KR810000412B1 - Process for the preparation of new prostaglandines - Google Patents
Process for the preparation of new prostaglandines Download PDFInfo
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- KR810000412B1 KR810000412B1 KR7602006A KR760002006A KR810000412B1 KR 810000412 B1 KR810000412 B1 KR 810000412B1 KR 7602006 A KR7602006 A KR 7602006A KR 760002006 A KR760002006 A KR 760002006A KR 810000412 B1 KR810000412 B1 KR 810000412B1
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- South Korea
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- 238000000034 method Methods 0.000 title claims description 31
- 125000003259 prostaglandin group Chemical group 0.000 title abstract 2
- 230000008569 process Effects 0.000 title description 8
- 238000002360 preparation method Methods 0.000 title description 5
- -1 1,1-dimethylpentyl Chemical group 0.000 claims abstract description 51
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 29
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 7
- 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 3
- 230000002378 acidificating effect Effects 0.000 claims abstract 2
- 125000006239 protecting group Chemical group 0.000 claims abstract 2
- 150000003180 prostaglandins Chemical class 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 229940094443 oxytocics prostaglandins Drugs 0.000 claims description 2
- 229920000858 Cyclodextrin Polymers 0.000 abstract description 11
- 206010020772 Hypertension Diseases 0.000 abstract description 6
- 230000007062 hydrolysis Effects 0.000 abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 5
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- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
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- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- NPRDHMWYZHSAHR-UHFFFAOYSA-N pyridine;trioxochromium Chemical compound O=[Cr](=O)=O.C1=CC=NC=C1.C1=CC=NC=C1 NPRDHMWYZHSAHR-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0016—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing only hydroxy, etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- 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
Abstract
Description
본 발명은 고혈압, 말초순환장해, 뇌혈전증, 위궤양, 심근경색 및 천식치료에 유용한 신규 프로스타글란딘 동족체에 관한 것이다. 이는 우리의 영국특허 제1416410호에 기술된 발명 내용을 개선 내지는 변형한 것이다.The present invention relates to novel prostaglandin analogs useful for the treatment of hypertension, peripheral circulatory disorders, thrombosis, gastric ulcers, myocardial infarction and asthma. This is an improvement or modification of the invention described in our UK patent no.
영국특허 제1416410호의 명세서에서는 그중에서도 특히 다음 일반식(I)의 트란스-Δ2-프로스타글란딘 동족체 및 탄소수 1 내지 10의 직쇄 또는 측쇄 알킬에스테르 및 이러한 산 또는 에스테르의 사이클로덱스트린 클래트레이트와 이러한 산의 비독성염을 기술 청구하고 있다(단 트란스 Δ2-PGE1제외).British Patent No. 1.41641 million in favor herein inter alia the following general formula (I) in the trans -Δ 2 - prostaglandin analogues and having 1 to 10 carbon atoms with linear or branched alkyl ester and non-toxic of such acid or cyclodextrin class tray agent and the acid of the ester of Sex is claimed (except trans Δ 2 -PGE 1 ).
상기식에서 A는 다음 일반식(Ⅱ), (Ⅲ)또는 (Ⅳ)를 나타내며Wherein A represents the following general formula (II), (III) or (IV)
X는 에틸렌(-CH2CH2-) 또는 트란스-비닐렌(-CH=CH-)을 나타내며X represents ethylene (-CH 2 CH 2- ) or trans-vinylene (-CH = CH-)
R1은 탄소수 1 내지 10의 직쇄 또는 측쇄알킬 라디칼 또는 탄소수 5 내지 7의 사이클로알킬 치환체 또는 페닐 치환체를 가지는 탄소수 1 내지 6의 직쇄 또는 측쇄알킬 라디칼을 나타내며R 1 represents a straight or branched chain alkyl radical having 1 to 10 carbon atoms or a cycloalkyl or cycloalkyl substituent having 5 to 7 carbon atoms or a phenyl substituent.
R2는 수소원자 또는 탄소수 1 내지 4의 직쇄 또는 측쇄알킬 라디칼을 나타내며R 2 represents a hydrogen atom or a straight or branched chain alkyl radical having 1 to 4 carbon atoms
파상선(
C2-C3이중결합은 트란스이다.C 2 -C 3 double bonds are trans.
앞서 언급된 명세서에서는 화합물들이 프로스타글란딘의 특히 저혈압 작용, 혈소판 응집억제작용, 위산분비 및 위궤양 형성에 대한 억제작용 및 기관지 확장작용등 선택적 양상을 가지는 전형적인 공지된 유효한 약리적 성질을 가지고 있으며 따라서 고혈압 치료, 말초순환계 장해의 치료, 뇌혈전증 및 심근경색증의 예방 및 치료, 위궤양의 치료 및 천식치료에 유용함을 기술하고 있다.In the above specification, the compounds have typical known effective pharmacological properties with selective aspects of prostaglandins, in particular hypotensive action, platelet aggregation inhibition, inhibition of gastric acid secretion and gastric ulcer formation, and bronchial dilatation, thus treating hypertension, peripheral It has been described as useful for the treatment of circulatory disorders, prevention and treatment of thrombosis and myocardial infarction, treatment of gastric ulcer and asthma.
더욱 연구와 실험을 거친 후 A가 다음 일반식(V)를 나타내며After further research and experiment, A represents the following general formula (V)
X가 트란스-비닐렌을 나타내고X represents trans-vinylene
R1이 1,1-디메틸펜틸기 (
R2가 수소원자를 나타내는 일반식(I)의 트란스-Δ2-프로스타클란딘 동족체(즉, 16,16-디메틸-트란스-Δ2-PGE1및 17(ξ)-에틸-ω-디호모-트란스-Δ2-PGE1) 및 이의 메틸에스테르, 이들 산과 에스테르의 사이클로덱스트린 클래트레이트 및 산의 비독성염이 뜻밖에도 현저한 약리적 성질을 가지고 있음을 발견했다.R 2 is trans -Δ 2 of formula (I) represents a hydrogen atom - prostasin Aklan Din congener (that is, 16,16- dimethyl-trans -Δ 2 -PGE 1 and 17 (ξ) - ethyl-di -ω- Homo-trans-Δ 2 -PGE 1 ) and methyl esters thereof, cyclodextrin clathrates of these acids and esters, and non-toxic salts of acids have surprisingly significant pharmacological properties.
따라서 본 발명은 이제까지 알려지지 않은 다음 일반식(VI)의 프로스타글란딘 동족체 및 이들 산 또는 에스테르의 사이클로덱스트린 클래트레이트와 이들 산의 비독성염(예 : 나트륨염)에 관한 것이다.The present invention therefore relates to the following prostaglandin homologues of the general formula (VI) and cyclodextrin clathrates of these acids or esters and non-toxic salts of these acids, such as sodium salts.
상기식에서In the above formula
R3는 1,1-디메틸펜틸 또는 2(ξ)에틸헵틸기를 나타내며R 3 represents a 1,1-dimethylpentyl or 2 (ξ) ethylheptyl group
R4는 수소원자 또는 메틸기를 나타내며R 4 represents a hydrogen atom or a methyl group
과상선은 하이드록시기의 베타 또는 알파(바람직) 배위연결을 나타내며Hyperphase represents the beta or alpha (preferred) coordination of hydroxyl groups
C2-C3및 C13-C14이중결합은 트란스이다.C 2 -C 3 and C 13 -C 14 double bonds are trans.
본 발명은 설명된 바의 ＂천연＂형태 화합물 전부와도 관련된다.The invention also relates to all of the "natural" form compounds as described.
그 분야의 숙련가에게는 자명한 바와같이 일반식(IV)의 화합물은 4개의 펀광 중심을 가지는데 이들 4개의 펀광중심은 8,11 및 12로 확인된 지환족환 탄소원자 및 하이드록시기가 연결되어 있는 C-15 탄소원자에 있다.As will be apparent to those skilled in the art, the compound of general formula (IV) has four funnel centers, the four funnel centers having an alicyclic ring carbon atom and a hydroxyl group identified as 8,11 and 12. Is at -15 carbon atoms.
R3가 2(ξ)-에틸헵틸기를 나타낼때 또 하나의 펀광 중심이 생긴다. 펀광성의 존재는, 잘 알려진 바와같이, 이성현상의 존재를 의미한다. 일반식(VI)의 모든 이성체 및 그의 혼합물은 일반식(VI)의 범주내에서 고려될 수 있다.Another funnel center is created when R 3 represents a 2 (ξ) -ethylheptyl group. The presence of fungal light, as is well known, means the presence of isomerism. All isomers of formula (VI) and mixtures thereof can be considered within the scope of formula (VI).
R3가 1,1-디메틸페닐기인 일반식(Ⅵ)의 동족체 및 그의 메틸에스테르와 그의 비독성염을 예외적으로 우수한 낙태작용 및 자궁수축에 대한 촉진작용을 가지고 있으며 따라서 임신 말기의 임신한 암포유 동물에서 분만의 유도 및 발정, 피임 및 월경조절에 유용함이 발견되었다(이들 활성은 영국특허 제1416410호에는 언급되어 있지 않다.) 이러한 화합물들은 저혈압 작용도 가지고 있다.Homologs of formula (VI), wherein R 3 is a 1,1-dimethylphenyl group, methyl esters thereof and nontoxic salts thereof, have exceptionally excellent abortion and stimulation for uterine contraction, and thus are pregnant with lactating animals at the end of pregnancy. It has been found to be useful for induction and estrus of birth, contraception and menstruation (these activities are not mentioned in British Patent 1414110). These compounds also have hypotensive action.
R3가 2(ξ)-에틸헵틸기를 나타내는 일반식(VI)의 프로스타글란딘 동족체 및 메틸에스테르와 그의 비독성염은 예외적으로 우수한 저혈압 작용을 가진다는 것이 발견되었으며 따라서 이는 고혈압 치료 및 말초순환계 장해치료에 유용하다.Prostaglandin analogs and methyl esters of formula (VI), wherein R 3 represents a 2 (ξ) -ethylheptyl group, and their nontoxic salts, have been found to have exceptionally low blood pressure and thus are useful for treating hypertension and peripheral circulatory disorders. Do.
본 발명의 프로스타글란딘 화합물은 앞서 언급된 가치있는 약리적 성질 면에서의 효능과 비교할때 설사 유도에는 비교적 낮은 효능을 가지고 있으며 따라서 적당한 투여율로서 원치않는 부작용으로서 설사를 유도치 않고도 진술된 목적을 위해 사용될 수 있다.The prostaglandin compounds of the present invention have relatively low efficacy in inducing diarrhea compared to the efficacy in terms of the above-mentioned valuable pharmacological properties and thus can be used for the stated purpose without inducing diarrhea as an unwanted side effect at an appropriate dosage. have.
낙태작용 및 자궁수축에 대한 촉진작용면에서 본 발명 화합물의 바람직한 화합물은 16,16-디메틸-트란스-Δ2-PGE1메틸에스테르이고 저혈압 작용면에서 바람직한 화합물은 17(ξ)-에틸-ω-디호모-트란스-Δ2-PGE1메틸에스테르이다.Preferred compounds of the compounds of the present invention in terms of abortion and promoting uterine contraction are 16,16-dimethyl-trans-Δ 2 -PGE 1 methylester and preferred compounds in terms of hypotensive action are 17 (ξ) -ethyl-ω- Dihomo-trans-Δ 2 -PGE 1 methylester.
예를들면, 표준 실험실 시험에서, 의식있는 특발성 고혈압 쥐에게 경구 투여하는 경우, 17(ξ)-에틸-ω-디호모-트란스-Δ2-PGE1메틸에스테르는 동물체중 kg당 0.1mg의 용량으로 투여한 후 0.5,1 및 3시간 후에 각각 15mmHg, 10mmHg 및 14mmHg의 혈압강하를 보였으며 0.3mg/kg의 용량에서는 투여후 0.5,1,3 및 5시간 후 각각 33mmHg, 19mmHg, 13mmHg 및 11mmHg의 혈압강하를 나타냈고 1.0mg/kg의 용량에서는 투여후 0.5,1,3 및 5시간 후 각각 44mmHg, 39mmHg, 21mmHg 및 20mmHg의 혈압강하를 나타냈다.For example, in a standard laboratory test, when administered orally to a conscious idiopathic hypertensive rat, the dose of 17 (ξ) -ethyl-ω-dihomo-trans-Δ 2 -PGE 1 methylester is 0.1 mg / kg body weight of the animal. 0.5, 1 and 3 hours after the administration of 15mmHg, 10mmHg and 14mmHg, respectively, and the dose of 0.3mg / kg at the dose of 0.5, 1, 3 and 5 hours after the administration of 33mmHg, 19mmHg, 13mmHg and 11mmHg respectively The blood pressure drop was shown and at the dose of 1.0 mg / kg, the blood pressure drop was 44 mmHg, 39 mmHg, 21 mmHg and 20 mmHg, respectively, 0.5, 1, 3 and 5 hours after administration.
