KR830002351B1 - Manufacturing Method of 4-Carbetoxy-carbonylamino-pyrimidines - Google Patents
Manufacturing Method of 4-Carbetoxy-carbonylamino-pyrimidines Download PDFInfo
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- KR830002351B1 KR830002351B1 KR1019790004409A KR790004409A KR830002351B1 KR 830002351 B1 KR830002351 B1 KR 830002351B1 KR 1019790004409 A KR1019790004409 A KR 1019790004409A KR 790004409 A KR790004409 A KR 790004409A KR 830002351 B1 KR830002351 B1 KR 830002351B1
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- carbetoxy
- carbonylamino
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- 238000004519 manufacturing process Methods 0.000 title description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- OWZFULPEVHKEKS-UHFFFAOYSA-N ethyl 2-chloro-2-oxoacetate Chemical compound CCOC(=O)C(Cl)=O OWZFULPEVHKEKS-UHFFFAOYSA-N 0.000 claims description 3
- 239000012454 non-polar solvent Substances 0.000 claims description 2
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 claims 1
- 229960004979 fampridine Drugs 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 20
- 239000000543 intermediate Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 229940092253 ovalbumin Drugs 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 108010058846 Ovalbumin Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- MXRMHVXYULMTFM-UHFFFAOYSA-N 6-(2-methoxyethoxy)pyrimidin-4-amine Chemical compound COCCOC1=CC(N)=NC=N1 MXRMHVXYULMTFM-UHFFFAOYSA-N 0.000 description 2
- DUKKRSPKJMHASP-UHFFFAOYSA-N 6-chloropyrimidin-4-amine Chemical compound NC1=CC(Cl)=NC=N1 DUKKRSPKJMHASP-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- -1 β-methoxyethyl Chemical group 0.000 description 2
- 0 *C1=CC(N)NC(*)=N1 Chemical compound *C1=CC(N)NC(*)=N1 0.000 description 1
- HKDULBGTGVPBAQ-UHFFFAOYSA-N 6-(2-methoxyethylsulfanyl)pyrimidin-4-amine Chemical compound COCCSC1=CC(N)=NC=N1 HKDULBGTGVPBAQ-UHFFFAOYSA-N 0.000 description 1
- XDIZJOWPBYQONT-UHFFFAOYSA-N 6-amino-1h-pyrimidine-4-thione Chemical compound NC1=CC(=S)N=CN1 XDIZJOWPBYQONT-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 201000005702 Pertussis Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 229960000905 indomethacin Drugs 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Abstract
내용 없음.No content.
Description
본 발명은 알레르기성 반응과 위궤양에 효과적인 다음 일반식(Ⅰ)인 카르베톡시-카르보닐아미노-피리미딘류의 제조방법에 관한 것이다.The present invention relates to a method for producing carbetoxy-carbonylamino-pyrimidines, the following general formula (I) effective for allergic reactions and gastric ulcers.
상기 식에서, R 은 H, CH3, C6H5, SCH3 Wherein R is H, CH 3 , C 6 H 5 , SCH 3
R1은 H, Cl, OCH3, OCH2CH2OCH3, SCH2CH2CH2COOC2H5, SCH3, SCH2CH2OH, SCH2CH2OCOCOOC2H5, OCH2CH2OCH2C6H5, SCH2CH2OCH3, SCH2CH2OCH2OCH3 R 1 is H, Cl, OCH 3 , OCH 2 CH 2 OCH 3 , SCH 2 CH 2 CH 2 COOC 2 H 5 , SCH 3 , SCH 2 CH 2 OH, SCH 2 CH 2 OCOCOOC 2 H 5 , OCH 2 CH 2 OCH 2 C 6 H 5 , SCH 2 CH 2 OCH 3 , SCH 2 CH 2 OCH 2 OCH 3
본 발명에 있어서 일반식(Ⅰ)의 화합물은 피리딘 또는 N,N-디메틸아닐린 같은 염산 수용체존재하 비극성용매에서 에톡살릴 클로라이드와 일반식(Ⅱ)의 화합물의 반응으로 얻어진다.In the present invention, the compound of formula (I) is obtained by reaction of ethoxalyl chloride with a compound of formula (II) in a nonpolar solvent in the presence of a hydrochloric acid receptor such as pyridine or N, N-dimethylaniline.
