JPS63126873A - 4-bromomethyl-5-methyl-1,3-dioxolen-2-one - Google Patents
4-bromomethyl-5-methyl-1,3-dioxolen-2-oneInfo
- Publication number
- JPS63126873A JPS63126873A JP62190516A JP19051687A JPS63126873A JP S63126873 A JPS63126873 A JP S63126873A JP 62190516 A JP62190516 A JP 62190516A JP 19051687 A JP19051687 A JP 19051687A JP S63126873 A JPS63126873 A JP S63126873A
- Authority
- JP
- Japan
- Prior art keywords
- compounds
- dioxolen
- methyl
- bromomethyl
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- GWFALVUXAGYMHR-UHFFFAOYSA-N 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one Chemical compound CC=1OC(=O)OC=1CBr GWFALVUXAGYMHR-UHFFFAOYSA-N 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 abstract description 24
- 238000006243 chemical reaction Methods 0.000 abstract description 9
- 230000002378 acidificating effect Effects 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 7
- 229940002612 prodrug Drugs 0.000 abstract description 7
- 239000000651 prodrug Substances 0.000 abstract description 7
- 239000003795 chemical substances by application Substances 0.000 abstract description 6
- 238000001727 in vivo Methods 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 150000002148 esters Chemical class 0.000 abstract description 4
- 230000000968 intestinal effect Effects 0.000 abstract description 4
- QYIOFABFKUOIBV-UHFFFAOYSA-N 4,5-dimethyl-1,3-dioxol-2-one Chemical compound CC=1OC(=O)OC=1C QYIOFABFKUOIBV-UHFFFAOYSA-N 0.000 abstract description 3
- 230000007935 neutral effect Effects 0.000 abstract description 3
- 108090000790 Enzymes Proteins 0.000 abstract description 2
- 102000004190 Enzymes Human genes 0.000 abstract description 2
- 150000001735 carboxylic acids Chemical class 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 150000002170 ethers Chemical class 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 2
- 150000002989 phenols Chemical class 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- 125000006239 protecting group Chemical group 0.000 abstract description 2
- 150000003566 thiocarboxylic acids Chemical class 0.000 abstract description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 12
- 229960000723 ampicillin Drugs 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- -1 methyl ester hydrochloride Chemical class 0.000 description 4
- 239000003607 modifier Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229960003311 ampicillin trihydrate Drugs 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000010998 test method Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- ZKUKMWMSYCIYRD-ZXFNITATSA-N lenampicillin Chemical compound O1C(=O)OC(COC(=O)[C@H]2C(S[C@H]3N2C([C@H]3NC(=O)[C@H](N)C=2C=CC=CC=2)=O)(C)C)=C1C ZKUKMWMSYCIYRD-ZXFNITATSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- VAYTZRYEBVHVLE-UHFFFAOYSA-N 1,3-dioxol-2-one Chemical compound O=C1OC=CO1 VAYTZRYEBVHVLE-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- MARXMDRWROUXMD-UHFFFAOYSA-N 2-bromoisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(Br)C(=O)C2=C1 MARXMDRWROUXMD-UHFFFAOYSA-N 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical compound ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- AOJDZKCUAATBGE-UHFFFAOYSA-N bromomethane Chemical compound Br[CH2] AOJDZKCUAATBGE-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- SOROUYSPFADXSN-SUWVAFIASA-N talampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(=O)OC2C3=CC=CC=C3C(=O)O2)(C)C)=CC=CC=C1 SOROUYSPFADXSN-SUWVAFIASA-N 0.000 description 1
- 229960002780 talampicillin Drugs 0.000 description 1
- 239000013077 target material Substances 0.000 description 1
- 229950011008 tetrachloroethylene Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は医薬品のプロドラッグ用修飾剤として有用な新
規4−ブロモメチル−5−メチル−1゜3−ジオキソレ
ン−2−オンに関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 4-bromomethyl-5-methyl-1°3-dioxolen-2-ones useful as modifiers for pharmaceutical prodrugs.
医薬品の中には、高い薬理活性を有しながら、化学的な
不安定性や生物学的利用率(パイオアベラビリティ−)
の不良等のために、医薬品としての有用性を充分に発揮
し得ないものがあり、又このような欠点を改善する方法
の1つとして化学的修飾によるプロドラッグがある。Although some drugs have high pharmacological activity, they have chemical instability and bioavailability (bioavailability).