위 실험에서, 묽은 변은 0.3mg/kg의 용량으로 투여한 6마리중 단 한마리에서만 관찰되었으며 0.1mg/kg 및 1.0mg/kg 용량으로 투여한 쥐에서는 한마리도 관찰되지 않았다. 이들 결과는 17(ξ)-에틸-ω-디호모-트란스-Δ2-PGE1메틸에스테르는 강한 저혈압 작용 및 매우 약한 설사유도(부작용)작용을 가짐을 나타낸다.In the above experiments, loose stools were observed in only one of the six doses administered at a dose of 0.3 mg / kg and not in rats administered at the doses of 0.1 mg / kg and 1.0 mg / kg. These results show that 17 (ξ) -ethyl-ω-dihomo-trans-Δ 2 -PGE 1 methylester has strong hypotension and very weak diarrhea induction (side action).
16,16-디메틸-트란소-Δ2-PGE1메틸에스테르는16,16-dimethyl-transo-Δ 2 -PGE 1 methylester
(i) 임신 20일째인 임신한 쥐에게 동물 체중 kg당 0.5㎍의 용량으로 정맥 투여할때 자궁수축을 촉진하며(i) Promote uterine contraction when administered intravenously at a dose of 0.5 µg / kg animal weight to pregnant rats on day 20
(ii) 동물 체중 kg당 1㎍의 용량으로 알로바르비탈 마취된 개에게 정맥 투여시 혈압강하를 보이며(ii) a blood pressure drop during intravenous administration of an allobarbital anesthetized dog at a dose of 1 μg / kg animal weight;
(iii) 동물 체중 kg당 1200㎍의 용량으로 경구 투여시 처리된 마우스 50%에서 설사를 유도한다.(iii) Induce diarrhea in 50% of mice treated upon oral administration at a dose of 1200 μg per kg body weight of the animal.
16,16-디메틸-트란스-Δ2-PGE1메틸에스테르의 약리작용중에서During the pharmacological action of 16,16-dimethyl-trans-Δ 2 -PGE 1 methyl ester
(i) 자궁수축 작용은 유용한 효과이며(i) uterine contraction is a useful effect
(ii) 저혈압작용 및(ii) hypotension and
(iii) 설사유도작용은 바람직하지 못한 효과로 생각된다.(iii) Diarrhea induction is thought to be an undesirable effect.
16,16-디메틸-트란스-Δ2-PGE1메틸에스테르와 영국특허 제1416410호에 이미 기술된 프로스타글란딘 동족체(예 : 16(R)-메틸-트란스-Δ2-PGE1, 16(ξ)-페닐-ω-트리노르-트란스-Δ2-PGE1및 15(ξ)-메틸-트란스-Δ2-PGE1)의 쥐에 대한 약리활성이 다음 표에 비교되어 있다.16,16-dimethyl-trans-Δ 2 -PGE 1 methylester and prostaglandin homologues already described in British Patent 1414110 (e.g. 16 (R) -methyl-trans-Δ 2 -PGE 1 , 16 (ξ)- The pharmacological activity of phenyl-ω-trinor-trans-Δ 2 -PGE 1 and 15 (ξ) -methyl-trans-Δ 2 -PGE 1 ) in mice is compared in the following table.
[표][table]
표에서 알 수 있는 바와 같이, 16,16-디메틸-트란스-Δ2-PGE1메틸에스테르는 원하는 강한(자궁수축) 작용을 나타내며 적어도 다른 화합물의 10배 이상의 효능을 가진다. 더우기, 16,16-디메틸-트란스-Δ2-PGE1메틸에스테르의 선택적 지수(부작용/원하는 효과비 즉 (ii)/(i) 또는 (iii)/(i)비)는 기지 화합물보다 훨씬 높다. 이들 데이타는 16,16-디메틸-트란스-Δ2-PGE1메틸에스테르가 시험된 다른 화합물에 비해 훨씬 우수한 강한 자궁수축 작용을 가지며 임신말기 및 임신한 포유동물에서 분만의 유도 및 발정, 피임 및 월경조절의 사용에 있어서 시험된 다른 화합물보다 우수하고 안전하다는 것을 나타낸다.As can be seen from the table, 16,16-dimethyl-trans-Δ 2 -PGE 1 methylester exhibits the desired strong (uterine contractile) action and at least 10 times more potency than other compounds. Furthermore, the selective index (side effect / desired effect ratio ie (ii) / (i) or (iii) / (i) ratio) of 16,16-dimethyl-trans-Δ 2 -PGE 1 methylester is much higher than known compounds . These data show much stronger uterine contractile action than other compounds tested with 16,16-dimethyl-trans-Δ 2 -PGE 1 methylester and induction and estrus, birth control and menstruation in late pregnancy and in pregnant mammals. It is shown to be better and safer than other compounds tested in the use of the control.
본 발명에 따라서, 일반식(VI)의 프로스타글란딘 동족체는 다음 일반식(VII) 화합물의 OR5기를 하이드록시기로 가수분해시키는 방법에 의해 제조된다.According to the invention, the prostaglandin homologue of general formula (VI) is prepared by the process of hydrolyzing the OR 5 group of the following general formula (VII) compound with a hydroxyl group.
상기식에서In the above formula
R5는 비치환 또는 적어도 하나의 알킬키에 의해 치환된 2-테트라하이드로피라닐기 또는 1-에톡시에틸기를 나타내며 기타의 기는 전술된 바와 같다.R 5 represents a 2-tetrahydropyranyl group or 1-ethoxyethyl group unsubstituted or substituted by at least one alkyl key, and other groups are as described above.
일반식(VII) 화합물의 OR5기는 유기산의 수성용액(예 : 아세트산) 또는 묽은 수성무기산(예 : 염산)으로 유리하게는 물과 혼화할 수 있는 유기용매(예 : 테트라하이드로푸란 또는 탄소수 1 내지 4의 알칸올(예 : 메탄올) 존재하에 완하한 가수분해에 의해 하이드록시기로 전환시킬 수 있다.The OR 5 group of the compound of formula (VII) is an organic solvent (e.g. tetrahydrofuran or C 1 to C) which is advantageously miscible with water in an aqueous solution of an organic acid (e.g. acetic acid) or dilute aqueous inorganic acid (e.g. hydrochloric acid). It can be converted to a hydroxyl group by gentle hydrolysis in the presence of an alkanol of 4 (eg methanol).
완화한 가수분해는 산 혼합물(예 : 염산과 테트라하이드로푸란 또는 메탄올과의 혼합물), 또는 아세트산, 물 및 테트라하이드로푸란의 혼합물을 사용하여 주변온도 내지 60℃(바람직하게는 45℃이하의 온도)에서 수행될 수 있다.Moderate hydrolysis is achieved by using an acid mixture (e.g., a mixture of hydrochloric acid with tetrahydrofuran or methanol), or a mixture of acetic acid, water and tetrahydrofuran, preferably from ambient to 60 ° C (preferably below 45 ° C). It can be performed in.
일반식(VI)의 생성물은 실리카겔상 칼럼크로마토그라피에 의해 정제될 수 있다.The product of formula (VI) can be purified by column chromatography on silica gel.
일반식(VII)의 화합물은 다음 일반식(VIII)의 화합물로부터 프로스타글란딘 화합물의 9-위치에 있는 하이드록시기를 예를들면 0℃에서 콜린스 시약(크로뮴트리옥사이드-피리딘 복합체)을 사용하거나 크롬(III)산용액(크로뮴트리옥사이드, 왕산망간, 황산 및 물로부터 수득됨) 또는 존스 시약을 사용하여 옥소기로 전환시킬 때 사용되는 공지된 방법에 의해 제조될 수 있다.The compound of formula (VII) may be prepared by using a hydroxy group at the 9-position of the prostaglandin compound, for example, at 0 ° C. using a Collins reagent (chromium trioxide-pyridine complex) or chromium (III) Acid solution (obtained from chromium trioxide, manganese sulphate, sulfuric acid, and water) or Jones reagent to convert to an oxo group.
상기 식에서In the above formula
기설명은 전술된 바와 같다.The description is as described above.
본 명세서에서 사용된 ＂공지된 방법＂이란 화학문헌에서 이제까지 사용 또는 기술된 방법을 의미한다.As used herein, “known methods” means methods used or described so far in the chemical literature.
일반식(VIII)의 화합물은 다음 일반식(IX)의 화합물로부터 제조될 수 있다.Compounds of formula (VIII) can be prepared from compounds of formula (IX)
상기식에서In the above formula
R6는 탄소수 2 내지 5의 알킬카보닐기를 나타내며 기타의 기설명은 전술된 바와 같다.R 6 represents an alkylcarbonyl group having 2 to 5 carbon atoms, and other groups are as described above.
알카리 조건하의 가수분해는 (1) 수혼화성 용매(예 : 테트라하이드로푸란 또는 탄소수 1 내지 4의 알칸올)존재하 알키리금속(에 : 나트륨 또는 포타슘) 하이드록사이드 또는 카보네이트를 사용하여 수행되어 R4가 수소원자를 나타내는 일반식(VIII)의 화합물을 얻거나, (2) 탄소수 1 내지 4의 무수 알칸올 바람직하게는 무수 메탄올중 무수 포타슘카보네이트를 사용하여 R4가 메틸기인 일반식(VIII)의 화합물을 얻을 수 있다.Hydrolysis under alkaline conditions is carried out using (1) an alkirimetal (e.g. sodium or potassium) hydroxide or carbonate in the presence of a water miscible solvent (e.g. tetrahydrofuran or an alkanol having 1 to 4 carbon atoms). Obtain a compound of the general formula (VIII) which represents a tetravalent hydrogen atom, or (2) General formula (VIII) whose R <4> is a methyl group using anhydrous potassium carbonate in C1-C4 anhydride, Preferably anhydrous methanol. The compound of can be obtained.
일반식(IX)의 화합물은 다음 일반식(X)의 화합물로부터 축합제(예 : P-톨루엔설폰산) 존재하 불활성 유기용매 중에서 디하이드로피란 또는 에틸비닐에테르와 반응시켜 제조할 수 있다.The compound of formula (IX) can be prepared by reacting with dihydropyran or ethyl vinyl ether in an inert organic solvent in the presence of a condensing agent (eg P-toluenesulfonic acid) from the compound of formula (X).
상기식에서 기설명 및 파상선은 전술된 바와 같다.The description and the broken line in the above formula are as described above.
일반식(X)의 화합물은 다음 일반식(XI)의 화합물로부터 공지된 방법을 사용하여 15-옥소기를 하이드록시기로 전환시켜 제조할 수 있다.Compounds of formula (X) can be prepared by converting 15-oxo groups to hydroxyl groups using known methods from the compounds of formula (XI).
상기식에서In the above formula
기설명은 전술된 바와 같다.The description is as described above.
환원은 (1) 저온 바람직하게는 -30℃ 내지 -60℃에서 탄소수 1 내지 4의 알칸올(예 : 메탄올)중에서 과량의 나트륨보로하이드라이드를 사용하여 적당히 수행되거나 (2) -10℃ 내지 10℃에서 적당한 불활성 유기용매(1,2-예 : 디메톡시에탄)중에서 아연 브로하이드라이드를 사용하여 수행될 수 있다.Reduction is suitably carried out using (1) an excess of sodium borohydride in alkanols having 1 to 4 carbon atoms (e.g. methanol) at low temperature, preferably from -30 ° C to -60 ° C, or (2) from -10 ° C to It may be carried out using zinc brohydride in a suitable inert organic solvent (1,2-e.g. Dimethoxyethane) at 10 ° C.
이렇게 수득된 생성물은 15-하이드록시기가 α- 또는 β-배위로 존재하는 이성체 혼합물이다. 필요하다면 α-배위의 하이드록시를 가지는 이성체는 β-배위의 하이드록시기를 가지는 이성체로부터 실리카겔상 칼럼크로마토그라피에 의해 분리될 수 있다. 분리된 이성체는 여기 설명된 조작에서 이용되어서 15위치의 하이드록시기가 α- 또는 β-배위인 일반식(VI)의 프로스타글란딘 동족체 또는 그의 메틸에스테르를 얻을 수 있다.The product thus obtained is an isomer mixture in which 15-hydroxy groups are present in the α- or β-configuration. If necessary, isomers having an α-coordinated hydroxy can be separated by column chromatography on silica gel from isomers having a β-coordinated hydroxy group. The isolated isomers can be used in the operations described herein to obtain prostaglandin homologs of the general formula (VI) or methylesters thereof, wherein the 15-hydroxy group is in the α- or β-coordination.
일반식(XI)의 화합물은 다음 일반식(XII)의 화합물을 다음 일반식(XIII)의 디알킬 또는 포스포네이트의 나트륨 유도체와 반응시키는 위티히 반응(wittig reaction)에 의해 제조될 수 있다.Compounds of formula (XI) may be prepared by a wittig reaction in which a compound of formula (XII) is reacted with a sodium derivative of dialkyl or phosphonate of formula (XIII).
상기식에서In the above formula
R7은 탄소수 1 내지 4의 알킬기를 나타내며 기타의 기설명은 전술된 바와 같다.R 7 represents an alkyl group having 1 to 4 carbon atoms, and other groups are as described above.
