KR20010024258A - 9,10-dihydro-9,10-ethanoanthracene derivatives as phospholipase inhibitors - Google Patents

9,10-dihydro-9,10-ethanoanthracene derivatives as phospholipase inhibitors Download PDF

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KR20010024258A
KR20010024258A KR1020007003134A KR20007003134A KR20010024258A KR 20010024258 A KR20010024258 A KR 20010024258A KR 1020007003134 A KR1020007003134 A KR 1020007003134A KR 20007003134 A KR20007003134 A KR 20007003134A KR 20010024258 A KR20010024258 A KR 20010024258A
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hexadeca
tetracyclo
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프리베발터-구나르
티베스율리히
쇼이어베르너
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로셰 디아그노스틱스 게엠베하
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Abstract

본 발명은 하기 일반 화학식 I 의 테트라시클로[6.6.2.02,7.09,14] 헥사데카-2(7), 3, 5, 9(14), 10, 12-헥사엔 유도체에 관한 것이다:The present invention relates to tetracyclo [6.6.2.0 2,7 9,14 ] hexadeca-2 (7), 3, 5, 9 (14), 10, 12- hexaene derivatives of the general formula (I) :

[화학식 I][Formula I]

[식중,[Meal,

R1 및 R2 는 동일하거나 상이하며 수소 또는 할로겐 원자를 나타내고,R1 and R2 are the same or different and represent a hydrogen or halogen atom,

X 는 수소를 나타내며,X represents hydrogen,

Y 는 기 -NR3R4 또는 기 -N+CH3R3R4 를 나타내거나, 또는Y represents a group -NR3R4 or a group -N + CH 3 R3R4, or

X 및 Y 는 함께 기 ＞CH2-NR5 를 형성하며,X and Y together form the group> CH 2 -NR 5,

Z 은 ＞CH2기 또는 ＞C=NH 기를 나타낸다.]Z represents a> CH 2 group or a> C = NH group.]

Description

포스포리파제 저해제로 사용되는 9,10-디히드로-9,10-에타노안트라센 유도체 {9,10-DIHYDRO-9,10-ETHANOANTHRACENE DERIVATIVES AS PHOSPHOLIPASE INHIBITORS}9,10-dihydro-9,10-ethanoanthracene derivative used as phospholipase inhibitor {9,10-DIHYDRO-9,10-ETHANOANTHRACENE DERIVATIVES AS PHOSPHOLIPASE INHIBITORS}

본 발명은 신규 테트라사이클, 그의 제조 방법 및 이들 화합물을 함유하는 약학 제제에 관한 것이다.The present invention relates to novel tetracycles, their preparation and pharmaceutical preparations containing these compounds.

본 발명은 하기 일반 화학식 I 의 테트라시클로[6.6.2.02,7.09,14] 헥사데카-2(7), 3, 5, 9(14), 10, 12-헥사엔 유도체 및 생리적으로 허용 가능한 염, 에스테르, 광학 활성 형태 및 그의 라세미체, 및 생체내에서 대사되어 하기 일반 화학식 I 의 화합물을 형성할 수 있는 유도체 및 약학 제제의 제조에 사용되는 이들 화합물의 용도에 관한 것이다:The present invention relates to tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3, 5, 9 (14), 10, 12- hexaene derivatives of the general formula Acceptable salts, esters, optically active forms and racemates thereof, and derivatives that can be metabolized in vivo to form compounds of the general formula (I) and the use of these compounds for use in the preparation of pharmaceutical formulations:

[식중,[Meal,

R1 및 R2 는 동일하거나 상이하며 수소 또는 할로겐 원자를 나타내고,R1 and R2 are the same or different and represent a hydrogen or halogen atom,

X 는 수소를 나타내며,X represents hydrogen,

Y 는 기 -NR3R4 또는 기 -N+CH3R3R4 를 나타내거나, 또는Y represents a group -NR3R4 or a group -N + CH 3 R3R4, or

X 및 Y 는 함께 기 ＞CH2-NR5 를 형성하며,X and Y together form the group> CH 2 -NR 5,

Z 은 ＞CH2기 또는 ＞C=NH 기를 나타낸다.Z represents a> CH 2 group or a> C = NH group.

(상기 식에서, R3 은 수소, 저급 알킬기를 나타내며,Wherein R3 represents hydrogen, a lower alkyl group,

R4 는 히드록실, 카르바모일, 아미디노, 헤테로아릴, N-아르알킬헤테로아릴 또는 저급 알킬기를 나타내거나, 또는R4 represents hydroxyl, carbamoyl, amidino, heteroaryl, N-aralkylheteroaryl or lower alkyl group, or

R3 및 R4 는 그들이 결합된 질소 원자와함께, 추가의 헤테로 원자에 의해 임의로 차단될 수 있으며 1 회 또는 수회 임의로 치환될 수 있는 헤테로시클릭 고리를 형성하며,R 3 and R 4 together with the nitrogen atom to which they are attached form a heterocyclic ring which may be optionally interrupted by an additional hetero atom and which may be optionally substituted one or several times,

R5 는 수소, 아미디노기 또는 하나 또는 수개의 헤테로 원자에 의해 임의로 단절된 헤테로사이클을 나타낸다)R 5 represents hydrogen, an amidino group or a heterocycle optionally interrupted by one or several hetero atoms)

단, R1 및 R2 가 동시에 수소를 나타낸다면Provided that R1 and R2 simultaneously represent hydrogen

(a) R4 는 저급 알킬기를 나타내지 않거나 또는(a) R4 does not represent a lower alkyl group or

(b) R5 는 수소를 나타내지 않거나 또는(b) R5 does not represent hydrogen or

(c) R3 및 R4 는 함께 비치환된 피페리딘 고리 또는 모르폴린 고리를 형성하지 않는다.](c) R3 and R4 together do not form an unsubstituted piperidine ring or morpholine ring.]

화학식 I 의 화합물은 유용한 약리학적 성질, 특히 포스포리파제의 작용을 저해할 수 있는 성질을 갖는다. 그러므로 이들은 급성 및 만성, 알레르기성, 비알레르기성 및 외상성 염증성 질환 예컨대, 류마티스성 관절염, 골관절염, 궤양성 대장염, 급성 췌장염, 접촉성 피부염, 염증성 및 알레르기성 호흡 질환, 패혈성 쇼크, 알레르기성 쇼크, 혈청 질환, 자기 면역질환, 그라프트 대 호스트 반응 (graft-versus-host reactions), 호스트-대-그라프트 질환 (host-versus-graft-diseases), 허혈성 또는 혈전 질환 예컨대, 관상 경색 또는 뇌 경색의 치료에 적당하다.Compounds of formula (I) have useful pharmacological properties, especially those that can inhibit the action of phospholipase. Therefore, they are acute and chronic, allergic, nonallergic and traumatic inflammatory diseases such as rheumatoid arthritis, osteoarthritis, ulcerative colitis, acute pancreatitis, contact dermatitis, inflammatory and allergic respiratory diseases, septic shock, allergic shock, Serum diseases, autoimmune diseases, graft-versus-host reactions, host-versus-graft-diseases, ischemic or thrombotic diseases such as coronary infarction or cerebral infarction It is suitable for treatment.

약리학적 활성을 갖는 식 I 의 화합물의 몇몇은 이미 공지되어 있다. 네덜란드 출원 제 6 412 205 호 (Chem. Abstr. 63, 14787) 는 진토제 및 마취 작용을 갖는 11-아미노메틸-9,10-디히드로-9,10-에타노안트라센을 기술하고 있다. 대응하는 물질이 항콜린작용, 저혈압, 항히스타민 및 국소 마취작용이 있다는 것은 문헌 [J. Med. Chem. 10, 86 (1967)] 에 기술되어 있다. 그러나, 항염증 작용 및 특히 포스포리파제의 억제 작용에 대하여는 아직 기술되어 있지 않다.Some of the compounds of formula I having pharmacological activity are already known. Dutch application 6 412 205 (Chem. Abstr. 63, 14787) describes 11-aminomethyl-9,10-dihydro-9,10-ethanoanthracene with an anti-nausea and anesthetic action. The corresponding substances have anticholinergic, hypotension, antihistamine and local anesthesia. Med. Chem. 10, 86 (1967). However, the anti-inflammatory action and in particular the inhibitory action of phospholipase have not been described yet.

