KR20010031699A - Biphenyl Derivatives as Pharmaceuticals - Google Patents

Biphenyl Derivatives as Pharmaceuticals Download PDF

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KR20010031699A
KR20010031699A KR1020007004762A KR20007004762A KR20010031699A KR 20010031699 A KR20010031699 A KR 20010031699A KR 1020007004762 A KR1020007004762 A KR 1020007004762A KR 20007004762 A KR20007004762 A KR 20007004762A KR 20010031699 A KR20010031699 A KR 20010031699A
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methoxy
trifluoromethyl
biphenyl
formula
compound
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KR1020007004762A
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에스테반 폼보빌라
마누엘 콜러
실비오 오프너
로베르트 스보보다
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한스 루돌프 하우스, 헨리테 브룬너, 베아트리체 귄터
노파르티스 아게
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Priority claimed from GBGB9723134.4A external-priority patent/GB9723134D0/en
Priority claimed from GBGB9723133.6A external-priority patent/GB9723133D0/en
Application filed by 한스 루돌프 하우스, 헨리테 브룬너, 베아트리체 귄터, 노파르티스 아게 filed Critical 한스 루돌프 하우스, 헨리테 브룬너, 베아트리체 귄터
Publication of KR20010031699A publication Critical patent/KR20010031699A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Abstract

약제로서 유용한 화학식 I의 화합물.Compounds of formula I useful as medicaments.

〈화학식 I〉<Formula I>

상기 식에서, R1, R2, R3, R4및 R5는 명세서에 정의된 바와 같다.Wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the specification.

Description

약제로서의 비페닐 유도체 {Biphenyl Derivatives as Pharmaceuticals}Biphenyl Derivatives as Pharmaceuticals

본 발명은 신규 비페닐 유도체, 그의 제조 방법, 약제로서의 그의 용도 및 그를 함유한 제약 조성물에 관한 것이다.The present invention relates to novel biphenyl derivatives, methods for their preparation, their use as medicaments and pharmaceutical compositions containing them.

더욱 구체적으로는, 본 발명은 유리 염기 또는 산 부가염의 형태의 화학식 I의 화합물을 제공한다.More specifically, the present invention provides a compound of formula I in the form of a free base or an acid addition salt.

상기 식에서,Where

R1및 R2는 독립적으로 수소, (C1-4)알킬, (C1-4)알콕시, (C1-4)알킬티오, 할로겐, 트리플루오로메틸, 트리플루오로메톡시, 시아노 또는 (C2-5)알카노일이고,R 1 and R 2 are independently hydrogen, (C 1-4 ) alkyl, (C 1-4 ) alkoxy, (C 1-4 ) alkylthio, halogen, trifluoromethyl, trifluoromethoxy, cyano or (C 2-5 ) alkanoyl,

R3은 수소, 히드록시, (C1-4)알킬, (C1-4)알콕시, (C3-6)시클로알킬옥시, 할로겐, 시아노, (C2-5)알카노일, 카르바모일, (C1-4)알킬술포닐옥시 또는 트리플루오로메틸술포닐옥시이고,R 3 is hydrogen, hydroxy, (C 1-4 ) alkyl, (C 1-4 ) alkoxy, (C 3-6 ) cycloalkyloxy, halogen, cyano, (C 2-5 ) alkanoyl, carba Moly, (C 1-4 ) alkylsulfonyloxy or trifluoromethylsulfonyloxy,

R4는 수소, 히드록시 또는 (C1-4)알콕시이고,R 4 is hydrogen, hydroxy or (C 1-4 ) alkoxy,

R5는 화학식또는의 기이며, 여기서,R 5 is a chemical formula or Where is

R6은 (C1-4)알킬이고,R 6 is (C 1-4 ) alkyl,

X는 탄소수 1 내지 4의 직쇄 또는 분지쇄 알킬렌이고,X is straight or branched chain alkylene having 1 to 4 carbon atoms,

R7및 R8은 독립적으로 수소, (C1-4)알킬, 히드록시(C2-4)알킬 또는 페닐(C1-4)알킬이거나, 또는 그들이 부착되어 있는 질소 원자와 함께 피롤리디닐, 피페리디노, 피페라지닐 또는 모르폴리노기 또는 화학식(e)의 기(여기서, Z는 O, CH2또는 CH2-CH2이고, R9, R10, R11, R12, R13및 R14는 독립적으로 H, 할로겐, (C1-4)알킬 또는 (C1-4)알콕시임)를 형성한다.R 7 and R 8 are independently hydrogen, (C 1-4 ) alkyl, hydroxy (C 2-4 ) alkyl or phenyl (C 1-4 ) alkyl, or pyrrolidinyl together with the nitrogen atom to which they are attached , Piperidino, piperazinyl or morpholino groups or chemical formulas groups of (e) wherein Z is O, CH 2 or CH 2 -CH 2 , and R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently H, halogen, (C 1- 4 ) alkyl or (C 1-4 ) alkoxy).

화학식 I의 화합물 및 그의 염에 비대칭 탄소 원자가 존재할 수 있으므로 이 화합물은 광학 활성 형태 또는 광학 이성질체의 혼합물, 예를 들면 라세미 혼합물의 형태로 존재할 수 있다. 모든 광학 이성질체 및 라세미 혼합물을 비롯한 그의 혼합물도 본 발명의 일부이다.Since asymmetric carbon atoms may be present in the compounds of formula (I) and salts thereof, these compounds may exist in optically active forms or in mixtures of optical isomers, for example in the form of racemic mixtures. All optical isomers and mixtures thereof, including racemic mixtures, are also part of the present invention.

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

임의의 알킬, 알콕시 및 알킬티오기는 바람직하게는 직쇄상 기이다. 이들은 바람직하게는 탄소수가 1 내지 3이고, 더욱 바람직하게는 메틸, 메톡시 및 메틸티오기이다.Optional alkyl, alkoxy and alkylthio groups are preferably linear groups. These preferably have 1 to 3 carbon atoms, more preferably methyl, methoxy and methylthio groups.

다음 의미 및 그의 조합이 바람직하다:The following meanings and combinations thereof are preferred:

R1및 R2는 독립적으로 수소, (C1-4)알킬, (C1-4)알콕시, 할로겐 또는 트리플루오로메틸이고,R 1 and R 2 are independently hydrogen, (C 1-4 ) alkyl, (C 1-4 ) alkoxy, halogen or trifluoromethyl,

R3은 수소이거나 또는 페닐 치환체에 대해 파라 위치에 있는 히드록시, (C1-4)알콕시, (C3-6)시클로알킬옥시, 시아노 또는 카르바모일이고,R 3 is hydrogen or hydroxy, (C 1-4 ) alkoxy, (C 3-6 ) cycloalkyloxy, cyano or carbamoyl in the para position relative to the phenyl substituent,

R4는 H이고,R 4 is H,

R5는 화학식 (a) 또는 (d)의 기이다.R 5 is a group of formula (a) or (d).

R5가 화학식 (a)의 기인 경우, R6은 바람직하게는 메틸 또는 프로필이다.When R 5 is a group of formula (a), R 6 is preferably methyl or propyl.

R5가 화학식 (d)의 기인 경우, R7및 R8은 바람직하게는 수소, (C1-4)알킬이거나 또는 그들이 부착되어 있는 질소 원자와 함께 화학식 (e)의 기를 형성한다.When R 5 is a group of formula (d), R 7 and R 8 are preferably hydrogen, (C 1-4 ) alkyl or together with the nitrogen atom to which they are attached form a group of formula (e).

R7및 R8은 그들이 부착되어 있는 질소 원자와 함께 화학식 (e)의 기를 형성하는 경우, Z는 바람직하게는 O이고, R9내지 R14는 독립적으로 바람직하게는 수소 또는 메틸이다.When R 7 and R 8 together with the nitrogen atom to which they are attached form a group of formula (e), Z is preferably O and R 9 to R 14 are independently preferably hydrogen or methyl.

화학식 I의 화합물의 한 군에서 R1, R2, R3및 R4는 상기 정의된 바와 같고, R5는 화학식 (a), (b) 또는 (c)의 기이다.In one group of compounds of formula I, R 1 , R 2 , R 3 and R 4 are as defined above and R 5 is a group of formula (a), (b) or (c).

화학식 I의 화합물의 한 군에서 R1, R2, R3및 R4는 상기 정의된 바와 같고, R5는 화학식 (d)의 기이다.In one group of compounds of formula I, R 1 , R 2 , R 3 and R 4 are as defined above and R 5 is a group of formula (d).

다른 특징에서, 본 발명은 화학식 II의 화합물을 화학식 III의 화합물과 반응시키고 생성된 화합물을 유리 염기 형태 또는 산 부가염 형태로 회수하는 것을 포함하는 화학식 I의 화합물 및 그의 염의 제조 방법을 제공한다.In another aspect, the present invention provides a process for preparing a compound of formula I and salts thereof comprising reacting a compound of formula II with a compound of formula III and recovering the resulting compound in free base form or in acid addition salt form.

상기 식에서, R1내지 R5는 상기 정의된 바와 같고, Y는 할로겐 또는 트리플루오로메틸 술포네이트이다.Wherein R 1 to R 5 are as defined above and Y is halogen or trifluoromethyl sulfonate.

이 반응은 공지된 방법, 바람직하게는 (예를 들면 실시예 1에 기재된 바와 같은) 전이 금속-촉매에 의한 아릴-아릴 커플링에 의해 일어난다. 할로겐은 바람직하게는 브롬 또는 요오드, 특히 요오드이다.This reaction takes place by known methods, preferably by aryl-aryl coupling by transition metal-catalyst (eg as described in Example 1). Halogen is preferably bromine or iodine, in particular iodine.

또한, 본 발명의 화합물은 예를 들면, 아릴-스타닐, -아연, -할라이드 또는 그리냐드 전구체를 사용한 공지된 다른 금속-촉매에 의한 아릴-아릴 커플링 방법에 의해서도 수득될 수 있다.The compounds of the invention can also be obtained by the aryl-aryl coupling method by other known metal-catalysts using, for example, aryl-stannyl, -zinc, -halide or Grignard precursors.

R5가 화학식 (c)의 기인 화학식 I의 화합물의 제조에 있어서, 화학식 (c)의 기 중의 질소는 예를 들면, 알콕시카르보닐기에 의해 보호될 수 있으며, 이 알콕시카르보닐기는 공지된 방법에 따라 화학식 III의 화합물과의 반응 후에 제거될 수 있다. 예를 들면, 실시예 11을 참조한다.In the preparation of compounds of formula (I) wherein R 5 is a group of formula (c), the nitrogen in the group of formula (c) can be protected by, for example, an alkoxycarbonyl group, which alkoxycarbonyl group is It can be removed after reaction with the compound of III. See, for example, Example 11.

R5가 화학식 (b)의 기인 화학식 I의 화합물의 제조에 있어서, R5가 3-피리딜기인 화학식 I의 화합물을 먼저 화학식 I의 화합물에 대해 상기 기재된 바와 같이 제조하고 이어서 피리딜기를 공지된 방법에 따라 상응하는 피리디늄염을 통해 (예를 들면, 실시예 1에 기재된 바와 같이 피리디늄 요오다이드를 통해) 목적하는 테트라히드로피리딜로 전환시킬 수 있다.In preparing compounds of formula (I) wherein R 5 is a group of formula (b), compounds of formula (I) wherein R 5 is a 3-pyridyl group are first prepared as described above for compounds of formula (I) and then known pyridyl groups According to the method it can be converted to the desired tetrahydropyridyl via the corresponding pyridinium salt (eg, via pyridinium iodide as described in Example 1).

R5가 화학식 (a)의 기인 화학식 I의 화합물의 제조에 있어서, R5가 화학식 (b)인 상응하는 화합물을 먼저 제조하고 이어서 예를 들면, 실시예 5에 기재된 바와 같은 공지된 방법에 따라 수소첨가반응시킬 수 있다.R 5 is in the manufacture of a resulting compound of formula (I) of formula (a), R 5 is in accordance with known methods, such as prepare a corresponding compound of formula (b) first and then for as example, as described in Example 5 Hydrogenation can be carried out.

상응하는 라세미체로부터 예를 들면, 실시예 9 및 10에 기재된 바와 같은 공지된 방법에 따라 광학적으로 순수한 형태의 화학식 I의 화합물을 수득할 수 있다. 또는, 광학적으로 순수한 출발 물질은 실시예 28 및 29에 기재된 바와 같이 사용될 수 있다.From the corresponding racemates, compounds of formula (I) in optically pure form can be obtained, for example, according to known methods as described in Examples 9 and 10. Alternatively, optically pure starting materials can be used as described in Examples 28 and 29.

산 부가염은 유리 염기 형태로부터 공지된 방법으로 제조할 수 있으며 그 반대로도 제조할 수 있다. 본 발명에 따라 사용하기에 적합한 제약학적으로 허용가능한 산 부가염은 예를 들면, 염산염, 말레산염, 푸마르산염 및 말론산염이 있다.Acid addition salts can be prepared from the free base form by known methods and vice versa. Pharmaceutically acceptable acid addition salts suitable for use according to the invention are, for example, hydrochlorides, maleates, fumarates and malonates.

화학식 II의 출발 물질은 공지되어 있거나 화학식 IV의 화합물을 공지된 방법에 따라 할로겐화하여 제조할 수 있다.Starting materials of formula (II) are known or can be prepared by halogenating the compounds of formula (IV) according to known methods.

상기 식에서, R3, R4및 R5는 상기 정의된 바와 같다.Wherein R 3 , R 4 and R 5 are as defined above.

화학식 III 및 IV의 출발 물질은 공지되어 있거나 또는 예를 들면, 실시예에 기재된 바와 같은 공지된 방법과 유사하게 제조될 수 있다.Starting materials of the formulas (III) and (IV) are known or can be prepared analogously to known methods, for example as described in the Examples.

화학식 I의 화합물 및 제약학적으로 허용가능한 그의 산 부가염 (이하, 총체적으로 ″본 발명의 약제″로 칭함)은 약리학적 활성을 나타내고 따라서 약제로서 유용하다.Compounds of formula (I) and pharmaceutically acceptable acid addition salts thereof (hereinafter collectively referred to as `` drugs of the invention '') exhibit pharmacological activity and are therefore useful as medicaments.

