KR100483869B1 - New Amino Acid Derivatives and Their Use as Thrombin Inhibitors - Google Patents

New Amino Acid Derivatives and Their Use as Thrombin Inhibitors Download PDF

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KR100483869B1
KR100483869B1 KR10-1998-0709975A KR19980709975A KR100483869B1 KR 100483869 B1 KR100483869 B1 KR 100483869B1 KR 19980709975 A KR19980709975 A KR 19980709975A KR 100483869 B1 KR100483869 B1 KR 100483869B1
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다비드 구스타프슨
쟌-에리크 니스트룀
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아스트라제네카 악티에볼라그
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
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    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

특히 트롬빈의 억제가 필요한 증상(예를 들면, 혈전증)에서 트롬빈과 같은 트립신형 프로테아제의 경쟁적 억제제로서 또는 항응고제로서 유용한 화학식 I의 화합물이 제공된다.Especially provided are compounds of formula (I) which are useful as competitive inhibitors of trypsin-type proteases such as thrombin or as anticoagulants in conditions requiring inhibition of thrombin (eg thrombosis).

<화학식 I><Formula I>

식 중, R1, R2, R3, Rx, Y, n 및 B는 명세서에서 주어진 의미를 갖는다.Wherein R 1 , R 2 , R 3 , R x , Y, n and B have the meanings given in the specification.

Description

신규한 아미노산 유도체 및 트롬빈 억제제로서의 그의 용도{New Amino Acid Derivatives and Their Use as Thrombin Inhibitors}New Amino Acid Derivatives and Their Use as Thrombin Inhibitors

본 발명은 신규한 제약적으로 유용한 화합물, 특히 트립신형 세린 프로테아제, 특별히 트롬빈의 경쟁적 억제제, 약제로서의 그의 용도, 그를 함유하는 제약 조성물 및 그의 제조를 위한 합성 경로에 관한 것이다.The present invention relates to novel pharmaceutically useful compounds, in particular trypsin-type serine proteases, in particular competitive inhibitors of thrombin, their use as medicaments, pharmaceutical compositions containing them and synthetic routes for their preparation.

혈액 응고는 지혈(즉, 손상된 혈관으로부터의 혈 손실의 저지) 및 혈전증(즉, 종종 혈관 폐색을 유도하는, 혈관 중의 혈 응괴 형성)에 관련되는 중요한 과정이다.Blood coagulation is an important process involved in hemostasis (ie, the inhibition of blood loss from damaged vessels) and thrombosis (ie, the formation of blood clots in the vessels, often leading to vascular occlusion).

응고는 복합적인 일련의 효소 반응의 결과이다. 일련의 반응에서 최종 단계들 중 하나는 전효소 프로트롬빈을 활성 효소 트롬빈으로 전환하는 것이다.Coagulation is the result of a complex series of enzymatic reactions. One of the final steps in the series of reactions is the conversion of proenzyme prothrombin to active enzyme thrombin.

트롬빈은 응고에서 중심적인 역할을 하는 것으로 알려져 있다. 트롬빈은 혈소판을 활성화시켜서 혈소판 응집을 유도하고, 피브리노겐을 피브린 단량체로 전환시키고 이 단량체가 자발적으로 피브린 중합체로 중합화되고, 또한 인자 XIII를 활성화시킴으로써 중합체를 가교시켜 불용성 피브린을 형성한다. 더욱이, 트롬빈은 인자 V 및 인자 VIII를 활성화시켜서, 프로트롬빈으로부터 트롬빈이 "양성 피드백" 생성되도록 한다. Thrombin is known to play a central role in coagulation. Thrombin activates platelets to induce platelet aggregation, converts fibrinogen into fibrin monomers, which polymerize spontaneously into fibrin polymers, and also crosslink the polymers by activating factor XIII to form insoluble fibrin. Moreover, thrombin activates factor V and factor VIII, such that thrombin is produced "positive feedback" from prothrombin.

혈소판 응집 및 피브린의 형성 및 가교를 억제함으로써, 트롬빈의 효과적인 억제제가 항혈전증 활성을 나타낼 것으로 예상된다. 또한, 항혈전증 활성은 양성 피드백 메카니즘의 효과적인 억제에 의해 향상될 것으로 예상된다.By inhibiting platelet aggregation and fibrin formation and crosslinking, it is expected that effective inhibitors of thrombin will exhibit antithrombogenic activity. In addition, antithrombogenic activity is expected to be enhanced by effective inhibition of the positive feedback mechanism.

트롬빈의 저분자량 억제제의 초기 발견은 클레손(Claesson)의 문헌[Blood Coagul. Fibrinol. (1994) 5, 411]에 기재되어 있다.An early discovery of low molecular weight inhibitors of thrombin is described by Claessson in Blood Coagul. Fibrinol. (1994) 5 , 411.

브롬백(Blombaeck) 등의 문헌[J. Clin. Lab. Invest. 24, suppl. 107, 59, (1969)]에는 피브리노겐 Aα 쇄에 대한 절단 부위 둘레에 위치한 아미노산 서열을 기재로 한 트롬빈 억제제가 보고되어 있다. 이 문헌의 저자들은 논의된 아미노산 서열 중에 트리펩티드 서열 Phe-Val-Arg(P9-P2-P1, 이후에 본 명세서에서 P3-P2-P1 서열로 칭한다)가 가장 효과적인 억제제인 것으로 교시하였다.Blombaeck et al., J. Clin. Lab. Invest. 24 , suppl. 107, 59, (1969) report thrombin inhibitors based on amino acid sequences located around the cleavage site for the fibrinogen Aα chain. The authors of this document taught that the tripeptide sequence Phe-Val-Arg (P9-P2-P1, hereinafter referred to herein as the P3-P2-P1 sequence) is the most effective inhibitor among the amino acid sequences discussed.

Pl-위치에서 α,ω-아미노알킬 구아니딘을 갖는 디펩티딜 유도체를 기재로 한 트롬빈 억제제가 미국 특허 제4,346,078호 및 국제 특허 출원 WO 제93/11152호로부터 공지되어 있다. 구조적으로 관련이 있는 유사한 디펩티딜 유도체가 또한 보고되어 있다. 예를 들면, 국제 특허 출원 WO 제94/29336호에는 P1-위치에서, 예를 들면 아미노메틸 벤즈아미딘, 시클릭 아미노알킬 아미딘 및 시클릭 아미노알킬 구아니딘을 갖는 화합물이 개시되어 있다. 유럽 특허 출원 제0 648 780호에는 P1-위치에서, 예를 들면 시클릭 아미노알킬 구아니딘을 갖는 화합물이 개시되어 있다.Thrombin inhibitors based on dipeptidyl derivatives having α, ω-aminoalkyl guanidines at the Pl-position are known from US Pat. No. 4,346,078 and International Patent Application WO 93/11152. Similar structurally related dipeptidyl derivatives have also been reported. For example, international patent application WO 94/29336 discloses compounds having, for example, aminomethyl benzamidine, cyclic aminoalkyl amidines and cyclic aminoalkyl guanidines at the P1-position. EP 0 648 780 discloses compounds having, for example, cyclic aminoalkyl guanidines at the P1-position.