반응은 불활성 유기용매(예 : 테트라하이드로푸란 또는 1,2-디메톡시에탄)중에 나트륨하이드라이드를 현탁시키고 일반식(XIII)의 디알킬포스포네이트를 가함으로써 바람직하게 수행된다. 결과로 생긴 디알킬 포스포네이트의 나트륨유도체를 20℃ 내지 45℃의 온도에서 일반식(XII)의 화합물과 반응시켜서 일반식(XI)의 트란스-에는 화합물을 입체 선택적으로 형성한다.The reaction is preferably carried out by suspending sodium hydride in an inert organic solvent such as tetrahydrofuran or 1,2-dimethoxyethane and adding a dialkylphosphonate of general formula (XIII). The resulting sodium derivative of the dialkyl phosphonate is reacted with a compound of general formula (XII) at a temperature of 20 ° C. to 45 ° C. to stereoselectively form a compound in the trans- of general formula (XI).
일반식(XIII)의 디알킬 포스포네이트는 디에틸에테르 또는 n-핵산중 n-부틸리륨의 용액을 다음 일반식(XIV)의 디알킬메틸포스포네이트(예 : 디메틸메틸포스포네이트 또는 디에틸메틸포스포네이트)와 테트라하이드로푸란중에서 -50℃이하의 온도로 반응시킨 뒤 이 반응 혼합물에 다음 일반식(XV)의 화합물이 용해된 테트라하이드로푸란용액을 -50℃이하에서 2 내지 4시간 동안 가한 뒤 주변온도내지 0℃에서 2 내지 18시간동안 교반하여 얻을 수 있다.The dialkyl phosphonate of general formula (XIII) may be prepared by diluting a solution of n-butyllilium in diethyl ether or n-nucleic acid with the following dialkylmethylphosphonate of general formula (XIV) (e.g. dimethylmethylphosphonate or Diethylmethylphosphonate) and tetrahydrofuran were reacted at a temperature of -50 ° C or lower, and then a tetrahydrofuran solution in which the compound of the following general formula (XV) was dissolved in the reaction mixture was carried out at -50 ° C. After adding for a period of time it can be obtained by stirring for 2 to 18 hours at ambient temperature to 0 ℃.
상기식에서In the above formula
R8은 탄소수 1 내지 4의 알킬기이며R 8 is an alkyl group having 1 to 4 carbon atoms
기타 기설명은 전술된 바와 같다.Other descriptions are as described above.
일반식(XII)의 화합물은 이후 설명된 일반식(XVI)의 기지 화합물로부터 도식 A에서 도식적으로는 설명되는 일련의 반응에 의해 제조될 수 있다.Compounds of formula (XII) may be prepared by a series of reactions schematically illustrated in Scheme A from known compounds of formula (XVI) described below.
이때 도식 A에서 Q는 -SeC6H5또는 -SR9를 나타내며 이때 R9는 탄소수 1 내지 4의 알킬기 또는 페닐기를 나타낸다.In Formula A, Q represents -SeC 6 H 5 or -SR 9 , and R 9 represents an alkyl group having 1 to 4 carbon atoms or a phenyl group.
기타의 기설명은 전술된 바와 같다.Other descriptions are as described above.
일반식(XVI)의 화합물은 환원시켜서 일반식(XVII)의 화합물을 얻을 수 있다.The compound of general formula (XVI) can be reduced to obtain a compound of general formula (XVII).
환원은 수소첨가촉매(예 : 팔라듐/목탄, 팔라듐블랙 또는 이산화백금) 존재하에 불활성 유기용매 예를들면 저급알칸(예 : 메탄올 또는 에탄올)중에서 실험실 온도, 정상압 또는 상승압하(예 : 대기압 내지는 15kg/cm2의 수소압하)에서 수소 첨가에 의해 수행될 수 있다.Reduction can be carried out under laboratory temperature, normal or elevated pressure (e.g. atmospheric to 15 kg) in an inert organic solvent such as lower alkanes (e.g. methanol or ethanol) in the presence of a hydrogenation catalyst (e.g. palladium / charcoal, palladium black or platinum dioxide). hydrogen under pressure of / cm 2 ).
일반식(XIX)의 화합물은 일반식(XVII)의 화합물은 다음 일반식(XXIII)의 화합물(예 : 리튬 디이소프로필아미드)과 반응시켜서 다음 일반식(XXIV)의 리튬 화합물을 얻고 이 리롬화합물을 벤젠설레닐 브로마이드(예 : C6H5SeBr) 또는 디페닐디셀레나이드 또는 일반식 R9SSR9(이때 R9는 위의 정의된 바와 같다)의 디알킬디설파이드 또는 디페닐디설파이드와 반응시키고 결과의 중간체를 가수분해시켜서 일반식(XVIII)의 화합물을 얻고 결과의 화합물을 과산화수소 또는 나트륨퍼요오 데이트로 처리하고 다음 일반식(XXV)의 화합물을 분해시켜서 사이클로펜탄 환의 8-위치에 붙어있는 그룹The compound of formula (XIX) is reacted with a compound of formula (XVII) with a compound of formula (XXIII) (e.g. lithium diisopropylamide) to obtain a lithium compound of formula (XXIV) Is reacted with benzenesulenyl bromide (e.g. C 6 H 5 SeBr) or diphenyldiselenide or dialkyldisulfide or diphenyldisulfide of the general formula R 9 SSR 9 , wherein R 9 is as defined above A group attached to the 8-position of the cyclopentane ring by hydrolysis of the resultant intermediate to obtain the compound of formula (XVIII), treatment of the resultant compound with hydrogen peroxide or sodium periodate and subsequent decomposition of the compound of formula (XXV)
상기식에서In the above formula
R5및 Q는 전술된 바와 같으며R 5 and Q are as described above
R10및 R11은 같거나 다를 수 있으며 각각은 탄소수 1 내지 6인 직쇄 또는 촉쇄의 알킬기 또는 탄소수 3 내지 6의 사이클로알킬기를 나타낸다.R 10 and R 11 may be the same or different and each represents a straight or cyclic alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms.
일반식(XVII)의 화합물과 일반식(XXIII)의 반응은 불활성 유기용매(예 : 테트라하이드로푸란)중에서 저온(예 : -78℃)으로 수행되며 반응혼합물중 일반식(XVII)대 (XXIII)화합물의 분자당량 비율은 일반식(XXIV)의 리튬화합물을 얻도록 적당히 조절된다.The reaction of the compound of formula (XVII) with formula (XXIII) is carried out at low temperature (e.g. -78 ° C) in an inert organic solvent (e.g. tetrahydrofuran) and in formula (XVII) to (XXIII) in the reaction mixture. The molecular equivalence ratio of the compound is suitably adjusted to obtain a lithium compound of the general formula (XXIV).
일반식(XXIV)의 리튬화합물과 벤젠설레네닐 브로마이드, 디페닐디셀레나이드 또는 디알킬디설파이드 또는 디페닐디설파이드와의 반응은 불활성 유기용매(예 : 테트라하이드로푸란, 헥사메틸포스포르아마이드, 디에틸에테르, n-헥산 또는 n-펜탄이나 이들의 둘 또는 그 이상의 혼합물)중에서 저온(예 : -78℃)으로 수행되는 것이 바람직하다.The reaction of the lithium compound of formula (XXIV) with benzenesullenyl bromide, diphenyldiselenide or dialkyldisulfide or diphenyldisulfide is carried out by an inert organic solvent (e.g. tetrahydrofuran, hexamethylphosphoramide, diethyl ether). , n-hexane or n-pentane or a mixture of two or more thereof, preferably at low temperature (eg -78 ° C).
일반식(XVIII)의 생성물이 Q가 -SeC6H5인 화합물일때 생성물은 (1) 에틸아세테이트와 테트라하이드로푸란 또는 메탄올의 혼합물중 30℃이하의 온도에서 과산화수소로 처리하거나 (2) 20℃이하에서 물 및 저급알칸올(메탄올이 바람직) 존재하에 나트륨퍼요오데이트로 처리하여 O=Q-가 -Se(O)C6H5를 나타내는 일반식(XXV)의 화합물을 형성하고 반응 혼합물을 25°내지 30C의 온도에서 교반하면 일반식(XXV)의 화합물이 분해되어서 일반식(XIX)의 트란스-Δ2-화합물이 얻어지며 이는 공지된 방법에 의해 반응혼합물로부터 분리될 수 있고 필요하다면 실리카겔상 컬럼크로마토그라피에 의해 정제될 수 있다.When the product of formula (XVIII) is a compound wherein Q is -SeC 6 H 5 , the product may be treated with (1) hydrogen peroxide at a temperature of 30 ° C. or lower in a mixture of ethyl acetate and tetrahydrofuran or methanol, or (2) 20 ° C. or lower. Treated with sodium periodate in the presence of water and lower alkanol (preferably methanol) to form a compound of formula (XXV) wherein O = Q- represents -Se (O) C 6 H 5 , and the reaction mixture is Stirring at a temperature between 30 ° C. and 30 ° C. decomposes the compound of formula (XXV) to yield the trans-Δ 2 -compound of formula (XIX), which can be separated from the reaction mixture by known methods and, if necessary, on silica gel. It can be purified by column chromatography.
일반식(XVIII)의 생성물이 Q가 -SR9(R9는 정의된 바와 같다)인 화합물일때 생성물을 Q가 벤젠셀레네닐인 일반식(XVIII)의 생성물에 대해 앞서 설명된 것과 동일한 방법으로 과산화수소 또는 나트륨퍼요오데이트로 처리해서 Q가 -SR9(R9는 전술된 바와 같다)인 일반식(XXV)의 화합물을 얻으며 이는 공지된 방법에 의해 반응매체로부터 분리될 수 있다.When the product of formula (XVIII) is a compound wherein Q is -SR 9 (R 9 is as defined), the product is hydrogen peroxide in the same manner as described above for the product of formula (XVIII), wherein Q is benzeneselenyl. Or by treatment with sodium periodate to obtain a compound of formula (XXV) wherein Q is -SR 9 (R 9 is as described above), which can be separated from the reaction medium by known methods.
일반식(XXV)의 화합물이 Q가 알킬티오기 -SR9(R9는 전술된 바와 동일)를 나타내는 것일때 화합물을 톨루엔에 용해시키고 이 용액을 바람직하게는 소량의 탄산칼슘 존재하 100°내지 120℃의 온도에서 교반시켜서 화합물을 일반식(XIX)의 트란스-Δ2-화합물로 분해시킨다. 일반식(XXV)의 화합물이 Q가 페닐티오기인 화합물일때 화합물을 4염화탄소에 용해시키고 용액은 약 50℃의 온도에서 소량의 탄산칼슘 존재하에 교반시켜서 화합물을 일반식(XIX)의 트란스-Δ2-화합물로 분해시킨다.When the compound of formula (XXV) is Q in which an alkylthio group -SR 9 (R 9 is the same as described above), the compound is dissolved in toluene and the solution is preferably 100 ° to 100 ° C in the presence of a small amount of calcium carbonate. Stirring at a temperature of 120 ° C. breaks the compound down into the trans-Δ 2 -compound of general formula (XIX). When the compound of formula (XXV) is a compound in which Q is a phenylthio group, the compound is dissolved in carbon tetrachloride and the solution is stirred in the presence of a small amount of calcium carbonate at a temperature of about 50 ° C. to give the compound trans-Δ of formula (XIX). 2 -Decompose into compounds.
일반식(XX)의 화합물은 일반식(XIX)의 화합물을 불활성 유기용매(예 : 메틸렌클로라이드)중에서 염기(예 : 피리딘 또는 3급아민)존재한 저온(예 : -30°내지 0℃)에서 트리메틸클로로실란과 반응시켜 제조할 수 있다.The compound of formula (XX) is a compound of formula (XIX) at low temperature (eg -30 ° to 0 ° C) in the presence of a base (eg pyridine or tertiary amine) in an inert organic solvent (eg methylene chloride). It can be prepared by reaction with trimethylchlorosilane.
일반식(XXI)의 화합물은 일반식(XX)의 트리메틸실릴에테르를 불활성 유기용매(예 : 메틸렌클로라이드)중에서 염기(예 : 피리딘 또는 3급아민)존재하에 저온(예 : 0°내지 30℃에서 적당한 아실클로라이드 또는 산무수물과 반응시켜 제조할 수 있다.Compounds of formula (XXI) are prepared at low temperature (e.g., 0 ° to 30 ° C) in the presence of a base (e.g. pyridine or tertiary amine) in an inert organic solvent (e.g. methylene chloride). It can be prepared by reaction with a suitable acylchloride or acid anhydride.
일반식(XXII)의 화합물은 완화한 중성 조건하 예를들면 적당히 낮은 온도에서 크롬트리옥사이드-피리딘 복합체 또는 존스 시약을 사용하여 일반식(XII)의 화합물로 전환시킬 수 있다.Compounds of formula (XXII) can be converted to compounds of formula (XII) using chromium trioxide-pyridine complexes or Jones reagents under moderately neutral conditions, for example at moderately low temperatures.