There are some drugs that cannot fully demonstrate their usefulness as pharmaceuticals due to poor quality, etc., and one way to improve these drawbacks is to create prodrugs by chemical modification.
例えば腸管吸収率の低い薬物を化学的に部分修飾して腸
管吸収を高め、生体内で化学的・生物学本来の薬理活性
を発現させるやり方である。For example, a drug with a low rate of intestinal absorption is chemically partially modified to increase its absorption in the intestinal tract and to express its inherent chemical and biological pharmacological activity in vivo.
従来から、この目的のために種々の修飾基が提案されて
いるが、それらを用いたプロドラッグの化学的安定性、
生体内での元の薬物への復元性、あるいは修飾基がもた
らす副作用等の点で未だ満足の域に達していない。Various modification groups have been proposed for this purpose, but the chemical stability of prodrugs using them,
The level of satisfaction has not yet been reached in terms of reconstitution properties in vivo to the original drug, side effects caused by modifying groups, etc.
本発明は、特に医薬品のプロドラッグ用の修飾剤として
有用かつ新規な下記式で示される4−ブロモメチル−5
−メチル−1,3−ジオキソレン−2−オンを提供する
ものである。The present invention provides a novel 4-bromomethyl-5 compound represented by the following formula, which is particularly useful as a modifier for prodrugs of pharmaceuticals.
-Methyl-1,3-dioxolen-2-one.
この4−ブロモメチル−5−メチル−1,3−ジオキソ
レン−2−オンは、カルボン酸類、チオカルボン酸類、
フェノール票等と容易に反応して対応するエステル型化
合物およびエーテル型化合物を生成するが、これらエス
テル型化合物およびエーテル型化合物は中性および酸性
媒質中で安定であり、又通常の化学反応におけるアルカ
リ加水分解条件下では容易に加水分解されるにかかわら
ず、腸液に相当するアルカリ性媒質中では比較的に安定
であって、しかも生体内酵素の存在下では容易に加水分
解されて元の化合物に復元する。This 4-bromomethyl-5-methyl-1,3-dioxolen-2-one is a carboxylic acid, a thiocarboxylic acid,
It easily reacts with phenol, etc. to produce corresponding ester-type compounds and ether-type compounds, but these ester-type compounds and ether-type compounds are stable in neutral and acidic media, and are resistant to alkali in normal chemical reactions. Although it is easily hydrolyzed under hydrolytic conditions, it is relatively stable in an alkaline medium equivalent to intestinal fluid, and is easily hydrolyzed and restored to its original compound in the presence of in vivo enzymes. do.
例えば、カルボン酸基を持つペニシリン類と上記式で示
される4−ブロモメチル−5−メチル−1,3−ジオキ
ソレン−2−オンを反応させると対応するエステルが生
成し、このエステルは胃液および腸液内では安定であっ
て、腸管から容易に吸収されると共に生体内で容易に加
水分解されて元のペニシリンに復元する。このように上
記式で示される4−ブロモメチル−5−メチル−1,3
−ジオキソレン−2−オンは特に医薬品のプロドラッグ
用修飾剤として有用である。なお、カルボン酸類および
フェノール類と本発明の4−ブロモメチル−5−メチル
−1,3−ジオキソレン−2=オンから導かれるエステ
ル類およびエーテル類は、前述のとおり中性媒質および
酸性媒質中で安定であるが、通常のアルカリ加水分解条
件下では容易に加水分解を受けるので、本発明の4−ブ
ロモメチル−5−メチル−1,3−ジオキソレン−2−
オンは化学反応における保護基の導入試薬としても有用
である。For example, when a penicillin having a carboxylic acid group is reacted with 4-bromomethyl-5-methyl-1,3-dioxolen-2-one represented by the above formula, a corresponding ester is produced, and this ester is present in gastric and intestinal fluids. It is stable, easily absorbed from the intestinal tract, and easily hydrolyzed in vivo to restore the original penicillin. In this way, 4-bromomethyl-5-methyl-1,3 represented by the above formula
-Dioxolen-2-one is particularly useful as a modifier for pharmaceutical prodrugs. As mentioned above, the carboxylic acids, phenols, and esters and ethers derived from 4-bromomethyl-5-methyl-1,3-dioxolene-2=one of the present invention are stable in neutral and acidic media. However, since it is easily hydrolyzed under normal alkaline hydrolysis conditions, the 4-bromomethyl-5-methyl-1,3-dioxolene-2-
ions are also useful as reagents for introducing protective groups in chemical reactions.