다른 언급이 없으면 잔기 R3 및 R4 와 치환기로서의 저급 알킬은 단독으로 또는 아릴 또는 아미노와 조합하여, 탄소수 1 내지 6 의 직쇄 또는 측쇄 알킬을 나타낸다. 바람직한 잔기는 메틸, 에틸, 프로필, 이소프로필, n-부틸, 이소부틸, t-부틸, n-펜틸 또는 3-펜틸 잔기이다.Unless stated otherwise, residues R3 and R4 and lower alkyl as substituents, alone or in combination with aryl or amino, represent straight or branched chain alkyl of 1 to 6 carbon atoms. Preferred residues are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl or 3-pentyl residues.

아릴은 할로겐 또는 저급 알킬로 임의로 치환될 수 있는 페닐 또는 나프틸 잔기이다.Aryl is a phenyl or naphthyl moiety which may be optionally substituted with halogen or lower alkyl.

할로겐은 불소, 염소, 브롬 또는 요오드이며, 바람직하게는 염소이다.Halogen is fluorine, chlorine, bromine or iodine, preferably chlorine.

잔기 R3 및 R4 및 R5 에 대하여 언급된 헤테로 원자는 N, O, S 이며 바람직하게는 N 또는 O 이다.The hetero atoms mentioned for the residues R3 and R4 and R5 are N, O, S and are preferably N or O.

N-아르알킬헤테로아릴은 헤테로 사이클의 N-원자를 통해 결합된 아르알킬 잔기이다.N-aralkylheteroaryl is an aralkyl moiety bound through the N-atom of a hetero cycle.

R4 로 명시된 헤테로아릴기는 피리디닐, 피페리디닐, 피리다지닐, 피리미디닐, 피라지닐 또는 피페라지닐 잔기이다. 피리디닐, 피페리디닐 또는 이미다졸리닐 잔기가 바람직하며 특히 3-피리디닐 또는 4-피리디닐 또는 3-피페리디닐 또는 4-피페리디닐 또는 4,5-디히드로-이미다졸-2일 잔기가 바람직하다.The heteroaryl group designated as R 4 is a pyridinyl, piperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl or piperazinyl moiety. Pyridinyl, piperidinyl or imidazolinyl moieties are preferred, especially 3-pyridinyl or 4-pyridinyl or 3-piperidinyl or 4-piperidinyl or 4,5-dihydro-imidazol-2yl Residues are preferred.

R3 및 R4 가 이들이 결합된 N-원자와 함께 형성한 상술한 바와 같은 헤테로시클릭 고리계는 피롤리딘, 피롤, 피라졸, 이미다졸, 피리딘, 피리다진, 피리미딘, 피라진, 피란, 피페리딘, 피페라진 또는 모르폴린 고리이다. 피롤리딘, 모르폴린 또는 피페리딘 잔기가 바람직하다.The heterocyclic ring systems described above, wherein R 3 and R 4 are formed with the N-atom to which they are attached, are pyrrolidine, pyrrole, pyrazole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine, pyran, piperi Dine, piperazine or morpholine rings. Pyrrolidine, morpholine or piperidine residues are preferred.

R3 및 R4 와 함께 형성될 수 있는 헤테로시클릭 고리계의 치환기는 일반적인 치환기외에, 바람직하게는 벤즈아미도, 벤질아미노, 아미노, 모노알킬아미노 또는 디알킬아미노이다. 4 위치에서의 단일 치환기가 바람직하다.Substituents of a heterocyclic ring system which may be formed together with R 3 and R 4 are preferably benzamido, benzylamino, amino, monoalkylamino or dialkylamino in addition to the general substituent. Single substituents at the 4 position are preferred.

잔기 R5 의 경우 헤테로사이클은 피리미딘, 피리다진, 피라졸, 피라진, 이미다졸, 인다졸 또는 푸린을 나타낸다. 그러나, 이미다졸 잔기가 특히 바람직하다.For residue R5 heterocycle represents pyrimidine, pyridazine, pyrazole, pyrazine, imidazole, indazole or purine. However, imidazole moieties are particularly preferred.

R1 및 R2 잔기에 대하여 특히 바람직한 잔기는 수소 및 염소이다. R3 에 대하여 특히 바람직한 잔기는 수소 또는 메틸이고, R4 에 대하여 특히 바람직한 잔기는 카르바모일, 아미디노, N-벤질아미노피리딘, 피페리딘, 피리딘, 메틸, 히드록시 또는 이미다졸릴이다. 특히 바람직하게, R3 및 R4 는 함께 4-벤즈아미디노피페리딘, 4-벤질-아미노피페리딘, 4-아미노피페리딘, 4-디메틸아미노피페리딘, 피롤리딘, 피페리딘 또는 모르폴린을 형성하는 것이 바람직하다. 바람직하게는 R5 가 수소, 이미다졸 또는 아미디노를 나타낸다.Particularly preferred residues for the R1 and R2 residues are hydrogen and chlorine. Particularly preferred residues for R3 are hydrogen or methyl, and particularly preferred residues for R4 are carbamoyl, amidino, N-benzylaminopyridine, piperidine, pyridine, methyl, hydroxy or imidazolyl. Especially preferably, R3 and R4 together represent 4-benzamidinopiperidine, 4-benzyl-aminopiperidine, 4-aminopiperidine, 4-dimethylaminopiperidine, pyrrolidine, piperidine or It is preferable to form morpholine. Preferably R 5 represents hydrogen, imidazole or amidino.

상술한 예로서 명시된 화합물외에, 본 발명은 특히 예로서 명시된 치환기의 가능한 조합을 갖는 모든 물질에 관한 것이다.In addition to the compounds specified as examples above, the present invention relates in particular to all materials having possible combinations of substituents specified as examples.

화학식 I 의 화합물은 문헌 (예: 표준 연구 예컨대, Houben-Weyl, "Methoden der Organischen Chemie, Georg Thime Verlag", Stuttgart; Organic Reactions, John Wiley ＆ Sons, Inc., 뉴욕) 및 예로서 인용된 참고문헌에 기술된 바와 같은 공지의 방법, 즉 상기 반응에 적당한 공지의 반응 조건하에서 제조된다. 본원에서 상세히 언급되지 않은 공지의 변형도 사용할 수도 있다. 또한, 화학식 I 의 화합물은 공지의 방법에 의해 화학식 I 의 다른 화합물로 전환될 수 있다.Compounds of formula (I) are described in, for example, standard studies such as Houben-Weyl, "Methoden der Organischen Chemie, Georg Thime Verlag", Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York, and references cited by way of example. It is prepared under the known method as described in ie under known reaction conditions suitable for the reaction. Known variations that are not mentioned in detail herein may also be used. In addition, the compounds of formula (I) can be converted to other compounds of formula (I) by known methods.