상기 식에서In the above formula
R과 R1은 상기 주어진 것이다.R and R 1 are given above.
일반식(Ⅱ)의 중간물은 문헌에 공지되어 있다.Intermediates of general formula (II) are known in the literature.
R1이 OCH2CH2OCH3, OCH2CH2O
OCH2CH2OCH2CH2OCH3인 중간물질(Ⅲ)는 문헌에 알려져 있지 않으며 다음 일반식(Ⅲ)화합물은 다음 일반식(Ⅳ)화합물과 반응시켜 제조한다.Intermediate (III), which is OCH 2 CH 2 OCH 2 CH 2 OCH 3 , is not known in the literature and the following general formula (III) compounds are prepared by reaction with the following general formula (IV) compounds.
상기 식에서,Where
R은 이미 언급한 것이며,R is already mentioned,
R1은 OCH2CH2OCH3, OCH2-CH2-OCH2 
OCH2CH2OCH2CH2OCH3 OCH 2 CH 2 OCH 2 CH 2 OCH 3
Me는 알칼리 금속인데 나트륨이 양호하다.Me is an alkali metal with good sodium.
R1이 OCH2CH2OCH3, OCH2CH2OCH2 
OCH2CH2OCH2CH2OCH3인 화합물(Ⅱ)는 식(Ⅲ)화합물을 식(Ⅴ)화합물 과량과 탄산나트륨 또는 칼륨 존재하에서 가열하여 제조한다.Compound (II), which is OCH 2 CH 2 OCH 2 CH 2 OCH 3 , is prepared by heating a compound of formula (III) in the presence of an excess of compound of formula (V) and sodium or potassium.
R1H (Ⅴ)R 1 H (Ⅴ)
상기 식에서,Where
R1은 OCH2CH2OCH3, OCH2CH2OCH2 
R1이 SCH2CH2CH2COOC2H5, SCH2CH2OH, SCH2CH2OCH3, SCH2CH2OCH2CH2OCH3인 중간물질(Ⅱ)는 화합물(Ⅲ)을 KSH와 반응시켜 식(Ⅵ)화합물을 얻고 차례대로 일반식(Ⅶ)화합물과 반응시켜 얻는다.Intermediate (II), wherein R 1 is SCH 2 CH 2 CH 2 COOC 2 H 5 , SCH 2 CH 2 OH, SCH 2 CH 2 OCH 3 , SCH 2 CH 2 OCH 2 CH 2 OCH 3 , KSH Compound (III) To a compound of formula (VI), which in turn reacts with a compound of formula (VII).
상기 식에서,Where
R은 이미 언급한 것이고,R is already mentioned,
R2는 CH2CH2CH2COOC2H5, CH2CH2OH, CH2CH2OCH3, CH2CH2OCH2CH2OCH2이고,R 2 is CH 2 CH 2 CH 2 COOC 2 H 5 , CH 2 CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 OCH 2 CH 2 OCH 2 ,
X는 할로겐 또는
중간물질과 최종 생성물의 구조는 성분분석과 IR과 NMR스펙트럼에 의해 확인된다.The structure of the intermediate and final product is confirmed by component analysis and IR and NMR spectra.