以下に本発明の有用性を示す実験データーを挙げる。The following is experimental data demonstrating the usefulness of the present invention.
[経口投与時の血中濃度]
1、供試化合物
A アンピシリン(5−メチル−2−オキソ−1゜3−
ジオキソレン−4−イル)メチルエステル塩酸塩(後述
の参考例1に従ってアンピシリン三水和物と4−ブロモ
メチル−5−メチル−1,3−ジオキソレン−2−オン
とから合成した。)
B アンピシリンフタリジルエステル塩酸塩(公知のア
ンピシリンエステル、対照化合物)Cアンピシリン三水
和物(対照化合物)2、試験方法
一夜絶食した4週令マウス(ddY系、体重的202、
一群5匹)にアンピシリン換算50.0mg / kg
相当の供試化合物(アンピシリン換算で濃度5 wni
/ mlの水溶液約0.2mjl>を経口投与し、経
時的に採血して血清中のアンピシリン濃度をバイオアッ
セイ法によって測定し、各供試化合物の血清中アンピシ
リン濃度の相対比を求めた。[Blood concentration during oral administration] 1. Test compound A ampicillin (5-methyl-2-oxo-1゜3-
dioxolen-4-yl) methyl ester hydrochloride (Synthesized from ampicillin trihydrate and 4-bromomethyl-5-methyl-1,3-dioxolen-2-one according to Reference Example 1 described below.) B Ampicillin phthalidyl Ester hydrochloride (known ampicillin ester, control compound) C ampicillin trihydrate (control compound) 2, test method 4-week-old mice fasted overnight (ddY strain, weight 202,
Ampicillin equivalent: 50.0 mg/kg per group of 5 animals)
Equivalent test compound (concentration 5 wni in terms of ampicillin)
/ml of an aqueous solution of about 0.2 mjl> was orally administered, blood was collected over time, the ampicillin concentration in the serum was measured by a bioassay method, and the relative ratio of ampicillin concentration in the serum of each test compound was determined.
3、結果
第 1 表
第1表から明らかなように、本発明の化合物から誘導さ
れたアンピシリンエステル(A)は、容易に吸収されて
生体内で元のアンピシリンに復元するが、アンピシリン
(C)および公知のアンピシリンエステル(B)に比し
長時間にわたり高い[酸性媒質(人口胃液に該当)中で
の加水分解]1、供試化合物 前記AおよびB
2、試験方法
10100Oの水中に食塩2.Og、10%塩酸24
ml、ペプシン3.2gを含む酸性媒質(pH1,2)
に供試化合物を溶解し、37℃で振盪しつつ経時的にサ
ンプリングして逆相分配カラムを用いた高速液体クロマ
ト法により、各供試化合物のピーク高の減少からその加
水分解率を求めた。3. Results 1 As is clear from Table 1, ampicillin ester (A) derived from the compound of the present invention is easily absorbed and restored to the original ampicillin in vivo, but ampicillin (C) and higher hydrolysis in an acidic medium (corresponding to artificial gastric fluid) over a long period of time than known ampicillin esters (B) 1. Test compound A and B above 2. Test method 10100 O salt in water 2. Og, 10% hydrochloric acid 24
ml, acidic medium (pH 1,2) containing 3.2 g of pepsin
The test compound was dissolved in the solution, sampled over time while shaking at 37°C, and the hydrolysis rate was determined from the decrease in peak height of each test compound using high performance liquid chromatography using a reversed phase partition column. .
3、結果
第 2 表
第2表に示すとおり、酸性媒質中ではAはBに比しW−
に安定である。3.Results Table 2 As shown in Table 2, A has a lower W− than B in acidic medium.
It is stable.
[塩基性媒質(人口腸液に該当)中での加水分解]1、
供試化合物 前記AおよびB
2.試験方法
1000−の水中に燐酸二ナトリウム35.82.10
%塩酸6.0aN、パンクレアチン2.82を含む塩基
性媒質(pH7,5)中に供試化合物を溶解し、前記の
酸性媒質の場合と同様にして、各供試化合物の加水分解
率を求めた。[Hydrolysis in basic medium (corresponding to artificial intestinal fluid)] 1.