공지 방식을 사용한 본 발명의 따른 화학식 I 의 화합물의 제조 방법은 하기를 특징으로 한다:The process for the preparation of the compounds of formula (I) according to the invention using known methods is characterized by the following:

a) R1, R2, X, Y 및 Z 은 상술한 의미이며, R4 또는 R5 는 수소를 나타내는 화학식 I 의 화합물을 활성화된 카르본산 유도체 또는 이미다졸린기 전이제와 반응시켜 R4 또는 R5 가 카르바모일, 아미디노 또는 이미다졸리닐인 화학식 I 의 화합물로 전환시키거나, 또는a) R1, R2, X, Y and Z have the meanings described above, and R4 or R5 is reacted with an activated carboxylic acid derivative or an imidazoline group transfer agent, wherein R4 or R5 is a carba Convert to a compound of formula (I) which is moyl, amidino or imidazolinyl, or

b) R1 및 R2 는 상술한 의미이며, X 는 수소이고, Y 는 수소 또는 뉴클레오퓨지기 (nucleofuge group) 이고 Z 은 카르보닐기를 나타내는 화학식 I 의 화합물을 일차 또는 이차 아민과 반응 시킨 후, 후속적으로 환원시켜 Z 이 CH2기를 나타내고 Y 가 NR3R4 를 나타내는 화학식 I 의 화합물로 전환시키거나, 또는b) R 1 and R 2 have the meanings described above, X is hydrogen, Y is hydrogen or a nucleoofuge group, and Z is a carbonyl group, followed by reacting a compound of formula I with a primary or secondary amine, followed by Reduced to a compound of formula I wherein Z represents a CH 2 group and Y represents NR 3 R 4, or

c) R1 및 R2 는 상술한 의미이며, X 는 수소이고, Z 은 시아노기를 나타내며, Y 가 없는 화학식 I 의 화합물을 히드록실아민 또는 그의 유도체와 반응시켜 Z 이 ＞C=NH 기를 나타내고 R4 는 히드록실을 나타내는 화학식 I 의 화합물을 형성하거나, 또는c) R1 and R2 have the meanings described above, X is hydrogen, Z represents a cyano group, and a compound of formula (I) without Y is reacted with hydroxylamine or a derivative thereof, where Z represents a> C = NH group and R4 represents To form a compound of formula I representing hydroxyl, or

d) R1 및 R2 는 상술한 의미이며, X-Y-Z 은 기 CO-NH-CO 를 나타내는 화학식 I 의 화합물을 환원시켜 X-Y-Z 이 기 CH2-NH-CH2를 나타내는 화학식 I 의 화합물로 전환시키며,d) R1 and R2 have the meanings described above and XYZ reduces the compound of formula (I) representing the group CO-NH-CO to convert XYZ to the compound of formula (I) representing the group CH 2 -NH-CH 2 ,

필요하다면 후속하여, 카르보닐기를 CH2로 환원시키고, 아릴메틸기는 분해시키거나 또는 삼차 질소 원자를 알킬화로 사차화시키며,If necessary subsequently, the carbonyl group is reduced to CH 2 , the arylmethyl group is decomposed or the tertiary nitrogen atom is quaternized by alkylation,

경우에 따라 염기는 약리학적으로 허용가능한 염으로 전환시키거나 또는 유리 화합물을 염으로 부터 생성하는 방법.Optionally, the base is converted to a pharmacologically acceptable salt or a free compound is produced from the salt.

화학식 I 의 화합물은 거울상 이성질체 및 라세미체로서 생성될 수 있다. 본 발명은 순수한 거울상 이성질체 및 라세미 혼합물에 관한 것이다.Compounds of formula (I) can be produced as enantiomers and racemates. The present invention relates to pure enantiomers and racemic mixtures.

뉴클레오퓨지기를 갖는 무기 이소시아네이트 및 이소우레아 유도체는 활성화된 카르본산 유도체가 고려된다.Inorganic isocyanate and isourea derivatives with nucleofuji groups are considered activated carboxylic acid derivatives.

이미다졸린기 전이제는 예를들어 2 위치에 뉴클레오퓨지기를 갖는 1H-이미다졸린이다.Imidazoline group transfer agents are, for example, 1H-imidazolines having nucleofugi groups at the 2 position.

뉴클레오퓨지기는 예를들어 할로겐 원자, 아지도기, 알콕시기, 아릴옥시기, 알킬티오기 및 아릴티오기이다.Nucleofuzzy groups are, for example, halogen atoms, azido groups, alkoxy groups, aryloxy groups, alkylthio groups and arylthio groups.

수소화붕소 나트륨 및 수소화알루미늄 리튬과 같은 복합 금속 수소화물이 환원제로서 바람직하게 사용된다.Complex metal hydrides such as sodium borohydride and lithium aluminum hydride are preferably used as reducing agents.

일반 화학식 I 의 화합물은 하나 또는 수개의 키랄 중심을 가질 수 있으며 따라서 라세미 또는 광학 활성 형태로 존재할 수 있다. 광학 이성질체는 공지의 방법에 의해 거울상 이성질체로 분할될 수 있다. 적절하다면, 기술된 방법은 최종 단계 및/또는 전구체의 분할을 의미한다. 부분입체이성질체 염은 예를들어, D- 또는 L-타르타르산, 만델산, 말산, 락트산 또는 캠포르술폰산과 같은 광학 활성산 또는 예를들어 결정화로 분리될 수 있는 D- 또는 L-α-페닐에틸아민, 에페드린, 퀴니딘 또는 신코니딘과 같은 광학 활성 아민, 또는 HPLC 로 분리되는 광학 이성질체와의 반응으로 라세미 혼합물로 부터 형성된다. 광학 이성질체를 분리하는 또 다른 방법은 합성하는 동안의 효소의 분리이다.General The compounds of formula (I) may have one or several chiral centers and therefore may exist in racemic or optically active forms. Optical isomers can be divided into enantiomers by known methods. If appropriate, the described method means final step and / or splitting of the precursor. Diastereomeric salts are optically active acids such as, for example, D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid or D- or L-α-phenylethyl, which can be separated by crystallization, for example. It is formed from racemic mixtures by reaction with amines, optically active amines, such as ephedrine, quinidine or cinchonidine, or optical isomers separated by HPLC. Another method of separating optical isomers is the separation of enzymes during synthesis.

적당한 약리학적으로 허용가능한 염은 특히 비독성 무기 또는 유기산 예컨대, 염산, 황산, 인산, 브롬화수소산, 아세트산, 락트산, 시트르산, 말산, 벤조산, 살리실산, 말론산, 말레산, 숙신산 또는 디아미노카프로산 및 임의의 알칼리류 염, 알칼리 토류 염 및 암모늄 염이다.Suitable pharmacologically acceptable salts are in particular non-toxic inorganic or organic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, lactic acid, citric acid, malic acid, benzoic acid, salicylic acid, malonic acid, maleic acid, succinic acid or diaminocaproic acid and Optional alkali salts, alkaline earth salts and ammonium salts.

염은 예컨대 적당한 산 또는 가성 알칼리 용액으로 화학식 I 의 화합물을 중화하는 일반적인 방식으로 수득된다. 이들은 일반적으로 물/아세톤으로 재침전하여 정화된다.Salts are obtained in a general manner, for example, by neutralizing the compound of formula I with a suitable acid or caustic alkaline solution. They are generally purified by reprecipitation with water / acetone.

약학 제제를 제조하기 위해 일반 화학식 I 의 화합물은 공지 방법으로 적당한 약학 담체 물질, 방향 물질, 향미제 및 염료와 혼합하고 예를들어 적당한 보조물질을 첨가하여 정제 또는 당의정 또는 물 또는 오일 (예를들어 올리브유) 중의 현탁제 또는 용액을 형성한다.To prepare pharmaceutical preparations, the compounds of general formula (I) may be mixed with suitable pharmaceutical carrier substances, fragrances, flavoring agents and dyes by known methods and, for example, by the addition of suitable auxiliaries to tablets or dragees or water or oil (e.g. Suspending agent or solution in olive oil).

일반 화학식 I 의 물질은 액체 또는 고체 형태로 경구 또는 비경구 투여될 수 있다. 주사 용액에 사용되는 통상의 안정화제, 가용화제 및/또는 완충제를 함유하는 주사 매질로서 물을 사용하는 것이 바람직하다. 적당한 첨가제는 예를들어 타르트레이트 또는 보레이트 완충액, 에탄올, 디메틸술폭시드, 착화제 (예컨대 에틸렌 디아민테트라아세트산), 점도를 조절하는 고분자 중합체 (예컨대 액체 폴리에틸렌 옥시드) 또는 솔비톨 무수물의 폴리에틸렌 유도체이다.The substances of general formula (I) can be administered orally or parenterally in liquid or solid form. Preference is given to using water as an injection medium containing conventional stabilizers, solubilizers and / or buffers used in injection solutions. Suitable additives are, for example, tartrate or borate buffers, ethanol, dimethylsulfoxide, complexing agents (such as ethylene diaminetetraacetic acid), polymer polymers for controlling viscosity (such as liquid polyethylene oxide) or polyethylene derivatives of sorbitol anhydride.