본 발명의 약제는 마우스에서 약 1 내지 100 mg/kg 경구 투여 및 약 0.32 내지 32 mg/kg 복강내 투여의 투여량에서 최대 전기쇼크에 의한 경련에 대해 지속적인 보호를 제공한다(문헌[E.A. Swinyard, J. Am. Pharm. Assoc. Scient. Ed. 38, 201 (1949)] 및 [J.Pharmacol. Exptl. Therap. 106, 319 (1952)] 참조).The medicament of the present invention provides continuous protection against convulsions by maximal electroshock at doses of about 1 to 100 mg / kg oral and about 0.32 to 32 mg / kg intraperitoneal administration in mice (EA Swinyard, J. Am. Pharm. Assoc. Scient.Ed. 38, 201 (1949) and J. Pharmacol. Exptl. Therap. 106, 319 (1952).

따라서, 본 발명의 약제는 고혈압 신경성 증후군과 같은 간질 및 다른 경련 증상의 치료에 유용하다.Thus, the medicaments of the present invention are useful for the treatment of epilepsy and other convulsive symptoms such as hypertensive neurological syndrome.

또한, 본 발명의 약제는 래트에서 1 내지 50 mg/kg 비경구, 정맥내 및 경구의 투여량에서 허혈증으로 인한 신경 손상 및 중뇌 동맥 (MCA) 폐색 모델에서의 후속 증상을 감소시킨다(문헌[A. Tamura et al., J. Cereb. Blood Flow Metabol. 1, 53-60 (1981), A. Sauter, M. Rudin, Stroke 17, 1228-1234 (1986)] 참조).In addition, the agents of the present invention reduce neuronal damage and subsequent symptoms in the middle cerebral artery (MCA) occlusion model due to ischemia at 1-50 mg / kg parenteral, intravenous and oral dosages in rats (A Tamura et al., J. Cereb. Blood Flow Metabol. 1, 53-60 (1981), A. Sauter, M. Rudin, Stroke 17, 1228-1234 (1986)).

따라서, 본 발명의 약제는 대뇌 산소결핍증, 저산소증 및(또는) 허혈증, 예를 들면 회백질 및 백질에 대한 허혈성 손상, 졸중, 재관류 손상, 지주막하성 출혈, 뇌 및 척수 손상/외상, 높은 두개골내 압력, 다중경색 치매증 또는 혈관성 치매증 및 대뇌 산소결핍증, 저산소증 및(또는) 허혈증과 잠재적으로 연관된 임의의 외과 방법 (예를 들면, 심장 바이패스, 대뇌외 혈관상 수술)중 한 구성요소를 수반하는 임의의 임상적 증상의 치료에 유용하다.Thus, the medicaments of the present invention are useful for cerebral oxygen deficiency, hypoxia and / or ischemia such as ischemic damage to gray and white matter, stroke, reperfusion injury, subarachnoid hemorrhage, brain and spinal cord injury / trauma, high intracranial pressure, Any clinical procedure involving one component of multiinfarct dementia or vascular dementia and any surgical method potentially associated with cerebral oxygen deficiency, hypoxia and / or ischemia (eg, heart bypass, extracerebral vascular surgery) It is useful for the treatment of symptoms.

본 발명의 약제는 약 0.1 내지 약 100 μM의 IC50을 갖는 베라트리딘-민감성 나트륨 채널에 대한 결합을 나타낸다. 결합 과정에 대한 것은 예를 들면, 문헌[J.B Brown, Journal of Neuroscience 6, 2064-2070 (1986)]을 참조한다. 이들은 약 0.1 내지 1 mM의 농도에서 래트의 해마 슬라이스 조제물로 베라트리딘에 의한 글루타메이트 방출을 차단한다. 이 실험은 문헌[M. J. Leach 등 inEpilepsia 27, 490-497 (1986) 및 Stroke 24, 1063-1067 (1993)]에 따라 외래 글루타메이트를 사용하여 수행한다.The medicament of the present invention exhibits a binding to veratridine-sensitive sodium channel having an IC 50 of about 0.1 to about 100 μM. For a binding process see, eg, JB Brown, Journal of Neuroscience 6, 2064-2070 (1986). They block glutamate release by veratridine in the hippocampus slice formulations of rats at a concentration of about 0.1-1 mM. This experiment is performed using foreign glutamate according to MJ Leach et al. In Epilpepsia 27, 490-497 (1986) and Stroke 24, 1063-1067 (1993).

따라서, 본 발명의 약제는 정신의학적 질환 (예를 들면, 정신분열증, 우울증, 불안증, 공황발작, 주의결핍 및 인식 장애, 사회적 이탈증상), 호르몬 질환 (과다 GH [예를 들면, 진성당뇨병, 맥관병 및 선단비대증의 치료시] 또는 LH [전립선 비대증, 폐경기 증후군] 분비, 스트레스시 코르티코스테론 분비), 대사에 의한뇌 손상 (저혈당증, 비케토성 고글라이신혈증 [글리신 뇌질환], 아황산 옥시다제 결핍증, 간기능 부전과 관련된 간에 의한 뇌질환), 구토, 경련성, 이명, 통증 (예를 들면, 암 통증, 관절염) 및 약물 (에탄올, 진정제 [진정제와 같은 효과를 갖는 합성제, 예를 들면 페티딘, 메타돈 등을 포함함], 코카인, 암페타민, 바르비투레이트 및 다른 진정제, 벤조디아제핀) 남용 및 금단을 비롯한 병인론에서 글루타메이트 방출과 관련된 임의의 병, 질환 또는 임상적 증상의 치료에 유용한 것으로 나타났다.Thus, the medicaments of the present invention may be used in psychiatric diseases (e.g., schizophrenia, depression, anxiety, panic attacks, attention deficit and cognitive impairment, social breakaway symptoms), hormonal diseases (excess GH [e.g. diabetes mellitus, vasculature) In the treatment of diseases and acromegaly] or LH [prostate hypertrophy, postmenopausal syndrome] secretion, corticosterone secretion under stress), brain injury by metabolism (hypoglycemia, nonketomic hyperglycineemia [glycine brain disease], sulfite oxidase deficiency) , Brain diseases caused by liver associated with liver failure), vomiting, convulsions, tinnitus, pain (eg cancer pain, arthritis) and drugs (ethanol, sedatives [synthetic agents with effects such as soothing agents, eg pettidine , Methadone, and the like], any disease, disorder associated with glutamate release in etiology, including ***e, amphetamine, barbiturate and other sedatives, benzodiazepines) abuse and withdrawal, or It has been shown to be useful for the treatment of clinical symptoms.

또한, 본 발명의 약제는 신경성 손상, 예를 들면 알츠하이머병, 헌팅톤병 또는 파킨슨병과 같은 신경퇴행성 질환, 바이러스 (HIV 포함)-유도된 신경퇴행증, 근위축성측삭경화증(ALS), 핵상 마비, 올리브교소뇌피질 위축증 (OPCA), 및 환경, 외인성 신경독소의 작용을 포함한 임의의 병의 치료에 사용되는 것으로 나타났다.In addition, the medicaments of the present invention can be used for neurological injuries, such as neurodegenerative diseases such as Alzheimer's disease, Huntington's disease or Parkinson's disease, viruses (including HIV) -induced neurodegeneration, amyotrophic lateral sclerosis (ALS), nuclear paralysis, olive It has been shown to be used for the treatment of glioblastoma cortical atrophy (OPCA) and any disease, including the action of the environment, exogenous neurotoxins.

상기 기재된 지시에 있어서, 물론 적합한 투여량은 예를 들면 사용되는 화합물, 복용자, 투여 방법 및 치료할 질병의 증상과 심각도에 따라 다르다. 그러나, 일반적으로 약 0.1 내지 약 100, 바람직하게는 약 0.5 내지 약 100 mg/kg 동물 체중의 일일 투여량이 동물에서 만족스러운 결과를 나타낸다. 더 큰 포유동물, 예를 들면 사람에 있어서 지시된 일일 투여량은 본 발명의 약제 약 1 내지 약 500, 바람직하게는 약 1 내지 약 300 mg의 일일 투여량으로 통상적으로 하루에 최대 4회 분할된 양으로 또는 서방형으로 투여하는 것이다.In the directions described above, of course suitable dosages depend, for example, on the compound used, the recipient, the method of administration and the symptoms and severity of the disease being treated. However, in general, a daily dose of about 0.1 to about 100, preferably about 0.5 to about 100 mg / kg animal body weight, results in satisfactory results in the animal. In larger mammals, such as humans, the indicated daily dosage is typically divided up to four times a day into a daily dosage of about 1 to about 500, preferably about 1 to about 300 mg of the medicament of the invention. Amount or sustained release.

본 발명의 약제는 임의의 통상적인 경로, 특히 장내로, 바람직하게는 경구로 예를 들면, 정제 또는 캡슐의 형태로 또는 비경구로 예를 들면, 주사가능한 용액 또는 현탁액의 형태로 투여될 수 있다.The agents of the present invention may be administered by any conventional route, in particular in the intestine, preferably orally, for example in the form of tablets or capsules or parenterally, for example in the form of injectable solutions or suspensions.

전술한 것에 따라, 본 발명은 또한 예를 들면 간질, 졸중 및 뇌 또는 척수 외상의 치료를 위한 약제로서 사용하기 위한 본 발명의 약제를 제공한다.As noted above, the present invention also provides a medicament of the invention for use as a medicament, for example for the treatment of epilepsy, stroke and brain or spinal cord trauma.

또한, 본 발명은 본 발명의 약제와 1 종 이상의 제약학적 담체 또는 희석제를 함께 포함하는 제약 조성물을 제공한다. 이러한 조성물은 통상적인 방법에 따라 제조될 수 있다. 단위 투여량은 예를 들면 본 발명에 따른 화합물 약 0.25 내지 약 150, 바람직하게는 0.25 내지 약 25 mg을 함유한다.The present invention also provides a pharmaceutical composition comprising a medicament of the invention together with one or more pharmaceutical carriers or diluents. Such compositions may be prepared according to conventional methods. The unit dosage contains, for example, about 0.25 to about 150, preferably 0.25 to about 25 mg of the compound according to the invention.

또한, 본 발명은 상기 기재된 증상, 예를 들면 간질, 졸중 및 뇌 또는 척수외상의 치료를 위한 약제의 제조를 위한 본 발명의 약제의 용도를 제공한다.The present invention also provides the use of a medicament of the invention for the preparation of a medicament for the treatment of the conditions described above, such as epilepsy, stroke and brain or spinal cord trauma.

또한, 본 발명의 추가의 특징에서 상기 기재된 임의의 증상, 예를 들면 간질, 졸중 및 뇌 또는 척수 외상의 치료를 필요로 하는 환자에게 본 발명의 약제의 치료적 유효량을 투여하는 것을 포함하는, 상기 증상의 치료 방법을 제공한다.Further, further features of the present invention include administering a therapeutically effective amount of a medicament of the invention to a patient in need of treatment of any of the conditions described above, such as epilepsy, stroke and brain or spinal cord trauma. Provide a method for treating symptoms.

다음 실시예는 본 발명을 예시한다. 온도는 섭씨를 나타내며 바뀌지 않는다.The following examples illustrate the invention. The temperature is in degrees Celsius and does not change.

실시예 1: 3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-1,2,5,6-테트라히드로피리딘Example 1: 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-1,2,5,6-tetrahydropyridine

A. 3-(5-브로모-2-메톡시-페닐)-피리딘A. 3- (5-Bromo-2-methoxy-phenyl) -pyridine

빙초산 (40 ml) 중의 브롬 (12.2 g, 3.9 ml, 0.076 몰) 용액을 빙초산 (140 ml) 중의 3-(2-메톡시페닐)-피리딘 (14.0 g, 0.076 몰) 및 무수 아세트산나트륨 (6.8 g, 0.083 몰)의 용액에 15분간 적가하고, 15 내지 20 ℃를 유지하였다. 침전물이 관찰되면, 현탁액을 교반시켜 서서히 용해시켰다. 이 현탁액을 실온에서 18 시간 동안 교반시킨 후 투명한 오렌지색 용액을 얻었다. 감압하에 아세트산을 제거하고 잔사를 EtOAc (250 ml)에 용해시켰다. 추출물을 물 (150 ml), 포화 NaHCO3수용액 (100 ml) 및 염수 (75 ml)로 세척하고, 건조 (MgSO4)시키고, 증발시켜 오렌지색 오일로 생성물을 얻었다. TLC(실리카겔, 톨루엔-EtOH-NH4OH 85:15:1) Rf=0.5A solution of bromine (12.2 g, 3.9 ml, 0.076 mol) in glacial acetic acid (40 ml) was added 3- (2-methoxyphenyl) -pyridine (14.0 g, 0.076 mol) and glacial acetic acid (6.8 g) in glacial acetic acid (140 ml). , 0.083 mol) was added dropwise for 15 minutes, and the temperature was maintained at 15 to 20 ° C. If a precipitate was observed, the suspension was slowly dissolved by stirring. This suspension was stirred for 18 hours at room temperature before a clear orange solution was obtained. Acetic acid was removed under reduced pressure and the residue was dissolved in EtOAc (250 ml). The extract was washed with water (150 ml), saturated aqueous NaHCO 3 (100 ml) and brine (75 ml), dried (MgSO 4 ) and evaporated to give the product as an orange oil. TLC (silica gel, toluene-EtOH-NH 4 OH 85: 15: 1) Rf = 0.5

B. 3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-피리딘B. 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -pyridine

3-(5-브로모-2-메톡시-페닐)-피리딘 (19.0 g, 0.072 몰), 4-트리플루오로메틸페닐붕소산 (14.3 g, 0.076 몰), 아세트산팔라듐(II)(520 mg, 0.0023 몰), 트리-o-톨루일포스핀 (2.1 g, 0.0069 몰), 2M 수성 Na2CO3(39 ml, 0.077 몰), MeOH (80 ml) 및 톨루엔 (350 ml)의 혼합물을 아르곤 분위기하에서 18 시간 동안 가열 환류하였다. 혼합물을 냉각시키고 히플로(Hyflo)를 통해 여과하고 물 (100 ml)로 희석하고 상을 분리하였다. 수성상을 톨루엔 (150 ml)으로 추출하고 합한 유기상을 물 (100 ml) 및 염수 (100 ml)로 세척하고 건조 (MgSO4)시키고 활성탄 (1 g)으로 처리하고, 히플로를 통해 여과하고 증발시켜 황색 오일을 얻었다. 이 오일을 EtOH (50 ml)에 용해시키고 3N 에탄올성 HCl (25 ml)로 처리하였다. 에테르 첨가시 히드로클로라이드염이 침전되었다(20 g, 76 %). 융점 229-231 ℃. TLC(실리카겔, 톨루엔-EtOH-NH4OH 85:15:1) Rf=0.55.3- (5-Bromo-2-methoxy-phenyl) -pyridine (19.0 g, 0.072 mol), 4-trifluoromethylphenylboronic acid (14.3 g, 0.076 mol), palladium (II) acetate (520 mg, 0.0023 mol), a mixture of tri-o-toluylphosphine (2.1 g, 0.0069 mol), 2M aqueous Na 2 CO 3 (39 ml, 0.077 mol), MeOH (80 ml) and toluene (350 ml) in an argon atmosphere Under reflux for 18 hours. The mixture was cooled, filtered through Hyflo, diluted with water (100 ml) and the phases separated. The aqueous phase is extracted with toluene (150 ml) and the combined organic phases are washed with water (100 ml) and brine (100 ml), dried (MgSO 4 ), treated with activated charcoal (1 g), filtered through hyflo and evaporated. To give a yellow oil. This oil was dissolved in EtOH (50 ml) and treated with 3N ethanol HCl (25 ml). Hydrochloride salt precipitated (20 g, 76%) upon ether addition. Melting point 229-231 ° C. TLC (silica gel, toluene-EtOH-NH 4 OH 85: 15: 1) Rf = 0.55.