Test compound A and B above 2. Test Method 1000 - Disodium Phosphate in Water 35.82.10
The test compound was dissolved in a basic medium (pH 7.5) containing % hydrochloric acid 6.0aN and pancreatin 2.82%, and the hydrolysis rate of each test compound was determined in the same manner as in the case of the acidic medium. I asked for it.
3、結果
第3表
第3表に示すように、塩基性媒質中ではAはBに比し安
定である。3. Results Table 3 As shown in Table 3, A is more stable than B in a basic medium.
[その他]
前記Aの毒性(L D s。)をマウス(4週令ddY
系)を用いて調べた結果は次のとおりである。[Others] The toxicity (L D s.) of the above A was tested in mice (4 weeks old ddY
The results of the investigation using the system) are as follows.
経口投与>5,000mg/kg、腹腔的投与1.43
0mg/kg、静脈内投与557mg/kg。Oral administration > 5,000 mg/kg, intraperitoneal administration 1.43
0 mg/kg, intravenous administration 557 mg/kg.
以上のとおり本発明の4−ブロモメチル−5−メチル−
1,3−ジオキソレン−2−オンは医薬のプロドラッグ
用修飾剤として極めて有用であるが、かかる有用性は従
来の知見からは全く予測し得ないところである。すなわ
ち、本発明の化合物の前駆物質である4、5−ジメチル
−1,3−ジオキソレン−2−オンがテトラヘドロン・
レタース、1972年、1701〜1704頁に開示さ
れているが、それらから導かれる本発明の化合物につい
ては何等の記載もない、又、ジービツヒズ・アンナレン
・デル・ヘミ−11977年、27〜32頁には、4,
5−ジメチル−1,3−ジオキソレン−2−オンをブロ
ム化することにより、重合体製造用中間原料である4、
5−ビス(ブロモメチル)−1,3−ジオキソレン−2
−オンが得られる旨記載されている。しかし該文献中に
は本発明の化合物およびその製法に関して具体的な記載
がないし、又、その用途に関しても何らの示唆もない。As described above, the 4-bromomethyl-5-methyl-
Although 1,3-dioxolen-2-one is extremely useful as a modifier for pharmaceutical prodrugs, such usefulness cannot be predicted from conventional knowledge. That is, 4,5-dimethyl-1,3-dioxolen-2-one, which is a precursor of the compound of the present invention, is converted into tetrahedron.
Letters, 1972, pp. 1701-1704, but there is no description of the compounds of the present invention derived therefrom. 4,
By brominating 5-dimethyl-1,3-dioxolen-2-one, 4, which is an intermediate raw material for polymer production, is produced.
5-bis(bromomethyl)-1,3-dioxolene-2
It is stated that -on can be obtained. However, this document does not contain any specific description regarding the compound of the present invention or its production method, nor does it provide any suggestion regarding its use.
本発明の4−ブロモメチル−5−メチル−1゜3−ジオ
キソレン−2−オンは、4.5−ジメチル−1,3−ジ
オキソレン−2−オンに、室温もしくは一般には加熱条
件下のラジカル発生条件下で、0.8〜1.2モル通常
等モル量ないしは過剰(160〜1.2倍モル)の臭素
化剤を反応させることによって得られる。The 4-bromomethyl-5-methyl-1゜3-dioxolen-2-one of the present invention can be added to 4,5-dimethyl-1,3-dioxolene-2-one under radical generation conditions at room temperature or generally under heating conditions. 0.8 to 1.2 mol, usually an equimolar amount or an excess (160 to 1.2 times mol) of the brominating agent.
出発原料である4、ら−ジメチル−1,3−ジオキソレ
ン−2−オンは、前述のテトラヘドロン・レターズ、1
972年、1701〜1704頁に開示されている公知
の方法に従って合成することができる。The starting material 4,ra-dimethyl-1,3-dioxolen-2-one was obtained from the aforementioned Tetrahedron Letters, 1.
972, pp. 1701-1704.
臭素化剤としては、例えば臭素、N−ブロモフタル酸イ
ミド、N−ブロモコハク酸イミド、等がある。出発原料
である4、5−ジメチル−1,3−ジオキソレン−2−
オンと臭素化剤との反応を進めるために、反応中葉外線
を照射するに〜、或は反−一清j−e −−’
−+P*〆し+ 1 ノ 1ノ イA−t+ −L
I+ +1過酸化ベンゾイルのようなラジカル化剤
を用いることが好ましい0反応溶媒は、原料の性質等に
応じて適当なものが選択され、例えば塩化メチレン、ク
ロロホルム、四塩化炭素、四塩化エチレン、ベンゼン等
が挙げられる。Examples of the brominating agent include bromine, N-bromophthalimide, N-bromosuccinimide, and the like. Starting material 4,5-dimethyl-1,3-dioxolene-2-
In order to proceed with the reaction between the on and the brominating agent, irradiation with external radiation during the reaction is carried out.