[실시예 1]Example 1
4-아미노-6-β-메톡시 에톡시-피리미딘(Ⅱ, R=H ; R1=OCH2CH2OCH3)4-amino-6-β-methoxy ethoxy-pyrimidine (II, R = H; R 1 = OCH 2 CH 2 OCH 3 )
나트륨 11.5g (0.5g 원자)을 메틸셀로솔브 용매 375ml에 용해시키고 4-아미노-6-클로로피리미딘 65g (0.5몰)을 용액에 첨가하고 반응 혼합물을 100℃에서 4시간 동안 가열한다.11.5 g (0.5 g atoms) of sodium are dissolved in 375 ml of methylcellosolve solvent and 65 g (0.5 mole) of 4-amino-6-chloropyrimidine are added to the solution and the reaction mixture is heated at 100 ° C. for 4 hours.
과량의 메틸셀로솔브 용매 진공에서 증발시키고 잔류물을 물 200ml로 회수한다.Excess methylcellosolve solvent is evaporated in vacuo and the residue is recovered in 200 ml of water.
용액을 탄산칼륨으로 포화시키고 에틸아세테이트로 추출한다. 추출물을 진공에서 증발시키고 고체 잔류물을 에틸아세테이트+페트롤륨에 테르로부터 결정화시킨다.The solution is saturated with potassium carbonate and extracted with ethyl acetate. The extract is evaporated in vacuo and the solid residue is crystallized from ethyl acetate + petroleum ether.
융점 114-16℃인 생성물 67g이 얻어진다(수율 80%).67 g of product having a melting point of 114-16 ° C. is obtained (yield 80%).
노우트Kout
금속성나트륨 대신 탄산칼륨을 사용한 반응으로도 똑같은 결과가 되었다(0.5몰 4-아미노-6-클로로-피리미딘 104g)The same result was obtained using potassium carbonate instead of metallic sodium (104 g of 0.5 mol 4-amino-6-chloro-pyrimidine).
[실시예 2]Example 2
4-아미노-6-β-메톡시 에틸티오-피리미딘(Ⅱ, R=H ; R1=SCH2CH2OCH3)4-amino-6-β-methoxy ethylthio-pyrimidine (II, R = H; R 1 = SCH 2 CH 2 OCH 3 )
수산화나트륨 20g (0.5몰)을 1 : 1의 에탄올/물 500ml에 용해시키고 4-아미노-6-메르캡토피리미딘 63.5g (0.5몰)을 용액에 첨가하고 용액의 온도를 60℃로 한다.20 g (0.5 mol) of sodium hydroxide are dissolved in 500 ml of 1: 1 ethanol / water, and 63.5 g (0.5 mol) of 4-amino-6-mercaptopyrimidine is added to the solution and the temperature of the solution is 60 ° C.
β-메톡시에틸(0.5몰)의 P-톨루엔설포네이트 115g을 30분 동안 적가하고 온도를 수욕에서 60℃로 유지 시킨다.115 g of P-toluenesulfonate of β-methoxyethyl (0.5 mol) is added dropwise for 30 minutes and the temperature is maintained at 60 ° C. in a water bath.
첨가가 종료된 후 반응 혼합물을 3시간 동안 환류시킨다. 용매를 증발시키고 잔류물을 물 250ml로 회수한다. 수성용액을 클로로포름(6×100ml)으로 반복하여 추출하고 아말감화된 추출물을 건조될때까지 증발시킨다.After the addition is complete, the reaction mixture is refluxed for 3 hours. The solvent is evaporated and the residue is recovered with 250 ml of water. The aqueous solution is extracted repeatedly with chloroform (6 × 100 ml) and the amalgamated extract is evaporated to dryness.
고체 잔류물을 에틸아세테이트+페트롤륨에테르로부터 결정화시키면 융점 78-80℃인 생성물 74g (80% 수율)이 얻어진다.Crystallization of the solid residue from ethyl acetate + petroleum ether gave 74 g (80% yield) of product having a melting point of 78-80 ° C.
표 1에서, 물리-화학적 특성은 실시예 1과 2에 기술된 진행에 따라서 제조되었고 문헌에는 기술되어 있지 않은 일반식(Ⅱ)의 화합물에 관한 것이다.In Table 1, the physico-chemical properties relate to compounds of formula (II) prepared according to the progress described in Examples 1 and 2 and not described in the literature.