C. 3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-피리디늄 요오다이드C. 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-pyridinium iodide

아세톤 (25 ml) 중의 메틸 요오다이드 (9.4 g, 66 밀리몰)의 용액을 아세톤 (100 ml) 중의 3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-피리딘 (10.9 g, 33 밀리몰)의 찬 (15 ℃) 용액에 15분간 적가하였다. 이어서, 반응 혼합물을 2 시간 동안 가열 환류한 후 메틸 요오다이드의 두번째 부분 (1 ml, 2.2 g, 0.015 밀리몰)을 첨가하고, 혼합물을 추가로 1.5시간 동안 환류하였다. 용매를 증발시킨 후, 황색 고체로 표제 화합물을 얻고 이를 다음 반응에 바로 사용하였다. TLC(실리카겔, 톨루엔-EtOH-NH4OH 85:15:1) Rf=0-0.02A solution of methyl iodide (9.4 g, 66 mmol) in acetone (25 ml) was added to 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl)-in acetone (100 ml). To a cold (15 ° C.) solution of pyridine (10.9 g, 33 mmol) was added dropwise for 15 minutes. The reaction mixture was then heated to reflux for 2 hours before the second portion of methyl iodide (1 ml, 2.2 g, 0.015 mmol) was added and the mixture was refluxed for an additional 1.5 hours. After evaporation of the solvent, the title compound was obtained as a yellow solid which was used directly in the next reaction. TLC (silica gel, toluene-EtOH-NH 4 OH 85: 15: 1) Rf = 0-0.02

D. 3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-1,2,5,6-테트라히드로-피리딘D. 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-1,2,5,6-tetrahydro-pyridine

물 (100 ml) 중의 수산화나트륨 (1.5 g, 36 밀리몰)의 용액을 MeOH (150 ml) 중의 3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-피리디늄 요오다이드의 용액에 가하였다. 생성된 혼합물에 수소화붕소나트륨 (2.5 g, 66 밀리몰)을 30분간 일부씩 가하고 혼합물을 실온에서 60시간 동안 교반하였다. 혼합물을 히플로를 통해 여과하고 여액을 약 100 ml로 농축시켜 황색 오일을 분리하였다. 이 혼합물을 EtOAc로 추출하였다(3 x 125 ml). 합한 유기 추출물을 염수 (75 ml)로 세척하고 건조(MgSO4)시키고 증발시켜 황갈색 오일로 표제 화합물을 얻었다. TLC(실리카겔, 톨루엔-EtOH-NH4OH 85:15:1) Rf=0.4. 말레인산염의 융점은 123-125 ℃ (EtOH/Et2O)였다.A solution of sodium hydroxide (1.5 g, 36 mmol) in water (100 ml) was added 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1- in MeOH (150 ml). To a solution of methyl-pyridinium iodide. To the resulting mixture was added sodium borohydride (2.5 g, 66 mmol) in portions for 30 minutes and the mixture was stirred at room temperature for 60 hours. The mixture was filtered through Hiflo and the filtrate was concentrated to about 100 ml to separate the yellow oil. This mixture was extracted with EtOAc (3 x 125 ml). The combined organic extracts were washed with brine (75 ml), dried (MgSO 4 ) and evaporated to afford the title compound as a tan oil. TLC (silica gel, toluene-EtOH-NH 4 OH 85: 15: 1) Rf = 0.4. The melting point of maleate was 123-125 ° C. (EtOH / Et 2 O).

화학식 I의 다음 화합물들은 실시예 1과 유사한 방법으로 제조하였다:The following compounds of formula I were prepared in a similar manner to Example 1:

실시예 2: 3-(4-메톡시-비페닐-3-일)-1-메틸-1,2,5,6-테트라히드로-피리딘Example 2: 3- (4-methoxy-biphenyl-3-yl) -1-methyl-1,2,5,6-tetrahydro-pyridine

히드로클로라이드염의 융점은 187-194 ℃였다.The melting point of the hydrochloride salt was 187-194 ° C.

실시예 3: 3-(2'-클로로-4-메톡시-비페닐-3-일)-1-메틸-1,2,5,6-테트라히드로-피리딘Example 3: 3- (2'-Chloro-4-methoxy-biphenyl-3-yl) -1-methyl-1,2,5,6-tetrahydro-pyridine

옥살산염의 융점은 137-142 ℃였다.The melting point of the oxalate was 137-142 ° C.

실시예 4: 3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-프로필-1,2,5,6-테트라히드로-피리딘Example 4: 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-propyl-1,2,5,6-tetrahydro-pyridine

화합물을 황색 오일로 수득하였다. TLC(실리카겔, 톨루엔-EtOH-NH4OH 85:15:1) Rf=0.25The compound was obtained as a yellow oil. TLC (silica gel, toluene-EtOH-NH 4 OH 85: 15: 1) Rf = 0.25

실시예 5: 3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-피페리딘Example 5: 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-piperidine

탄소상 팔라듐 (10 %, 700 mg)을 빙초산 (75 ml) 중의 (실시예 1에 따라 수득한) 3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-1,2,5,6-테트라히드로피리딘 (5.3 g, 15.9 밀리몰)의 탈기된 용액에 첨가하고 혼합물을 파르 수소첨가반응기상에서 실온 및 5 atm 수소 압력에서 18시간 동안 수소첨가반응시켰는데 이 시간 동안 수소 70 ml가 사용되었다. 이어서, 촉매를 여과하고 새로운 촉매를 가하고 (0.800 g), 혼합물을 45 ℃ 및 5 atm 수소 압력에서 추가로 18 시간 동안 수소첨가반응시켰는데, 이 시간 동안 수소 400 ml가 사용되었다. 이어서, 현탁액을 여과하고 고체를 AcOH로 세척하고 여액을 증발시켰다. 잔사를 포화 수성 K2CO3로 염기성 용액이 생길 때까지 처리하고 EtOAc로 추출하였다. 유기 추출물을 염수 (30 ml)로 세척하고 건조 (MgSO4)시키고 증발시켜 밝은 갈색 오일로 생성물을 얻었다. 말레인산염의 융점은 93-96 ℃였다(EtOH/Et2O, 분해).Palladium on carbon (10%, 700 mg) in 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl)-(obtained according to example 1) in glacial acetic acid (75 ml)- To a degassed solution of 1-methyl-1,2,5,6-tetrahydropyridine (5.3 g, 15.9 mmol) and the mixture was hydrogenated over 18 hours at room temperature and 5 atm hydrogen pressure on a Parr hydroreactor. 70 ml of hydrogen was used during this time. The catalyst was then filtered and fresh catalyst added (0.800 g) and the mixture was hydrogenated at 45 ° C. and 5 atm hydrogen pressure for an additional 18 hours, during which time 400 ml of hydrogen was used. The suspension was then filtered, the solid was washed with AcOH and the filtrate was evaporated. The residue was treated with saturated aqueous K 2 CO 3 until a basic solution was obtained and extracted with EtOAc. The organic extract was washed with brine (30 ml), dried (MgSO 4 ) and evaporated to afford the product as a light brown oil. The melting point of maleate was 93-96 ° C. (EtOH / Et 2 O, decomposition).

화학식 I의 다음 화합물들은 실시예 5와 유사한 방법으로 제조하였다:The following compounds of formula I were prepared in a similar manner to Example 5:

실시예 6: 3-(4-메톡시-비페닐-3-일)-1-메틸-피페리딘Example 6: 3- (4-methoxy-biphenyl-3-yl) -1-methyl-piperidine

히드로클로라이드염의 융점은 254-262 ℃였다.The melting point of the hydrochloride salt was 254-262 ° C.

실시예 7: 3-(2'-클로로-4-메톡시-비페닐-3-일)-1-메틸-피페리딘Example 7: 3- (2'-Chloro-4-methoxy-biphenyl-3-yl) -1-methyl-piperidine

히드로클로라이드염의 융점은 237-247 ℃였다.The melting point of the hydrochloride salt was 237-247 ° C.

실시예 8: 3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-프로필-피페리딘Example 8: 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-propyl-piperidine

라세미체의 푸마르산염의 융점은 178-180 ℃였다(EtOH/Et2O, 분해).The melting point of the fumarate of racemate was 178-180 ° C. (EtOH / Et 2 O, decomposition).

라세미체를 키랄셀(Chiralcel) OJ상에서 (칼럼 25 x 0.46 cm, 이동상: 헥산-EtOH 9:1) 0.1 % TFA로 HPLC를 사용하여 그의 에난시오머에 분리시켰다. 유속: 1 ml/분. 제1 에난시오머는 8.35 분, 제2 에난시오머는 10.25 분의 체류 시간으로 용출되었다. 에난시오머는 그의 상응하는 푸마르산염으로 결정화되었다, 제1 결정의 [α]D 20= +24.4 (c=1.0, MeOH)이고, 제2 결정의 [α]D 20= -24.3 (c=1.0, MeOH).Racemates were separated on their enantiomers using 0.1% TFA on Chiralcel OJ (column 25 × 0.46 cm, mobile phase: hexane-EtOH 9: 1). Flow rate: 1 ml / min. The first enantiomer was eluted with a residence time of 8.35 minutes and the second enantiomer was 10.25 minutes. The enantiomer was crystallized with its corresponding fumarate, [α] D 20 = +24.4 (c = 1.0, MeOH) of the first crystal and [α] D 20 = -24.3 (c = 1.0, of the second crystal). MeOH).

실시예 9: (-)-3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-피페리딘Example 9: (-)-3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-piperidine

가온시킨 (70 ℃) EtOH (100 ml) 중의 (실시예 5에 따라 수득한) 3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-피페리딘 (7.7 g, 22 밀리몰) 및 (-)-2,3-디-o-톨루일타르타르산 수화물 (8.9 g, 22 밀리몰)의 용액을 실온으로 냉각시키고 18시간 동안 방치하였다. 생성된 결정을 여과하고 100 ml EtOH로부터 재결정하여 융점이 155-156 ℃인 결정을 얻었다; [α]D 20= -77.8 (c=1.0 MeOH). 수득한 결정으로부터 유리 염기가 형성되었다(오일; [α]D 20= -9.3 (c=0.95, MeOH). 이러한 결정을 다시 EtOH (80 ml)로부터 재결정하여 융점이 159-160 ℃인 결정을 얻었다, [α]D 20= -83.0 (c=1.0, MeOH); 유리 염기 (오일): [α]D 20= -12.5 (c=0.9, MeOH). 말레산염의 융점은 124-126 ℃였다(EtOH/Et2O); [α]D 20= -6.2 (c=1.0, MeOH).3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-pi in warmed (70 ° C.) EtOH (100 ml) (obtained according to example 5) A solution of ferridine (7.7 g, 22 mmol) and (-)-2,3-di-o-toluyltartaric acid hydrate (8.9 g, 22 mmol) was cooled to room temperature and left for 18 hours. The resulting crystals were filtered and recrystallized from 100 ml EtOH to give crystals having a melting point of 155-156 ° C; [a] D 2 ° = -77.8 (c = 1.0 MeOH). A free base was formed from the obtained crystals (oil; [α] D 20 = -9.3 (c = 0.95, MeOH) .These crystals were again recrystallized from EtOH (80 ml) to obtain crystals having a melting point of 159-160 ° C. [a] D 20 = -83.0 (c = 1.0, MeOH); free base (oil): [α] D 20 = -12.5 (c = 0.9, MeOH) The melting point of maleate was 124-126 ° C ( EtOH / Et 2 O): [α] D 20 = −6.2 (c = 1.0, MeOH).