반응도식 A에서 설명된 일련의 반응에서 출발물질로 사용된 일반식(XVI)의 화합물은 일반식(XXVI)의 기지화합물[J.Arner. Chem. Soc., 91, 5675(1969) 및 ibid, 92, 397(1970)에서 설명된 바와같이 제조]로부터 일본 특허공보 제49-102646호에서 설명된 방법에 의해 아래 도식 B에서 설명되는 일련의 반응에 따라 제조될 수 있다. 아래 반응도식에서 Ac는 아세틸기를 나타내며 R5는 전술된 바와 같다.Compounds of the general formula (XVI) used as starting materials in the series of reactions described in Scheme A are known compounds of the general formula (XXVI) [J. Arner. Chem. Manufactured as described in Soc., 91, 5675 (1969) and ibid, 92, 397 (1970), to the series of reactions described in Scheme B below by the method described in Japanese Patent Publication No. 49-102646. Can be prepared accordingly. In the following scheme, Ac represents an acetyl group and R 5 is as described above.
일반식(XXVII)의 화합물을 일반식(XXVI)의 화합물을 알카리 조건하 예를들면 메탄올중 포타슘카보네이트를 사용하여 가수분해시킴으로써 제조될 수 있다.Compounds of formula (XXVII) can be prepared by hydrolyzing compounds of formula (XXVI) under alkaline conditions, for example with potassium carbonate in methanol.
일반식(XXVIII)의 화합물은 완화한 조건하 일반식(XXVII)의 화합물을 아세틸화시켜 얻을 수 있으며 축합제(예 : P-톨루엔설폰산) 존재하에 불활성 유기용매(예 : 메틸렌클로라이드)중에서 디하이드로피란 또는 에틸비닐에테르와 반응시켜 일반식(XXIX)의 화합물로 전환시킬 수 있다.Compounds of the general formula (XXVIII) can be obtained by acetylating the compounds of the general formula (XXVII) under mild conditions, and di-inert in an inert organic solvent (e.g. methylene chloride) in the presence of a condensing agent (e.g. P-toluenesulfonic acid). It can be converted into a compound of the general formula (XXIX) by reacting with hydropyran or ethyl vinyl ether.
일반식(XXX)의 화합물은 일반식(XXIX)의 화합물을 톨루엔중 -60℃이하에서 디이소부틸알루미늄하드라이드로 환원시켜 제조할 수 있다. 나트륨하이드라이드 및 디메틸설폭사이드로부터 이미 제조된 딤실 음이온을 4-카복시-n-부틸트리페닐포스포늄 브로마이드와 반응시켜서 4-카복시-n-부틸리덴트리페닐포스포란을 형성한다.The compound of formula (XXX) can be prepared by reducing the compound of formula (XXIX) with diisobutylaluminum hydride at -60 ° C. or less in toluene. The dimsil anion already prepared from sodium hydride and dimethylsulfoxide is reacted with 4-carboxy-n-butyltriphenylphosphonium bromide to form 4-carboxy-n-butylidenetriphenylphosphorane.
그 화합물에 일반식(XXX)의 화합물을 가하고 디메틸설폭시드중 혼합물을 실온에서 반응시켜서 일반식(XXXI)의 화합물을 얻는다. 일반식(XXXI)의 산을 공지된 방법 예를들면 디아조메탄과의 반응에 의해 에스테르화시켜서 일반식(XVI)의 화합물을 얻는다.To the compound is added a compound of formula (XXX) and the mixture in dimethylsulfoxide is reacted at room temperature to obtain a compound of formula (XXXI). The acid of formula (XXXI) is esterified by a known method, for example by reaction with diazomethane, to give a compound of formula (XVI).
R4가 메틸기를 나타내는 일반식(VI)의 트란스-Δ2-프로스타글란딘의 메틸은 R4가 수소원자를 나타내는 일반식(VI)의 상응하는 산을 (i) 디아조메탄과 (ii) 축합제로서 디사이클로헥실카보디이미드 존재하 메탄올과 또는 (iii) 메탄올과 반응시킨 다음 3급아민을 가한 뒤 피발로일할라이드 또는 아릴설포닐 또는 알킬설포닐할라이드를 가하여 혼합된 산무수물을 형성시킴으로써 제조될 수 있다(영국특허 제1362956호와 제1364125호 비교).R 4 is trans -Δ 2 of the general formula (VI) represents a methyl group - the corresponding acid (i) diazomethane and (ii) of the general formula (VI) of the prostaglandin is a methyl R 4 represents a hydrogen atom condensing agent Prepared by reacting with methanol in the presence of dicyclohexylcarbodiimide or (iii) methanol, followed by addition of tertiary amine followed by addition of pivaloyl halide or arylsulfonyl or alkylsulfonyl halide to form a mixed acid anhydride. (Compared to British Patents 1362956 and 1364125).
R4가 수소원자인 일반식(VI)의 화합물은 필요하다면 공지된 방법에 의해 비독성염으로 전환시킬 수 있다.Compounds of formula (VI) wherein R 4 is a hydrogen atom can be converted to non-toxic salts by known methods if necessary.
본 명세서에서 사용되는 ＂비독성염＂이란 치료용량으로 사용될 때 동물에 비교적 무해하며 따라서 일반식(VI) 화합물의 유용한 약리적 성질이 이들 양이온에 기인된 부작용에 의해 손상되지 않는 양이온염을 의미한다. 적당한 염에는 알카리금속(예 : 나트륨 및 포타슘) 및 암모늄염과 약제학적으로 무독한(즉, 비독성) 아민염이 포함된다. 카복실산과 이러한 염을 형성하는데 적합한 아민은 잘 알려져 있으며 예를들면 암모니아중 하나 또는 그 이상의 수소원자가 하나이상의 수소원자가 치환될 때 동일하거나 다를 수 있는 기, 예를 들면 탄소수 1 내지 6의 알킬기 및 탄소수 1 내지 3의 하이드록시알킬기중에서 선택된 기에 의해 치환됨으로써 이론상 유도되는 아민을 포함한다.As used herein, "non-toxic salt" means a cationic salt that is relatively harmless to an animal when used in therapeutic doses and therefore the useful pharmacological properties of the general formula (VI) compounds are not compromised by the side effects caused by these cations. Suitable salts include alkali metal (eg sodium and potassium) and ammonium salts and pharmaceutically nontoxic (ie non-toxic) amine salts. Suitable amines for forming such salts with carboxylic acids are well known, for example groups in which one or more hydrogen atoms of ammonia may be the same or different when one or more hydrogen atoms are substituted, for example alkyl groups having 1 to 6 carbon atoms and 1 carbon atom. Amines theoretically derived by substitution by a group selected from hydroxyalkyl groups of from 3 to 3;
비독성염은 일반식(VI)의 산으로부터 예를 들면 일반식(VI)의 산의 화학식량과 적당한 염기 예를 들면 알카리금속하이드록사이드 또는 카보네이트, 암모늄하이드록사이드, 암모니아 또는 아미과의 적당한 용매중에서의 반응에 의해 제조될 수 있다. 염은 용액의 동일건조나 반응매체중에 충분히 불용성이라면 여과(필요하다면 용매일부 제거후)에 의해 분리될 수 있다.Non-toxic salts can be prepared from the acid of general formula (VI), for example, by the formula weight of the acid of general formula (VI) and in a suitable base such as alkali metal hydroxide or a suitable solvent of carbonate, ammonium hydroxide, ammonia or amiaceae. It can be prepared by the reaction of. Salts may be separated by filtration (if necessary, after removal of some of the solvent) if the solution is insoluble in the reaction medium or the same drying.
일반식(VI)의 트란스-Δ2-프로스타글란딘 동족체는 필요하다면 사이클로덱스트린 클래트레이트로 전환시킬 수 있다. 클래트레이트는 사이클로덱스트린을 물 및/또는 물과 혼화될 수 있는 유기용매에 용해시키고 이 용액에 물혼화성 유기용매중 프로스타글란딘 화합물이 함유된 용액을 가한다. 다음 혼합물을 가열시키고 원하는 사이클로덱스트린 클래트레이트 생성물을 감압 건조하 혼합물을 농축시키거나 냉각시키고 생성물을 여과 또는 경사에 의해 분리함으로써 단리시킨다.The trans-Δ 2 -prostaglandin homologue of formula (VI) can be converted to cyclodextrin clathrate if necessary. The clathrate dissolves the cyclodextrin in water and / or an organic solvent that can be miscible with water and adds to this solution a solution containing a prostaglandin compound in a water miscible organic solvent. The mixture is then heated and the desired cyclodextrin clathrate product is dried under reduced pressure and isolated by concentrating or cooling the mixture and separating the product by filtration or decantation.
유기용매와 물의 비율은 출발물질 및 생성물의 용해도에 따라 다양할 수 있다. 사이클로덱스트린 클래트 레이트 제조동안 바람직하게 온도는 70℃를 초과하지 않도록 해야 한다.The ratio of organic solvent and water may vary depending on the solubility of the starting materials and the product. During cyclodextrin clathrate preparation preferably the temperature should not exceed 70 ° C.
α,β 또는 τ-사이클로덱스트린 또는 그의 혼합물은 사이클로덱스트린 클래트레이트 제조에 사용될 수 있다. 사이클로덱스트린 클래트레이트의 전환은 프로스타글란딘 화합물의 안정도를 증가시키는 작용을 한다.α, β or τ-cyclodextrin or mixtures thereof can be used for the preparation of cyclodextrin clathrate. The conversion of cyclodextrin clathrate acts to increase the stability of the prostaglandin compound.
다음 참조 실시예 및 실시예는 본 발명의 신규 프로스타글란딘 동족청의 제조를 설명한다. 이때 사용되는 ＂IR＂, ＂NMR＂ 및 ＂TLC＂는 각각 ＂적외부 흡수스펙트럼＂, ＂핵자기공명스펙트럼＂ 및 ＂박충크로마토그라피＂를 나타낸다.The following reference examples and examples illustrate the preparation of the novel prostaglandin cognate of the present invention. The "IR", "NMR" and "TLC" used at this time represent "infrared absorption spectrum", "nuclear magnetic resonance spectrum", and "filling chromatography".
용매비율이 크로마토그라프적 분리에서 명시되는 경우 그 비율은 용량비이다.If the solvent ratio is specified in the chromatographic separation, that ratio is the capacity ratio.
[참조 실시예 1]Reference Example 1
2α-(6-메톡시카보닐헥실)-3β-하이드록시메틸-4α-(2-테트라하이드로피란일옥시) 사이클로-펜탄-1α-올2α- (6-methoxycarbonylhexyl) -3β-hydroxymethyl-4α- (2-tetrahydropyranyloxy) cyclo-pentane-1α-ol
14.2g의 2α-(6-메톡시카보닐헥스-시스-2-엔일)-3β-하이드록시메틸-4α-(2-테트라하이드로피란일옥시) 사이클로펜탄-1α-올(일본특허공보 제49-102646호에 기술된 것과 같이 제조한다) 3g의 5% 팔라듐/카본을 함유하는 300ml의 메탄올 중에서 1기압의 압력으로 수소 첨가시킨다.14.2 g of 2α- (6-methoxycarbonylhex-cis-2-enyl) -3β-hydroxymethyl-4α- (2-tetrahydropyranyloxy) cyclopentane-1α-ol (Japanese Patent Publication No. 49 Prepared as described in -102646) in 300 ml of methanol containing 3 g of 5% palladium / carbon at a pressure of 1 atmosphere.
환원은 1당량의 수소가스 흡수후에 정지한다. 촉매는 여과 제거되며 여액은 감압하에서 농축되어 13.8g의 표제 화합물을 수득하여 화합물은 다음과 같은 물리적 성질을 가지고 있다.Reduction stops after one equivalent of hydrogen gas absorption. The catalyst is filtered off and the filtrate is concentrated under reduced pressure to yield 13.8 g of the title compound, which has the following physical properties.
TLC(전개용매, 벤젠-에틸 아세테이트=1 : 1)TLC (developing solvent, benzene-ethyl acetate = 1: 1)
Rf=0.28;Rf = 0.28;
IR(액체필름) :
NMR(CDCl3용액) : δ=5.00-4.55(1H,m), 3.70(3H, S).NMR (CDCl 3 solution): δ = 5.00-4.55 (1H, m), 3.70 (3H, S).
[참조실시예 2]Reference Example 2
2α-(6-페닐셀레노-6-메톡시카보닐헥실)-3β-하이드록시메틸-4α-(2-테트라하이드로피란일옥시) 사이클로펜틴-1α-올2α- (6-phenylseleno-6-methoxycarbonylhexyl) -3β-hydroxymethyl-4α- (2-tetrahydropyranyloxy) cyclopentin-1α-ol
질소 대기하에서, 350ml의 테트라하이드로푸란중 19.4ml의 디이소프로필아민을 함유하는 용액을 -78℃로 냉각시키고 여기에 n-헥산중 n-부틸리튬 1.2M 용액 114ml을 적가하고 혼합물을 -78℃에서 20분간 교반하여 리튬디이소 프로필 아미드를 수득한다.Under a nitrogen atmosphere, a solution containing 19.4 ml of diisopropylamine in 350 ml of tetrahydrofuran was cooled to −78 ° C., and 114 ml of a 1.2 M solution of n-butyllithium in n-hexane were added dropwise and the mixture was −78 ° C. Stir for 20 minutes to give lithium diisopropyl amide.