[표 1]TABLE 1
[실시예 3]Example 3
4-카르베톡시카보닐아미노-6-(β-메톡시에톡시)-피리미딘(Ⅰ,R=H ; R1=OCH2CH2OCH3)4-Carbetoxycarbonylamino-6- (β-methoxyethoxy) -pyrimidine (I, R = H; R 1 = OCH 2 CH 2 OCH 3 )
4-아미노-6-β-메톡시-에톡시피리미딘 85g (0.5몰)을 무수피리미딘 300ml에 용해시킨다.85 g (0.5 mole) of 4-amino-6-β-methoxy-ethoxypyrimidine is dissolved in 300 ml of anhydrous pyrimidine.
에톡살릴클로라이드 82g (0.6몰)을 0℃에서 교반하면서 적가한다. 첨가 종료된 후 40℃에서 2시간 동안 가열한다. 과량 피리딘을 진공하에서 증발시키고 잔류물을 H2O로 회수한다.82 g (0.6 mol) of ethoxalyl chloride are added dropwise with stirring at 0 ° C. After the addition is completed, it is heated at 40 ° C. for 2 hours. Excess pyridine is evaporated under vacuum and the residue is recovered with H 2 O.
고체를 여과하며 에틸알콜로부터 결정화시키고 생성물을 진공하 40℃에서 건조시키면 융점 88-9℃인 생성물 107g이 얻어진다. (수율 80%)The solid was filtered off and crystallized from ethyl alcohol and the product dried at 40 ° C. in vacuo to give 107 g of product having a melting point of 88-9 ° C. (Yield 80%)
표2에 열거된 모든 다른 화합물은 유사한 진행으로 얻어진다. 일반식(Ⅰ)화합물은 극히 낮은 독성이고 (모든 화합물에 있어서 쥐에서의 OS당 DL50은 1600mg/kg보다 높다), 본 화합물은 경구투여시 빠르게 흡수되므로 쥐에서의 피동적 피부과민증 실험에서 DE50 50(50%에 의한 유독한 자극의 감소효과의 가능한 투여량)은 경구적으로 투여할때나 복강내 투여할때나 거의 같다.All other compounds listed in Table 2 are obtained with similar runs. Compound (I) has extremely low toxicity (DL50 per OS in rats is higher than 1600 mg / kg in all compounds), and the compound is rapidly absorbed upon oral administration, so DE50 50 ( Possible doses of a 50% reduction in toxic stimuli) are nearly the same when administered orally or intraperitoneally.
본 발명과 일치해서 생물학적 작용의 평가는 다음에 상세히 기술된다.In line with the present invention the assessment of biological activity is described in detail below.
쥐에서 피동적 피부과민증(PCA시험)Passive skin hypersensitivity in rats (PCA test)
a) 항오발부민 반응혈성의 생성, 300 내지 400g 중량 수컷 쥐(COBS-CD)를 살린 1ml에 오발부민(시그마) 20mg을 용해시켜 얻어진 오발부민용액 0.1ml/kg을 근육내 주입하고 백일해 왁진(아베틴스크라보) 1ml를 복강내 주입하여 면역시킨다.a) Anti-Ovalbumin-reactive hemolytic production, 0.1 ml / kg of Ovalbumin solution obtained by dissolving 20 mg of Ovalbumin (Sigma) in 1 ml of 300-400 g male rats (COBS-CD) were injected intramuscularly and pertussis wax ( 1 ml of Avetin Scrabbo) is immunized by intraperitoneal injection.