실시예 10: (+)-3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-피페리딘Example 10: (+)-3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-piperidine

실시예 9의 모액을 보관해 두고 각각을 포화 수성 K2CO3로 처리하고 EtOAc로 추출하여 유리 염기를 제조하였다. 제1 모액으로부터 얻은 유리 염기 (2.4 g, 6.88 밀리몰)를 끓는 EtOH (40 ml) 중의 (+)-2,3-디-o-톨루일타르타르산 수화물 (2.6 g, 6.88 밀리몰)로 처리하고 냉각시켜 얻은 결정을 EtOH (25 ml)로부터 재결정하여 [α]D 20이 +11.3 (c=1.0, MeOH)인 유리 염기로부터 융점이 164-165 ℃인 무색 결정을 얻었다, [α]D 20= +81.1 (c = 1.1, MeOH). 합한 제2 및 제3 모액으로부터의 유리 염기 (3.6 g, 10.3 밀리몰)를 끓는 EtOH (50 ml) 중의 (+)-2,3-디-o-톨루일타르타르산 수화물 (3.9 g, 10.3 밀리몰)과 합하였다. 완전히 결정화시킨 후, 결정을 EtOH (45 ml)로부터 재결정하여 [α]D 20이 +9.8 (c = 1.4, MeOH)인 유리 염기로부터 [α]D 20이 +85.2 (c = 1.0, MeOH)인 결정을 얻고, EtOH (30 ml)로부터 추가로 재결정하여 융점이 164-165 ℃인 결정을 얻었다; [α]D 20이 +11.3 (c = 1.0, MeOH)인 유리 염기로부터 [α]D 20= +87.3 (c = 1.0, MeOH). 말레산염의 융점은 125-127 ℃ (EtOH/Et2O); [α]D 20= +5.4 (c = 1.1, MeOH).The mother liquor of Example 9 was stored and each treated with saturated aqueous K 2 CO 3 and extracted with EtOAc to prepare a free base. The free base (2.4 g, 6.88 mmol) obtained from the first mother liquor was treated with (+)-2,3-di-o-toluyltartaric acid hydrate (2.6 g, 6.88 mmol) in boiling EtOH (40 ml) and cooled The obtained crystals were recrystallized from EtOH (25 ml) to obtain colorless crystals having a melting point of 164-165 ° C. from a free base having [α] D 20 of +11.3 (c = 1.0, MeOH), [α] D 20 = +81.1 (c = 1.1, MeOH). Free base (3.6 g, 10.3 mmol) from the combined second and third mother liquors with (+)-2,3-di-o-toluyltartaric acid hydrate (3.9 g, 10.3 mmol) in boiling EtOH (50 ml) Combined. After complete crystallization, the crystals were recrystallized from EtOH (45 ml) [α] D 20 is +9.8 (c = 1.4, MeOH) from which the free base [α] D 20 is +85.2 (c = 1.0, MeOH) of Crystals were obtained and further recrystallized from EtOH (30 ml) to give crystals having a melting point of 164-165 ° C; [α] D 20 = +87.3 (c = 1.0, MeOH) from the free base [α] D 20 is +11.3 (c = 1.0, MeOH). The melting point of maleate is 125-127 ° C. (EtOH / Et 2 O); [a] D 2 ° = +5.4 (c = 1.1, MeOH).

실시예 11: 3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-피롤리딘Example 11: 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-pyrrolidine

A. 1-에톡시카르보닐-3-(2-메톡시페닐)-피롤리딘A. 1-Ethoxycarbonyl-3- (2-methoxyphenyl) -pyrrolidine

CH2Cl2(3 ml) 중의 에틸클로로포르메이트 (0.61 ml, 673 mg, 6.21 밀리몰)의 용액을 CH2Cl2(15 ml) 중의 N-에틸-N,N-디이소프로필아민 (1.3 ml, 911 mg, 7.01 밀리몰) 및 3-(2-메톡시페닐)-피롤리딘 (1.00 g, 5.65 밀리몰)의 찬 (0-5 ℃, 얼음조) 용액에 10분간 적가하였다. 황색 반응 혼합물을 실온에서 3.5시간 동안 교반시킨 후, 1N HCl (15 ml), 포화 수성 NaHCO3(15 ml) 및 염수 (10 ml)로 세척하고 건조 (MgSO4)시키고, 용매를 증발시켜 황색 오일로 생성물을 얻었다. TLC(실리카겔, 톨루엔-EtOH-NH4OH 85:15:1) Rf=0.6.CH 2 Cl 2 (3 ml) ethyl chloroformate (0.61 ml, 673 mg, 6.21 mmol) was added to CH 2 Cl 2 (15 ml) of N- ethyl -N, N- diisopropylamine in a (1.3 ml , 911 mg, 7.01 mmol) and 3- (2-methoxyphenyl) -pyrrolidine (1.00 g, 5.65 mmol) were added dropwise to the cold (0-5 ° C, ice bath) solution for 10 minutes. The yellow reaction mixture was stirred at rt for 3.5 h, then washed with 1N HCl (15 ml), saturated aqueous NaHCO 3 (15 ml) and brine (10 ml), dried (MgSO 4 ) and the solvent evaporated to a yellow oil. To give the product. TLC (silica gel, toluene-EtOH-NH 4 OH 85: 15: 1) Rf = 0.6.

B. 1-에톡시카르보닐-3-(5-브로모-2-메톡시페닐)-피롤리딘B. 1-Ethoxycarbonyl-3- (5-bromo-2-methoxyphenyl) -pyrrolidine

빙초산 (3 ml) 중의 브롬 (835 mg, 5.22 밀리몰) 용액을 빙초산 (15 ml) 중의 1-에톡시카르보닐-3-(2-메톡시페닐)-피롤리딘 (1.300 g, 5.22 밀리몰) 및 아세트산나트륨 (470 mg, 5.70 밀리몰)의 용액에 적가하고, 실온에서 18 시간 동안 교반시켰다. 혼합물을 히플로를 통해 여과시키고 용매를 증발시켰다. 잔사를 에틸 아세테이트 (30 ml)에 용해시키고 용액을 물 (20 ml), 포화 수성 Na2CO3(20 ml) 및 염수 (15 ml)로 세척하였다. 수성상을 EtOAc (25 ml)로 추출하고 합한 유기 추출물을 건조 (MgSO4)시키고 증발시켜 황갈색 오일로 생성물을 얻고[TLC (실리카겔, 톨루엔-EtOH-NH4OH 85:15:1) Rf=0.6] 다음 반응에 바로 사용하였다.A solution of bromine (835 mg, 5.22 mmol) in glacial acetic acid (3 ml) was added 1-ethoxycarbonyl-3- (2-methoxyphenyl) -pyrrolidine (1.300 g, 5.22 mmol) in glacial acetic acid (15 ml) and To the solution of sodium acetate (470 mg, 5.70 mmol) was added dropwise and stirred for 18 hours at room temperature. The mixture was filtered through hiflo and the solvent was evaporated. The residue was dissolved in ethyl acetate (30 ml) and the solution was washed with water (20 ml), saturated aqueous Na 2 CO 3 (20 ml) and brine (15 ml). The aqueous phase was extracted with EtOAc (25 ml) and the combined organic extracts were dried (MgSO 4 ) and evaporated to afford the product as a tan oil [TLC (silica gel, toluene-EtOH-NH 4 OH 85: 15: 1) Rf = 0.6 Used directly in the next reaction.

C. 1-에톡시카르보닐-3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-피롤리딘C. 1-Ethoxycarbonyl-3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -pyrrolidine

실시예 1B와 유사한 방법으로 팔라듐-촉매화된 커플링으로 1-에톡시카르보닐-3-(5-브로모-2-메톡시페닐)-피롤리딘 및 4-트리플루오로메틸페닐-붕소산으로부터 수득하였다. TLC (실리카겔, 톨루엔-EtOH-NH4OH 85:15:1) Rf=0.78. 조 생성물을 다음 반응에 바로 사용하였다.1-ethoxycarbonyl-3- (5-bromo-2-methoxyphenyl) -pyrrolidine and 4-trifluoromethylphenyl-boronic acid in a palladium-catalyzed coupling in a similar manner to Example 1B Obtained from. TLC (silica gel, toluene-EtOH-NH 4 OH 85: 15: 1) Rf = 0.78. The crude product was used directly for the next reaction.

D. 3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-피롤리딘D. 3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-pyrrolidine

C에서 수득한 조 생성물 (2.00 g)을 THF (15 ml)에 용해시키고 THF (25 ml) 중의 수소화알루미늄리튬 (350 mg, 9.2 밀리몰)의 찬(0-5 ℃) 현탁액에 15분간 적가하였다. 반응 혼합물을 실온에서 1시간 동안 교반하고 18시간 동안 가열 환류한 후 실온으로 냉각시키고 포화 수성 Na2SO4(2 ml), 2N NaOH (2 ml), 및 Et2O (50 ml)을 차례로 조심스럽게 가하여 처리하였다. 혼합물을 실온에서 1시간 동안 격렬히 교반하고, 침전물을 여과하였다. 침전물을 Et2O-THF (1:1 30 ml)로 추가로 세척하고 합한 여액을 건조 (MgSO4)시키고 증발시켜 적색빛 오일을 얻었다. 이 조 생성물을 Et2O (50 ml)에 용해시키고 2N HCl로 추출하였다(2 x 15 ml). 합한 산 상을 Et2O (20 ml)로 추가로 추출하고 냉각시키고 (얼음조) 포화 수성 K2CO3로 알칼리화시키고 Et2O (50 ml)로 추출하였다. 에테르 추출물을 염수 (30 ml)로 세척하고 건조 (MgSO4)시키고 증발시켜 적색빛 오일로 생성물을 얻었다. TLC (실리카겔, 톨루엔-EtOH-NH4OH 85:15:1) Rf=0.1. 푸마르산염의 융점은 176-180 ℃ (분해)였다.The crude product (2.00 g) obtained in C was dissolved in THF (15 ml) and added dropwise to a cold (0-5 ° C.) suspension of lithium aluminum hydride (350 mg, 9.2 mmol) in THF (25 ml) for 15 minutes. The reaction mixture was stirred at room temperature for 1 hour, heated to reflux for 18 hours, then cooled to room temperature and carefully watched with saturated aqueous Na 2 SO 4 (2 ml), 2N NaOH (2 ml), and Et 2 O (50 ml). Treatment was added gently. The mixture was vigorously stirred at rt for 1 h and the precipitate was filtered off. The precipitate was further washed with Et 2 O-THF (1: 1 30 ml) and the combined filtrates were dried (MgSO 4 ) and evaporated to give a reddish oil. This crude product was dissolved in Et 2 O (50 ml) and extracted with 2N HCl (2 × 15 ml). The combined acid phases were further extracted with Et 2 O (20 ml), cooled (ice bath), alkalined with saturated aqueous K 2 CO 3 and extracted with Et 2 O (50 ml). The ether extract was washed with brine (30 ml), dried (MgSO 4 ) and evaporated to afford the product as a reddish oil. TLC (silica gel, toluene-EtOH-NH 4 OH 85: 15: 1) Rf = 0.1. The melting point of fumarate was 176-180 ° C. (decomposition).

실시예 12: 2-(4'-트리플루오로메틸-비페닐-3-일)에틸아민Example 12: 2- (4'-trifluoromethyl-biphenyl-3-yl) ethylamine

3-(브로모페닐)-에틸아민 (1.400 g, 7.0 밀리몰), 4-트리플루오로메틸페닐붕소산 (1.33 g, 7.0 밀리몰), 트리스-(오르토-톨루일)포스핀 (212 mg, 0.70 밀리몰), 아세트산팔라듐(II) (160 mg, 0.70 밀리몰), 탄산나트륨 수용액 (2M, 3.5 ml), MeOH (2 ml) 및 톨루엔 (25 ml)의 혼합물을 아르곤 하에서 18 시간 동안 가열 환류하였다. 이어서, 혼합물을 실온으로 냉각시키고 상을 분리하였다. 수성상을 톨루엔 (25 ml)으로 추출하였다. 합한 유기상을 물 (25 ml) 및 염수 (30 ml)로 세척하고 건조 (MgSO4)시키고 증발시켰다. 잔사를 크로마토그래피 (실리카겔, 톨루엔-에탄올-NH4OH 85:15:1)시켜 밝은 황색 오일로 생성물을 얻었다. TLC (실리카겔, 톨루엔-에탄올-NH4OH 85:15:1) Rf=0.30.3- (bromophenyl) -ethylamine (1.400 g, 7.0 mmol), 4-trifluoromethylphenylboronic acid (1.33 g, 7.0 mmol), tris- (ortho-toluyl) phosphine (212 mg, 0.70 mmol) ), A mixture of palladium (II) acetate (160 mg, 0.70 mmol), aqueous sodium carbonate solution (2M, 3.5 ml), MeOH (2 ml) and toluene (25 ml) was heated to reflux under argon for 18 hours. The mixture was then cooled to room temperature and the phases separated. The aqueous phase was extracted with toluene (25 ml). The combined organic phases were washed with water (25 ml) and brine (30 ml), dried (MgSO 4 ) and evaporated. The residue was chromatographed (silica gel, toluene-ethanol-NH 4 OH 85: 15: 1) to give the product as a light yellow oil. TLC (silica gel, toluene-ethanol-NH 4 OH 85: 15: 1) Rf = 0.30.

실시예 13: N,N-디메틸-[2-(4'-트리플루오로메틸-비페닐-3-일)에틸]아민Example 13: N, N-dimethyl- [2- (4'-trifluoromethyl-biphenyl-3-yl) ethyl] amine

실시예 12와 유사한 방법으로 얻었다. 말레산염의 융점은 150-153 ℃였다(EtOH/Et2O).Obtained in a similar manner to Example 12. The melting point of maleate was 150-153 ° C. (EtOH / Et 2 O).

또한, 화합물을 공지된 방법, 예를 들면 에쉬바일러-클라케(Eschweiler-Clarke) 메틸화에 따라 실시예 12의 화합물의 디메틸화에 의해 얻을 수도 있다.The compounds may also be obtained by dimethylation of the compounds of Example 12 according to known methods, for example Eschweiler-Clarke methylation.

실시예 14: 2-(6-메톡시-4'-트리플루오로메틸-비페닐-3-일)에틸아민Example 14 2- (6-methoxy-4'-trifluoromethyl-biphenyl-3-yl) ethylamine

실시예 12와 유사한 방법으로 황색 오일로 얻었다. TLC (실리카겔, 톨루엔-EtOH-NH4OH 85:15:1) Rf=0.30.Obtained as a yellow oil in a similar manner as in Example 12. TLC (silica gel, toluene-EtOH-NH 4 OH 85: 15: 1) Rf = 0.30.

실시예 15: N,N-디메틸-[2-(6-메톡시-4'-트리플루오로메틸-비페닐-3-일)에틸]아민Example 15 N, N-dimethyl- [2- (6-methoxy-4'-trifluoromethyl-biphenyl-3-yl) ethyl] amine

실시예 12와 유사한 방법으로 얻었다. 히드로클로라이드염의 융점은 210-212 ℃였다(EtOH/Et2O).Obtained in a similar manner to Example 12. The melting point of the hydrochloride salt was 210-212 ° C. (EtOH / Et 2 O).

또한, 화합물을 실시예 14의 화합물의 에쉬바일러-클라케 메틸화에 따라 얻을 수도 있다.Compounds may also be obtained according to Eschweiler-Clark methylation of the compounds of Example 14.