Pl-위치에서 또한 시클릭 아미노알킬 구아니딘(예를 들면, 3- 또는 4-아미노메틸-1-아미디노피페리딘)을 갖는 펩티딜 유도체 기재의 트롬빈 억제제가 유럽 특허 출원 제0 468 231호, 동 0 559 046호 및 동 0 641 779호로부터 공지되어 있다.Thrombin inhibitors based on peptidyl derivatives also having cyclic aminoalkyl guanidines (eg 3- or 4-aminomethyl-1-amidinopiperidine) at the Pl-position are described in European Patent Application No. 0 468 231, Known from WO 0 559 046 and WO 0 641 779.

Pl-위치에서 아르기닌 알데히드를 갖는 트리펩티딜 유도체를 기재로 한 트롬빈 억제제가 유럽 특허 출원 제0 185 390호에 최초로 개시되었다.Thrombin inhibitors based on tripeptidyl derivatives having arginine aldehydes at the Pl-position were first disclosed in European Patent Application No. 0 185 390.

보다 최근에, P3-위치에서 개질된, 아르기닌 알데히드 기재의 펩티딜 유도체가 보고되었다. 예를 들면, 국제 특허 출원 WO 제93/18060호에는 P3-위치에서의 히드록시산, 유럽 특허 출원 제0 526 877호에는 데스-아미노산, 및 유럽 특허 출원 제0 542 525호에는 O-메틸 만델산이 개시되어 있다.More recently, arginine aldehyde based peptidyl derivatives modified at the P3-position have been reported. For example, hydroxy acids at the P3-position in International patent application WO 93/18060, des-amino acids in European patent application 0 526 877, and O-methyl mandel in European patent application 0 542 525. Acids are disclosed.

Pl-위치에서의 친전자성 케톤을 기재로 한 세린 프로테아제(예를 들면, 트롬빈)의 억제제가 또한 공지되어 있다. 예를 들면, 유럽 특허 출원 제0 195 212호에는 Pl-위치에서의 펩티딜 α-케토 에스테르 및 아미드, 유럽 특허 출원 제0 362 002호에는 플루오로알킬아미드 케톤, 유럽 특허 출원 제0 364 344호에는 α,β,δ-트리케토화합물, 및 유럽 특허 출원 제0 530 167호에는 아르기닌의 α-알콕시 케톤 유도체가 개시되어 있다.Inhibitors of serine proteases (eg thrombin) based on electrophilic ketones at the Pl-position are also known. For example, European Patent Application No. 0 195 212 discloses peptidyl α-keto esters and amides in the Pl-position, European Patent Application No. 0 362 002 discloses fluoroalkylamide ketones, European Patent Application No. 0 364 344 Α, β, δ-triketo compounds, and European Patent Application No. 0 530 167 disclose α-alkoxy ketone derivatives of arginine.

아르기닌의 C-말단 보론산 유도체 및 그의 이소티오우로늄 동족체를 기재로 한 트립신형 세린 프로테아제의 구조적으로 상이한 다른 억제제가 유럽 특허 출원 제0 293 881호로부터 공지되어 있다.Other structurally different inhibitors of trypsin-type serine proteases based on C-terminal boronic acid derivatives of arginine and isothiouronium homologs thereof are known from European Patent Application No. 0 293 881.

보다 최근에는, 펩티딜 유도체 기재의 트롬빈 억제제가 유럽 특허 출원 제0 669 317호 및 국제 특허 출원 WO 제95/35309호, 동 제95/23609호 및 동 제94/29336호에 개시되어 있다.More recently, thrombin inhibitors based on peptidyl derivatives are disclosed in European Patent Application Nos. 0 669 317 and International Patent Applications WO 95/35309, 95/23609 and 94/29336.

그러나, 트롬빈과 같은 트립신형 세린 프로테아제의 효과적인 억제제에 대한 필요성은 여전하다. 다른 세린 프로테아제에 비해 트롬빈의 억제에 경구적으로 생체이용효율이 있고 선택적인 화합물이 특히 필요하다. 트롬빈에 대해 경쟁적인 억제 활성을 나타내는 화합물이 항응고제로서, 따라서 혈전증 및 관련 질환의 치료적 처리에 특히 유용한 것으로 예상된다.However, there is still a need for effective inhibitors of trypsin-type serine proteases such as thrombin. There is a particular need for orally bioavailable and selective compounds for thrombin inhibition compared to other serine proteases. Compounds that exhibit competitive inhibitory activity against thrombin are expected to be particularly useful as anticoagulants and therefore for the therapeutic treatment of thrombosis and related diseases.

본 발명에 따라 하기 화학식 I의 화합물 또는 그의 제약상 허용되는 염이 제공된다.According to the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof.

식 중, R1은 H, C(O)R11, SiR12R13R14 또는 C1-6 알킬(이 기는 OR15 또는 (CH2)qR16으로부터 선택된 1개 이상의 치환체로 임의 치환되거나 종결된다)을 나타내고,Wherein, R 1 is H, C (O) R 11 , SiR 12 R 13 R 14 or C 1-6 alkyl (the group OR 15 or (CH 2) optionally substituted with one or more substituents selected from R 16, or q Is terminated),

R12, R13 및 R14는 독립적으로 H, 페닐 또는 C1-6 알킬을 나타내고,R 12 , R 13 and R 14 independently represent H, phenyl or C 1-6 alkyl,

R16은 C1-4 알킬, 페닐, OH, C(O)OR17 또는 C(O)N(H)R18을 나타내고,R 16 represents C 1-4 alkyl, phenyl, OH, C (O) OR 17 or C (O) N (H) R 18 ,

R18은 H, C1-4 알킬 또는 CH2C(O)OR19를 나타내고,R 18 represents H, C 1-4 alkyl or CH 2 C (O) OR 19 ,

R15 및 R17은 독립적으로 H, C1-6 알킬 또는 C7-9 알킬페닐을 나타내고,R 15 and R 17 independently represent H, C 1-6 alkyl or C 7-9 alkylphenyl,

R11 및 R19는 독립적으로 H 또는 C1-4 알킬을 나타내고,R 11 and R 19 independently represent H or C 1-4 alkyl,

q는 0, 1 또는 2를 나타내고; q represents 0, 1 or 2;

R2 및 R3는 독립적으로 H, C1-4 알킬, 시클로헥실 또는 페닐을 나타내고;R 2 and R 3 independently represent H, C 1-4 alkyl, cyclohexyl or phenyl;

Rx는 하기 화학식 IIa, IIb 또는 IIc의 구조 프래그먼트를 나타내고R x represents the structural fragment of formula (IIa), (IIb) or (IIc)

[여기서, k, l 및 m은 독립적으로 0, 1, 2, 3 또는 4를 나타내고,[Wherein k, l and m independently represent 0, 1, 2, 3 or 4,