리튬디이소프로필아미드 용액에 100ml의 테트라하이드로푸란중 13.8g의 2α-(6-메톡시카보닐헥실)-3β-하이드록시메틸-4α-(2-테트라하이드로피란일옥시) 사이클로펜탄-1α-올[참조 실시예 1에서 기술한 방법으로 제조]이 함유된 용액을 -78℃에서 적가하고 혼합물을 같은 온도에서 30분간 교반시킨다.13.8 g of 2α- (6-methoxycarbonylhexyl) -3β-hydroxymethyl-4α- (2-tetrahydropyranyloxy) cyclopentane-1α- in 100 ml of tetrahydrofuran in a lithium diisopropylamide solution The solution containing all (produced by the method described in Reference Example 1) is added dropwise at -78 ° C and the mixture is stirred at the same temperature for 30 minutes.
50ml의 테트라하이드로푸란중 18.2g의 디페닐 디셀레나이드가 함유된 용액을 반응혼합물에 -78℃에서 적가하고 용액을 같은 온도에서 1시간 교반 후 0℃에서 20분간 교반한다. 반응혼합물을 암모니움 클로라이드의 수성용액에 붓고 에틸아세테이트로 추출한다. 추출물은 물 및 염화나트륨의 수성용액으로 세척하고 황산마그네슘으로 건조시켜 감압하에서 농축시킨다. 잔류물은 벤젠과 에틸아세테이트(3 : 2)의 용출액으로 실리카겔상 컬럼 크로마토그라피로 정제하여 15.8g의 표제화합물을 수득하며 화합물은 다음과 같은 물리적 성질을 가지고 있다 :A solution containing 18.2 g of diphenyl diselenide in 50 ml of tetrahydrofuran was added dropwise to the reaction mixture at -78 ° C, and the solution was stirred at the same temperature for 1 hour and then stirred at 0 ° C for 20 minutes. The reaction mixture is poured into an aqueous solution of ammonium chloride and extracted with ethyl acetate. The extract is washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with an eluent of benzene and ethyl acetate (3: 2) to afford 15.8 g of the title compound. The compound had the following physical properties:
TLC(전개용매, 벤젠-에틸 아세테이트=1 : 1) : Rf=0.37;TLC (developing solvent, benzene-ethyl acetate = 1: 1): Rf = 0.37;
IR(액체필름) :
NMR(CDCl3용액) : δ=7.75-7.10(5H,m), 5.00-4.55(1H,m), 3.70(3H, S).NMR (CDCl 3 solution): δ = 7.75-7.10 (5H, m), 5.00-4.55 (1H, m), 3.70 (3H, S).
[참조실시예 3]Reference Example 3
2α-(6-메톡시카보닐헥실-트란스-5-엔일)-3β-하이드록시 메틸-4α-(2-테트라하이드로피란일옥시) 사이클로펜탄-1α-올2α- (6-methoxycarbonylhexyl-trans-5-enyl) -3β-hydroxy methyl-4α- (2-tetrahydropyranyloxy) cyclopentan-1α-ol
15.8g의2α-(6-페닐셀레노-6-메톡시카보닐-헥실)-3β-하이드록시메틸-4α-(2-테트라하이드로피란일옥시) 사이클로펜탄-1α-올[참조실시예 2에 기술한 방법으로 제조]이 함유된 에틸아세테이트 200ml와 테트라하이드로푸란 100ml의 혼합용액에 4.5g의 나트륨 카보네이트와 6.2ml의 30% 과산화수소를 가하고 30℃에서 30분간 교반시킨다. 반응혼합물을 물에 붓고 나트륨 카보네이트의 수성용액, 물 및 염화나트륨의 수용액으로 세척하고 황산마그네슘으로 건조시키고 감압하에서 농축시켜 10.4g의 표제화합물을 수득한다. 화합물은 다음과 같은 물리적 성질을 가지고 있다.15.8 g of 2α- (6-phenylseleno-6-methoxycarbonyl-hexyl) -3β-hydroxymethyl-4α- (2-tetrahydropyranyloxy) cyclopentane-1α-ol [Reference Example 2 4.5 g of sodium carbonate and 6.2 ml of 30% hydrogen peroxide are added to a mixed solution of 200 ml of ethyl acetate containing 100 ml of tetrahydrofuran and containing 30 ml of hydrogen peroxide. The reaction mixture is poured into water, washed with an aqueous solution of sodium carbonate, water and an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to afford 10.4 g of the title compound. The compound has the following physical properties.
TLC(전개용매, 벤젠-에틸 아세테이트=1 : 1) : Rf=0.28;TLC (developing solvent, benzene-ethyl acetate = 1: 1): Rf = 0.28;
IR(액체필름) :
NMR(CDCl3용액) : δ=6.90(1H,dt), 5.82(1H,d), 5.00-4.55(1H,m), 3.70(3H, S)NMR (CDCl 3 solution): δ = 6.90 (1H, dt), 5.82 (1H, d), 5.00-4.55 (1H, m), 3.70 (3H, S)
[참조실시예 4]Reference Example 4
1α-아세톡시-2α-(6-메톡시카보닐헥스-트란스-5-엔일)-3β-하이드록시 메틸-4α-(2-테트라하이드로피란일옥시) 사이클로펜탄1α-acetoxy-2α- (6-methoxycarbonylhex-trans-5-enyl) -3β-hydroxy methyl-4α- (2-tetrahydropyranyloxy) cyclopentane
질소 대기하에서, 20ml의 메틸렌클로라이드중 4.3ml의 트리메틸클로로실란이 함유된 용액을 150ml의 메틸렌클로라이드와 18.8ml의 피리딘의 혼합물중 10.4g의 2α-(6-메톡시카보닐헥스-트란스-5-엔일)-3β-하이드록시메틸-4α-(2-테트라하이드로피란일옥시) 사이클로펜탄-1α-올[참조실시예 3에 기술한 방법으로 제조]이 함유된 용액에 -20℃에서 적가하고 같은 온도에서 20분간 교반한다. 이렇게 수득된 용액에 -20℃에서 50ml의 메틸렌클로라이드중 2.45ml의 아세틸 클로라이드가 함유된 용액을 적가하고 혼합물을 실온에서 30분간 교반시킨다. 그후 과량의 아세틸 클로라이드를 분해시키기 위하여 반응혼합물에 3ml의 에탄올을 가한다. 용액중 피리딘을 80g의 나트륨 비셀페이트로 침전시키고 결과 침전물을 여과 제거한다. 여액은 감압하 농축시킨다. 잔류물은 300ml의 에틸 아세테이트에 용해시키고 100ml의 옥살산 포화수용액을 가하고 혼합물을 실온에서 30분간 맹렬히 교반시킨다. 반응혼합물은 에틸아세테이트로 추출하고 추출물은 물과 나트륨비설페이트의 수성용액, 물과 염화나트륨의 수성용액으로 세척하고 황산마그네슘으로 건조시켜 감압하 농축시킨다. 잔류물은 벤젤과 에틸 아세테이트(3 : 1) 혼합용출액을 사용하여 실리카겔상 컬럼 크로마토그라피로 정제하여 7.2g의 표제화합물을 수득한다. 화합물은 다음과 같은 물리적 성질을 가지고 있다.Under nitrogen atmosphere, a solution containing 4.3 ml of trimethylchlorosilane in 20 ml of methylene chloride was added to 10.4 g of 2α- (6-methoxycarbonylhex-trans-5- in a mixture of 150 ml of methylene chloride and 18.8 ml of pyridine. Enyl) -3β-hydroxymethyl-4α- (2-tetrahydropyranyloxy) cyclopentane-1α-ol (prepared by the method described in Reference Example 3) was added dropwise at -20 ° C Stir at temperature for 20 minutes. To this solution was added dropwise a solution containing 2.45 ml of acetyl chloride in 50 ml of methylene chloride at −20 ° C. and the mixture was stirred at room temperature for 30 minutes. 3 ml of ethanol is then added to the reaction mixture to decompose excess acetyl chloride. Pyridine in solution is precipitated with 80 g of sodium bisulfate and the resulting precipitate is filtered off. The filtrate is concentrated under reduced pressure. The residue is dissolved in 300 ml of ethyl acetate, 100 ml of saturated aqueous oxalic acid solution is added and the mixture is stirred vigorously for 30 minutes at room temperature. The reaction mixture is extracted with ethyl acetate, and the extract is washed with an aqueous solution of water and sodium bisulfate, an aqueous solution of water and sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solution of benzel and ethyl acetate (3: 1) to afford 7.2 g of the title compound. The compound has the following physical properties.
TLC(전개용매, 벤젠-에틸 아세테이트=1 : 1) : Rf=0.51;TLC (developing solvent, benzene-ethyl acetate = 1: 1): Rf = 0.51;
IR(액체필름) :
NMR(CDCl3용액) : δ=6.90(1H,dt), 5.82(1H,d), 5.25-4.90(1H,m), 4.85-4.45(1H,m), 3.71(3H, S), 2.05(3H,S)NMR (CDCl 3 solution): δ = 6.90 (1H, dt), 5.82 (1H, d), 5.25-4.90 (1H, m), 4.85-4.45 (1H, m), 3.71 (3H, S), 2.05 ( 3H, S)
[참조실시예 5]Reference Example 5
1α-아세톡시-2α-(6-메톡시카보닐헥스-트란스-5-엔일)-3β-포름일-4α-(2-테트라하이드로피란일옥시) 사이클로펜탄1α-acetoxy-2α- (6-methoxycarbonylhex-trans-5-enyl) -3β-formyl-4α- (2-tetrahydropyranyloxy) cyclopentane
질소 대기하에서 34ml의 피리딘을 440ml의 메틸렌클로라이드에 용해시키고 20.2g의 크로뮴 트리옥사이드를 교반하면서 가한 후 실온에서 15분간 교반시킨다. 반응혼합물에 88g의 규조토를 가하고 용액을 0℃로 냉각시키고 여기에 0℃에서 100ml의 메틸렌 클로라이드중 7.2g의 1α-아세톡시-2α-(6-메톡시-카보닐헥스-트란스-5-엔일)-3β-하이드록시메틸-4α-(2-테트라하이드로피란일옥시) 사이클로펜탄[참조실시예 4에 기술한 방법으로 제조]이 함유된 용액을 가한다. 0℃에서 교반 10분후, 155g의 나트륨 비설페이트를 반응혼합물에 가하고 10분 더 교반시킨다. 결과 침전물은 마그네슘 설페이트층을 통과시켜 여과시키고 여액은 감압하 농축시킨다. 잔류물은 벤젠과 에틸 아세테이트(5 : 1) 혼합 용출액을 사용하여 실리카겔상 컬럼크로마토그라피로 정제하여 5.85g의 표제화합물을 수득한다. 화합물은 다음과 같은 물리적 성질을 가지고 있다.In a nitrogen atmosphere, 34 ml of pyridine is dissolved in 440 ml of methylene chloride, 20.2 g of chromium trioxide is added with stirring, followed by stirring at room temperature for 15 minutes. 88 g of diatomaceous earth was added to the reaction mixture and the solution was cooled to 0 ° C., and 7.2 g of 1α-acetoxy-2α- (6-methoxy-carbonylhex-trans-5-enyl in 100 ml of methylene chloride at 0 ° C. A solution containing) -3β-hydroxymethyl-4α- (2-tetrahydropyranyloxy) cyclopentane (prepared by the method described in Reference Example 4) is added. After 10 minutes of stirring at 0 ° C., 155 g of sodium bisulfate is added to the reaction mixture and stirred for another 10 minutes. The resulting precipitate is filtered through a magnesium sulphate layer and the filtrate is concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed eluent of benzene and ethyl acetate (5: 1) to afford 5.85 g of the title compound. The compound has the following physical properties.
TLC(전개용매, 벤젠-에틸 아세테이트=2 : 1) : Rf=0.67TLC (developing solvent, benzene-ethyl acetate = 2: 1): Rf = 0.67
IR(액체필름) :
NMR(CDCl3용액) : δ=10.00-9.70(1H,m), 6.90(1H,dt), 5.82(1H,d), 5.30-4.96(1H,m), 4.75-4.10(2H,m), 3.72(3H, S), 2.06(3H,S)NMR (CDCl 3 solution): δ = 10.00-9.70 (1H, m), 6.90 (1H, dt), 5.82 (1H, d), 5.30-4.96 (1H, m), 4.75-4.10 (2H, m), 3.72 (3H, S), 2.06 (3H, S)
[참조실시예 6]Reference Example 6
메틸 9α-아세톡시-11α-(2-테트라하이드로피란일옥시)-15-옥소-16,16-디메틸프로스타-트란스-2, 트란스-13-디에노에이트Methyl 9α-acetoxy-11α- (2-tetrahydropyranyloxy) -15-oxo-16,16-dimethylprostar-trans-2, trans-13-dienoate
질소 대기하에서, 6ml의 테트라하이드로푸란중 1.62g의 디메틸 2-옥소-3,3-디메틸헵틸포스포네이트[영국 특허 제1398291호에 기술한 방법으로 제조]가 함유된 용액을 50ml의 테트라하이드로푸란중 230mg의 나트륨하이드라이드(함량 63%) 현탁액에 가하고 이 혼합물을 실온에서 30분간 교반시킨다. 수득된 용액에 실온에서 10ml의 테트라하이드로푸란중 1.98g의 1α-아세톡시-2α-(6-메톡시카보닐헥스-트란스-5-엔일)-3β-포름일-4α-(2-테트라하이드로피란일옥시) 사이클로펜탄[참조실시예 5에 기술한 방법으로 제조]이 함유된 용액을 가하고 이 용액을 같은 온도에서 1시간 동안 교반시킨다. 반응 혼합물은 아세트산으로 침전시키고 실리카겔층을 통과시켜 여과하고 여액은 감압하 농축시킨다. 잔류물은 벤젠과 에틸 아세테이트(8 : 1) 혼합용출액을 사용하여 실리카겔상 컬럼 크로마토그라피로 정제하여 2.36g의 표제화합물을 수득하여 화합물은 다음과 같은 물리적 성질을 가지고 있다.Under a nitrogen atmosphere, a solution containing 1.62 g of dimethyl 2-oxo-3,3-dimethylheptylphosphonate (prepared by the method described in 1398291) in 6 ml of tetrahydrofuran was added to 50 ml of tetrahydrofuran. To 230 mg sodium hydride (content 63%) suspension is added and the mixture is stirred at room temperature for 30 minutes. To the resulting solution was obtained 1.98 g of 1α-acetoxy-2α- (6-methoxycarbonylhex-trans-5-enyl) -3β-formyl-4α- (2-tetrahydro in 10 ml of tetrahydrofuran at room temperature. A solution containing pyranyloxy) cyclopentane (prepared by the method described in Reference Example 5) is added and the solution is stirred at the same temperature for 1 hour. The reaction mixture is precipitated with acetic acid and filtered through a silica gel layer and the filtrate is concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of benzene and ethyl acetate (8: 1) to obtain 2.36 g of the title compound. The compound had the following physical properties.