고체 담체 물질은 예를들어 전분, 락토오스, 만니톨, 메틸셀룰로오스, 활석, 고 분산된 규산, 고분자 중합체 (예컨대 폴리에틸렌 글리콜) 이다.Solid carrier materials are, for example, starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acid, high molecular polymers (such as polyethylene glycol).

경구 적용을 위한 적당한 제제는 필요하다면 풍미제 및 향미제를 함유할 수 있다. 외부 적용을 위해 본 발명에 따른 물질 I 은 분말 및 연고의 형태로 사용될 수 있다. 이를 위해 이들은 생리학적으로 허용가능한 희석 분말 또는 통상의 연고 기재와 혼합된다.Suitable formulations for oral application may contain flavoring and flavoring agents, if desired. For external applications the material I according to the invention can be used in the form of powders and ointments. For this purpose they are mixed with physiologically acceptable dilution powders or conventional ointment bases.

투여량은 수령인의 연령, 건강 및 체중, 질환의 정도, 동시에 수행될 수 있는 추가 치료의 형태, 치료 빈도 및 원하는 효과의 타입에 따라 변한다. 활성 화합물의 일일 투여량은 일반적으로 0.1 내지 50 mg/kg 체중이다. 일반적으로 원하는 결과를 얻기 위해 일회 또는 수회 0.5 내지 40 및 바람직하게는 1.0 내지 20 mg/kg/day 로 적용하하는 것이 효과적이다.The dosage will vary depending on the age, health and weight of the recipient, the severity of the disease, the type of additional treatment that can be performed simultaneously, the frequency of treatment and the type of effect desired. The daily dose of the active compound is generally 0.1 to 50 mg / kg body weight. Generally it is effective to apply one or several times 0.5 to 40 and preferably 1.0 to 20 mg / kg / day to achieve the desired result.

예로서 명시된 물질 이외에 하기 화합물은 본 발명의 범주에 속하는 바람직한 것이다:In addition to the substances specified as examples, the following compounds are preferred within the scope of the invention:

1-{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-4-아미노-피페리딘 히드로클로라이드1- {3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaene-15- Mono-methyl} -4-amino-piperidine hydrochloride

1-벤질-4-{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]-헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸-아미노}-피페리딘 히드로클로라이드1-benzyl-4- {3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] -hexadeca -2 (7), 3,5,9 (14), 10,12- Hexaen-15-yl-methyl-amino} -piperidine hydrochloride

4-{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸-아미노}피페리딘 히드로클로라이드4- {3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaene-15- Mono-methyl-amino} piperidine hydrochloride

1'-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-1,4'-비피페리딘1'-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl-methyl} -1 , 4'-bipiperidine

1'-{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-1,4'-비피페리딘1 '-{3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaene-15 -Yl-methyl} -1,4'-bipiperidine

하기 실시예가 본 발명을 예시하고 있으나, 이에 국한되지 않는다.The following examples illustrate the invention but are not limited thereto.

실시예 1Example 1

N-{테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-우레아N- {tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl-methyl} -urea

200 ml 의 온수중 2.85 g (10 mmol) 의 {테트라시클로 [6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-아민 히드로클로라이드 (J. Org. Chem. 42, 1131 (1977))의 용액에 1.21 g (15 mmol)의 시안산칼륨을 첨가하고, 1 시간 동안 가열하여 환류시킨다. 냉각 후, 융점이 182-184 ℃ 인 표제 화합물 2.4 g (이론 수율의 86 %) 을 여과에 의해 단리한다.2.85 g (10 mmol) of {tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexa in 200 ml hot water To a solution of en-15-yl-methyl} -amine hydrochloride (J. Org. Chem. 42, 1131 (1977)) is added 1.21 g (15 mmol) of potassium cyanate and heated to reflux for 1 hour. . After cooling, 2.4 g (86% of theory yield) of the title compound having a melting point of 182-184 ° C. are isolated by filtration.

실시예 2Example 2

N-{테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-구아니딘N- {tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl-methyl} -guanidine

30 ml의 n-프로판올중 3.8 g (16.4 mmol) 의 {테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-아민 및 3.1 g (18 mmol) 의 S-메틸-이소티오우레아 히드로브로마이드의 혼합물을 5 시간 동안 가열하여 질소하에서 환류시키고, 냉각하고, 디에틸 에테르와 부가혼합하고, 물로 추출하여 추출물을 알칼리화시키며, 에틸 아세테이트로 추출하고 유기상을 건조시켜 증발에 의해 농축한 다음 디에틸 에테르로 분쇄한다. 융점이 128-130 ℃ 인 표제 화합물 2.0 g (이론 수율의 44 %)가 단리된다.3.8 g (16.4 mmol) of {tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12 in 30 ml of n-propanol A mixture of -hexaen-15-yl-methyl} -amine and 3.1 g (18 mmol) of S-methyl-isothiourea hydrobromide was heated for 5 hours to reflux under nitrogen, cooled, and addition with diethyl ether Mix, extract with water to alkalinize the extract, extract with ethyl acetate, dry the organic phase, concentrate by evaporation and triturate with diethyl ether. 2.0 g (44% of theory yield) of the title compound having a melting point of 128-130 ° C. are isolated.

실시예 3Example 3

1-{테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-4-벤즈아미도-피페리딘1- {tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl-methyl} -4 -Benzamido-piperidine

4.8 g (20 mmol)의 {테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14), 10,12-헥사엔-15-일-메틸}-카르발데히드 (Bull. Soc. Chim. France 1964, 550), 4.0 g (20 mmol)의 4-벤즈아미도-피페리딘, 100 ml 의 톨루엔 및 0.2 g 의 p-톨루엔-술폰산의 혼합물을 물 분별기상에서 2 시간 동안 환류하에 가열한다. 이어서, 이를 농축한 후, 100 ml 의 메탄올중에 용해시키고, 0.96 g 의 수소화붕소나트륨을 2 회 도입하는데 매번 1 시간 동안 가열하여 환류시킨다. 이를 농축하고, 잔류물을 에틸 아세테이트중에 용해시키고, 물로 세척한 다음, 유기상을 건조시키고 실리카 겔상에서 크로마토그래피한다. 융점이 168-170 ℃인 표제 화합물 5.8 g (이론 수율의 69 %)이 이소헥산/에틸 아세테이트 3:1 로 용출된다.4.8 g (20 mmol) {tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl -Methyl} -carbaldehyde (Bull. Soc. Chim. France 1964, 550), 4.0 g (20 mmol) of 4-benzamido-piperidine, 100 ml of toluene and 0.2 g of p-toluene-sulfonic acid Is heated under reflux for 2 hours on a water separator. It is then concentrated and then dissolved in 100 ml of methanol and heated to reflux for 1 hour each time introducing 0.96 g of sodium borohydride twice. It is concentrated and the residue is dissolved in ethyl acetate and washed with water, then the organic phase is dried and chromatographed on silica gel. 5.8 g (69% of theory yield) of the title compound having a melting point of 168-170 ° C. are eluted with isohexane / ethyl acetate 3: 1.

실시예 4Example 4

1-{테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-4-벤질아미노-피페리딘 히드로클로라이드1- {tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl-methyl} -4 -Benzylamino-piperidine hydrochloride

50 ml의 테트라히드로푸란중 실시예 3 의 화합물 5.4 g (12.8 mmol) 용액을 100 ml 의 테트라히드로푸란중 1.5 g 수소화 알루미늄 리튬의 현탁액에 적가하고, 이어서 3 시간 동안 가열하여 환류시키고, 염화나트륨 용액과 부가 혼합하고, 여과시킨 다음 여액을 건조 및 농축시킨다. 메탄올 용액에 과량의 에테르 염화수소 용액을 첨가한 후, 5.1 g (이론 수율의 98 %)의 표제 화합물을 조생성물로서 단리한다.A solution of 5.4 g (12.8 mmol) of the compound of Example 3 in 50 ml of tetrahydrofuran is added dropwise to a suspension of 1.5 g lithium aluminum hydride in 100 ml of tetrahydrofuran, followed by heating to reflux for 3 hours, and with sodium chloride solution The addition is mixed, filtered and the filtrate is dried and concentrated. After addition of excess ether hydrogen chloride solution to the methanol solution, 5.1 g (98% of theory yield) of the title compound are isolated as crude product.