R4 및 R5는 독립적으로 H, Si(Me)3, 1- 또는 2-나프틸, 폴리시클릭 히드로카르빌기, CHR41R42 또는 C1-4 알킬(이 기는 1개 이상의 불소 원자로 임의 치환된다), 또는 C3-8 시클로알킬페닐, 메틸렌디옥시페닐, 벤조디옥사닐, 벤조푸라닐, 디히드로벤조푸라닐, 벤조티아졸릴, 벤즈옥사졸릴, 벤즈이미다졸릴, 쿠마라노닐, 쿠마리닐 또는 디히드로쿠마리닐(뒤로부터 12 개의 기들은 C1-4 알킬(이 기는 1개 이상의 할로 치환체로 임의 치환된다), C1-4 알콕시, 할로, 히드록시, 시아노, 니트로, SO2NH2, C(O)OH 또는 N(H)R43 중 1개 이상으로 임의 치환된다)을 나타내고,R 4 and R 5 are independently H, Si (Me) 3 , 1- or 2-naphthyl, polycyclic hydrocarbyl group, CHR 41 R 42 or C 1-4 alkyl, which is optionally substituted with one or more fluorine atoms Or C 3-8 cycloalkylphenyl, methylenedioxyphenyl, benzodioxanyl, benzofuranyl, dihydrobenzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, coumaranonyl, kumari Nyl or dihydrocoumarinyl (12 groups from the back are C 1-4 alkyl (which is optionally substituted with one or more halo substituents), C 1-4 alkoxy, halo, hydroxy, cyano, nitro, SO 2 Optionally substituted with one or more of NH 2 , C (O) OH, or N (H) R 43 );

R41 및 R42는 독립적으로 시클로헥실 또는 페닐을 나타내고,R 41 and R 42 independently represent cyclohexyl or phenyl,

R6 및 R7은 독립적으로 H, C1-4 알킬, C3-8 시클로알킬, 페닐(이 기는 C1-4 알킬(이 기는 1개 이상의 할로 치환체로 임의 치환된다), C1-4 알콕시, 할로, 히드록시, 시아노, 니트로, SO2NH2, C(O)OH 또는 N(H)R44 중 1개 이상으로 임의 치환된다) 이거나, 또는 이들이 부착된 탄소 원자와 함께 C3-8 시클로알킬환을 형성하고,R 6 and R 7 are independently H, C 1-4 alkyl, C 3-8 cycloalkyl, phenyl (this group is C 1-4 alkyl, which is optionally substituted with one or more halo substituents), C 1-4 Alkoxy, halo, hydroxy, cyano, nitro, SO 2 NH 2 , optionally substituted with one or more of C (O) OH or N (H) R 44 ), or C 3 together with the carbon atom to which they are attached To form an -8 cycloalkyl ring,

R43 및 R44는 독립적으로 H 또는 C(O)R45를 나타내고,R 43 and R 44 independently represent H or C (O) R 45 ,

R45는 H, C1-4 알킬 또는 C1-4 알콕시를 나타낸다];R 45 represents H, C 1-4 alkyl or C 1-4 alkoxy;

Y는 CH2, (CH2)2, CH=CH, (CH2)3, CH2CH=CH 또는 CH=CHCH2(뒤로부터 3개의 기들은 C1-4 알킬, 메틸렌, 옥소 또는 히드록시로 임의 치환된다)를 나타내고;Y is CH 2 , (CH 2 ) 2 , CH = CH, (CH 2 ) 3 , CH 2 CH = CH or CH = CHCH 2 (three groups from the back are C 1-4 alkyl, methylene, oxo or hydroxy Optionally substituted with;

n은 0, 1, 2, 3 또는 4를 나타내고;n represents 0, 1, 2, 3 or 4;

B는 하기 화학식 IVa, IVb 또는 IVc의 구조 프레그먼트를 나타낸다B represents a structural fragment of formula IVa, IVb or IVc

(여기서, X1 및 X2는 독립적으로 단일 결합 또는 CH2를 나타낸다).Wherein X 1 and X 2 independently represent a single bond or CH 2 .

화학식 I의 화합물은 호변 이성질 현상을 나타낼 수 있다. 모든 호변 이성질체 형 및 그의 혼합물은 본 발명의 범위에 속한다.Compounds of formula (I) may exhibit tautomerism. All tautomeric forms and mixtures thereof are within the scope of the present invention.

화학식 I의 화합물은 또한 1개 이상의 비대칭 탄소 원자를 함유할 수 있고, 따라서 광학 및(또는) 부분입체 이성질화를 나타낼 수 있다. 모든 부분입체 이성질체가 통상의 기술, 예를 들면 크로마토그래피법 또는 분별 결정법을 사용하여 분리될 수 있다. 다양한 입체 이성질체가 통상의 기술, 예를 들면 분별 결정법 또는 HPLC법을 사용하여 화합물의 라세믹 또는 기타 혼합물을 분리하여 단리될 수 있다. 다른 방법으로, 목적하는 광학 이성질체는 라세미화 또는 에피머화를 유발하지 않는 조건에서 적합한 광학 활성 출발 물질의 반응에 의해, 또는 예를 들면 호모키랄 산에 의한 유도체화, 및 후속적으로 통상의 방법(예를 들면, HPLC, 실리카 상에서의 크로마토그래피)에 의한 부분입체 이성질성 유도체의 분리에 의해 제조될 수 있다. 모든 부분입체 이성질체는 본 발명의 범위에 포함된다.The compounds of formula (I) may also contain one or more asymmetric carbon atoms and thus may exhibit optical and / or diastereoisomerization. All diastereomers can be separated using conventional techniques, such as chromatography or fractional crystallization. Various stereoisomers can be isolated by separating racemic or other mixtures of compounds using conventional techniques such as fractional crystallization or HPLC. Alternatively, the desired optical isomers can be reacted by reaction of a suitable optically active starting material in conditions that do not cause racemization or epimerization, or for example by derivatization with homochiral acid, and subsequently conventional methods By separation of diastereoisomeric derivatives (eg, HPLC, chromatography on silica). All diastereomers are included within the scope of the present invention.

R1, R2, R3, R4, R5, R6, R7, R11, R12, R13, R14, R15, R16, R17, R18, R19 및 R45가 나타낼 수 있고, 이에 의해 R4, R5 및 Y가 치환될 수 있는 알킬기; R45가 나타낼 수 있고, 이에 의해 R4 및 R5가 치환될 수 있는 알콕시기; R2, R3, R4, R5, R6, R7, R41 및 R42가 나타낼 수 있는 시클로알킬기; 및 R15 및 R17이 나타낼 수 있는 알킬페닐기는 선형 또는 분지형일 수 있고, 포화 또는 불포화될 수 있다.R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 and R 45 An alkyl group wherein R 4 , R 5 and Y may be substituted; An alkoxy group where R 45 may represent, whereby R 4 and R 5 may be substituted; Cycloalkyl groups represented by R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 41 and R 42 ; And the alkylphenyl group which R 15 and R 17 may represent may be linear or branched, and may be saturated or unsaturated.

이에 의해 R4, R5, R6 및 R7이 치환될 수 있고, 그리고 이에 의해 R4, R5, R6 및 R7 상의 치환체가 치환될 수 있는 할로기로는 플루오로, 클로로 및 브로모가 있다.Thereby, R 4 , R 5 , R 6 and R 7 may be substituted, whereby halo groups in which substituents on R 4 , R 5 , R 6 and R 7 may be substituted include fluoro, chloro and bromo have.

화학식 IIa, IIb 및 IIc의 프레그먼트 내의 탄소 원자에 인접한 점은 프레그먼트가 화학식 I의 화합물에 부착되는 지점을 의미한다.The point adjacent to the carbon atoms in the fragments of formulas IIa, IIb and IIc means the point where the fragment is attached to the compound of formula (I).

화학식 IVa, IVb 및 IVc의 프레그먼트 내의 탄소 원자 상의 파선은 프레그먼트의 결합 위치를 의미한다.The dashed line on the carbon atom in the fragments of Formulas IVa, IVb and IVc means the bonding position of the fragment.