TLC(전개용매, 벤젠-에틸 아세테이트=2 : 1) : Rf:0.71TLC (developing solvent, benzene-ethyl acetate = 2: 1): Rf: 0.71
IR(액체필름) :
NMR(CDCl3용액) : δ=7.20-6.50(2H,m), 6.16(1H,d), 5.80(1H,d), 5.30-4.90(1H,m), 4.80-4.50(1H,m), 3.72(3H, S), 2.06(3H,S), 1.10-0.70(9H,m).NMR (CDCl 3 solution): δ = 7.20-6.50 (2H, m), 6.16 (1H, d), 5.80 (1H, d), 5.30-4.90 (1H, m), 4.80-4.50 (1H, m), 3.72 (3H, S), 2.06 (3H, S), 1.10-0.70 (9H, m).
[참조실시예 7]Reference Example 7
메틸 9α-아세톡시-11α-(2-테트라하이드로피란일옥시)-15α-하이드록시-16,16-디메틸-프로스타-트란스-2, 트란스-13-디에노에이트Methyl 9α-acetoxy-11α- (2-tetrahydropyranyloxy) -15α-hydroxy-16,16-dimethyl-prostar-trans-2, trans-13-dienoate
40ml의 메탄올중 2.36g의 메틸 9α-아세톡시-11α-(2-테트라하이드로피란일옥시)-15-옥소-16,16-디메틸-프로스타-트란스-2, 트란스-13-디에노에이트[참조실시예 6에 기술한 방법으로 제조]가 함유된 용액에 -40℃에서 700mg의 나트륨브로하이드라이드를 가하고 용액을 이 온도에서 20분간 교반시킨다. 반응혼합물을 아세트산으로 침적시켜 감압하에서 농축시킨다. 잔류물은 에틸 아세테이트에 용해시키고 용액은 나트륨 비카보네이트의 수성용액과 염화나트륨 수성용액으로 세척하고 황산 마그네슘으로 건조시켜서 감압하 농축시킨다. 잔류물은 벤젠과 에틸 아세테이트(4 : 1) 혼합 용출액을 사용하여 실리카겔상컬럼크로마토그라피로 정제하여 790mg의 표제화합물, 810mg의 15β-하이드록시 이성체 및 이들 혼합물 480mg을 수득한다.2.36 g of methyl 9α-acetoxy-11α- (2-tetrahydropyranyloxy) -15-oxo-16,16-dimethyl-prosta-trans-2, trans-13-dienoate in 40 ml methanol [ 700 mg of sodium brohydride was added to a solution containing [prepared by reference to Example 6] at -40 ° C, and the solution was stirred at this temperature for 20 minutes. The reaction mixture is deposited with acetic acid and concentrated under reduced pressure. The residue is dissolved in ethyl acetate and the solution is washed with an aqueous solution of sodium bicarbonate and an aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed eluent of benzene and ethyl acetate (4: 1) to afford 790 mg of the title compound, 810 mg of 15β-hydroxy isomer and 480 mg of these mixtures.
표제화합물은 다음과 같은 물리적 성질을 나타낸다.The title compound exhibits the following physical properties:
TLC(전개용매, 벤젠-에틸 아세테이트=2 : 1) : Rf:0.38(15β-하이드록시 이성체, Rf=0.47);TLC (developing solvent, benzene-ethyl acetate = 2: 1): Rf: 0.38 (15β-hydroxy isomer, Rf = 0.47);
IR(액체필름) :
NMR(CDCl3용액) : δ=7.20-6.70(1H,m), 6.10-4.90(4H,m), 4.80-4.50(1H,m), 3.72(3H, S), 2.06(3H,S), 1.10-0.70(9H,m).NMR (CDCl 3 solution): δ = 7.20-6.70 (1H, m), 6.10-4.90 (4H, m), 4.80-4.50 (1H, m), 3.72 (3H, S), 2.06 (3H, S), 1.10-0.70 (9H, m).
[참조실시예 8]Reference Example 8
메틸 9α-아세톡시-11α, 15α-비스(2-테트라하이드로 피란일옥시)-16,16-디메틸프로스타-트란스-2, 트란스-13-디에노에이트Methyl 9α-acetoxy-11α, 15α-bis (2-tetrahydro pyranyloxy) -16,16-dimethylprostar-trans-2, trans-13-dienoate
15ml의 메틸렌클로라이드중 790mg의 메틸 9α-아세톡시-11α-(2-테트라하이드로피란일옥시)-15α-하이드록시-16,16-디메틸프로스타-트란스-2, 트란스-13-디에노에이트[참조실시예 7에 기술한 방법으로 제조]가 함유된 용액에 5mg의 P-톨루엔설폰산과 0.3ml의 2,3-디하이드로 피란을 가하고 혼합물을 실온에서 20분간 교반한다. 반응혼합물을 50ml의 에틸아세테이트로 희석해서, 염화나트륨 수성용액으로 세척하여 황산마그네슘으로 건조하고 감압하에서 농축하여 930mg의 조(粗)표제화합물을 수득하며 화합물은 다음과 같은 물리적 성질을 가지고 있다.790 mg of methyl 9α-acetoxy-11α- (2-tetrahydropyranyloxy) -15α-hydroxy-16,16-dimethylprosta-trans-2, trans-13-dienoate in 15 ml of methylene chloride [ 5 mg of P-toluenesulfonic acid and 0.3 ml of 2,3-dihydropyran are added to the solution containing [prepared by the method described in Reference Example 7], and the mixture is stirred at room temperature for 20 minutes. The reaction mixture was diluted with 50 ml of ethyl acetate, washed with aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure to yield 930 mg of the crude title compound. The compound had the following physical properties.
TLC(전개용매, 벤젠-에틸 아세테이트=2 : 1) : Rf : 0.67;TLC (developing solvent, benzene-ethyl acetate = 2: 1): Rf: 0.67;
IR(액체필름) :
NMR(CDCl3용액) : δ=7.20-6.70(1H,m), 6.10-4.90(4H,m), 4.80-4.50(2H,m), 3.72(3H, S), 2.06(3H,S), 1.10-0.70(9H,m).NMR (CDCl 3 solution): δ = 7.20-6.70 (1H, m), 6.10-4.90 (4H, m), 4.80-4.50 (2H, m), 3.72 (3H, S), 2.06 (3H, S), 1.10-0.70 (9H, m).
[실시예 1]Example 1
메틸 9α-하이드록시-11α, 15α-비스(2-테트라하이드로피란일옥시)-16,16-디메틸프로스타-트란스-2, 트란스-13-디에노에이트Methyl 9α-hydroxy-11α, 15α-bis (2-tetrahydropyranyloxy) -16,16-dimethylprostar-trans-2, trans-13-dienoate
12ml의 메탄올중 930mg의 메틸 9α-아세톡시-11α, 15α-비스-(2-테트라하이드로피란일옥시)-16,16-디메틸프로스타-트란스-2, 트란스-13-디에노에이트[참조실시예 8에 기술한 방법으로 제조]가 함유된 용액에 400mg의 포타슘 카보네이트를 가하고 혼합물을 40℃에서 1.5시간 교반한다. 반응 혼합물은 아세트산으로 침전시키고 에틸아세테이트로 추출한다. 추출물은 나트륨 비카보네이트의 수성용액, 물과 염화나트륨의 수성용액으로 세척하고 황산마그네슘으로 건조하여 감압하 농축시킨다. 잔류물은 벤젠과 에틸아세테이트(6 : 1) 혼합용출액을 사용하여 실리카겔상 컬럼 크로마토그라피로 정제하여 745mg의 표제화합물을 수득한다. 화합물은 다음과 같은 물리적 성질을 가지고 있다.930 mg of methyl 9α-acetoxy-11α, 15α-bis- (2-tetrahydropyranyloxy) -16,16-dimethylprostar-trans-2, trans-13-dienoate in 12 ml methanol [Reference Examples 400 mg of potassium carbonate was added to the solution containing [prepared by the method described in Example 8] and the mixture was stirred at 40 DEG C for 1.5 hours. The reaction mixture is precipitated with acetic acid and extracted with ethyl acetate. The extract is washed with an aqueous solution of sodium bicarbonate, an aqueous solution of water and sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed eluent of benzene and ethyl acetate (6: 1) to afford 745 mg of the title compound. The compound has the following physical properties.
TLC(전개용매, 벤젠-에틸아세테이트=2 : 1) : Rf : 0.47;TLC (developing solvent, benzene-ethyl acetate = 2: 1): Rf: 0.47;
IR(액체필름) :
NMR(CDCl3용액) : δ=7.20-6.70(1H,m), 6.10-5.30(3H,m), 4.80-4.50(2H,m), 3.72(3H, S), 1.10-0.70(9H,m).NMR (CDCl 3 solution): δ = 7.20-6.70 (1H, m), 6.10-5.30 (3H, m), 4.80-4.50 (2H, m), 3.72 (3H, S), 1.10-0.70 (9H, m ).
[실시예 2]Example 2
메틸 9-옥소 -11α, 15α-디하이드록시-16,16-디메틸프로스타-트란스-2, 트란스-13-디에노에이트[또는 16,16-디메틸-트란스-Δ2-PGE1메틸에스테르]Methyl 9-oxo-11α, 15α-dihydroxy-16,16-dimethylprostar-trans-2, trans-13-dienoate [or 16,16-dimethyl-trans-Δ 2 -PGE 1 methylester]
22ml의 디에틸에테르중 745mg의 메틸 9α-하이드록시-11α, 15α-비스(2-테트라하이드로 피란일옥시)-16,16-디메틸프로스타-트란스-2, 트란스-13-디에노에이트[실시예 1에 기술한 방법으로 제조]가 함유된 용액에 크롬산용액[크로뮴트리옥사이드 0.94g, 망간설페이트 4.55g과 물 22ml중 황산 1.06ml로부터 수득된다]을 가하고 혼합물을 0℃에서 1시간 교반한다. 반응혼합물은 디에틸에테르로 추출하여 추출물은 염화나트륨의 수성용액으로 세척, 황산마그네슘으로 건조하고 감압에서 농축하여 732mg의 메틸 9-옥소-11α, 15α-비스-(2-테트라하이드로 피란일옥시)-16,16-디메틸프로스타-트란스-2, 트란스-13-디에노에이트를 수득한다. 화합물은 다음과 같은 물리적 성질을 가지고 있다 :745 mg of methyl 9α-hydroxy-11α, 15α-bis (2-tetrahydro pyranyloxy) -16,16-dimethylprostar-trans-2, trans-13-dienoate in 22 ml diethyl ether To a solution containing [manufactured by Example 1] is added chromic acid solution (0.94 g of chromium trioxide, 4.55 g of manganese sulfate and 1.06 ml of sulfuric acid in 22 ml of water), and the mixture is stirred at 0 DEG C for 1 hour. The reaction mixture was extracted with diethyl ether, and the extract was washed with an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to give 732 mg of methyl 9-oxo-11α, 15α-bis- (2-tetrahydropyranyloxy)- 16,16-Dimethylprostar-trans-2, trans-13-dienoate is obtained. The compound has the following physical properties:
TLC(전개용매, 벤젠-에틸 아세테이트=2 : 1) : Rf=0.74TLC (developing solvent, benzene-ethyl acetate = 2: 1): Rf = 0.74
1.9ml의 테트라하이드로푸란중 732mg의 9-옥소-화합물[상기에서 기술한 방법으로 제조]이 함유된 용액에 19ml의 65%(V/V) 아세트산 수성용액을 가하고 용액을 55°내지 60℃에서 1시간 교반한다. 반응혼합물은 에틸 아세테이트로 추출하고 추출물은 물과 염화나트륨의 수성용액으로 세척하여 황산마그네슘으로 건조시키고 감압하에서 농축하여 119mg의 표제화합물을 수득한다. 화합물은 다음과 같은 물리적 성질을 가지고 있다.To a solution containing 732 mg of 9-oxo-compound [prepared by the method described above] in 1.9 ml of tetrahydrofuran was added 19 ml of 65% (V / V) acetic acid aqueous solution and the solution was stirred at 55 ° to 60 ° C. Stir for 1 hour. The reaction mixture is extracted with ethyl acetate and the extract is washed with water and an aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to yield 119 mg of the title compound. The compound has the following physical properties.