-+P*〆shi+ 1 no 1 no iA-t+ -L
I+ +1 It is preferable to use a radicalizing agent such as benzoyl peroxide. The reaction solvent is selected appropriately depending on the properties of the raw materials, such as methylene chloride, chloroform, carbon tetrachloride, ethylene tetrachloride, benzene. etc.
以下実施例および参考例を挙げて本発明を具体的に説明
する。The present invention will be specifically explained below with reference to Examples and Reference Examples.
実施例1
4−ブロモメチル−5−メチル−1,3−ジオキソレン
−2−オンの製造
4.5−ジメチル−1,3−ジオキソレン−2−オン(
テトラヘドロン・レターズ、1972年、1701〜1
704頁に従って合成した)3,422を四塩化炭素1
50−に溶解し、これに5゜342のN−ブロモコハク
酸イミドおよび触媒址のα、α′−アゾビスイソブチロ
ニトリルを加え、15分間加熱還流した1反応液を半量
まで濃縮し不溶物を枦去した後、炉液を濃縮した。シラ
ツブ状の残渣を減圧蒸留し無色液体、沸点115〜12
0℃/ 5 m m Hgの目的物4.2&(収率73
%)を得た。Example 1 Preparation of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one 4.5-dimethyl-1,3-dioxolene-2-one (
Tetrahedron Letters, 1972, 1701-1
3,422 (synthesized according to page 704) with carbon tetrachloride 1
To this was added N-bromosuccinimide of 5°342 and α,α'-azobisisobutyronitrile as a catalyst, and the reaction solution was heated under reflux for 15 minutes and concentrated to half its volume to remove insoluble matter. After removing the liquid, the furnace liquid was concentrated. Distillation of the slag-like residue under reduced pressure yields a colorless liquid with a boiling point of 115-12
0 °C/5 m m Hg target material 4.2 & (yield 73
%) was obtained.
元素分析(%)、分子式C5HsBrOs:理論値C1
31,12:H12,61:Br、41,40゜実験値
C131,30:H52,49:Br、41.31゜
IRに−ト、vcm−’> : 1825付近(カルボ
ニル)
NMR(CCN、)δ(PPm):2.10(CH3、
s)、4.10 (CH2Br、s)参考例1
アンピシリン三水和物500mgをジメチルホルムアミ
ド6mlに分散させ、これに重炭酸カリウム126mg
を加えて0℃に冷却し、更にベンズアルデヒド0.25
m1を加えて0℃で2.5時間撹拌した。次に重炭酸カ
リウム125麟8と4−ブロモメチル−5−メチル−1
,3−ジオキソレン−2−オン250mgを加え更に0
℃で3時間撹拌した。Elemental analysis (%), molecular formula C5HsBrOs: theoretical value C1
31,12:H12,61:Br, 41,40° Experimental value C131,30:H52,49:Br, 41.31°IR, vcm-'>: around 1825 (carbonyl) NMR (CCN, ) δ (PPm): 2.10 (CH3,
s), 4.10 (CH2Br, s) Reference Example 1 500 mg of ampicillin trihydrate was dispersed in 6 ml of dimethylformamide, and 126 mg of potassium bicarbonate was added thereto.
was added, cooled to 0°C, and further added 0.25% of benzaldehyde.
ml was added and stirred at 0°C for 2.5 hours. Next, potassium bicarbonate 125rin8 and 4-bromomethyl-5-methyl-1
, 250 mg of 3-dioxolen-2-one was added and further 0
Stirred at ℃ for 3 hours.
反応終了後、反応液を氷水中に注ぎ込み、析出する固型
物を酢酸エチル30m1で抽出し、有機層を水20@e
で3回洗浄し、無水硫酸マグネシウムで乾燥した後、酢
酸エチルを減圧上留去し黄色シラツブを得た。After the reaction, the reaction solution was poured into ice water, the precipitated solid was extracted with 30 ml of ethyl acetate, and the organic layer was poured into 20 ml of water.
After washing with water three times and drying with anhydrous magnesium sulfate, ethyl acetate was distilled off under reduced pressure to obtain a yellow syrup.