본 명세서의 끝에 약어를 수록한다.Abbreviations are included at the end of this specification.

본 발명의 다른 측면에 따르면, According to another aspect of the invention,

(a) Rx가 화학식 IIa의 구조 프레그먼트를 나타내는 경우, R4 및(또는) R5는(적합하게는) (i) 할로치환된 C1-6 알킬에 의해 치환된 페닐; (ii) 메틸렌디옥시페닐, 벤조디옥사닐, 벤조푸라닐, 디히드로벤조푸라닐, 벤조티아졸릴, 벤조옥사졸릴, 벤즈이미다졸릴, 쿠마라노닐, 쿠마리닐 또는 디히드로쿠마리닐을 나타내지 않고,(a) when R x represents a structural fragment of formula (IIa), R 4 and / or R 5 (suitably) is (i) phenyl substituted by halosubstituted C 1-6 alkyl; (ii) does not represent methylenedioxyphenyl, benzodioxanyl, benzofuranyl, dihydrobenzofuranyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, coumaranyl, coumarinyl or dihydrocoumarinyl ,

(b) Rx가 화학식 IIc의 구조 프레그먼트를 나타내는 경우, R6 및(또는) R7는(적합하게는) 비치환 페닐을 나타내는, 상기 정의한 바와 같은 화학식 I의 화합물이 제공된다.(b) When R x represents a structural fragment of formula (IIc), compounds of formula (I) are provided as defined above wherein R 6 and / or R 7 (suitably) represent unsubstituted phenyl.

본 발명의 또 다른 측면에 따르면, According to another aspect of the invention,

(a) Rx가 화학식 IIa의 구조 프레그먼트를 나타내는 경우, R4 및(또는) R5는 (적합하게는) (i) 할로치환된 C1-6 알킬에 의해 치환된 페닐; (ii) 메틸렌디옥시페닐, 벤조디옥사닐, 벤조푸라닐, 디히드로벤조푸라닐, 벤조티아졸릴, 벤조옥사졸릴, 벤즈이미다졸릴, 쿠마라노닐, 쿠마리닐 또는 디히드로쿠마리닐을 나타내고,(a) when R x represents a structural fragment of formula (IIa), R 4 and / or R 5 (suitably) (i) phenyl substituted by halosubstituted C 1-6 alkyl; (ii) methylenedioxyphenyl, benzodioxanyl, benzofuranyl, dihydrobenzofuranyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, coumaranonil, coumarinyl or dihydrocoumarinyl,

(b) Rx가 화학식 IIc의 구조 프레그먼트를 나타내는 경우, R6 및(또는) R7는(적합하게는) 치환된 페닐을 나타내는, 상기 정의한 바와 같은 화학식 I의 화합물이 제공된다.(b) When R x represents a structural fragment of formula (IIc), compounds of formula (I) are provided as defined above wherein R 6 and / or R 7 represent (suitably) substituted phenyl.

n이 2를 나타내고 B가 화학식 IVb의 구조 프레그먼트를 나타내는 경우, 화학식 I의 바람직한 화합물로는 X1 및 X2가 동시에 CH2를 나타내지 않는 것이 있다.When n represents 2 and B represents a structural fragment of formula IVb, preferred compounds of formula (I) include those in which X 1 and X 2 do not simultaneously represent CH 2 .

화학식 I의 바람직한 화합물로는, Preferred compounds of formula I include

R1이 임의로 치환된 C1-6 알킬 또는, 특히 H를 나타내고,R 1 represents optionally substituted C 1-6 alkyl or in particular H,

Rx가 화학식 IIa의 구조 프레그먼트를 나타내고,R x represents a structural fragment of formula (IIa),

Y가 CH2 또는 (CH2)2를 나타내고,Y represents CH 2 or (CH 2 ) 2 ,

n이 1을 나타내고,n represents 1,

B가 화학식 IVa의 구조 프레그먼트를 나타내는 화합물이 있다. There are compounds in which B represents the structural fragment of formula IVa.

프레그먼트Fragment

가 S 배위인 화학식 I의 화합물이 바람직하다. 상기 프레그먼트에서 질소 및 탄소 원자 상의 파선은 프레그먼트의 결합 위치를 의미한다.Preferred are those compounds of formula I, wherein The dashed lines on the nitrogen and carbon atoms in the fragment mean the bonding position of the fragment.

화학식 I의 바람직한 화합물로는 실시예1 내지 7, 11, 12, 16 내지 39, 41, 42, 43의 화합물 및 (R,S)-Ph-C(Me)(CH2OMe)-C(O)-Aze-Pab가 있다.Preferred compounds of formula (I) include the compounds of Examples 1-7, 11, 12, 16-39, 41, 42, 43 and (R, S) -Ph-C (Me) (CH 2 OMe) -C (O ) -Aze-Pab.

제법quite

본 발명에 따라, 예를 들면 커플링계(예를 들면 DMF, EDC, DCC, HBTU 또는 TBTU 중의 옥살릴 클로라이드), 적합한 염기(예를 들면, 피리딘, DMAP, TEA 또는 DIPEA) 및 적합한 유기 용매(예를 들면, 디클로로메탄, 아세토니트릴 또는 DMF)의 존재하에서, According to the invention, for example, coupling systems (eg oxalyl chloride in DMF, EDC, DCC, HBTU or TBTU), suitable bases (eg pyridine, DMAP, TEA or DIPEA) and suitable organic solvents (eg For example, in the presence of dichloromethane, acetonitrile or DMF)

(a) 하기 화학식 V의 화합물과 하기 화학식 VI의 화합물을 커플링시키거나; 또는(a) coupling a compound of Formula V to a compound of Formula VI: or

(b) 하기 화학식 VII의 화합물과 하기 화학식 VIII의 화합물을 커플링시키는 것을 포함하는 화학식 I의 화합물의 제조 방법이 또한 제공된다.(b) There is also provided a process for the preparation of a compound of formula (I) comprising coupling a compound of formula (VII) to a compound of formula (VIII):

[화학식 VIII][Formula VIII]

식 중, R1, R2, R3, Rx, Y, n 및 B는 상기 정의한 바와 같다.In the formula, R 1 , R 2 , R 3 , R x , Y, n and B are as defined above.

화학식 V의 화합물은 시판되고, 문헌에 공지되어 있고, 또는 공지의 기술에 의해 수득할 수 있다. 예를 들면, 화학식 V의 화합물은, 예를 들면 실온에서, 적합한 염기(예를 들면, 수산화리듐) 및 적합한 용매(예를 들면, THF 및(또는) 물)의 존재하에서, 하기 화학식 IX의 화합물의 가수분해에 의해 제조될 수 있다.Compounds of formula V are commercially available and known in the literature or can be obtained by known techniques. For example, the compound of formula (V) may be a compound of formula (IX), for example at room temperature, in the presence of a suitable base (eg lithium hydroxide) and a suitable solvent (eg THF and / or water) It can be prepared by the hydrolysis of.

[화학식 IX][Formula IX]

식 중, R은 C1-6 알킬 또는 C1-3 알킬페닐이고, R1, R2, R3 및 Rx는 상기 정의한 바와 같다. Wherein R is C 1-6 alkyl or C 1-3 alkylphenyl and R 1 , R 2 , R 3 and R x are as defined above.