TLC(전기용매, 클로로포름-테트라하이드로푸란-아세트산=10 : 2 : 1) : Rf = 0.51;TLC (electrosolvent, chloroform-tetrahydrofuran-acetic acid = 10: 2: 1): Rf = 0.51;
IR(액체필름) :
NMR(CDCl3용액) : δ=7.10-6.75(1H,m), 5.95-5.40(3H,m), 3.71(3H,S), 4.20-3.60(2H,m), 2.75(1H,dd), 1.00-0.75(9H,m)NMR (CDCl 3 solution): δ = 7.10-6.75 (1H, m), 5.95-5.40 (3H, m), 3.71 (3H, S), 4.20-3.60 (2H, m), 2.75 (1H, dd), 1.00-0.75 (9H, m)
[참조실시예 9]Reference Example 9
메틸9α-아세톡시-11α-(2-테트라하이드로피란일옥시)-15-옥소-17ξ-에틸-ω-디호모-프로스타-트란스-2, 트란스-13-디에노에이트Methyl 9α-acetoxy-11α- (2-tetrahydropyranyloxy) -15-oxo-17ξ-ethyl-ω-dihomo-prostar-trans-2, trans-13-dienoate
참조실시예 6에 기술한 공정에 따르나 디메틸 2-옥소-3,3-디메틸 헵틸포스포네이트 대신에 6ml의 테트라하이드로푸란에 용해시킨 1.62g의 디메틸 2-옥소-4ξ-에틸노닐-포스포네이트(이후에 기술된 방법에 의합 제조됨) 및 50ml의 테트라 하이드로푸란에 현탁시킨 230mg의 나트륨 하이드라이드 현탁액(63%)과 10ml의 테트라하이드로푸란에 용해시킨 1.98g의 1α-아세톡시-2α-(6-메톡시카보닐헥스-트란스-5-에틸)-3β-포밀-4α-(2-테트라하이드로피란일옥시)사이클로펜탄[참조실시예 5에 기술된 방법에 의해 제조됨]용액을 사용하여 다음과 같은 물리적 성질을 가진 표제 화합물 2.3g을 수득한다.1.62 g of dimethyl 2-oxo-4ξ-ethylnonyl-phosphonate according to the process described in Reference Example 6 but dissolved in 6 ml of tetrahydrofuran instead of dimethyl 2-oxo-3,3-dimethyl heptylphosphonate (Prepared according to the method described below) and 1.98 g of 1α-acetoxy-2α- (dissolved in 230 ml of sodium hydride suspension (63%) suspended in 50 ml of tetrahydrofuran and 10 ml of tetrahydrofuran. 6-methoxycarbonylhex-trans-5-ethyl) -3β-formyl-4α- (2-tetrahydropyranyloxy) cyclopentane (prepared by the method described in Example 5) using a solution 2.3 g of the title compound having the following physical properties are obtained.
TLC(전개용매, 벤젠-에틸아세테이트=2 : 1) : Rf : 0.70TLC (developing solvent, benzene-ethyl acetate = 2: 1): Rf: 0.70
IR(액체필름) :
NMR(CDCl3용액) : δ=7.20-6.50(2H,m), 6.16(1H,d), 5.80(1H,d), 5.35-4.90(1H,m), 4.85-4.50(1H,m), 3.72(3H,S), 2.06(3H,S), 1.10-0.70(6H,m)NMR (CDCl 3 solution): δ = 7.20-6.50 (2H, m), 6.16 (1H, d), 5.80 (1H, d), 5.35-4.90 (1H, m), 4.85-4.50 (1H, m), 3.72 (3H, S), 2.06 (3H, S), 1.10-0.70 (6H, m)
상기 진행에서 출발물질로 사용한 디메틸 2-옥소-4-에틸노닐포스포네이트는 다음과 같이 제조된다.Dimethyl 2-oxo-4-ethylnonylphosphonate used as starting material in the above process is prepared as follows.
65g의 디메틸 메틸포스포네이트를 465ml의 테트라하이드로 푸란에 용해하고 용액을 질소대기중 -70℃로 냉각시킨다. 400ml의 디에틸에테르중 85.3g의 부틸 브로마이드와 10.7g의 리튬으로 부터 생성된 부틸리튬 용액을 -50℃ 이하에서 약 15분동안 다른 제조용액 속으로 적가한다. 10분 교반후 140ml의 테트라 하이드로푸란중 44g의 에틸 3(ξ)-에틸-옥타노에이트를 -50℃이하에서 적가하고 혼합물을 같은 온도에서 2시간 교반한 후 실온에서 2시간동안 더 교반하고 92g의 아세트산을 가한다.65 g of dimethyl methylphosphonate are dissolved in 465 ml of tetrahydrofuran and the solution is cooled to -70 ° C in nitrogen atmosphere. A solution of butyllithium produced from 85.3 g of butyl bromide and 10.7 g of lithium in 400 ml of diethyl ether is added dropwise into another preparation solution at -50 ° C. for about 15 minutes. After stirring for 10 minutes, 44 g of ethyl 3 (ξ) -ethyl-octanoate in 140 ml of tetrahydrofuran was added dropwise at -50 ° C or lower, and the mixture was stirred at the same temperature for 2 hours, followed by further stirring at room temperature for 2 hours, 92 g Acetic acid is added.
반응혼합물을 감압하에서 농축하고 잔류물을 물에 용해시켜서 디에틸에테르로 추출하고 에테르추출물을 물로 세척하여 황산마그네슘으로 건조시키고 감압하 농축시킨다.The reaction mixture is concentrated under reduced pressure, the residue is dissolved in water, extracted with diethyl ether, the ether extract is washed with water, dried over magnesium sulfate and concentrated under reduced pressure.
전류물을 감압하 증류하여 55g의 디메틸 2-옥소-4(ξ)-에틸-노닐 포스포네이트(비점 113°내지 121℃/0.2mmHg)을 무색 오일로 수득한다.The current was distilled off under reduced pressure to afford 55 g of dimethyl 2-oxo-4 (ξ) -ethyl-nonyl phosphonate (boiling point 113 ° to 121 ° C./0.2 mmHg) as a colorless oil.
IR(액체필름) : 2950, 2860, 1710, 1455, 1270, 1190, 1040 및 820cm-1.IR (Liquid Film): 2950, 2860, 1710, 1455, 1270, 1190, 1040 and 820 cm -1 .
[참조실시예 10]Reference Example 10
메틸 9α-아세톡시-11α-(2-테트라하이드로피란일옥시)-15α-하이드록시-17ξ-에틸-ω-디호모-프로스타-트란스-2, 트란스-13-디에노에이트Methyl 9α-acetoxy-11α- (2-tetrahydropyranyloxy) -15α-hydroxy-17ξ-ethyl-ω-dihomo-prostar-trans-2, trans-13-dienoate
참조 실시예 7에 기술한 공정에 따르나 메틸 9α-아세톡시-11α-(2-테트라하이드로피란일옥시)-15-옥소-16,16-디메틸 프로스타-트란스-2, 트란스-13-디에노에이트 대신에 40ml의 메탄올에 용해시킨 2.3g의 메틸 9α-아세톡시-11α-(2-테트라하이드로피란일옥시)-15-옥소-17ξ-에틸-ω-디호모프로스타-트란스-2, 트란스-13-디에노에이트[참조실시예 9에 기술한 방법으로 제조] 및 700mg의 나트륨 보로하이드라이드를 사용하여 720mg의 표제화합물, 740mg의 표제화합물의 15β-하이드록시 이성체와 이들 혼합물 500mg을 수득한다. 표제화합물은 다음과 같은 물리적 성질을 나타낸다.Methyl 9α-acetoxy-11α- (2-tetrahydropyranyloxy) -15-oxo-16,16-dimethyl prostar-trans-2, trans-13-dieno, according to the process described in Reference Example 7 2.3 g of methyl 9α-acetoxy-11α- (2-tetrahydropyranyloxy) -15-oxo-17ξ-ethyl-ω-dihomoprostar-trans-2, trans, dissolved in 40 ml of methanol instead of ate 720 mg of the title compound, 740 mg of the 15β-hydroxy isomer of the title compound, and 500 mg of these mixtures are obtained using -13-dienoate (manufactured by the method described in Reference Example 9) and 700 mg of sodium borohydride. . The title compound exhibits the following physical properties:
TLC(전개용매, 벤젠-에틸 아세테이트=2 : 1) : Rf : 0.40(15β-하이드록시 이성체 Rf=0.47)TLC (developing solvent, benzene-ethyl acetate = 2: 1): Rf: 0.40 (15β-hydroxy isomer Rf = 0.47)
IR(액체필름) :
NMR(CDCl3용액) : δ=7.20-6.70(1H,m), 6.10-4.90(4H,m), 4.80-4.50(1H,m), 3.72(3H, S), 2.06(3H, S), 1.10-0.70(9H,m)NMR (CDCl 3 solution): δ = 7.20-6.70 (1H, m), 6.10-4.90 (4H, m), 4.80-4.50 (1H, m), 3.72 (3H, S), 2.06 (3H, S), 1.10-0.70 (9H, m)
[참조실시예 11]Reference Example 11
메틸9α-아세톡시-11α,15α-비스(2-테트라하이드로피란일옥시)-17ξ-에틸-ω-디호모-프로스타-트란스-2, 트란스-13-디에노에이트Methyl 9α-acetoxy-11α, 15α-bis (2-tetrahydropyranyloxy) -17ξ-ethyl-ω-dihomo-prostar-trans-2, trans-13-dienoate
참조실시예 8에 기술한 공정에 따르나 메틸 9α-아세톡시-11α-(2-테트라하이드로피란일옥시)-15α-하이드록시-16,16-디메틸프로스타-트란스-2, 트란스-13-디에노에이트 대신에 13ml의 메틸렌클로라이드에 용해시킨 720mg이 메틸9α-아세톡시-11α-(2-테트라하이드록시피란일옥시)-15α-하이드록시-17ξ-에틸-ω-디호모프로스타-트란스-2, 트란스-13-디에노에이트[참조실시예 10에 기술한 방법으로 제조] 및 5mg의 P-톨루엔 설폰산과 0.3ml의 2,3-디하이드로피란을 사용하여 다음과 같은 물리적 성질을 가지는 870mg의 표제화합물을 수득한다.Methyl 9α-acetoxy-11α- (2-tetrahydropyranyloxy) -15α-hydroxy-16,16-dimethylprosta-trans-2, trans-13-die according to the process described in Reference Example 8 720 mg dissolved in 13 ml of methylene chloride instead of noate was methyl 9α-acetoxy-11α- (2-tetrahydroxypyranyloxy) -15α-hydroxy-17ξ-ethyl-ω-dihomoprostar-trans- 2, trans-13-dienoate (manufactured by the method described in Reference Example 10) and 870 mg of 5 mg of P-toluene sulfonic acid and 0.3 ml of 2,3-dihydropyran having the following physical properties: To give the title compound.
TLC(전개용매, 벤젠-에틸 아세테이트=2 : 1) : Rf : 0.64;TLC (developing solvent, benzene-ethyl acetate = 2: 1): Rf: 0.64;
IR(액체필름) :
NMR(CDCl3용액) : δ=7.20-6.70(1H,m), 6.10-4.90(4H,m), 4.80-4.50(2H,m), 3.72(3H, S), 2.06(3H, S), 1.10-0.70(6H,m)NMR (CDCl 3 solution): δ = 7.20-6.70 (1H, m), 6.10-4.90 (4H, m), 4.80-4.50 (2H, m), 3.72 (3H, S), 2.06 (3H, S), 1.10-0.70 (6H, m)
[실시예 3]Example 3
메틸 9α-하이드록시-11α,15α-비스(2-테트라하이드로피란일옥시)-17ξ-에틸-ω-디호모-프로스타-트란스-2, 트란스-13-디에노에이트Methyl 9α-hydroxy-11α, 15α-bis (2-tetrahydropyranyloxy) -17ξ-ethyl-ω-dihomo-prostar-trans-2, trans-13-dienoate
실시예 1에 기술한 공정에 따르나 메틸 9α-아세톡시-11α,15α-비스(2-테트라하이드로피란일옥피)-16,16-디메틸프로스타-트란스-2, 트란스-13-디에노에이트 대신에 11ml의 메탄올에 용해시킨 870mg의 메틸 9α-아세톡시-11α,15α-비스(2-테트라하이드로피란일옥시)-17ξ-에틸-ω-디호모프로스타-트란스-2, 트란스-13-디에노에이트[참조실시예 11에 기술한 방법으로 제조] 및 380mg의 포타슘 카보네이트를 사용하여 다음과 같은 물리적 성질을 가지는 표제화합물 700mg을 수득한다.According to the process described in Example 1, but instead of methyl 9α-acetoxy-11α, 15α-bis (2-tetrahydropyranyloxy) -16,16-dimethylprosta-trans-2, trans-13-dienoate 870 mg of methyl 9α-acetoxy-11α, 15α-bis (2-tetrahydropyranyloxy) -17ξ-ethyl-ω-dihomoprostar-trans-2, trans-13-die Noate (manufactured by the method described in Reference Example 11) and 380 mg of potassium carbonate were obtained 700 mg of the title compound having the following physical properties.
