyl wherein) acceptable salt on butenoic acid acid amides or its a kind of pharmacology, a kind of by using according to any one method in the claim 3 to 6, with carrier that is generally used for pharmaceutical industries and/or additive, and they are converted into a kind of medicine form.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU873011A HU198012B (en) | 1987-07-03 | 1987-07-03 | Process for producing cyclic amino-acid derivatives and pharmaceutical compositions containing them |
| HU3011/87 | 1987-07-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1030408A true CN1030408A (en) | 1989-01-18 |
Family
ID=10962111
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN88104162A Pending CN1030408A (en) | 1987-07-03 | 1988-07-02 | Derivatives of cyclic amino acids, their salt, the medicine that contains it are formed and preparation method thereof |
Country Status (4)
| Country | Link |
|---|---|
| KR (1) | KR890701572A (en) |
| CN (1) | CN1030408A (en) |
| HU (1) | HU198012B (en) |
| WO (1) | WO1989000159A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU204040B (en) * | 1989-07-11 | 1991-11-28 | Richter Gedeon Vegyeszet | Process for producing new thiazoles and thiazines and pharmaceutical compositions comprising same |
| US7595311B2 (en) | 2002-05-24 | 2009-09-29 | Exelixis, Inc. | Azepinoindole derivatives as pharmaceutical agents |
| TWI329111B (en) | 2002-05-24 | 2010-08-21 | X Ceptor Therapeutics Inc | Azepinoindole and pyridoindole derivatives as pharmaceutical agents |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ190995A (en) * | 1978-09-05 | 1982-03-09 | American Cyanamid Co | Substituted omega propionyl or butyryl l-prolines and pharmaceutical compositions |
| US4374249A (en) * | 1980-12-23 | 1983-02-15 | American Cyanamid Company | [4R]-3-(ω-Aroylpropionyl)-4-thiazolidinecarboxylic acids and esters |
-
1987
- 1987-07-03 HU HU873011A patent/HU198012B/en not_active IP Right Cessation
-
1988
- 1988-07-01 WO PCT/HU1988/000047 patent/WO1989000159A1/en unknown
- 1988-07-01 KR KR1019890700412A patent/KR890701572A/en not_active Application Discontinuation
- 1988-07-02 CN CN88104162A patent/CN1030408A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| WO1989000159A1 (en) | 1989-01-12 |
| HU198012B (en) | 1989-07-28 |
| HUT47903A (en) | 1989-04-28 |
| KR890701572A (en) | 1989-12-21 |
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