화학식 VI의 화합물은, 예를 들면 화학식 I의 화합물의 합성에 대해 상기한 바와 같은 조건하에서, 하기 화학식 X의 화합물을 상기 정의한 바와 같은 화학식 VIII의 화합물과 반응시켜 제조될 수 있다.Compounds of formula (VI) can be prepared by reacting a compound of formula (X) with a compound of formula (VIII) as defined above, for example under the conditions as described above for the synthesis of a compound of formula (I).

[화학식 X][Formula X]

식 중, Y는 상기 정의한 바와 같다. In the formula, Y is as defined above.

화학식 VII의 화합물은 공지의 기술을 사용하여 쉽게 수득할 수 있다. 예를 들면, 화학식 VII의 화합물은, 예를 들면 화학식 I의 화합물의 합성에 대한 상기한 바와 같은 조건하에서 상기 정의한 화학식 V의 화합물을 상기 정의한 화학식 X의 화합물과 반응시켜 제조될 수 있다.Compounds of formula (VII) can be readily obtained using known techniques. For example, a compound of formula VII can be prepared by reacting a compound of formula V as defined above with a compound of formula X as defined above, for example under the conditions as described above for the synthesis of a compound of formula I.

R1 및 R3가 모두 H를 나타내는 화학식 IX의 화합물은, 예를 들면 저온(예를 들면, -70 ℃ 내지 -5 ℃)에서, 적합한 환원제(예를 들면, 붕수소산나트륨) 및 적합한 유기 용매(예를 들면, MeOH 또는 EtOH)의 존재하에서, 화학식 XI의 화합물을 환원시켜 제조될 수 있다.Compounds of formula (IX) in which R 1 and R 3 both represent H are suitable reducing agents (eg sodium borohydride) and suitable organic solvents, for example, at low temperatures (eg -70 ° C to -5 ° C) In the presence of (eg, MeOH or EtOH), it can be prepared by reducing the compound of formula (XI).

[화학식 XI]Formula XI

식 중, R, Rx 및 R2는 상기 정의한 바와 같다.In the formula, R, R x and R 2 are as defined above.

R1이 H를 나타내고, R3가 C1-4 알킬, 시클로헥실 또는 페닐을 나타내는 화학식 IX의 화합물은, 적합한 유기 용매(예를 들면 THF)의 존재하에 당업계 숙련자에게 공지된 조건하에, 상기 정의한 바와 같은 화학식 XI의 화합물을 화학식 XII의 유기금속 시약과 반응시켜 제조될 수 있다.Compounds of formula (IX) wherein R 1 represents H and R 3 represents C 1-4 alkyl, cyclohexyl or phenyl are prepared under the conditions known to those skilled in the art in the presence of a suitable organic solvent (eg THF). Compounds of formula (XI) as defined may be prepared by reaction with organometallic reagents of formula (XII).

[화학식 XII][Formula XII]

식 중, R3a는 C1-4 알킬, 시클로헥실 또는 페닐이고,Wherein R 3a is C 1-4 alkyl, cyclohexyl or phenyl,

M은 Li 또는 MgHal이고, M is Li or MgHal,

Hal은 Cl, Br 또는 I이다.Hal is Cl, Br or I.

R1이 H를 나타내는 화학식 IX의 화합물은 또한, 당업계 숙련자에게 공지된 조건하에서, 화학식 XIII의 화합물을 화학식 XIV의 화합물과 반응시켜 제조될 수 있다.Compounds of formula (IX) wherein R 1 represents H may also be prepared by reacting a compound of formula (XIII) with a compound of formula (XIV) under conditions known to those skilled in the art.

[화학식 XIII][Formula XIII]

식 중, R 및 Rx는 상기 정의한 바와 같다.In the formula, R and R x are as defined above.

[화학식 XIV][Formula XIV]

식 중, R2 및 R3는 상기 정의한 바와 같다.In the formula, R 2 and R 3 are as defined above.

R1, R2 및 R3가 모든 H를 나타내고, Rx가 상기 정의한 바와 같은 화학식 IIa(k 및 l은 모두 0이 아니다)의 구조 프레그먼트를 나타내는 화학식 IX의 화합물이, 적합한 환원제(예를 들면, 보란)의 존재하에서, 적합한 유기 용매(예를 들면, THF)의 존재하에서, 하기 화학식 XV의 화합물의 환원에 의해 제조될 수 있다.Compounds of formula (IX) in which R 1 , R 2 and R 3 represent all H and R x represents a structural fragment of formula (IIa) wherein k and l are not all 0 as defined above are suitable reducing agents (eg For example, in the presence of borane), in the presence of a suitable organic solvent (eg THF), can be prepared by reduction of a compound of formula XV.

[화학식 XV][Formula XV]

식 중, Rxa는 상기 정의한 바와 같은 화학식 IIa(k 및 l은 모두 0이 아니다)의 구조 프레그먼트이고, R이 상기 정의한 바와 같다.Wherein R xa is a structural fragment of formula (IIa) wherein k and l are both zero as defined above, and R is as defined above.

화학식 XI의 화합물은 문헌[J. Org. Chem. 54, 3831(1989)]에 기재된 방법으로부터 공지되어 있는 것이거나, 또는 이 방법과 유사한 방법으로 제조될 수 있다.Compounds of formula (XI) are described in J. Org. Chem. 54 , 3831 (1989), which are known from the methods described, or can be prepared by methods analogous to this method.

화학식 XV의 화합물은 문헌에 공지되어 있고, 또는 공지된 기술을 사용하여, 예를 들면 적합한 염기(예를 들면, 수소화나트륨 또는 에톡시화나트륨) 및 적합한 유기 용매의 존재하에서, 예를 들면 적합한 말론산 유도체를 하기 화학식 XVI의 알킬화제와 반응시켜 제조될 수 있다.Compounds of formula (XV) are known in the literature, or using known techniques, for example in the presence of a suitable base (eg sodium hydride or sodium ethoxylate) and a suitable organic solvent, for example suitable malonic acid Derivatives may be prepared by reacting with alkylating agents of formula XVI.

[화학식 XVI][Formula XVI]

식 중, L은 이탈기(예를 들면, 할로(Cl, Br, I) 또는 토실)이고,Wherein L is a leaving group (eg halo (Cl, Br, I) or tosyl),

Rxa는 상기 정의한 바와 같다.R xa is as defined above.

상기 화학식 VIII, X, XII, XIII, XIV, 및 XVI의 화합물은 시판되고, 문헌에 공지되어 있거나, 또는 공지의 기술을 사용하여 수득할 수 있다.The compounds of formula (VIII), (X), (XII), (XIII), (XIV), and (XVI) are commercially available and known in the literature or can be obtained using known techniques.

특히, 화학식 I, V, VII, IX, XI, XIII, XV 및 XVI의 화합물에 포함된 특히 페닐기 상의 치환체는 표준 기술을 사용하여 상호전환될 수 있다.In particular, substituents on the phenyl group in particular included in the compounds of the formulas (I), (V), (VII), (IX), (XI), (XIII), (XV) and (XVI) can be interconverted using standard techniques.

화학식 I의 화합물은 통상의 기술을 사용하여 그의 반응 혼합물로부터 단리될 수 있다.Compounds of formula (I) can be isolated from their reaction mixtures using conventional techniques.