11일 후 동물들을 죽이고 피를 수집하고 4℃에서 철야방치 후, 원심분리시키고 혈청을-20℃에서 저장한다.After 11 days the animals are killed, blood is collected and left overnight at 4 ° C., then centrifuged and the serum stored at −20 ° C.
b) PCA시험-중량 125 내지 135g인 암컷 쥐(COBS-CD)에 항오발부민 혈청 0.1ml을 등에 피부내 주사하여 감작시킨다. 24시간 후, 오발부민 25ml/kg과 에스반 블루 25ml/kg을 정맥내 주사하고 30분 후 동물을 죽인 후 등의 표피를 제거하고 반사된 피부상의 두점의 최대와 최소 직경을 측정한다.b) PCA Test—Female rats weighing 125-135 g (COBS-CD) are sensitized by intradermal injection of 0.1 ml of anti-ovalbumin serum in the back. After 24 hours, 25 ml / kg of Ovalbumin and 25 ml / kg of S-Ban Blue are injected intravenously, 30 minutes later the animal is killed, the epidermis is removed and the maximum and minimum diameters of the two points on the reflected skin are measured.
투여된 화합물의 작용 5분전에 항원은 표 2에서 ED50 (조절과 비교된 것으로서 두점의 직경 평균을 50% 감소시키는 투여량)으로서 표현된다.Five minutes prior to the action of the administered compound, the antigen is expressed in Table 2 as ED50 (a dose that reduces the mean of the diameter of the two points by 50% as compared to the control).
본 발명에 의한 화합물의 항궤양 작용의 약학적 연구로서 Shay etal., in Gastroenterology 26, 906, 1954에 의해 기술된 방법에 따라 유문 결찰된 쥐(세이쥐)에서 위산 분비를 50%(ED 50)로 억제하는 투여량, Le etal. in Arch., Int. Pharmacodyne. 191, 370, 1971에 기술된 방법에 따라 인도메타신-유발된 궤양을 50%(ED 50)를 감소시키는 투여량과 Senay와 Levinein Proc. Soc. Exp. Biol. Med. 124, 1221, 1967에 의해 기술된 방법에 따라 냉각과 억제에 의한 궤양 50%(ED 50)를 감소시키는 투여량이 결정되었다.As a pharmaceutical study of the anti-ulcerative action of the compounds according to the present invention, gastric acid secretion was reduced by 50% (ED 50) in pyloric mice (Sey mice) according to the method described by Shay et al., In Gastroenterology 26, 906, 1954. Inhibitory dose, Le etal. in Arch., Int. Pharmacodyne. 191, 370, 1971, and a dose that reduces indomethacin-induced ulcer by 50% (ED 50) and Senay and Levinein Proc. Soc. Exp. Biol. Med. Doses that reduce ulceration 50% (ED 50) by cooling and suppression were determined according to the method described by 124, 1221, 1967.
결과는 표 2에 나타나 있다.The results are shown in Table 2.
본 발명에 의한 화합물은 천식과 그밖의 알레르기성 질병의 예방과 치료를 위한 인간치료에 특히 유용한 것이다. 화합물은 정제 또는 캡슐 또는 다른 형태로 사용할 수 있으며 나이와 성별에 관계없이 환자에게 경투여할 수 있다. 예를 들면 딱딱한 젤라틴 캡슐은 활성성분 20 내지 100mg, 락토오즈 100mg과 마그네슘 스태아레이트 2mg을 포함하거나 또는 캡슐은 활성성분 20 내지 100mg, 전분 200mg과 활석 5mg을 포함한다. 권장된 일일 투여량은 50 내지 100mg 사이에서 변화될 수 있으며, 본 발명 화합물은 비The compounds according to the invention are particularly useful for the treatment of humans for the prevention and treatment of asthma and other allergic diseases. The compounds may be used in tablet or capsule or other forms and may be administered to the patient regardless of age and gender. For example, a hard gelatin capsule may contain 20 to 100 mg of active ingredient, 100 mg of lactose and 2 mg of magnesium stearate, or the capsule may contain 20 to 100 mg of active ingredient, 200 mg of starch and 5 mg of talc. Recommended daily dosages can vary between 50 and 100 mg and the compounds of the present invention
[표 2]TABLE 2
* 보여준 더이타는 하이드로 클로라이드에 관한 것이다.Deutera shown is for hydrochloride.
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