실시예 5Example 5

1-{테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-4-아미노-피페리딘 히드로클로라이드1- {tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl-methyl} -4 -Amino-piperidine hydrochloride

실시예 4 의 화합물 5.0 g (12.3 mmol)을 50 ℃ 및 1 바의 수소압하에 1 g의 10% 팔라듐 카본상에서 50 ml의 메탄올중에서 수소화시킨다. 이를 여과시켜 농축하고 실리카겔상에서 크로마토그래피한다. 2.9 g의 표적 화합물을 에틸 아세테이트/메탄올 1:1 로 용출시킨다. 아세톤으로 분쇄한 후, 융점이 225-230 ℃ 인 표제 화합물 2.3 g (이론 수율의 60 %)이 남는다.5.0 g (12.3 mmol) of the compound of Example 4 are hydrogenated in 50 ml of methanol on 1 g of 10% palladium carbon under 50 ° C. and 1 bar of hydrogen pressure. It is concentrated by filtration and chromatographed on silica gel. 2.9 g of the target compound is eluted with ethyl acetate / methanol 1: 1. After trituration with acetone, 2.3 g (60% of theory yield) of the title compound with a melting point of 225-230 ° C. are left.

실시예 6Example 6

1-벤질-4-{테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸아미노}-피페리딘 히드로클로라이드1-benzyl-4- {tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl- Methylamino} -piperidine hydrochloride

{테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일}-카르발데히드 및 4-아미노-1-벤질-피페리딘으로부터, 실시예 3과 유사한 방식으로 표제 화합물을 조생성물로서 80 % 수율로 수득한다.{Tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl} -carbaldehyde and 4 From -amino-1-benzyl-piperidine, the title compound is obtained as crude product in 80% yield in a similar manner to Example 3.

실시예 7Example 7

4-{테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸아미노}-피페리딘 히드로클로라이드4- {tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl-methylamino}- Piperidine Hydrochloride

융점이 226-228 ℃ 인 표제 화합물을 실시예 5 에 기재된 것과 유사한 방식으로 89% 수율로 수득한다.The title compound, having a melting point of 226-228 ° C., is obtained in 89% yield in a manner similar to that described in Example 5.

실시예 8Example 8

1-{테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-4-디메틸아미노-피페리딘 히드로클로라이드1- {tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl-methyl} -4 -Dimethylamino-piperidine hydrochloride

{테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일}-카르발데히드 및 4-디메틸아미노-피페리딘으로부터, 실시예 3 에 기재된 것과 유사한 방식으로 표제 화합물을 무정형 고체로서 65% 수율로 수득한다.{Tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl} -carbaldehyde and 4 From -dimethylamino-piperidine, the title compound is obtained in 65% yield as an amorphous solid in a manner similar to that described in Example 3.

실시예 9Example 9

4-{테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸아미노}-피리딘4- {tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl-methylamino}- Pyridine

4-{테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-카르보닐아미노}-피리딘을 환원시킨 다음 디에틸 에테르로 분쇄함으로써, 실시예 4 에 기재된 것과 유사한 방식으로 융점이 164-166 ℃인 표제 화합물을 이론 수율의 71 % 를 수득한다.4- {tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl-carbonylamino} Reduction of pyridine and trituration with diethyl ether gives 71% of theoretical yield of the title compound having a melting point of 164-166 ° C. in a similar manner to that described in Example 4.

상기 사용된 출발 물질은 하기와 같이 수득될 수 있다 :The starting materials used can be obtained as follows:

50 ml의 테트라히드로푸란중 5.4 g (20 mmol)의 {테트라시클로 [6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일}-카르보닐 클로라이드 [J. Am. Chem. Soc. 94, 1193 (1972)] 및 4.7 g (50 mmol)의 4-아미노피리딘의 혼합물을 1 시간동안 실온에서 교반하고 2 시간 동안 환류하에 교반시킨 다음, 이를 여과시키고, 여액을 실리카겔상에서 크로마토그래피한다. 에틸 아세테이트로 용출한 후, 융점이 217-219 ℃ 인 2.5 g 의 {테트라시클로[6.6.2.02,7.09,14] 헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-카르보닐아미노}-피리딘 (이론 수율의 38 %) 을 수득한다.5.4 g (20 mmol) of {tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12 in 50 ml of tetrahydrofuran -Hexaen-15-yl} -carbonyl chloride [J. Am. Chem. Soc. 94, 1193 (1972)] and a mixture of 4.7 g (50 mmol) of 4-aminopyridine are stirred at room temperature for 1 hour and under reflux for 2 hours, then filtered and the filtrate is chromatographed on silica gel. After eluting with ethyl acetate, 2.5 g of {tetracyclo [6.6.2.0 2,7 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl-carbonylamino} -pyridine (38% of theory yield) is obtained.

실시예 10Example 10

4-{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸아미노}-피리딘4- {3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaene-15- Yl-methylamino} -pyridine

{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10, 12-헥사엔-15-일}-카르보닐 클로라이드 [Tetrahedron 28, 1435 (1972)] 및 4-아미노-피리딘으로부터 수득될 수 있는 카르보닐아미노 화합물을 환원시킴으로서 실시예 9에 기재된 것과 유사한 방식으로 융점이 322-325 ℃ 인 표제 화합물을 수율 61% 로 수득한다.{3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10, 12-hexaen-15-yl} Reducing the carbonylamino compound obtainable from -carbonyl chloride [Tetrahedron 28, 1435 (1972)] and 4-amino-pyridine to give the title compound having a melting point of 322-325 ° C. in a manner similar to that described in Example 9. Obtained in the yield 61%.

실시예 11Example 11

{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10, 12-헥사엔-15-일-메틸}-디메틸아민{3,10-Dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10, 12-hexaen-15-yl- Methyl} -dimethylamine

{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10, 12-헥사엔-15-일}-카르보닐 클로라이드 및 디메틸아민으로부터 수득될 수 있는 카르보닐아미노 화합물을 환원시킴으로서 실시예 9에 기재된 것과 유사한 방식으로 융점이 88-90 ℃ 인 표제 화합물을 64 % 수율로 수득한다.{3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10, 12-hexaen-15-yl} By reducing the carbonylamino compound obtainable from carbonyl chloride and dimethylamine, the title compound is obtained in 64% yield having a melting point of 88-90 ° C. in a manner similar to that described in Example 9.

실시예 12Example 12

N-{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-피페리딘N- {3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaene-15- Yl-methyl} -piperidine

{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10, 12-헥사엔-15-일}-카르보닐 클로라이드 및 피페리딘으로부터 수득가능한 카르보닐아미노 화합물을 환원시킴으로서 실시예 9에 기재된 것과 유사한 방식으로 표제 화합물을 무정형 고체로서 40 % 수율로 수득한다.{3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10, 12-hexaen-15-yl} The title compound is obtained in 40% yield as an amorphous solid in a manner similar to that described in Example 9 by reducing the carbonylamino compound obtainable from carbonyl chloride and piperidine.

실시예 13Example 13

N-{6,13-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-피페리딘N- {6,13-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaene-15- Yl-methyl} -piperidine

이전 화합물의 크로마토그래피 정제중에 표제 화합물이 무정형 부생성물로서 15% 수율로 용출된다.During chromatography purification of the previous compound, the title compound is eluted in 15% yield as an amorphous byproduct.