당업계 숙련자는 상기 방법에서 중간체 화합물의 작용기가 보호기에 의해 보호될 필요가 있음을 이해할 것이다.Those skilled in the art will understand that the functional groups of the intermediate compounds in this method need to be protected by protecting groups.

보호하는 것이 바람직한 작용기로는 히드록시, 아미노산 및 카르복실산이 있다. 히드록시에 대해 적합한 보호기로는 트리알킬실릴 또는 다아릴알킬실릴기(예를 들면, t-부틸디메틸실릴, t-부틸디페닐실릴 또는 트리메틸실릴) 및 테트라히드로피라닐이 있다. 카르복실산에 대해 적합한 보호기로는 C1-6 알킬 또는 벤질 에스테르가 있다. 아미노, 아미디노 및 구아니디노에 대해 적합한 보호기로는 t-부틸옥시카르보닐 또는 벤질옥시카르보닐이 있다. 아미디노 및 구아니디노 질소는 단일 또는 이중 보호될 수 있다.Preferred functional groups to protect are hydroxy, amino acids and carboxylic acids. Suitable protecting groups for hydroxy include trialkylsilyl or polyarylalkylsilyl groups (eg t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable protecting groups for carboxylic acids are C 1-6 alkyl or benzyl esters. Suitable protecting groups for amino, amidino and guanidino are t-butyloxycarbonyl or benzyloxycarbonyl. Amidino and guanidino nitrogen may be single or double protected.

작용기의 보호 및 탈보호는 커플링 전 또는 후에 일어날 수 있다.Protection and deprotection of functional groups can occur before or after coupling.

특히, 화학식 I의 화합물은 N-아실화 아미노산 또는 N-보호된 아미노산의 커플링을 포함하는 방법에 의해 제조될 수 있다. N-보호된 아미노산이 사용되는 경우, 커플링 후 아실기가 첨가될 수 있고, 이어서 그의 표준법을 사용하여 질소 원자의 탈보호가 수행될 수 있다.In particular, compounds of formula (I) may be prepared by methods comprising coupling N-acylated amino acids or N-protected amino acids. If an N-protected amino acid is used, an acyl group can be added after coupling, and then deprotection of the nitrogen atom can be carried out using its standard method.

당업계에 공지되고 이후에 기재하는 기술에 따라 보호기가 제거될 수 있다.The protecting group can be removed according to techniques known in the art and described later.

화학식 I의 화합물을 형성하는 최종 탈보호 단계 전에 제조될 수 있는 화학식 I의 화합물의 특정한 보호 유도체가 신규하다.Certain protective derivatives of the compounds of formula (I) which can be prepared before the final deprotection step of forming the compounds of formula (I) are novel.

본 발명의 다른 측면에 따라, 하기 화학식 Ia의 화합물 또는 그의 제약상 허용되는 염이 제공된다.According to another aspect of the present invention, there is provided a compound of formula la or a pharmaceutically acceptable salt thereof.

[화학식 Ia]Formula Ia

식 중, B1은 하기 화학식 IVd, IVe 또는 IVf의 구조 프레그먼트를 나타내고Wherein B 1 represents a structural fragment of the formula (IVd), (IVe) or (IVf)

[화학식 IVd]Formula IVd

[화학식 IVe][Formula IVe]

[화학식 IVf]Formula IVf]

(여기서, D1 및 D2는 독립적으로 H, OH, ORa, OC(O)Rb, OC(O)ORc, C(O)ORd, C(O)Re를 나타내고, Ra, Rb, Rc, Rd 및 Re는 독립적으로 페닐, 벤질, (CH2)2OC(O)CH3 또는 C1-6 알킬(이 기는 산소 원자가 임의 개재된다)을 나타내고, 단 D1 및 D2가 동시에 H를 나타내지 않는다);Wherein D 1 and D 2 independently represent H, OH, OR a , OC (O) R b , OC (O) OR c , C (O) OR d , C (O) R e , and R a , R b , R c , R d and R e independently represent phenyl, benzyl, (CH 2 ) 2 OC (O) CH 3 or C 1-6 alkyl, in which the group is optionally interrupted by an oxygen atom; 1 and D 2 do not represent H at the same time;

R1, R2, R3, Rx, Y, n, X1 및 X2는 상기 정의한 바와 같다.R 1 , R 2 , R 3 , R x , Y, n, X 1 and X 2 are as defined above.

Ra, Rb, Rc, Rd 및 Re가 나타낼 수 있는 알킬기는 선형 또는 분지형일 수 있고, 포화 또는 불포화될 수 있다.The alkyl group represented by R a , R b , R c , R d and R e may be linear or branched, and may be saturated or unsaturated.

화학식 IVd, IVe 및 IVf의 프레그먼트 내의 탄소 원자 상의 파선은 프레그먼트의 결합 위치를 의미한다.The dashed line on the carbon atom in the fragments of formulas IVd, IVe and IVf means the bonding position of the fragment.

화학식 Ia의 바람직한 화합물로는 D1이 H를 나타내고, D2가 OH, OCH3, OC(O)Rb 또는 C(O)ORd(여기서, Rb 및 Rd는 상기 정의한 바와 같다)를 나타내는 화합물을 들 수 있다.Preferred compounds of formula (Ia) include those in which D 1 represents H and D 2 represents OH, OCH 3 , OC (O) R b or C (O) OR d , wherein R b and R d are as defined above. The compound shown can be mentioned.

화학식 Ia의 바람직한 화합물로는 실시예 8, 9, 10, 13, 14, 15, 40의 화합물 및 (R,S)-Ph-C(Me)(CH2OMe)-C(O)-Pro-Pab(Z)를 들 수 있다.Preferred compounds of formula (Ia) include the compounds of Examples 8, 9, 10, 13, 14, 15, 40 and (R, S) -Ph-C (Me) (CH 2 OMe) -C (O) -Pro- Pab (Z) is mentioned.

화학식 Ia의 화합물은 또한 당업계 숙련자에게 공지된 기술에 따라 화학식 I의 화합물로부터 직접 제조될 수 있다. 예를 들면, D1 또는 D2가 OH를 나타내는 화학식 Ia의 화합물은, 예를 들면 40 ℃에서, 적합한 염기(예를 들면, TEA) 및 적합한 유기 용매(예를 들면, THF)의 존재하에서, D1 또는 D2가 (적합하게는) COORd를 나타내고 Rd가 상기 정의한 바와 같은 화학식 Ia의 상응하는 화합물을 히드록시아민(또는 그의 히드로할라이드 염)과 반응시켜 제조될 수 있다.Compounds of formula (Ia) may also be prepared directly from compounds of formula (I) according to techniques known to those skilled in the art. For example, a compound of formula (Ia) in which D 1 or D 2 represents OH, for example at 40 ° C., in the presence of a suitable base (eg TEA) and a suitable organic solvent (eg THF), D 1 or D 2 may (preferably) represent COOR d and R d may be prepared by reacting the corresponding compound of formula (Ia) as defined above with hydroxyamine (or a hydrohalide salt thereof).