실시예 16: 2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)에틸아민Example 16: 2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) ethylamine

실시예 12와 유사한 방법으로 얻었다. 말레산염의 융점은 157-160 ℃였다(EtOH).Obtained in a similar manner to Example 12. The melting point of maleate was 157-160 ° C. (EtOH).

실시예 17: N,N-디메틸-2-[(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)에틸]아민Example 17 N, N-Dimethyl-2-[(4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) ethyl] amine

실시예 12와 유사한 방법으로 얻었다. 말레산염의 융점은 136-137 ℃였다(EtOH).Obtained in a similar manner to Example 12. The melting point of maleate was 136-137 ° C. (EtOH).

또한, 화합물을 실시예 16의 화합물의 에쉬바일러-클라케 메틸화에 따라 얻을 수도 있다.Compounds may also be obtained following Eschweiler-Clark methylation of the compounds of Example 16.

실시예 18: N-프로필-2-[4-메톡시-4'-트리플루오로메틸-비페닐-3-일)]에틸아민Example 18 N-propyl-2- [4-methoxy-4'-trifluoromethyl-biphenyl-3-yl)] ethylamine

실시예 12와 유사한 방법으로 얻었다. 말레산염의 융점은 178-180 ℃였다(EtOH/Et2O).Obtained in a similar manner to Example 12. The melting point of maleate was 178-180 ° C. (EtOH / Et 2 O).

실시예 19: 1-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)에틸]피롤리딘Example 19: 1- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) ethyl] pyrrolidine

실시예 12와 유사한 방법으로 얻었다. 말레산염의 융점은 131-133 ℃였다(EtOH/Et2O).Obtained in a similar manner to Example 12. The melting point of maleate was 131-133 ° C. (EtOH / Et 2 O).

화합물은 다음과 같이 얻을 수 있다:The compound can be obtained as follows:

A. 1-[2-(4-메톡시-4'-트리플루오로에틸-비페닐-3-일)-에틸-피롤리딘-2,5-디온A. 1- [2- (4-methoxy-4'-trifluoroethyl-biphenyl-3-yl) -ethyl-pyrrolidine-2,5-dione

THF (60 ml) 중의 2-(4-메톡시-4'-트리플루오로메틸비페닐-3-일)-에틸아민 (1.4 g, 4.74 밀리몰) 및 숙신산 무수물 (475 mg, 4.74 밀리몰)의 용액을 18시간 동안 가열 환류하였다. 이어서, 용액을 증발 건조시키고 잔사를 190 ℃로 가열하여 오일로 만든 후 방치하여 결정화시키고 재결정(Et2O)하여 생성물을 얻었다, 융점 116-120 ℃.Solution of 2- (4-methoxy-4'-trifluoromethylbiphenyl-3-yl) -ethylamine (1.4 g, 4.74 mmol) and succinic anhydride (475 mg, 4.74 mmol) in THF (60 ml) Heated to reflux for 18 h. The solution was then evaporated to dryness and the residue heated to 190 ° C. to make an oil which was then left to crystallize and recrystallized (Et 2 O) to give the product, melting point 116-120 ° C.

B. 1-[2-(4-메톡시-4'-트리플루오로에틸-비페닐-3-일)-에틸]피롤리딘B. 1- [2- (4-methoxy-4'-trifluoroethyl-biphenyl-3-yl) -ethyl] pyrrolidine

THF (10 ml) 중의 1-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3- 일)-에틸-피롤리딘-2,5-디온 (1.3 g, 3.45 밀리몰)의 용액을 THF (15 ml) 중의 수소화알루미늄리튬 (262 mg, 6.9 밀리몰)의 현탁액에 10분간 적가하고 0-10 ℃에서 유지시켰다. 첨가를 완결하고 혼합물을 실온으로 가온하고 1시간 동안 교반시킨 후 18시간 동안 가열 환류하였다. 냉각시킨 후 반응 혼합물을 포화 수성 Na2SO4(2 ml) 및 수성 NaOH (2N, 1 ml)로 차례로 처리하였다. Et2O (25 ml)을 첨가한 후 생성된 혼합물을 1시간 동안 교반하고, 여과하였다. 침전물을 Et2O로 세척하고 세척액을 여액과 합하였다. Et2O 용액을 건조 (MgSO4)시키고 증발시켜 황색 오일을 얻고 결정화로 정제하여 말레산염을 얻었다.1- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethyl-pyrrolidine-2,5-dione (1.3 g, 3.45 mmol) in THF (10 ml) ) Was added dropwise to a suspension of lithium aluminum hydride (262 mg, 6.9 mmol) in THF (15 ml) for 10 minutes and maintained at 0-10 ° C. The addition was complete and the mixture was allowed to warm to rt, stirred for 1 h and then heated to reflux for 18 h. After cooling the reaction mixture was treated sequentially with saturated aqueous Na 2 SO 4 (2 ml) and aqueous NaOH (2N, 1 ml). After addition of Et 2 O (25 ml) the resulting mixture was stirred for 1 h and filtered. The precipitate was washed with Et 2 O and the wash was combined with the filtrate. The Et 2 O solution was dried (MgSO 4 ) and evaporated to give a yellow oil which was purified by crystallization to give maleate.

실시예20:(1S*,2S*,6R*,7R*)-4-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-에틸]-10-옥사-4-아자-트리시클로[5.2.1.0(2,6)]데칸Example 20: (1S * , 2S * , 6R * , 7R * )-4- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethyl] -10- Oxa-4-aza-tricyclo [5.2.1.0 (2,6)] decane

실시예 12와 유사한 방법으로 얻었다. 말레산염의 융점은 163-164 ℃였다(EtOH/Et2O). 또한, 화합물은 다음과 같이 얻을 수 있다:Obtained in a similar manner to Example 12. The melting point of maleate was 163-164 ° C. (EtOH / Et 2 O). In addition, the compound can be obtained as follows:

A. (1S*,2R*,6S*,7R*)-4-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-에틸]-10-옥사-4-아자-트리시클로[5.2.1.0(2,6)]데칸-3,5-디온A. (1S * , 2R * , 6S * , 7R * )-4- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethyl] -10-oxa- 4-aza-tricyclo [5.2.1.0 (2,6)] decane-3,5-dione

THF (60 ml) 중의 2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-에틸아민 (1.4 g, 4.74 밀리몰) 및 (1S*,2R*,6S*,7R*)-4,10-디옥사-트리시클로[5.2.1.0 (2,6)]데칸-3,5-디온 (850 mg, 5.1 밀리몰)의 용액을 실시예 8A와 유사한 방법으로 18시간 동안 가열 환류하여 생성물을 얻었다, 융점 166-168 ℃.2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethylamine (1.4 g, 4.74 mmol) in THF (60 ml) and (1S * , 2R * , 6S * , A solution of 7R * )-4,10-dioxa-tricyclo [5.2.1.0 (2,6)] decane-3,5-dione (850 mg, 5.1 mmol) for 18 hours in a similar manner to Example 8A The product was heated to reflux to obtain a product having a melting point of 166-168 占 폚.

B. (1S*,2S*,6R*,7R*)-4-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-에틸]-10-옥사-4-아자-트리시클로[5.2.1.0(2,6)]데칸B. (1S * , 2S * , 6R * , 7R * )-4- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethyl] -10-oxa- 4-aza-tricyclo [5.2.1.0 (2,6)] decane

실시예 20A로부터의 생성물을 THF 중의 수소화알루미늄리튬으로 환원시켜 갈색 오일로 생성물을 수득하고 말레산염으로 결정화하였다.The product from Example 20A was reduced with lithium aluminum hydride in THF to give the product as a brown oil and crystallized with maleate.

실시예21:(1S*,2S*,6R*,7R*)-4-[2-(4-메톡시-4'-트리플루오로메틸-비페 닐-3-일)-에틸]-10-옥사-4-아자-2,6-디메틸-트리시클로[5.2.1.0(2,6)]데칸Example 21: (1S * , 2S * , 6R * , 7R * )-4- [2- (4-methoxy-4'-trifluoromethyl-biphenylyl-3-yl) -ethyl] -10- Oxa-4-aza-2,6-dimethyl-tricyclo [5.2.1.0 (2,6)] decane

실시예 12와 유사한 방법으로 얻었다. 히드로클로라이드염의 융점은 229-231 ℃였다. 또한, 화합물은 다음과 같이 얻을 수도 있다:Obtained in a similar manner to Example 12. The melting point of the hydrochloride salt was 229-231 ° C. The compound may also be obtained as follows:

A. (1S*,2R*,6S*,7R*)-4-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-에틸]-10-옥사-4-아자-2,6-디메틸-트리시클로[5.2.1.0(2,6)]데칸-3,5-디온A. (1S * , 2R * , 6S * , 7R * )-4- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethyl] -10-oxa- 4-aza-2,6-dimethyl-tricyclo [5.2.1.0 (2,6)] decane-3,5-dione

실시예 20A와 유사한 방법으로 2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-에틸아민 및 (1R*,2S*,6R*,7S*)-2,6-디메틸-4,10-디옥사-트리시클로[5.2.1.0 (2,6)]데칸-3,5-디온으로부터 얻었다. 융점 115-117 ℃ (Et2O/헥산).In a similar manner as in Example 20A, 2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethylamine and (1R * , 2S * , 6R * , 7S * )-2, Obtained from 6-dimethyl-4,10-dioxa-tricyclo [5.2.1.0 (2,6)] decane-3,5-dione. Melting point 115-117 ° C. (Et 2 O / hexane).

B. (1S*,2S*,6R*,7R*)-4-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-에틸]-10-옥사-4-아자-2,6-디메틸-트리시클로[5.2.1.0(2,6)]데칸B. (1S * , 2S * , 6R * , 7R * )-4- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethyl] -10-oxa- 4-aza-2,6-dimethyl-tricyclo [5.2.1.0 (2,6)] decane

실시예 20B와 유사한 방법으로 (1R*,2S*,6R*,7S*)-4-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-에틸]-10-옥사-4-아자-2,6-디메틸-트리시클로[5.2.1.0(2,6)]데칸-3,5-디온으로부터 얻었다.In a similar manner as in Example 20B, (1R * , 2S * , 6R * , 7S * )-4- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethyl] Obtained from -10-oxa-4-aza-2,6-dimethyl-tricyclo [5.2.1.0 (2,6)] decane-3,5-dione.

실시예 22: 2-(4'-이소프로필-4-메톡시-비페닐-3-일)-에틸아민Example 22: 2- (4'-Isopropyl-4-methoxy-biphenyl-3-yl) -ethylamine

실시예 12와 유사한 방법으로 얻었다. TLC (실리카겔, EtOAc-NH4OH 0:20:2) Rf=0.22.Obtained in a similar manner to Example 12. TLC (silica gel, EtOAc-NH 4 OH 0: 20: 2) Rf = 0.22.

실시예 23: N,N-디메틸-2-(4'-이소프로필-4-메톡시-비페닐-3-일)-에틸아민Example 23 N, N-dimethyl-2- (4'-isopropyl-4-methoxy-biphenyl-3-yl) -ethylamine

실시예 12와 유사한 방법으로 얻었다. 말레산염의 융점은 123-124 ℃였다(EtOH/Et2O).Obtained in a similar manner to Example 12. The melting point of maleate was 123-124 ° C. (EtOH / Et 2 O).

또한, 화합물을 실시예 22의 화합물의 에쉬바일러-클라케 메틸화에 따라 얻을 수도 있다.The compounds can also be obtained according to Eschweiler-Clark methylation of the compounds of Example 22.

실시예 24: 2-(2'-클로로-4-메톡시-비페닐-3-일)-에틸아민Example 24: 2- (2'-Chloro-4-methoxy-biphenyl-3-yl) -ethylamine

실시예 12와 유사한 방법으로 얻었다. 히드로클로라이드염의 융점은 191-205 ℃였다.Obtained in a similar manner to Example 12. The melting point of the hydrochloride salt was 191-205 ° C.

실시예 25: N,N-디메틸-2-(2'-클로로-4-메톡시-비페닐-3-일)-에틸아민Example 25 N, N-dimethyl-2- (2'-chloro-4-methoxy-biphenyl-3-yl) -ethylamine

실시예 12와 유사한 방법으로 얻었다. 히드로클로라이드염의 융점은 151-159 ℃였다.Obtained in a similar manner to Example 12. The melting point of the hydrochloride salt was 151-159 ° C.

또한, 화합물을 실시예 24의 화합물의 에쉬바일러-클라케 메틸화에 따라 얻을 수도 있다.Compounds may also be obtained following Eshweiler-Clark methylation of the compounds of Example 24.

실시예 26: (2'-클로로-4-메톡시-비페닐-3-일-메틸)-N,N-디메틸아민Example 26: (2'-Chloro-4-methoxy-biphenyl-3-yl-methyl) -N, N-dimethylamine

실시예 12와 유사한 방법으로 얻었다. 옥살산염의 융점은 145-159 ℃였다.Obtained in a similar manner to Example 12. The melting point of the oxalate was 145-159 ° C.

실시예 27: N,N-디메틸-2-(2'-클로로-4-메톡시-비페닐-3-일)-1-메틸-에틸아민Example 27 N, N-dimethyl-2- (2'-chloro-4-methoxy-biphenyl-3-yl) -1-methyl-ethylamine

실시예 12와 유사한 방법으로 얻었다. 히드로클로라이드염의 융점은 141-145 ℃였다.Obtained in a similar manner to Example 12. The melting point of the hydrochloride salt was 141-145 ° C.

실시예 28: (+)-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-에틸]-N,N-디메틸-아민Example 28: (+)-[2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -N, N-dimethyl-amine

A. Z-1-메톡시-2-(2-니트로프로페닐)-벤젠A. Z-1-methoxy-2- (2-nitropropenyl) -benzene

1-부틸아민 0.8 ml 및 에탄올 30 ml 중의 2-메톡시벤즈알데히드 10 g, 니트로에탄 6.07 g의 용액을 3일간 환류시키고, 에탄올을 증발시키고 남은 혼합물을 에틸 아세테이트에 용해시켰다. 물과 염수로 추출한 후, 용매를 증발시키고 남은 벌브를 부풀려 증발시켰다. 120-170 ℃/0.01 mbar에서 증발된 분획을 실리카겔상에서 1:1 염화메틸렌/시클로헥산으로 용출시킴으로써 정제하여 황색 플레이트로 표제 화합물을 얻었다, 융점 39-42 ℃.A solution of 10 g of 2-methoxybenzaldehyde and 6.07 g of nitroethane in 0.8 ml of 1-butylamine and 30 ml of ethanol was refluxed for 3 days, ethanol was evaporated and the remaining mixture was dissolved in ethyl acetate. After extraction with water and brine, the solvent was evaporated and the remaining bulb was inflated to evaporate. Fractions evaporated at 120-170 ° C./0.01 mbar were purified by eluting with 1: 1 methylene chloride / cyclohexane on silica gel to give the title compound as a yellow plate, melting point 39-42 ° C.