실시예 14Example 14

N-{6,13-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-피롤리딘N- {6,13-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaene-15- Yl-methyl} -pyrrolidine

{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10, 12-헥사엔-15-일}-카르보닐 클로라이드 및 피롤리딘으로부터 수득가능한 카르보닐아미노 화합물을 환원시킴으로서 실시예 9에 기재된 것과 유사한 방식으로 표제 화합물을 오일로서 28 % 수율로 수득한다.{3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10, 12-hexaen-15-yl} The title compound is obtained as an oil in 28% yield in a manner similar to that described in Example 9 by reducing the carbonylamino compound obtainable from carbonyl chloride and pyrrolidine.

실시예 15Example 15

N-{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-모르폴린N- {3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaene-15- Yl-methyl} -morpholine

{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10, 12-헥사엔-15-일}-카르보닐 클로라이드 및 모르폴린으로부터 수득가능한 카르보닐아미노 화합물을 환원시킴으로서 실시예 9에 기재된 것과 유사한 방식으로 융점이 175-177 ℃ 인 표제 화합물을 41 % 수율로 수득한다.{3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10, 12-hexaen-15-yl} By reducing the carbonylamino compound obtainable from carbonyl chloride and morpholine, the title compound having a melting point of 175-177 ° C. is obtained in 41% yield in a manner similar to that described in Example 9.

실시예 16Example 16

1-{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-4-디메틸-아미노-피페리딘 히드로클로라이드1- {3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaene-15- Mono-methyl} -4-dimethyl-amino-piperidine hydrochloride

{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10, 12-헥사엔-15-일}-카르보닐 클로라이드 및 4-디메틸아미노-피페리딘으로부터 수득가능한 카르보닐아미노 화합물을 환원시킨 다음 히드로클로라이드를 침전시킴으로서 실시예 9에 기재된 것과 유사한 방식으로 융점이 295 ℃ (분해)인 표제 화합물을 70 % 수율로 수득한다.{3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10, 12-hexaen-15-yl} The title compound having a melting point of 295 ° C. (decomposition) in a manner similar to that described in Example 9 was reduced by reducing the carbonylamino compound obtainable from carbonyl chloride and 4-dimethylamino-piperidine and then precipitating hydrochloride. Obtained in% yield.

실시예 17Example 17

{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-트리메틸암모늄 요오드{3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl- Methyl} -trimethylammonium iodine

0.5 g (1.5 mmol)의 실시예 11의 화합물, 10 ml의 아세톤 및 0.47 ml (7.5 mmol)의 메틸 요오드의 혼합물을 실온에서 8 시간 동안 교반한 다음, 이어서 침전물을 여과 제거한다. 융점이 172-175 ℃ 인 표제 화합물 0.5 g (이론 수율의 70 %)이 남는다.A mixture of 0.5 g (1.5 mmol) of Example 11, 10 ml of acetone and 0.47 ml (7.5 mmol) of methyl iodine is stirred at room temperature for 8 hours, and then the precipitate is filtered off. 0.5 g (70% of theory yield) of the title compound with a melting point of 172-175 ° C remain.

실시예 18Example 18

N-{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-N-메틸-피페리디늄 요오드N- {3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaene-15- Yl-methyl} -N-methyl-piperidinium iodine

실시예 12의 화합물 및 요오드화메틸로부터 실시예 17에 기재된 것과 유사한 방식으로 융점이 254-256 ℃인 표제 화합물을 43 % 수율로 수득한다.From the compound of Example 12 and methyl iodide in a similar manner to that described in Example 17, the title compound having a melting point of 254-256 ° C. is obtained in 43% yield.

실시예 19Example 19

N-히드록시-{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일}-카르복시미다미드N-hydroxy- {3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaene -15-yl} -carboxymidamide

8.25 g (25 mmol)의 {3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일}-카르보니트릴 [Tetrahedron 28, 1435 (1972)], 5.3 g 의 탄산나트륨, 7.0 g 의 히드록실아민 히드로클로라이드, 100 ml의 에탄올 및 25 ml의 물의 혼합물을 20 시간 동안 환류시킨다. 이를 여과하고 침전물을 실리카겔상에서 크로마토그래피한다. 융점이 203-205 ℃인 표제 화합물 0.75 g (이론 수율의 9 %)이 에틸 아세테이트로 단리된다.8.25 g (25 mmol) {3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12- Hexaen-15-yl} -carbonitrile [Tetrahedron 28, 1435 (1972)], a mixture of 5.3 g sodium carbonate, 7.0 g hydroxylamine hydrochloride, 100 ml ethanol and 25 ml water are refluxed for 20 hours. . It is filtered and the precipitate is chromatographed on silica gel. 0.75 g (9% of theory yield) of the title compound having a melting point of 203-205 ° C. are isolated with ethyl acetate.

N-히드록시-{6,13-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3, 5,9(14),10,12-헥사엔-15-일}-카르복시미다미드의 이성질체가 부생성물로서 검출될 수 있다.N-hydroxy- {6,13-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaene Isomers of -15-yl} -carboximidamide can be detected as by-products.

실시예 20Example 20

2-{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸아미노}-4,5-디히드로-1H-이미다졸2- {3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaene-15- Mono-methylamino} -4,5-dihydro-1H-imidazole

4.55 g (15 mmol)의 {3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-아민 (수소화 알루미늄 리튬으로 환원시켜 실시예 19에서 사용된 니트릴로부터 제조된다) 및 3.36 g (17 mmol)의 2-메틸술파닐-4,5-디히드로-1H-이미다졸 히드로브로마이드의 혼합물을 15 mbar에서 160 ℃로 30분간 가열하고 180 ℃에서 10분간 가열한다. 냉각 후, 아세톤을 첨가하고, 이를 여과시켜 침전물을 에탄올로 재결정한다. 융점이 194-195 ℃인 표제 화합물 5.0 g (이론 수율의 73 %)이 단리된다.4.55 g (15 mmol) of {3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12- Hexaen-15-yl-methyl} -amine (prepared from nitrile used in Example 19 by reduction with lithium aluminum hydride) and 3.36 g (17 mmol) 2-methylsulfanyl-4,5-dihydro- The mixture of 1H-imidazole hydrobromide is heated at 160 ° C. for 30 minutes at 15 mbar and for 10 minutes at 180 ° C. After cooling, acetone is added and it is filtered to recrystallize the precipitate with ethanol. 5.0 g (73% of theory yield) of the title compound having a melting point of 194-195 ° C. are isolated.

실시예 21Example 21

2-{테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸아미노}-4,5-디히드로-1H-이미다졸2- {tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl-methylamino}- 4,5-dihydro-1H-imidazole

{테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-아민으로부터 실시예 20에 기재된 것과 유사한 방식으로 융점이 160-162 ℃인 표제 화합물이 수득된다 (이론 수율의 57 %).{Tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl-methyl} -amine In a similar manner to that described in Example 20, the title compound is obtained having a melting point of 160-162 ° C. (57% of theory yield).

실시예 22Example 22

N-{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-구아니딘N- {3,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaene-15- Yl-methyl} -guanidine

{3,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10, 12-헥사엔-15-일-메틸}-아민으로부터 실시예 2에 기재된 것과 유사한 방식으로 융점이 211-213 ℃인 표제 화합물이 58 % 수율로 수득된다.{3,10-Dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10, 12-hexaen-15-yl- From methyl} -amine, the title compound is obtained in 58% yield having a melting point of 211-213 ° C. in a similar manner to that described in Example 2.

실시예 23Example 23

2-{6,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸아미노}-4,5-디히드로-1H-이미다졸 히드로브로마이드2- {6,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaene-15- Mono-methylamino} -4,5-dihydro-1H-imidazole hydrobromide

상응하는 니트릴의 환원에 의해 수득가능한 {6,10-디클로로-테트라시클로 [6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-아민으로부터 실시예 20에 기재된 것과 유사한 방식으로 융점이 155-158 ℃ (분해)인 표제 화합물이 이론 수율의 28 % 로 수득된다.{6,10-dichloro-tetracyclo [6.6.2.0 2,7 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10, obtainable by reduction of the corresponding nitrile From the 12-hexaen-15-yl-methyl} -amine in a similar manner to that described in Example 20, the title compound having a melting point of 155-158 ° C. (decomposition) is obtained in 28% of theoretical yield.