별법으로, 화학식 Ia의 화합물은 당업계 숙련자에게 공지된 기술에 따라 화학식 Ia의 기타 보호된 유도체에 의해 제조될 수 있다. 예를 들면, D1 또는 D2가 OC(O)ORc를 나타내고, Rc가 상기 정의한 바와 같은 화학식 Ia의 화합물은, 예를 들면 실온에서, 적합한 염기(예를 들면, TEA, 피리딘 또는 DMAP) 및 적합한 유기 용매의 존재하에서, D1 또는 D2가 (적합하게는) OH를 나타내는 화학식 Ia의 상응하는 화합물을 하기 화학식 XVII의 화합물과 반응시켜 제조될 수 있다.Alternatively, compounds of formula (Ia) may be prepared by other protected derivatives of formula (Ia) according to techniques known to those skilled in the art. For example, a compound of formula (Ia) wherein D 1 or D 2 represents OC (O) OR c and R c is as defined above, for example at room temperature, may be a suitable base (eg TEA, pyridine or DMAP). ) And in the presence of a suitable organic solvent can be prepared by reacting a corresponding compound of formula (Ia) in which D 1 or D 2 (suitably) represents OH with a compound of formula (XVII).

[화학식 XVII]Formula XVII]

식 중, Rc는 상기 정의한 바와 같다.In the formula, R c is as defined above.

B1이 화학식 IVd 또는 IVf의 구조 프레그먼트를 나타내고, D1이 H를 나타내고, D2가 OH 또는 ORa(여기서, Ra가 상기 정의한 바와 같다)인 화학식 Ia의 화합물은, 별법으로 예를 들면 40 내지 60 ℃에서, 적합한 염기(예를 들면, TEA) 및 적합한 유기 용매(예를 들면, THF, CH3CN, DMF 또는 DMSO)의 존재하에서, 하기 화학식 XVIII의 화합물을 하기 화학식 XIX의 화합물과 반응시켜 제조될 수 있다.Compounds of formula (Ia) in which B 1 represents a structural fragment of formula (IVd) or (IVf), D 1 represents H, and D 2 is OH or OR a , wherein R a is as defined above, are alternatively For example, at 40 to 60 ° C., in the presence of a suitable base (eg TEA) and a suitable organic solvent (eg THF, CH 3 CN, DMF or DMSO), a compound of formula XVIII is represented by It can be prepared by reacting with a compound.

[화학식 XVIII][Formula XVIII]

식 중, Ba는 페닐-1,4-엔 또는 시클로헥실-1,4-엔이고,Wherein B a is phenyl-1,4-ene or cyclohexyl-1,4-ene,

R1, R2, R3, Rx, Y 및 n이 상기 정의한 바와 같다.R 1 , R 2 , R 3 , R x , Y and n are as defined above.

[화학식 XIX][Formula XIX]

식 중, Ra1은 H 또는 Ra를 나타내고,In the formula, R a1 represents H or R a ,

Ra는 상기 정의한 바와 같다.R a is as defined above.

화학식 XVIII의 화합물은 펩티드 커플링 기술에 따라, 예를 들면 화학식 I의 화합물에 대해 상기한 방법과 유사한 형태로 제조될 수 있다. 화학식 XVII 및 XIX의 화합물은 시판되고, 문헌에 공지되어 있거나, 또는 공지의 기술을 사용하여 입수할 수 있다.Compounds of formula (XVIII) can be prepared according to peptide coupling techniques, for example in a form similar to the methods described above for compounds of formula (I). Compounds of formula (XVII) and (XIX) are commercially available and known in the literature or can be obtained using known techniques.

보호기의 사용에 대해서는 문헌['Protective Groups in Organic Chemistry', 발행처: J W F McOmie, Plenum Press(1973)] 및 ['Protective Groups in Organic Synthesis', 제2판, T W Greene & P G M Wutz, Wiley-Interscience(1991)]에 충분히 기재되어 있다.For the use of protecting groups, see 'Protective Groups in Organic Chemistry', published by JWF McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 2nd edition, TW Greene & PGM Wutz, Wiley-Interscience ( 1991).

또한, 화학식 I의 화합물의 이와 같은 보호된 유도체(즉, 화학식 Ia의 화합물)가 자체로 제약 활성을 보유하지 않을 지라도, 이들은 비경구 또는 경구 투여되고 이후에 체내에서 신진대사되어 제약적으로 활성인 본 발명의 화합물을 형성할 수 있음을 당업계 숙련자가 이해할 것이다. 즉, 이들 유도체는 "약물 전구체"로 기재될 수 있다. 화학식 I의 화합물의 모든 약물 전구체가 본 발명의 범위에 포함된다.In addition, even though such protected derivatives of the compounds of formula (I) (ie, compounds of formula (Ia)) do not possess pharmaceutical activity by themselves, they are parenterally or orally administered and subsequently metabolized in the body to be pharmaceutically active It will be understood by those skilled in the art that the compounds of the invention can be formed. That is, these derivatives may be described as “drug precursors”. All drug precursors of the compounds of formula I are included in the scope of the present invention.

약물 전구체로서 특히 유용한 화학식 I의 화합물의 보호된 유도체가 화학식 Ia의 화합물에 포함된다.Protected derivatives of compounds of formula (I) which are particularly useful as drug precursors are included in compounds of formula (Ia).

화학식 I의 화합물, 그의 제약상 허용되는 염, 호변 이성질체 및 입체 이성질체, 뿐만 아니라 약물 전구체(화학식 I의 화합물의 약물 전구체인 화학식 Ia의 화합물을 포함한다)는 이후에 함께 "본 발명의 화합물"로 명명된다.Compounds of formula (I), pharmaceutically acceptable salts, tautomers and stereoisomers thereof, as well as drug precursors (including compounds of formula (Ia) which are drug precursors of compounds of formula (I)) are subsequently referred to as "compounds of the invention" It is named.

의약 및 제약적 용도Medicinal and Pharmaceutical Uses

본 발명의 화합물은 약학적 활성을 보유하므로 유용하다. 따라서, 이들은 제약으로서 표현된다.Compounds of the present invention are useful because they possess pharmaceutical activity. Thus, they are expressed as constraints.

따라서, 본 발명의 다른 측면에 따라 제약으로 유용한 본 발명의 화합물이 제공된다.Accordingly, there is provided a compound of the present invention useful as a pharmaceutical according to another aspect of the present invention.

특히, 본 발명의 화합물은 그 자체로서 또는 약물 전구체의 경우에, 예를 들면 하기의 시험에서 예증되는 바와 같이 투여 후에 트롬빈의 효능있는 억제제이다.In particular, the compounds of the present invention are potent inhibitors of thrombin after administration, either as such or in the case of drug precursors, for example as exemplified in the tests below.

따라서, 본 발명의 화합물은 트롬빈의 억제가 요구되는 증상에서 유용한 것으로 예상된다.Thus, the compounds of the present invention are expected to be useful in conditions where inhibition of thrombin is required.

즉, 인간을 포함하는 동물의 혈액 및 조직에서 혈전증 및 과응고능의 치료 또는 예방에 본 발명의 화합물이 사용된다.That is, the compounds of the present invention are used for the treatment or prevention of thrombosis and hypercoagulation in the blood and tissues of animals, including humans.