B. rac-2-(2-메톡시-페닐)-1-메틸-에틸아민B. rac-2- (2-methoxy-phenyl) -1-methyl-ethylamine

에테르 250 ml 중의 Z-1-메톡시-2-(2-니트로프로페닐)-벤젠 45.01 g (233 밀리몰)의 용액을 기계 교반기, 온도계 및 환류 냉각기가 장착되고 디에틸 에테르 600 ml 중의 LiAlH440.84 g을 함유한 플라스크에 서서히 적가하였다. 발열 반응을 얼음으로 냉각하고 5-10 ℃ 사이에 유지시켰다. 실온에서 밤새 교반시킨 후 2M Na2CO3330 ml를 가하고, 생성된 현탁액을 여과하고 에테르상을 2M HCl로 추출하였다. 산성 수성상을 진한 암모니아 1.2 당량으로 알칼리화하고 디에틸 에테르로 추출하였다. 에테르상을 염수로 세척하고 Na2SO4로 건조시키고 농축시켜 황색 오일로 표제 화합물을 얻었다.1H-NMR (360 MHz, CDCl3): 7.2 t, 1H; 7.1 d, 1H; 7.0-6.8 m, 2H; 3.9 s, 3H; 3.2 m, 1H; 2.8 m, 1H; 2.6 m, 1H; 1.1 d, 3H.A solution of 45.01 g (233 mmol) of Z-1-methoxy-2- (2-nitropropenyl) -benzene in 250 ml of ether was loaded with a mechanical stirrer, thermometer and reflux condenser and LiAlH 4 40.84 in 600 ml of diethyl ether. It was slowly added dropwise to the flask containing g. The exothermic reaction was cooled with ice and kept between 5-10 ° C. After stirring overnight at room temperature 330 ml of 2M Na 2 CO 3 were added, the resulting suspension was filtered and the ether phase was extracted with 2M HCl. The acidic aqueous phase was alkalined with 1.2 equivalents of concentrated ammonia and extracted with diethyl ether. The ether phase was washed with brine, dried over Na 2 SO 4 and concentrated to give the title compound as a yellow oil. 1 H-NMR (360 MHz, CDCl 3 ): 7.2 t, 1H; 7.1 d, 1 H; 7.0-6.8 m, 2 H; 3.9 s, 3 H; 3.2 m, 1H; 2.8 m, 1 H; 2.6 m, 1H; 1.1 d, 3 H.

화합물을 나프탈렌-1,5-디술폰산염으로 전환시켜 추가의 정제를 수행하였다.Further purification was performed by converting the compound to naphthalene-1,5-disulfonate.

C.1 (-)-2-(2-메톡시-페닐)-1-메틸-에틸아민C.1 (-)-2- (2-methoxy-phenyl) -1-methyl-ethylamine

메탄올 300 ml 중에 용해된 rac-2-(2-메톡시-페닐)-1-메틸-에틸아민 19.16 g에 메탄올 334 ml 중의 D-(-)-타르타르산 17.49 g의 용액을 가하고 혼합물을 4 ℃에서 3시간 동안 유지하였다. 고체를 여과하고, 모액을 보관하고 필터 케이트를 빙냉 메탄올로 세척하고 광학회전도가 일정해질 때까지 메탄올로부터 2회 재결정하였다. (-)-2-(2-메톡시-페닐)-1-메틸-에틸아민 D-타르타르산염 11.11 g을 미세 백색 플레이트로 얻었다, 융점 144-149 ℃. 유리 염기는 [α]589= -35.4°(c=1, MeOH)의 고유광회전도를 나타냈다. 유리 염기의 분석용 키랄 모세관 전기이동은 98 %를 넘는 광학적 순도를 나타냈다.To 19.16 g of rac-2- (2-methoxy-phenyl) -1-methyl-ethylamine dissolved in 300 ml of methanol was added a solution of 17.49 g of D-(-)-tartaric acid in 334 ml of methanol and the mixture was stirred at 4 ° C. Hold for 3 hours. The solid was filtered, the mother liquor was stored and the filter kit was washed with ice cold methanol and recrystallized twice from methanol until the optical rotation was constant. 11.11 g of (-)-2- (2-methoxy-phenyl) -1-methyl-ethylamine D-tartarate was obtained as a fine white plate, and the melting point was 144-149 ° C. The free base exhibited an intrinsic light rotation of [α] 589 = -35.4 ° (c = 1, MeOH). Analytical chiral capillary electrophoresis of the free base showed optical purity greater than 98%.

C.2 (+)-2-(2-메톡시-페닐)-1-메틸-에틸아민C.2 (+)-2- (2-methoxy-phenyl) -1-methyl-ethylamine

C.1의 (-)-에난시오머의 제조에서 얻은 제1 모액을 농축하고 타르트르산염으로부터 유리된 잔사를 진한 암모니아 및 에틸 아세테이트로 처리하였다. 유기층을 증발시킨 후, 황색 오일 11.14 g을 얻고 메탄올의 총 부피 140 ml 중에서 L-(+)-타르타르산 10.12 g과 합하였다. 4 ℃에서 3시간 후에 생성된 고체를 수집하고 빙냉 메탄올로 세척하고 고유광회전도가 일정할 때까지 메탄올로부터 재결정하였다. (+)-2-(2-메톡시-페닐)-1-메틸-에틸아민-L-타르트르산염 11.92 g을 백색 플레이트로 얻었다. 유리 염기는 [α]589= +37.7°(c=1, MeOH)의 고유광회전도를 나타냈다. 분석용 키랄 모세관 전기이동은 98 %를 넘는 광학적 순도를 나타냈다.The first mother liquor obtained in the preparation of the (-)-enantiomer of C.1 was concentrated and the residue liberated from tartrate was treated with concentrated ammonia and ethyl acetate. After evaporating the organic layer, 11.14 g of a yellow oil was obtained and combined with 10.12 g of L-(+)-tartaric acid in 140 ml of total volume of methanol. After 3 hours at 4 ° C., the resulting solid was collected, washed with ice-cold methanol and recrystallized from methanol until the natural light rotation was constant. 11.92 g of (+)-2- (2-methoxy-phenyl) -1-methyl-ethylamine-L-tartrate was obtained as a white plate. The free base showed an intrinsic light rotation of [α] 589 = + 37.7 ° (c = 1, MeOH). Analytical chiral capillary electrophoresis showed optical purity of over 98%.

D. (-)-[2-(2-메톡시-페닐)-1-메틸-에틸]-N,N-디메틸-아민D. (-)-[2- (2-methoxy-phenyl) -1-methyl-ethyl] -N, N-dimethyl-amine

(+)-2-(2-메톡시-페닐)-1-메틸-에틸아민의 타르타르산염 11.8 g을 에틸 아세테이트 중의 진한 암모니아로 유리시키고 수득한 오일을 메탄올 56 ml에 용해시켰다. 이 용액에 36.5 % 수성 포름알데히드 용액 22.3 ml를 가하고 혼합물을 3 ℃로 냉각시키고 NaCNBH310.66 g으로 조금씩 처리하였다. 실온에서 22시간 교반시킨 후, 용매를 증발시키고 잔사를 에틸 아세테이트 및 물에 분배하였다. 유기상을 물과 염수로 세척하고 Na2SO4로 건조시키고 농축하고 잔사를 실리카겔상에서 60:30:10:1 톨루엔/에틸 아세테이트/메탄올/진한 암모니아로 용출시켜 [α]589= -19.9°(c=1, MeOH)인 황색 오일로 표제 화합물을 얻었다.1H-NMR (360 MHz, CDCl3): 7.2 dxt, 1H; 7.1 dxd, 1H; 7.0-6.8 m, 2H; 3.85 s, 3H; 3.1-3.0 m, 1H; 2.95-2.85 m, 1H; 2.4 br s, 7H; 0.95 d, 3H.11.8 g of tartarate of (+)-2- (2-methoxy-phenyl) -1-methyl-ethylamine were liberated with concentrated ammonia in ethyl acetate and the oil obtained was dissolved in 56 ml of methanol. To this solution was added 22.3 ml of a 36.5% aqueous formaldehyde solution and the mixture was cooled to 3 ° C. and treated slightly with 10.66 g of NaCNBH 3 . After stirring for 22 hours at room temperature, the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over Na 2 SO 4 , concentrated and the residue was eluted with 60: 30: 10: 1 toluene / ethyl acetate / methanol / conc. Ammonia on silica gel [α] 589 = -19.9 ° (c = 1, MeOH) to give the title compound. 1 H-NMR (360 MHz, CDCl 3 ): 7.2 dxt, 1H; 7.1 dxd, 1 H; 7.0-6.8 m, 2 H; 3.85 s, 3 H; 3.1-3.0 m, 1 H; 2.95-2.85 m, 1 H; 2.4 br s, 7H; 0.95 d, 3 H.

E. (+)-[2-(5-브로모-2-메톡시-페닐)-1-메틸-에틸]-N,N-디메틸-아민E. (+)-[2- (5-Bromo-2-methoxy-phenyl) -1-methyl-ethyl] -N, N-dimethyl-amine

20-30 ℃에서 기계적으로 교반되는 플라스크 중의 (-)-[2-(2-메톡시-페닐)-1-메틸-에틸]-디메틸-아민 4.47 g, 아세트산나트륨 2.09 g 및 빙초산 40 ml의 혼합물에 빙초산 8.5 ml 중의 브롬 1.19 ml를 적가하였다. 반응 혼합물을 16시간 동안 교반하고 진한 암모니아로 중화시키고 에틸 아세테이트로 추출하였다. 유기층을 염수 및 Na2SO4로 건조시키고 용매를 증발시키고 실리카겔상에서 수득한 잔사를 60:30:10:1 톨루엔/에틸 아세테이트/메탄올/진한 암모니아로 정제하여 [α]589= +1.5°(c=1.01, MeOH)인 갈색 오일로 표제 화합물 4.32 g을 얻었다.1H-NMR (360 MHz, CDCl3): 7.2-7.0 m, 2H; 6.60 d, 1H; 3.70 s, 3H; 2.95-2.75 m, 2H; 2.3-2.2 m+s, 7H; 0.85 d, 3H.A mixture of 4.47 g of (-)-[2- (2-methoxy-phenyl) -1-methyl-ethyl] -dimethyl-amine, 2.09 g of sodium acetate and 40 ml of glacial acetic acid in a flask mechanically stirred at 20-30 ° C To this was added dropwise 1.19 ml of bromine in 8.5 ml of glacial acetic acid. The reaction mixture was stirred for 16 h, neutralized with concentrated ammonia and extracted with ethyl acetate. The organic layer was dried over brine and Na 2 SO 4 , the solvent was evaporated, and the residue obtained on silica gel was purified with 60: 30: 10: 1 toluene / ethyl acetate / methanol / condensed ammonia [α] 589 = + 1.5 ° (c = 1.01, MeOH) gave 4.32 g of the title compound. 1 H-NMR (360 MHz, CDCl 3 ): 7.2-7.0 m, 2H; 6.60 d, 1 H; 3.70 s, 3 H; 2.95-2.75 m, 2H; 2.3-2.2 m + s, 7H; 0.85 d, 3 H.

F. (+)-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-에틸]-N,N-디메틸-아민F. (+)-[2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -N, N-dimethyl-amine

500 ml 플라스크를 톨루엔 140 ml 및 2M Na2CO328 ml로 채우고 1시간 동안 아르곤 가스로 처리하였다. 이어서, (+)-[2-(5-브로모-2-메톡시-페닐)-1-메틸-에틸]-디메틸-아민 3.94 g, 4-트리플루오로메틸-페닐붕소산 4.95 g 및 테트라키스(트리페닐포스핀)팔라듐 374 mg을 가하고 혼합물을 12시간 동안 환류시켰다. 수성층을 에틸 아세테이트로 추출하고 합한 유기상을 염수로 세척하고 Na2SO4로 건조하고 농축시켜 갈색 오일을 얻었다. 이 오일의 나프탈렌-1,5-디술폰산염을 형성시키고 유리 염기를 유리시켜 디에틸 에테르 중의 HCl로부터 히드로클로라이드염으로 생성물을 결정화하였다. 에탄올/에테르로부터 재결정시켜 미세 백색 플레이트로 표제 화합물의 히드로클로라이드염을 얻었다, 융점 155-163 ℃.The 500 ml flask was filled with 140 ml of toluene and 28 ml of 2M Na 2 CO 3 and treated with argon gas for 1 hour. Then 3.94 g of (+)-[2- (5-bromo-2-methoxy-phenyl) -1-methyl-ethyl] -dimethyl-amine, 4.95 g of 4-trifluoromethyl-phenylboronic acid and tetra 374 mg of kiss (triphenylphosphine) palladium were added and the mixture was refluxed for 12 hours. The aqueous layer was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over Na 2 SO 4 and concentrated to give a brown oil. Naphthalene-1,5-disulfonate of this oil was formed and the free base was liberated to crystallize the product from HCl in diethyl ether to a hydrochloride salt. Recrystallization from ethanol / ether gave the hydrochloride salt of the title compound in a fine white plate, melting point 155-163 ° C.