실시예 24Example 24

N-{6,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-구아니딘 히드로브로마이드N- {6,10-dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaene-15- Yl-methyl} -guanidine hydrobromide

{6,10-디클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10, 12-헥사엔-15-일-메틸}-아민으로부터 실시예 2에 기재된 것과 유사한 방식으로 융점이 93-95 ℃ (분해)인 표제 화합물이 이론 수율의 24 % 로 수득된다.{6,10-Dichloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10, 12-hexaen-15-yl- From the methyl} -amine the title compound having a melting point of 93-95 ° C. (decomposition) is obtained in a manner similar to that described in Example 2 in 24% of the theoretical yield.

실시예 25Example 25

N-{6-클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-구아니딘 히드로브로마이드N- {6-Chloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl- Methyl} -Guanidine Hydrobromide

{6-클로로-테트라시클로[6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15-일-메틸}-아민으로부터 실시예 22에 기재된 것과 유사한 방식으로 융점이 151-153 ℃ (분해)인 표제 화합물이 이론 수율의 32 % 로 수득된다.{6-Chloro-tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexaen-15-yl-methyl} From the amine a title compound having a melting point of 151-153 ° C. (decomposition) is obtained in a similar manner to that described in Example 22 in 32% of the theoretical yield.

실시예 26Example 26

5,10-디클로로-3a,4,9,9a-테트라히드로-4,9-o-벤제노-벤즈[f]이소인돌5,10-dichloro-3a, 4,9,9a-tetrahydro-4,9-o-benzeno-benz [f] isoindole

290 ml 의 테트라히드로푸란중 23.0 g (67 mmol)의 5,10-디클로로-3a,4,9,9a-테트라히드로-4,9-o-벤제노-벤즈[f]이소인돌-1,3-디온의 용액을 45 ml의 디에틸 에테르중 5.1 g (134 mmol)의 수소화 알루미늄 리튬의 현탁액에 적가하고, 이어서 8 시간 동안 환류하고, 염화나트륨 용액과 부가 혼합시키고, 유기상을 농축하고 잔류물을 히드로클로라이드로 전환시켜 정제한 다음 염기가 방출된다. 융점이 126-130 ℃인 표제 화합물 11.0 g (이론 수율의 52 %)이 단리된다.23.0 g (67 mmol) of 5,10-dichloro-3a, 4,9,9a-tetrahydro-4,9-o-benzeno-benz [f] isoindole-1,3 in 290 ml of tetrahydrofuran A solution of dione is added dropwise to a suspension of 5.1 g (134 mmol) of lithium aluminum hydride in 45 ml of diethyl ether, then refluxed for 8 hours, further mixed with sodium chloride solution, the organic phase is concentrated and the residue After purification by conversion to chloride the base is released. 11.0 g (52% of theory yield) of the title compound having a melting point of 126-130 ° C. are isolated.

출발물질로서 사용된 5,10-디클로로-3a,4,9,9a-테트라히드로-4,9-o-벤제노-벤즈-[f]이소인돌-1,3-디온을 하기와 같이 수득할 수 있다:The 5,10-dichloro-3a, 4,9,9a-tetrahydro-4,9-o-benzeno-benz- [f] isoindole-1,3-dione used as starting material was obtained as follows. Can:

83 g (0.24 mol)의 5,10-디클로로-3a,4,9,9a-테트라히드로-4,9-o-벤제노-벤즈[f]이소벤조푸란-1,3-디온 [Bull, Soc. Chim. France 1973, 190]을 370 ml의 클로로포름과 370 ml의 액화 암모니아의 혼합물에 도입하고, 이를 3 시간 더 교반시키고, 여과하여 침전물을 다량의 물에 용해시키고, 비점까지 가열하고, 여과한 다음 여액을 산성화시킨다. 융점이 274-276 ℃인 3,10-디클로로-테트라시클로 [6.6.2.02,7.09,14]헥사데카-2(7),3,5,9(14),10,12-헥사엔-15,16-디카르복실산 모노아미드 77 g (이론 수율의 88 %)가 침전된다.83 g (0.24 mol) of 5,10-dichloro-3a, 4,9,9a-tetrahydro-4,9-o-benzeno-benz [f] isobenzofuran-1,3-dione [Bull, Soc . Chim. France 1973, 190] were introduced into a mixture of 370 ml of chloroform and 370 ml of liquefied ammonia, which were stirred for another 3 hours, filtered to dissolve the precipitate in a large amount of water, heated to boiling point, filtered and the filtrate Acidify. 3,10-dichloro-tetracyclo [6.6.2.0 2,7 9,14 ] hexadeca-2 (7), 3,5,9 (14), 10,12-hexa 77 g of ene-15,16-dicarboxylic acid monoamide (88% of theory yield) are precipitated.

400 ml 크실렌중 상기 기재된 아미드 27.5 g 을 물 분별기상에서 30분간 환류시킨다. 냉각시 형성된 침전물을 여과 제거하고 디에틸 에테르로 세척한다. 융점이 279-281 ℃인 5,10-디클로로-3a,4,9,9a-테트라히드로4,9-o-벤제노-벤즈[f]이소인돌-1,3-디온 23.5 g (이론 수율의 90 %)이 수득된다.27.5 g of the amide described above in 400 ml xylene are refluxed for 30 minutes on a water separator. The precipitate formed upon cooling is filtered off and washed with diethyl ether. 23.5 g of 5,10-dichloro-3a, 4,9,9a-tetrahydro4,9-o-benzeno-benz [f] isoindole-1,3-dione having a melting point of 279-281 ° C. (of theoretical yield 90%) is obtained.

실시예 27Example 27

5,10-디클로로-2-(4,5-디히드로-1H-이미다졸-2-일)-3a,4,9,9a-테트라히드로-4,9-o-벤제노-벤즈[f] 이소인돌5,10-dichloro-2- (4,5-dihydro-1H-imidazol-2-yl) -3a, 4,9,9a-tetrahydro-4,9-o-benzeno-benz [f] Isoindole

5,10-디클로로-3a,4,9,9a-테트라히드로-4,9-o-벤제노-벤즈[f]이소인돌 및 2-메틸술파닐-4,5-디히드로-1H-이미다졸 히드로브로마이드로부터 실시예 20에 기재된 바와 유사한 방식으로 융점이 325-326 ℃ 인 표제 화합물을 41% 수율로 수득한다.5,10-dichloro-3a, 4,9,9a-tetrahydro-4,9-o-benzeno-benz [f] isoindole and 2-methylsulfanyl-4,5-dihydro-1H-imidazole From hydrobromide the title compound is obtained in 41% yield having a melting point of 325-326 ° C. in a similar manner as described in Example 20.

실시예 28Example 28

5,10-디클로로-3a,4,9,9a-테트라히드로-4,9-o-벤제노-벤즈[f]이소인돌-2-일-카르복시미다미드5,10-Dichloro-3a, 4,9,9a-tetrahydro-4,9-o-benzeno-benz [f] isoindol-2-yl-carboximidamide

5,10-디클로로-3a,4,9,9a-테트라히드로-4,9-o-벤제노-벤즈[f]이소인돌 및 S-메틸-이소티오우레아 히드로브로마이드로부터 실시예 2에 기재된 바와 유사한 방식으로 융점이 236-238 ℃인 표제 화합물을 27% 수율로 수득한다.5,10-dichloro-3a, 4,9,9a-tetrahydro-4,9-o-benzeno-benz [f] isoindole and S-methyl-isothiourea hydrobromide similar to those described in Example 2 In this manner the title compound having a melting point of 236-238 ° C. is obtained in 27% yield.

실시예 29Example 29

효소 검정 및 약리학적 시험Enzyme Assays and Pharmacological Tests

본 출원의 대표적인 화합물로서, 실시예 28의 화합물을 PLA2-효소 검정 및 동물 실험에서 시험하였다.As a representative compound of the present application, the compound of Example 28 was tested in the PLA 2 -enzyme assay and animal experiments.