TLC(전개용매, 벤젠-에틸아세테이트=2 : 1) : Rf : 0.46,TLC (developing solvent, benzene-ethyl acetate = 2: 1): Rf: 0.46,
IR(액체필름) :
NMR(CDCl3용액) : δ=7.20-6.70(1H,m), 6.10-5.30(3H,m), 4.80-4.50(2H,m), 3.72(3H, S), 1.10-0.70(6H,m)NMR (CDCl 3 solution): δ = 7.20-6.70 (1H, m), 6.10-5.30 (3H, m), 4.80-4.50 (2H, m), 3.72 (3H, S), 1.10-0.70 (6H, m )
[실시예 4]Example 4
메틸 9-옥시-11α,15α-디하이드록시-17ξ-에틸-ω-디호모프로스타-트란스-2, 트란스-13-디에노에이트[또는 17ξ-에틸-W-디호모-트란스-Δ2-PGE1메틸 에스테르]Methyl 9-oxy-11α, 15α-dihydroxy-17ξ-ethyl-ω-dihomoprostar-trans-2, trans-13-dienoate [or 17ξ-ethyl-W-dihomo-trans-Δ 2 -PGE 1 methyl ester]
실시예 2에 기술한 공정에 따르나 메틸 9α-하이드록시-11α,15α-비스(2-테트라하이드로피란일옥시)-16,16-디메틸프로스타-트란스-2, 트란스-13-디에노에이트 대신에 21ml의 700mlg의 메틸 9α-하이드록시-11α,15α-비스(2-테트라하이드로-피란일옥시)-17ξ-에틸-ω-디호모프로스타-트란스-2, 트란스-13-디에노에이트[실시예 3에 기술한 방법으로 제조] 및 21mg의 크롬산 용액을 사용하여 다음과 같은 물리적 성질을 가진 9-옥소-화합물을 수득한다.According to the process described in Example 2, but instead of methyl 9α-hydroxy-11α, 15α-bis (2-tetrahydropyranyloxy) -16,16-dimethylprostar-trans-2, trans-13-dienoate To 21 ml of 700 mlg methyl 9α-hydroxy-11α, 15α-bis (2-tetrahydro-pyranyloxy) -17ξ-ethyl-ω-dihomoprostar-trans-2, trans-13-dienoate [ Prepared by the method described in Example 3] and using a 21 mg solution of chromic acid to obtain a 9-oxo-compound having the following physical properties.
TLC(전개용매, 벤젠-에틸 아세테이트=2 : 1) : Rf=0.68; 그후 1.8ml의 테트라하이드로푸란에 용해시키고 18ml(65%(V/V))의 아세트산 수성용액을 사용하여 다음과 같은 물리적 성질을 가진 표제화합물 99mg을 수득한다.TLC (developing solvent, benzene-ethyl acetate = 2: 1): Rf = 0.68; Then, dissolving in 1.8 ml of tetrahydrofuran and using 18 ml (65% (V / V)) aqueous acetic acid solution to obtain 99 mg of the title compound having the following physical properties.
TLC(전개용매, 클로로포름 : 테트라하이드로푸란 : 아세트산=10 : 2 : 1) : Rf : 0.33TLC (developing solvent, chloroform: tetrahydrofuran: acetic acid = 10: 2: 1): Rf: 0.33
IR(액체필름) : 3470, 2920, 2840, 1735, 1720, 1650, 1450, 1430, 1270, 1165, 1080, 980cm-1;IR (liquid film): 3470, 2920, 2840, 1735, 1720, 1650, 1450, 1430, 1270, 1165, 1080, 980 cm -1 ;
NMR(CDCl3용액) : 6.93(1H,dt), 5.79(1H,d), 5.67-5.40(2H,m), 4.37-3.83(2H,m), 3.71(3H,S), 2.92-2.53(1H,dd), 1.06-0.65(6H,m)NMR (CDCl 3 solution): 6.93 (1H, dt), 5.79 (1H, d), 5.67-5.40 (2H, m), 4.37-3.83 (2H, m), 3.71 (3H, S), 2.92-2.53 ( 1H, dd), 1.06-0.65 (6H, m)
본 발명은 활성성분으로서 구조식(VI)의 적어도 하나의 프로스타글란딘 동족체 또는 이들의 메틸 에스테르, 또는 프로스타글란딘 동족체 또는 이들의 에스테르의 사이클로 덱스트린 클래트레이트 또는 프로스타 글란딘 동족체의 비독성염을 약제화적 담체 또는 제피와 함께 함유하는 약제학적 조성물도 범주내에 포함하고 있다. 임상실험에서 본 발명의 새로운 화합물은 정상적으로 경구적으로 질좌약으로, 직장으로 또는 비경구적으로 투여된다.The present invention provides a pharmaceutical carrier or coating for a non-toxic salt of cyclodextrin clathrate or prostaglandin analog of at least one prostaglandin analog or a methyl ester thereof, or a prostaglandin analog or an ester thereof as an active ingredient. Pharmaceutical compositions contained together with are included within the scope. In clinical trials, the new compounds of the invention are normally administered orally, vaginal suppositories, rectally or parenterally.
경구 투여용 고형조성물은 압축 정제, 환약, 분산할 수 있는 산제 및 과립등을 포함한다. 이러한 고형조성물에서 하나 또는 그 이상의 활성 화합물은 적어도 하나의 칼슘 카보네이트, 감자전분, 알긴산, 만니톤 또는 락토즈 같은 불활성 희석제와 혼합한다. 조성물은 실제적으로 다른 불활성 희석제 이외의 첨가물질 예를 들면 마그네슘 스테아레이트같은 활탁제를 포함할 수도 있다. 경구 투여용 액상조성물에는 약제학적으로 무독한 유화제, 액제, 현탁제, 시럽제 및 물과 액상 파라핀 같은 이 분야에서 통상 사용되는 불활성 희석제를 함유하는 엘릭실제 등이 포함된다. 불활성 희석제 이외에도 조성물은 습윤제와 현탁제, 감미제, 풍미제, 방향제 및 보존제와 같은 보조약을 포함할 수도 있다.Solid compositions for oral administration include compressed tablets, pills, dispersible powders and granules, and the like. In this solid composition one or more active compounds are mixed with at least one inert diluent such as calcium carbonate, potato starch, alginic acid, mannitol or lactose. The composition may also comprise additives other than other inert diluents, such as lubricants such as magnesium stearate. Liquid compositions for oral administration include pharmaceutically acceptable emulsifiers, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin. In addition to inert diluents, the composition may also include adjuvant agents such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances and preservatives.
경구투여를 위한 본 발명에 따른 조성물은 하나 또는 그 이상의 활성물질을 희석제나 부형제와 함께 또는 없이 함유하는 젤라틴같은 캡슐 또는 흡수성 물질을 포함한다.Compositions according to the invention for oral administration include capsules or absorbent materials such as gelatin containing one or more active substances with or without diluents or excipients.
질내투여를 위한 고형 조성물은 공지된 방법으로 펫서리로 제조되며 하나유하고 있다.Solid compositions for vaginal administration are prepared in pessary in a known manner and are one.
직장투여를 위한 고형조성물은 공지된 방법으로 죄약 형태로 제조되며 하나 또는 그 이상의 활성성분을 포함하고 있다.Solid compositions for rectal administration are prepared in the form of drugs in a known manner and contain one or more active ingredients.
비경구 투여를 위한 본 발명에 따른 제제는 무균 수성 또는 비수성액제, 현탁제 또는 유화제등이다.Formulations according to the invention for parenteral administration are sterile aqueous or non-aqueous solutions, suspensions or emulsifiers and the like.
비수성 용매의 예 또는 현탁매제는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브유 같은 식물유, 에틸올레이트 같은 주사할 수 있는 유기 에스테르이다.Examples of non-aqueous solvents or suspending agents are injectable organic esters such as propylene glycol, polyethylene glycol, vegetable oils such as olive oil, ethyl oleate.
조성물은 방부제, 습윤 유화제와 분산제와 같은 보조약을 포함할 수도 있다.The composition may comprise adjuvant such as preservatives, wetting emulsifiers and dispersants.
조성물은 박테리아-보유 여과기를 통해 여과하거나 조성물에 멸균제를 넣거나 자외선 조사에 의해서 멸균시킬 수 있다.The composition may be filtered through a bacteria-bearing filter, sterilized by the composition or sterilized by UV irradiation.
조성물은 멸균 고체 형태로 제조될 수 있으며 사용 바로 전멸균수나 기타 멸균 주사용 매체에 용해시킬 수 있다.The compositions can be prepared in sterile solid form and dissolved in pre-sterilized water or other sterile injectable medium immediately after use.
본 발명 조성물중 활성성분의 퍼센트는 다양하며 원하는 치료효과에 적합한 양으로 구성되는 것이 필요하다. 수회의 단위용량을 거의 같은 시간에 투여할 수 있다.The percentage of active ingredient in the compositions of the invention may vary and need to be comprised in an amount suitable for the desired therapeutic effect. Several unit doses may be administered at about the same time.
일반적으로 제제는 주사로 투여할 때 적어도 0.025중량%의 활성물질을 함유해야하며 경구투여시는 최소한 0.1중량%의 활성물질을 함유해야 한다. 투여양은 원하는 치료효과, 투여경로와 치료기간에 따라 결정된다.In general, the formulations should contain at least 0.025% by weight of active substance when administered by injection and at least 0.1% by weight of active substance when administered orally. Dosage depends on the desired therapeutic effect, route of administration and duration of treatment.
고혈압 치료시 성인의 투여량은 경구투여로 0.01 내지 1mg이고 여성의 피임 및 월경조절 및 임신만기와 분만유도를 위한 경구투여, 질내투여, 정맥투여 또는 양막의 투여시는 1 내지 1000μg이다.In the treatment of hypertension, the dosage of an adult is 0.01 to 1 mg by oral administration and 1 to 1000 μg by oral, vaginal administration, intravenous administration, or amniotic membrane for contraception and menstrual control and pregnancy induction and delivery.
암소, 암말, 암돼지, 암양 또는 암케와 같은 암컷 가축의 투여량은 근육내투여, 피하투여, 자궁내투여, 질내투여 또는 정맥내투여로 발정 유발, 손상된 임신률의 치료, 낙태 및 분만유도를 위해 보통 0.001 내지 50mg/동물이다.Doses of female livestock such as cows, mares, sows, ewes or amke may cause estrus by intramuscular, subcutaneous, intrauterine, vaginal or intravenous administration, treatment of impaired pregnancy rates, abortion and delivery Usually between 0.001 and 50 mg / animal.
다음 실시예는 본 발명에 따른 화합물의 약학적 조성물을 설명한다.The following examples illustrate the pharmaceutical compositions of the compounds according to the invention.
[실시예 5]Example 5
16,16-디메틸-트란스-Δ2-PGE, 메틸 에스테르(2mg)를 에탄올(10ml)에 녹이고 만니톨(18.5g)과 혼합하고 30메쉬체로 걸른다음, 30℃에서 90분간 건조하고 다시 30메쉬체로 걸른다. 에로실(마이크로핀실리키 : 200mg)을 가하고 얻어진 분말을 100개의 2호 경질 제라틴 캡슐에 기계로 충진하여 캡슐당 20㎍의 16,16-디메틸-트란스-Δ2-PGE, 메틸에스테르를 함유하게 하며 이 캡슐제는 복용후 위속으로 방출된다.Dissolve 16,16-dimethyl-trans-Δ 2 -PGE, methyl ester (2 mg) in ethanol (10 ml), mix with mannitol (18.5 g), filter through 30 mesh sieves, dry at 30 ° C. for 90 minutes, and again with 30 mesh sieves. Filter Erosyl (Micropinsiliki: 200mg) was added and the powder obtained was filled into 100 No. 2 hard gelatine capsules by machine to contain 20 µg of 16,16-dimethyl-trans-Δ 2 -PGE and methyl ester per capsule. This capsule is released into the stomach after taking.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR7602006A KR810000412B1 (en) | 1976-08-17 | 1976-08-17 | Process for the preparation of new prostaglandines |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR7602006A KR810000412B1 (en) | 1976-08-17 | 1976-08-17 | Process for the preparation of new prostaglandines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR810000412B1 true KR810000412B1 (en) | 1981-04-29 |
Family
ID=19202591
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR7602006A KR810000412B1 (en) | 1976-08-17 | 1976-08-17 | Process for the preparation of new prostaglandines |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR810000412B1 (en) |
-
1976
- 1976-08-17 KR KR7602006A patent/KR810000412B1/en active
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