上記の様にして得られたシラツブ状残渣をアセトニトリ
ル4社に溶解し希塩酸でpH2,0に調整し0℃で30
分間撹拌した。これに水10m1を加え減圧下アセトニ
トリルを留去し、水層を酢酸エチルでくりかえし洗浄し
た後食塩を飽和させ析出する油状物質を塩化メチレン5
0m1で抽出し、飽和食塩水で洗浄した。塩化メチレン
溶液を無水硫酸ナトリウムで乾燥した後半量まで濃縮し
、イソプロピルアルコール30m1を加え再び減圧濃縮
すると淡黄色固体が得られた。The slag-like residue obtained as above was dissolved in acetonitrile 4, adjusted to pH 2.0 with dilute hydrochloric acid, and heated to 30°C at 0°C.
Stir for a minute. 10 ml of water was added to this, the acetonitrile was distilled off under reduced pressure, and the aqueous layer was washed repeatedly with ethyl acetate, then saturated with common salt, and the precipitated oily substance was extracted with methylene chloride (5 ml).
It was extracted with 0ml and washed with saturated saline. The methylene chloride solution was concentrated to half the volume of drying over anhydrous sodium sulfate, 30 ml of isopropyl alcohol was added, and the mixture was concentrated again under reduced pressure to obtain a pale yellow solid.
この固体をFMしイソプロピルアルコール、エーテルで
洗浄しアンピシリン(5−メチル−2−オキソ−1,3
−ジオキソレン−4−イル)メチルエステル塩酸塩を得
た。This solid was washed with FM, isopropyl alcohol and ether, and ampicillin (5-methyl-2-oxo-1,3
-dioxolen-4-yl) methyl ester hydrochloride was obtained.
収量50.6%、無色無定型固体。Yield 50.6%, colorless amorphous solid.
融点141℃より着色し始め145℃で発泡する。It begins to color at a melting point of 141°C and foams at 145°C.
IR(KBr、l/C11−’) : 1825.17
85.1750.1690(カルボニル)
元素分析(C21H23N 307 S−HC1・H2
O)、計算値:C148,8:H2S、08:N、8.
14、S、6.21.実験値:C,48,51: H2
S。IR (KBr, l/C11-'): 1825.17
85.1750.1690 (carbonyl) Elemental analysis (C21H23N 307 S-HC1・H2
O), calculated value: C148, 8: H2S, 08: N, 8.
14, S, 6.21. Experimental value: C, 48, 51: H2
S.
15:N、8.02、S、6.44゜
このアンピシリン(5−メチル−2−オキソ−1,3−
ジオキソレン−4−イル)メチルエステル塩酸塩を40
%マウス血液中で37℃に15分間インキュベートした
のちバイオオートダラムを行ったところ完全にアンピシ
リンに変化していた。15:N, 8.02, S, 6.44゜This ampicillin (5-methyl-2-oxo-1,3-
dioxolen-4-yl) methyl ester hydrochloride 40
After incubating in mouse blood for 15 minutes at 37°C, bioautodurum was performed, and the product was completely converted to ampicillin.
ほか2名2 others
Claims (1)
−2−オン。4-Bromomethyl-5-methyl-1,3-dioxolen-2-one.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP62190516A JPS63126873A (en) | 1987-07-31 | 1987-07-31 | 4-bromomethyl-5-methyl-1,3-dioxolen-2-one |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP62190516A JPS63126873A (en) | 1987-07-31 | 1987-07-31 | 4-bromomethyl-5-methyl-1,3-dioxolen-2-one |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP58013077A Division JPS58150597A (en) | 1983-01-29 | 1983-01-29 | Preparation of drug having improved bioavailability |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS63126873A true JPS63126873A (en) | 1988-05-30 |
JPH0368029B2 JPH0368029B2 (en) | 1991-10-25 |
Family
ID=16259391
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP62190516A Granted JPS63126873A (en) | 1987-07-31 | 1987-07-31 | 4-bromomethyl-5-methyl-1,3-dioxolen-2-one |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPS63126873A (en) |
-
1987
- 1987-07-31 JP JP62190516A patent/JPS63126873A/en active Granted
Non-Patent Citations (1)
Title |
---|
LIEBIGS ANN CHEM=1977 * |
Also Published As
Publication number | Publication date |
---|---|
JPH0368029B2 (en) | 1991-10-25 |
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