유리 염기는 고체화 (융점 36-37 ℃)하고 [α]589= +13.0°(c=0.995, MeOH)인 고유광회전도를 나타냈다. 분석용 키랄 HPLC (키랄셀 OJ)는 99 %를 넘는 광학적 순도를 나타냈다.1H-NMR (360 MHz, CDCl3): 7.70 s, 4H; 7.45 dxd, 1H; 7.40 d, 1H; 6.95 d, 1H; 3.90 s, 3H; 3.25-3.20 m, 1H; 3.0-2.9 m, 1H; 2.55-2.45 m, 1H; 2.40 s, 6H; 1.00 d, 1H.The free base solidified (melting point 36-37 ° C.) and exhibited an intrinsic light rotation rate of [α] 589 = + 13.0 ° (c = 0.995, MeOH). Analytical chiral HPLC (chiralcel OJ) showed optical purity greater than 99%. 1 H-NMR (360 MHz, CDCl 3 ): 7.70 s, 4H; 7.45 dxd, 1 H; 7.40 d, 1 H; 6.95 d, 1 H; 3.90 s, 3 H; 3.25-3.20 m, 1 H; 3.0-2.9 m, 1 H; 2.55-2.45 m, 1 H; 2.40 s, 6 H; 1.00 d, 1 H.

실시예 29: (-)-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-에틸]-N,N-디메틸-아민Example 29: (-)-[2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -N, N-dimethyl-amine

A. (+)-[2-(2-메톡시-페닐)-1-메틸-에틸]-N,N-디메틸-아민A. (+)-[2- (2-methoxy-phenyl) -1-methyl-ethyl] -N, N-dimethyl-amine

실시예 28C.1에 기재된 바와 같이 제조된 생성물을 실시예 28D의 설명에 따라 NaCNBH3및 포름알데히드로 환원시켜 황색 오일로 표제 화합물을 얻었다, [α]589= +21.6°(c=1.03, MeOH).The product prepared as described in Example 28C.1 was reduced with NaCNBH 3 and formaldehyde according to the description of Example 28D to give the title compound as a yellow oil, [α] 589 = + 21.6 ° (c = 1.03, MeOH). ).

B. (-)-[2-(5-브로모-2-메톡시-페닐)-1-메틸-에틸]-N,N-디메틸-아민B. (-)-[2- (5-Bromo-2-methoxy-phenyl) -1-methyl-ethyl] -N, N-dimethyl-amine

A에서 제조된 생성물을 실시예 28E에 기재된 바와 같이 브롬화하여 황색 오일로 표제 화합물을 얻었다, [α]589= -1.0°(c=1.05, MeOH).The product prepared in A was brominated as described in Example 28E to give the title compound as a yellow oil, [a] 589 = -1.0 ° (c = 1.05, MeOH).

C. (-)-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-에틸]-N,N-디메틸-아민C. (-)-[2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -N, N-dimethyl-amine

B에서 제조된 생성물을 실시예 28F에 따라 4-트리플루오로메틸-페닐붕소산으로 아릴화하여 백색 플레이트로 표제 화합물의 히드로클로라이드염을 얻었다, 융점 148-163°.The product prepared in B was arylated with 4-trifluoromethyl-phenylboronic acid according to Example 28F to give the hydrochloride salt of the title compound as a white plate, melting point 148-163 °.

유리 염기는 고체화 (융점 31 ℃)하고 [α]589= -12.8°(c=1.0, MeOH)인 고유광회전도를 나타냈다. 분석용 키랄 HPLC (키랄셀 OJ)은 99 %를 넘는 광학적 순도를 나타냈다.The free base solidified (melting point 31 ° C.) and exhibited an intrinsic light rotation of [α] 589 = -12.8 ° (c = 1.0, MeOH). Analytical chiral HPLC (chiralcel OJ) showed optical purity greater than 99%.

실시예 30: [1-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일메틸)-프로필]-N,N-디메틸-아민Example 30: [1- (4-methoxy-4'-trifluoromethyl-biphenyl-3-ylmethyl) -propyl] -N, N-dimethyl-amine

A. 1-메톡시-2-(2-니트로-부트-1-엔일)-벤젠A. 1-methoxy-2- (2-nitro-but-1-enyl) -benzene

1-부틸아민 0.4 ml 및 톨루엔 10 ml 중의 2-메톡시벤즈알데히드 2.72 g, 1-니트로프로판 1.96 g의 용액을 16시간 동안 환류시켰다. 톨루엔을 증발시키고 잔사를 에틸 아세테이트에 용해시키고 물과 염수로 추출하였다. 유기상을 농축시켜 황색 오일로 표제 화합물을 얻었는데, 이는 다음 단계에 사용하기에 충분히 순수했다.1H-NMR (360 MHz, CDCl3): 8.6 s (E-이성질체의 올레핀성 H); 8.2 s (Z-이성질체의 올레핀성 H).A solution of 2.72 g of 2-methoxybenzaldehyde and 1.96 g of 1-nitropropane in 0.4 ml of 1-butylamine and 10 ml of toluene was refluxed for 16 hours. Toluene was evaporated and the residue was dissolved in ethyl acetate and extracted with water and brine. The organic phase was concentrated to give the title compound as a yellow oil, which was pure enough for the next step. 1 H-NMR (360 MHz, CDCl 3 ): 8.6 s (olefinic H of E-isomer); 8.2 s (olefinic H of Z-isomer).

B. 1-(2-메톡시벤질)-프로필아민B. 1- (2-methoxybenzyl) -propylamine

0-5 ℃에서 디에틸 에테르 35 ml 중의 LiAlH42.28 g의 기계적으로 교반된 혼합물에 디에틸 에테르 15 ml 중의 1-메톡시-2-(2-니트로-부트-1-엔일)-벤젠 3.79 g의 용액을 적가하였다. 실온에서 밤새 교반한 후 2M Na2CO320 ml를 가하고 생성된 현탁액을 여과하고 유기상을 2M HCl로 추출하였다. 산성 수성상을 2M NaOH로 알칼리화하고 메틸-t-부틸 에테르로 추출하였다. 유기상을 염수로 세척하고 Na2SO4로 건조시키고 농축시켜 황색 오일로 표제 화합물을 얻었다.1H-NMR (360 MHz, CDCl3): 7.2-7.0 m, 2H; 6.9-6.7 m, 2H; 3.8 s, 3H; 2.9 m, 1H; 2.8 dxd, 1H; 2.4 dxd, 1H; 1.5 m, 1H; 1.3 m, 1H; 0.9 t, 3H.3.79 g of 1-methoxy-2- (2-nitro-but-1-enyl) -benzene in 15 ml of diethyl ether in a mechanically stirred mixture of 2.28 g of LiAlH 4 in 35 ml of diethyl ether at 0-5 ° C. Solution was added dropwise. After stirring at room temperature overnight, 20 ml of 2M Na 2 CO 3 was added and the resulting suspension was filtered and the organic phase was extracted with 2M HCl. The acidic aqueous phase was alkalized with 2M NaOH and extracted with methyl-t-butyl ether. The organic phase was washed with brine, dried over Na 2 SO 4 and concentrated to give the title compound as a yellow oil. 1 H-NMR (360 MHz, CDCl 3 ): 7.2-7.0 m, 2H; 6.9-6.7 m, 2H; 3.8 s, 3 H; 2.9 m, 1 H; 2.8 dxd, 1 H; 2.4 dxd, 1 H; 1.5 m, 1 H; 1.3 m, 1H; 0.9 t, 3 H.

C. 1-(5-브로모-2-메톡시-벤질)-프로필아민C. 1- (5-Bromo-2-methoxy-benzyl) -propylamine

20-30 ℃에서 기계적으로 교반되는 플라스크 중의 1-(2-메톡시벤질)-프로필아민 2.25 g, 아세트산나트륨 1.13 g 및 빙초산 57 ml의 혼합물에 빙초산 3 ml 중의 브롬 0.65 ml를 적가하였다. 반응 혼합물을 4시간 동안 교반하고 농축시키고 얻은 잔사를 물과 에틸 아세테이트에 분배하였다. 유기상을 2M 아세트산으로 추출하고 합한 산성 수성상을 진한 암모니아로 알칼리화하였다. 에틸 아세테이트로 재추출하고 유기상을 Na2SO4로 건조시키고 농축시켜 무색 분말로 표제 화합물을 얻었다.1H-NMR (360 MHz, CDCl3): 7.2 d, 1H; 7.1 s, 1H; 6.7 d, 1H; 3.8 s, 3H; 2.9 m, 1H; 2.7 m, 1H; 2.5 m, 1H; 1.6-1.3 m, 2H; 1.0 t, 3H.0.65 ml of bromine in 3 ml of glacial acetic acid was added dropwise to a mixture of 2.25 g of 1- (2-methoxybenzyl) -propylamine, 1.13 g of sodium acetate and 57 ml of glacial acetic acid in a flask mechanically stirred at 20-30 ° C. The reaction mixture was stirred for 4 hours, concentrated and the residue obtained was partitioned between water and ethyl acetate. The organic phase was extracted with 2M acetic acid and the combined acidic aqueous phases were alkalized with concentrated ammonia. Re-extract with ethyl acetate and dry the organic phase with Na 2 SO 4 and concentrate to give the title compound as a colorless powder. 1 H-NMR (360 MHz, CDCl 3 ): 7.2 d, 1H; 7.1 s, 1 H; 6.7 d, 1 H; 3.8 s, 3 H; 2.9 m, 1 H; 2.7 m, 1 H; 2.5 m, 1H; 1.6-1.3 m, 2H; 1.0 t, 3 H.

D. 1-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일메틸)-프로필]-아민D. 1- (4-Methoxy-4'-trifluoromethyl-biphenyl-3-ylmethyl) -propyl] -amine

1-(5-브로모-2-메톡시-벤질)-프로필아민 1.91 g, 테트라키스(트리페닐포스핀)팔라듐 0.3 g, 4-트리플루오로메틸-페닐붕소산 2.61 g, 2M Na2CO324 ml 및 톨루엔 25 ml의 혼합물을 7시간 동안 아르곤하에 환류하였다. 수성상을 디에틸 에테르로 추출한 후, 유기상을 합하고 Na2SO4로 건조시키고 농축시켜 갈색 오일로 표제 화합물을 얻고 실리카겔상에서 85:15:1 톨루엔/에탄올/진한 암모니아로 용출시켜 정제하였다.1H-NMR (360 MHz, CDCl3): 7.65 s, 4H; 7.5 dxd, 1H; 7.4 d, 1H; 7.0 d, 1H; 3.9 s, 3H; 3.1 m, 1H; 2.9 dxd, 1H; 2.6 dxd, 1H; 1.6 m, 1H; 1.4 m, 1H; 1.1 t, 3H.1.91 g of 1- (5-bromo-2-methoxy-benzyl) -propylamine, 0.3 g of tetrakis (triphenylphosphine) palladium, 2.61 g of 4-trifluoromethyl-phenylboronic acid, 2M Na 2 CO A mixture of 3 24 ml and 25 ml of toluene was refluxed under argon for 7 hours. The aqueous phase was extracted with diethyl ether, then the organic phases were combined, dried over Na 2 SO 4 and concentrated to afford the title compound as a brown oil which was purified by eluting with 85: 15: 1 toluene / ethanol / conc. Ammonia on silica gel. 1 H-NMR (360 MHz, CDCl 3 ): 7.65 s, 4H; 7.5 dxd, 1 H; 7.4 d, 1 H; 7.0 d, 1 H; 3.9 s, 3 H; 3.1 m, 1 H; 2.9 dxd, 1 H; 2.6 dxd, 1 H; 1.6 m, 1 H; 1.4 m, 1 H; 1.1 t, 3 H.

E. [1-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일메틸)-프로필]-N,N-디메 틸-아민 히드로클로라이드E. [1- (4-Methoxy-4'-trifluoromethyl-biphenyl-3-ylmethyl) -propyl] -N, N-dimethyl-amine hydrochloride

아르곤하의 3 ℃에서 1-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일메틸)-프로필]-아민 1.25 g, 36.5 % 포르말린 용액 2.5 ml 및 메탄올 10 ml의 혼합물에 NaCNBH31.66 g을 몇 번에 걸쳐 가하였다. 실온에서 밤새 교반한 후 용매를 증발시키고 잔사를 에틸 아세테이트 및 물에 분배하였다. 유기상을 물과 염수로 세척하고 농축시켜 조 생성물을 얻고 이를 디에틸 에테르 중의 HCl로 처리하였다. 생성된 고체를 여과하고 아세톤/디에틸 에테르로부터 재결정하여 백색 침상으로 표제 화합물을 얻었다, 융점 155-172 ℃.To a mixture of 1.25 g of 1- (4-methoxy-4'-trifluoromethyl-biphenyl-3-ylmethyl) -propyl] -amine at 3 ° C. under argon, 2.5 ml of a 36.5% formalin solution and 10 ml of methanol 1.66 g of NaCNBH 3 was added several times. After stirring at room temperature overnight the solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water and brine and concentrated to give the crude product which was treated with HCl in diethyl ether. The resulting solid was filtered and recrystallized from acetone / diethyl ether to give the title compound as white needles, melting point 155-172 ° C.

실시예 31: 1-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-에틸]-피페리딘Example 31: 1- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -piperidine

A. 2-(5-브로모-2-메톡시-페닐)-1-메틸-에틸아민A. 2- (5-Bromo-2-methoxy-phenyl) -1-methyl-ethylamine

2-(2-메톡시-페닐)-1-메틸-에틸아민 (유리 염기, 실시예 28B에 기재된 바와 같이 제조됨) 6.54 g, 아세트산나트륨 3.56 g 및 빙초산 180 ml의 혼합물을 실시예 30C에 기재된 바와 같이 브롬 6.31 g으로 처리하고 황색 오일로 표제 화합물을 얻었다.1H-NMR (360 MHz, CDCl3): 7.4-7.2 m, 2H; 6.7 d, 1H; 3.8 s, 3H; 3.2 hex, 1H; 2.8-2.5 m, 2H; 1.1 d, 3H.A mixture of 6.54 g of 2- (2-methoxy-phenyl) -1-methyl-ethylamine (free base, prepared as described in Example 28B), 3.56 g of sodium acetate and 180 ml of glacial acetic acid was described in Example 30C. Treated with 6.31 g bromine and yield the title compound as a yellow oil. 1 H-NMR (360 MHz, CDCl 3 ): 7.4-7.2 m, 2H; 6.7 d, 1 H; 3.8 s, 3 H; 3.2 hex, 1 H; 2.8-2.5 m, 2H; 1.1 d, 3 H.