1. PLA2-효소 검정에서, 실시예 28의 화합물은 세포솔성 PLA2-효소 활성의 억제를 나타내지만, 분비성 PLA2-효소 활성의 억제를 나타내지는 않는다.1. PLA 2 - compound of Example 28 in the enzyme test, the cell solseong PLA 2 - represents the inhibition of the enzyme activity, secretory PLA 2 - does not indicate inhibition of the enzyme activity.

2. 동물 실험 (쥐)에서, 복강내 투여된 실시예 28의 화합물은 급성 염증성 카라기닌 부종의 억제 (ED50=16 mg/kg) 및 일반화된 아쥬반스 관절염의 억제를 나타낸다.2. In animal experiments (rats), the compound of Example 28 administered intraperitoneally shows inhibition of acute inflammatory carrageenan edema (ED 50 = 16 mg / kg) and inhibition of generalized adjuvants arthritis.

Claims (4)

포스포리파제 저해 작용을 갖는 약학 제제의 제조에 사용되는 하기 일반 화학식 I 의 테트라시클로[6.6.2.02,7.09,14] 헥사데카-2(7), 3, 5, 9(14), 10, 12-헥사엔 유도체 및 생리적으로 허용 가능한 염, 에스테르, 광학 활성 형태 및 그의 라세미체, 및 생체내에서 대사되어 하기 일반 화학식 I 의 화합물을 형성할 수 있는 유도체의 용도:Tetracyclo [6.6.2.0 2,7 .0 9,14 ] hexadeca-2 (7), 3, 5, 9 (14) of the general formula (I) used for the preparation of pharmaceutical preparations having phospholipase inhibitory activity , 10, 12-hexaene derivatives and the use of physiologically acceptable salts, esters, optically active forms and racemates thereof, and derivatives which can be metabolized in vivo to form compounds of the general formula [화학식 I][Formula I] [식중,[Meal, R1 및 R2 는 동일하거나 상이하며 수소 또는 할로겐 원자를 나타내고,R1 and R2 are the same or different and represent a hydrogen or halogen atom, X 는 수소를 나타내며,X represents hydrogen, Y 는 기 -NR3R4 또는 기 -N+CH3R3R4 를 나타내거나, 또는Y represents a group -NR3R4 or a group -N + CH 3 R3R4, or X 및 Y 는 함께 기 ＞CH2-NR5 를 형성하며,X and Y together form the group> CH 2 -NR 5, Z 은 ＞CH2기 또는 ＞C=NH 기를 나타낸다.Z represents a> CH 2 group or a> C = NH group. (상기 식에서, R3 은 수소, 저급 알킬기를 나타내며,Wherein R3 represents hydrogen, a lower alkyl group, R4 는 히드록실, 카르바모일, 아미디노, 헤테로아릴, N-아르알킬헤테로아릴 또는 저급 알킬기를 나타내거나, 또는R4 represents hydroxyl, carbamoyl, amidino, heteroaryl, N-aralkylheteroaryl or lower alkyl group, or R3 및 R4 는 그들이 결합된 질소 원자와함께, 추가의 헤테로 원자에 의해 임의로 단절될 수 있으며 1 회 또는 수회 임의로 치환될 수 있는 헤테로시클릭 고리를 형성하며,R 3 and R 4 together with the nitrogen atom to which they are attached form a heterocyclic ring which may be optionally interrupted by an additional hetero atom and optionally substituted one or several times, R5 는 수소, 아미디노기 또는 하나 또는 수개의 다른 헤테로 원자에 의해 임의로 단절된 헤테로사이클을 나타낸다.)]R 5 represents a heterocycle optionally interrupted by hydrogen, an amidino group or one or several other hetero atoms.)] 하기 일반 화학식 I 의 화합물 및 생리적으로 허용 가능한 염, 에스테르, 광학 활성 형태 및 그의 라세미체, 및 생체내에서 대사되어 하기 일반 화학식 I 의 화합물을 형성할 수 있는 유도체:Compounds of the general formula (I) and physiologically acceptable salts, esters, optically active forms and racemates thereof, and derivatives which can be metabolized in vivo to form compounds of the general formula (I): [화학식 I][Formula I] [식중,[Meal, R1 및 R2 는 동일하거나 상이하며 수소 또는 할로겐 원자를 나타내고,R1 and R2 are the same or different and represent a hydrogen or halogen atom, X 는 수소를 나타내며,X represents hydrogen, Y 는 기 -NR3R4 또는 기 -N+CH3R3R4 를 나타내거나, 또는Y represents a group -NR3R4 or a group -N + CH 3 R3R4, or X 및 Y 는 함께 기 ＞CH2-NR5 를 형성하며,X and Y together form the group> CH 2 -NR 5, Z 은 ＞CH2기 또는 ＞C=NH 기를 나타낸다.Z represents a> CH 2 group or a> C = NH group. (상기 식에서, R3 은 수소, 저급 알킬기를 나타내며,Wherein R3 represents hydrogen, a lower alkyl group, R4 는 히드록실, 카르바모일, 아미디노, 헤테로아릴, N-아르알킬헤테로아릴 또는 저급 알킬기를 나타내거나, 또는R4 represents hydroxyl, carbamoyl, amidino, heteroaryl, N-aralkylheteroaryl or lower alkyl group, or R3 및 R4 는 그들이 결합된 질소 원자와함께, 추가의 헤테로 원자에 의해 임의로 단절될 수 있으며 1 회 또는 수회 임의로 치환될 수 있는 헤테로시클릭 고리를 형성하며,R 3 and R 4 together with the nitrogen atom to which they are attached form a heterocyclic ring which may be optionally interrupted by an additional hetero atom and optionally substituted one or several times, R5 는 수소, 아미디노기 또는 하나 또는 수개의 다른 헤테로 원자에 의해 임의로 단절된 헤테로사이클을 나타낸다.),R 5 represents a heterocycle optionally interrupted by hydrogen, an amidino group or one or several other hetero atoms), 단, R1 및 R2 가 동시에 수소를 나타낸다면Provided that R1 and R2 simultaneously represent hydrogen (a) R4 는 저급 알킬기를 나타내지 않거나 또는(a) R4 does not represent a lower alkyl group or (b) R5 는 수소를 나타내지 않거나 또는(b) R5 does not represent hydrogen or (c) R3 및 R4 는 함께 비치환된 피페리딘 고리 또는 모르폴린 고리를 형성하지 않는다.](c) R3 and R4 together do not form an unsubstituted piperidine ring or morpholine ring.] 통상의 담체 및 보조 물질외에 제 2 항에서 청구된 화학식 I 의 화합물 하나 이상을 함유하는 약학 제제.A pharmaceutical formulation containing at least one compound of the formula (I) as claimed in claim 2 in addition to the usual carriers and auxiliary substances. 포스포리파제 저해 작용을 갖는 약학 제제의 제조에 사용되는 제 2 항에서 청구된 화학식 I 의 화합물의 용도.Use of a compound of formula (I) as claimed in claim 2 for the preparation of a pharmaceutical formulation having a phospholipase inhibitory action.
KR1020007003134A 1997-09-24 1998-09-24 9,10-dihydro-9,10-ethanoanthracene derivatives as phospholipase inhibitors KR20010024258A (en)

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DE19742014A DE19742014A1 (en) 1997-09-24 1997-09-24 Use of new and known tetracyclene compounds as phospholipase inhibitors
DE19742014.1 1997-09-24
PCT/EP1998/006096 WO1999015493A1 (en) 1997-09-24 1998-09-24 9,10-dihydro-9,10-ethanoanthracene derivatives as phospholipase inhibitors

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US7625921B2 (en) 2004-01-16 2009-12-01 Bristol-Myers Squibb Company Modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
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US7411071B2 (en) 2005-01-13 2008-08-12 Bristol-Myers Squibb Company Modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
US7642273B2 (en) 2005-01-13 2010-01-05 Bristol-Myers Squibb Company Modulators of the glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
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ZA988711B (en) 2000-03-23
AU9746698A (en) 1999-04-12

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