B. 2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-에틸아민-히드로클로라이드B. 2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethylamine-hydrochloride

2-(5-브로모-2-메톡시-페닐)-1-메틸-에틸아민 7.62 g, 테트라키스(트리페닐포스핀)팔라듐 0.71 g, 4-트리플루오로메틸-페닐붕소산 7.98 g, 2M Na2CO324 ml, 톨루엔 40 ml 및 에탄올 10 ml의 혼합물을 아르곤하에 9시간 동안 환류하였다. 실시예 30D와 유사하게 수행한 후, 조 오일을 히드로클로라이드염으로 전환시켜 정제하여 백색 플레이트의 형태로 얻었다.1H-NMR (360 MHz, CDCl3): 7.90-7.75 dxd, 4H; 7.65 dxd, 1H; 7.60 d, 1H; 7.15 d, 1H; 3.85 s, 3H; 3.5 m, 1H; 3.1-2.8 m, 2H; 1.15 d, 3H.7.62 g of 2- (5-bromo-2-methoxy-phenyl) -1-methyl-ethylamine, 0.71 g of tetrakis (triphenylphosphine) palladium, 7.98 g of 4-trifluoromethyl-phenylboronic acid, A mixture of 24 ml 2M Na 2 CO 3 , 40 ml toluene and 10 ml ethanol was refluxed under argon for 9 hours. After performing similarly to Example 30D, the crude oil was purified by conversion to hydrochloride salt to give in the form of a white plate. 1 H-NMR (360 MHz, CDCl 3 ): 7.90-7.75 dxd, 4H; 7.65 dxd, 1 H; 7.60 d, 1 H; 7.15 d, 1 H; 3.85 s, 3 H; 3.5 m, 1H; 3.1-2.8 m, 2H; 1.15 d, 3 H.

C. 4-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-에틸-카르바모일]부티르산C. 4- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl-carbamoyl] butyric acid

2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-에틸아민 히드로클로라이드 1.1 g의 염기를 유리시키고 20 시간 동안 환류하에 THF 중의 글루타르산 무수물 0.37 g과 반응시켰다. 용매를 증발시키고 잔사를 에틸 아세테이트에 용해시켰다. 유기상을 1M HCl, 물 및 염수로 추출한 후, Na2SO4로 건조하고 증발시켜 백색 분말로 표제 화합물을 얻었다, 융점 88 ℃(분해).1.1 g of 2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethylamine hydrochloride was liberated and glutaric anhydride in THF under reflux for 20 hours Reacted with 0.37 g. The solvent was evaporated and the residue dissolved in ethyl acetate. The organic phase was extracted with 1M HCl, water and brine, dried over Na 2 SO 4 and evaporated to afford the title compound as a white powder, melting point 88 ° C. (decomposition).

D. 1-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-에틸]-피페리딘-2,6-디온D. 1- [2- (4-Methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -piperidine-2,6-dione

클로로포름 20 ml 중의 C에서 얻은 카르복실산 1.02 g 및 아세틸 클로라이드 4.3 g의 혼합물을 17시간 동안 환류하고 냉각한 후 물과 2M Na2CO3로 추출하였다. 유기상을 Na2SO4로 건조시킨 후 용매를 증발시키고 잔사를 실리카겔상에서 1:2 에틸 아세테이트/시클로헥산으로 용출함으로써 정제하여 밝은 황색 오일로 표제 화합물을 얻고 냉장고에서 고체화하였다.1H-NMR (360 MHz, CDCl3): 7.6-7.5 m, 4H; 7.4 dxd, 1H; 7.2 d, 1H; 6.8 d, 1H; 5.2 m, 1H; 3.8 s, 3H; 3.2-3.0 m, 2H; 2.4-2.3 m, 4H; 1.5 br m 약 2H (+HCD); 1.35 d, 3H.A mixture of 1.02 g of carboxylic acid and 4.3 g of acetyl chloride obtained in C in 20 ml of chloroform was refluxed for 17 hours, cooled and extracted with water and 2M Na 2 CO 3 . The organic phase was dried over Na 2 SO 4 and then the solvent was evaporated and the residue was purified by eluting with 1: 2 ethyl acetate / cyclohexane on silica gel to give the title compound as a light yellow oil and solidified in the refrigerator. 1 H-NMR (360 MHz, CDCl 3 ): 7.6-7.5 m, 4H; 7.4 dxd, 1 H; 7.2 d, 1 H; 6.8 d, 1 H; 5.2 m, 1H; 3.8 s, 3 H; 3.2-3.0 m, 2H; 2.4-2.3 m, 4H; 1.5 br m about 2H (+ HCD); 1.35 d, 3 H.

E. 1-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-에틸]-피페리딘 히드로클로라이드E. 1- [2- (4-Methoxy-4′-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -piperidine hydrochloride

아르곤하에 디에틸 에테르 6 ml 중의 LiAlH40.054 g의 현탁액에 디에틸 에테르 2 ml 중의 1-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-에틸]-피페리딘-2,6-디온 0.3 g의 용액을 약간 냉각하에 적가하였다. 30분간 교반 후 2M Na2CO30.5 ml를 가하고 생성된 혼합물을 여과하고 여액을 산성화하고 1M HCl로 추출하였다. 수성상을 진한 암모니아로 알칼리화시키고 디에틸 에테르로 추출하였다. 유기상을 Na2SO4로 건조한 후 농축시키고 잔사를 디에틸 에테르 중의 HCl 용액으로 처리하여 무색 플레이트로 표제 화합물을 얻었다, 융점 185 ℃(분해).To argon suspension of 0.054 g of LiAlH 4 in 6 ml of diethyl ether under argon, 1- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1- in 2 ml of diethyl ether. A solution of 0.3 g of methyl-ethyl] -piperidine-2,6-dione was added dropwise under slight cooling. After stirring for 30 minutes 0.5 ml of 2M Na 2 CO 3 was added and the resulting mixture was filtered, the filtrate was acidified and extracted with 1M HCl. The aqueous phase was alkalized with concentrated ammonia and extracted with diethyl ether. The organic phase was dried over Na 2 SO 4 and concentrated and the residue was treated with a solution of HCl in diethyl ether to give the title compound as a colorless plate, melting point 185 ° C. (decomposition).

실시예 32: N,N-디에틸-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-에틸]-아민Example 32: N, N-diethyl- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -amine

(실시예 31B에 기재된 바와 같이 수득한) 2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-에틸아민을 에틸아세테이트 중의 10 % Pd/C상의 아세트알데히드로 환원성 알킬화하여 수득하였다. 히드로클로라이드의 융점은 105-107 ℃였다.2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethylamine (obtained as described in Example 31B) was diluted with 10% Pd / C in ethyl acetate. Obtained by acetaldehyde reductive alkylation on a bed. The melting point of the hydrochloride was 105-107 ° C.

Claims (10)

유리 염기 또는 산 부가염 형태의 화학식 I의 화합물.Compound of formula I in free base or acid addition salt form. 〈화학식 I〉<Formula I> 상기 식에서,Where R1및 R2는 독립적으로 수소, (C1-4)알킬, (C1-4)알콕시, (C1-4)알킬티오, 할로겐, 트리플루오로메틸, 트리플루오로메톡시, 시아노 또는 (C2-5)알카노일이고,R 1 and R 2 are independently hydrogen, (C 1-4 ) alkyl, (C 1-4 ) alkoxy, (C 1-4 ) alkylthio, halogen, trifluoromethyl, trifluoromethoxy, cyano or (C 2-5 ) alkanoyl, R3은 수소, 히드록시, (C1-4)알킬, (C1-4)알콕시, (C3-6)시클로알킬옥시, 할로겐, 시아노, (C2-5)알카노일, 카르바모일, (C1-4)알킬술포닐옥시 또는 트리플루오로메틸술포닐옥시이고,R 3 is hydrogen, hydroxy, (C 1-4 ) alkyl, (C 1-4 ) alkoxy, (C 3-6 ) cycloalkyloxy, halogen, cyano, (C 2-5 ) alkanoyl, carba Moly, (C 1-4 ) alkylsulfonyloxy or trifluoromethylsulfonyloxy, R4는 수소, 히드록시 또는 (C1-4)알콕시이고,R 4 is hydrogen, hydroxy or (C 1-4 ) alkoxy, R5는 화학식또는의 기이며, 여기서,R 5 is a chemical formula or Where is R6은 (C1-4)알킬이고,R 6 is (C 1-4 ) alkyl, X는 탄소수 1 내지 4의 직쇄 또는 분지쇄 알킬렌이고,X is straight or branched chain alkylene having 1 to 4 carbon atoms, R7및 R8은 독립적으로 수소, (C1-4)알킬, 히드록시(C2-4)알킬 또는 페닐(C1-4)알킬이거나, 또는 그들이 부착되어 있는 질소 원자와 함께 피롤리디닐, 피페리디노, 피페라지닐 또는 모르폴리노기 또는 화학식(e)의 기(여기서, Z는 O, CH2또는 CH2-CH2이고, R9, R10, R11, R12, R13및 R14는 독립적으로 H, 할로겐, (C1-4)알킬 또는 (C1-4)알콕시임)를 형성한다.R 7 and R 8 are independently hydrogen, (C 1-4 ) alkyl, hydroxy (C 2-4 ) alkyl or phenyl (C 1-4 ) alkyl, or pyrrolidinyl together with the nitrogen atom to which they are attached , Piperidino, piperazinyl or morpholino groups or chemical formulas groups of (e) wherein Z is O, CH 2 or CH 2 -CH 2 , and R 9 , R 10 , R 11 , R 12 , R 13 and R 14 are independently H, halogen, (C 1- 4 ) alkyl or (C 1-4 ) alkoxy). 제1항에 있어서, R1, R2, R3및 R4가 제1항에 정의된 바와 같고 R5가 제1항에 정의된 바와 같은 화학식 (a), (b) 또는 (c)의 기인, 유리 염기 또는 산 부가염 형태의 화학식 I의 화합물.The compound of formula (a), (b) or (c) according to claim 1 , wherein R 1 , R 2 , R 3 and R 4 are as defined in claim 1 and R 5 is as defined in claim 1. The compound of formula I in the form of a free base or acid addition salt. 제1항에 있어서, R1, R2, R3및 R4가 제1항에 정의된 바와 같고 R5가 제1항에 정의된 바와 같은 화학식 (d)의 기인 유리 염기 또는 산 부가염 형태의 화학식 I의 화합물.The free base or acid addition salt form of claim 1 , wherein R 1 , R 2 , R 3 and R 4 are as defined in claim 1 and R 5 is a group of formula (d) as defined in claim 1 . Of compounds of formula (I). 제1항에 있어서,The method of claim 1, (+)-3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-프로필-피페리딘,(+)-3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-propyl-piperidine, (-)-3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-프로필-피페리딘,(-)-3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-propyl-piperidine, (-)-3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-피페리딘,(-)-3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-piperidine, (+)-3-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-피페리딘,(+)-3- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-piperidine, (1S*,2S*,6R*,7R*)-4-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-에틸]-10-옥사-4-아자-트리시클로[5.2.1.0(2,6)]데칸,(1S * , 2S * , 6R * , 7R * )-4- [2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -ethyl] -10-oxa-4- Aza-tricyclo [5.2.1.0 (2,6)] decane, (+)-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-에틸]-N,N-디메틸-아민,(+)-[2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -N, N-dimethyl-amine, (-)-[2-(4-메톡시-4'-트리플루오로메틸-비페닐-3-일)-1-메틸-에틸]-N,N-디메틸-아민 중에서 선택된 유리 염기 또는 산 부가염 형태의 화합물.Free base or acid addition selected from (-)-[2- (4-methoxy-4'-trifluoromethyl-biphenyl-3-yl) -1-methyl-ethyl] -N, N-dimethyl-amine Compound in salt form. 화학식 II의 화합물을 화학식 III의 화합물과 반응시키고, 생성된 화합물을 유리 염기 형태 또는 산 부가염 형태로 회수함으로써 유리 염기 형태 또는 산 부가염 형태의 화학식 I의 화합물을 제조하는 방법.A process for preparing a compound of formula I in free base form or in acid addition salt form by reacting a compound of formula II with a compound of formula III and recovering the resulting compound in free base form or in acid addition salt form. 〈화학식 II〉<Formula II> 〈화학식 III〉<Formula III> 상기 식에서, R1내지 R5는 제1항에 정의된 바와 같고, Y는 할로겐 또는 트리플루오로메틸 술포네이트이다.Wherein R 1 to R 5 are as defined in claim 1 and Y is halogen or trifluoromethyl sulfonate. 제1항 내지 제4항 중 어느 한 항에 있어서, 약제로서 사용하기 위한 유리 염기 또는 제약학적으로 허용가능한 산 부가염 형태의 화합물.5. The compound according to claim 1, in the form of a free base or a pharmaceutically acceptable acid addition salt for use as a medicament. 제1항 내지 제4항 중 어느 한 항에 있어서, 간질, 졸중 및 뇌 또는 척수 외상의 치료에 사용하기 위한 유리 염기 또는 제약학적으로 허용가능한 산 부가염 형태의 화합물.The compound according to any one of claims 1 to 4 in the form of a free base or pharmaceutically acceptable acid addition salt for use in the treatment of epilepsy, stroke and brain or spinal cord trauma. 유리 염기 또는 제약학적으로 허용가능한 산 부가염 형태의 제1항 내지 제4항 중 어느 한 항의 화합물을 제약학적 담체 또는 희석제와 함께 포함하는 제약 조성물.A pharmaceutical composition comprising the compound of any one of claims 1-4 in free base or pharmaceutically acceptable acid addition salt form together with a pharmaceutical carrier or diluent. 유리 염기 또는 제약학적으로 허용가능한 산 부가염 형태의 제1항 내지 제4항 중 어느 한 항의 화합물의, 간질, 졸중 및 뇌 또는 척수 외상의 치료용 약제의 제조를 위한 용도.Use of a compound of any one of claims 1 to 4 in free base or pharmaceutically acceptable acid addition salt form for the preparation of a medicament for the treatment of epilepsy, stroke and brain or spinal cord trauma. 유리 염기 또는 제약학적으로 허용가능한 산 부가염 형태의 제1항 내지 제4항 중 어느 한 항의 화합물의 치료적 유효량을 간질, 졸중 및 뇌 또는 척수 외상 환자에게 투여하는 것을 포함하는 상기 질환의 치료 방법.A method of treating said disease comprising administering to a patient with epilepsy, stroke and brain or spinal cord trauma a therapeutically effective amount of a compound of any one of claims 1 to 4 in free base or pharmaceutically acceptable acid addition salt form. .
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