과응고능에 의해 혈전색전 질병이 유도될 수 있음이 공지되어 있다. 과응고능 및 혈전색전 질병에 관련된 언급할 만한 증상으로는 인자 V-돌연변이(인자 V 라이덴(Leiden))과 같은 활성화된 단백질 C 저항증, 및 안티트롬빈 III, 단백질 C, 단백질 S, 헤파린 조인자 II의 선척성 또는 후천성 결핍증이 있다. 과응고능 및 혈전색전 질병에 관련된 것으로 알려진 기타 증상으로는 순환 항인지질 항체(낭창 항응고제), 호모시스테인미(homocysteinemi), 헤파민 유도 혈소판감소증 및 섬유소용해소 결핍증을 들 수 있다. 즉, 본 발명의 화합물이 이들 증상의 치료 및(또는) 예방적 처리 모두에 사용된다.It is known that thromboembolic diseases can be induced by hypercoagulation. Notable symptoms associated with hypercoagulation and thromboembolic disease include activated protein C resistance, such as factor V-mutation (factor V Leiden), and antithrombin III, protein C, protein S, heparin cofactor II There is a congenital or acquired deficiency. Other symptoms known to be associated with hypercoagulant and thromboembolic diseases include circulating antiphospholipid antibodies (anti-coagulants), homocysteinemi, hepamine-induced thrombocytopenia and fibrinolytic deficiency. That is, the compounds of the present invention are used for both the treatment and / or prophylactic treatment of these symptoms.

본 발명의 화합물은 또한 과응고능의 징후없이 바람직하지 않은 과량의 트롬빈이 존재하는 증상, 예를 들면 알츠하이머병과 같은 신경퇴행성 질병의 치료에 사용된다.The compounds of the present invention are also used in the treatment of neurodegenerative diseases such as Alzheimer's disease, in which there is an undesirable excess of thrombin without signs of overcoagulation.

언급할만한 특정 질병 상태로는 정맥 혈전증 및 폐 색전증, 동맥 혈전증(예를 들면, 심근 경색, 불안정한 협심증, 혈전증에 의한 발작 및 말초 동맥 혈전증) 및 일반적으로 동맥 섬유성 연축 중에 심방으로부터의 또는 경벽 심근 경색 이후에 좌심실로부터의 전신 색전증의 치료적 및(또는) 예방적 처리를 들 수 있다.Specific disease states worth mentioning are venous thrombosis and pulmonary embolism, arterial thrombosis (eg, myocardial infarction, unstable angina, thrombosis and peripheral arterial thrombosis), and usually from atrium or wall wall myocardial infarction during arterial fibrillation And then therapeutic and / or prophylactic treatment of systemic embolism from the left ventricle.

더욱이, 본 발명의 화합물은 혈전붕괴, 경피경관혈관성형술(PTA) 및 관상 부행로 작동 이후의 재폐색(즉, 혈전증)의 예방; 및 일반적인 미소수술 및 혈관수술 이후의 재혈전증의 방지에 유용한 것으로 예상된다.Moreover, the compounds of the present invention can be used for the prevention of thrombotic collapse, percutaneous transvascular angioplasty (PTA) and re-obstruction after coronary bypass operation (ie, thrombosis); And prevention of rethrombosis after general microsurgery and vascular surgery.

추가의 적용으로는 박테리아, 다수의 외상, 중독 또는 임의의 기타 메카니즘에 기인하는 분산성 혈관내 응고의 치료적 및(또는) 예방적 처리; 혈관 이식조직, 혈관 스텐트, 혈관 카테테르, 기계적 및 생물학적 보결 밸브 또는 임의의 기타 의료용 장치와 같은 신체 내의 이종 면에 혈액이 접할 경우의 항응고 처리; 및 심장-허파 기관을 사용하는 심장혈관 수술 중에 또는 혈액투석 시에서와 같이 신체 외부의 의료 장치와 혈관이 접할 때의 항응고 처리를 들 수 있다.Further applications include therapeutic and / or prophylactic treatment of dispersible intravascular coagulation due to bacteria, numerous traumas, poisonings or any other mechanisms; Anticoagulant treatment when blood is in contact with xenografts in the body, such as vascular grafts, vascular stents, vascular catheters, mechanical and biological prosthetic valves or any other medical device; And anticoagulant treatment when blood vessels come into contact with medical devices external to the body, such as during cardiovascular surgery using cardiac-lung organs or during hemodialysis.

트롬빈은 응고 과정에 미치는 효과 이외에, 다수의 세포(예를 들면, 호중구, 섬유아세포, 내피세포 및 평활근 세포)를 활성화하는 것으로 공지되어 있다. 따라서, 본 발명의 화합물은 또한 특발성 및 성인 호흡 곤란 증후군, 복사 또는 화학요법에 의한 처리 이후의 폐 섬유증, 폐혈성 쇼크증, 폐혈증; 부종, 급성 또는 만성 아테롬성 경화증, 예를 들면 관상 동맥 질병, 대뇌 동맥 질병, 말초 동맥 질병, 재환류 손상 및 경피경관혈관성형술(PTA) 이후의 협착증을 포함하는(이에 제한되지 않는다) 염증성 반응의 치료 및(또는) 예방적 처리에 유용하다.Thrombin is known to activate a number of cells (eg, neutrophils, fibroblasts, endothelial cells and smooth muscle cells) in addition to its effect on the coagulation process. Thus, the compounds of the present invention also include idiopathic and adult respiratory distress syndrome, pulmonary fibrosis, pulmonary shock, pneumonia after treatment by radiation or chemotherapy; Treatment of inflammatory reactions including, but not limited to, edema, acute or chronic atherosclerosis, such as coronary artery disease, cerebral artery disease, peripheral arterial disease, recurrent injuries, and stenosis after percutaneous transvascular angioplasty (PTA) And / or for prophylactic treatment.

트립신 및(또는) 트롬빈을 억제하는 본 발명의 화합물은 또한 췌장염의 처리에 유용하다.Compounds of the invention that inhibit trypsin and / or thrombin are also useful for the treatment of pancreatitis.

본 발명의 다른 측면에 따르면, 트롬빈의 억제가 필요한 증상에 걸려 있거나 이에 감염되기 쉬운 사람에게 본 발명의 화합물 또는 그의 제약상 허용되는 염을 치료 유효량 투여하는 것을 포함하는, 트롬빈의 억제가 필요한 증상의 치료 방법이 제공된다. According to another aspect of the present invention, there is provided a method for treating a condition requiring inhibition of thrombin, comprising administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof to a person suffering from or susceptible to a condition requiring inhibition of thrombin. Treatment methods are provided.

본 발명의 화합물은 보통 유리 염기 또는 제약상 허용되는 비독성 유기 또는 무기산 부가염 중 어느 하나의 형태로 활성 화합물을 포함하는 제약 제제의 형태로, 제약상 허용되는 투약 형태로, 경구, 정맥내, 피하, 구강, 직장내, 경피, 비내, 기관내, 기관지내, 임의의 기타 비경구 경로 또는 흡입에 의해 투여될 수 있다. 처리될 질환 및 환자 및 투여 경로에 따라, 조성물은 다양한 투약량으로 투여될 수 있다.The compounds of the invention are usually in the form of pharmaceutical preparations comprising the active compound in the form of either a free base or a pharmaceutically acceptable non-toxic organic or inorganic acid addition salt, in a pharmaceutically acceptable dosage form, orally, intravenously, It may be administered subcutaneously, orally, rectally, transdermally, intranasally, intratracheally, intratracheally, by any other parenteral route or by inhalation. Depending on the disease to be treated and the patient and the route of administration, the composition can be administered in various dosages.

본 발명의 화합물은 또한 다양한 작용 메카니즘을 갖는 임의의 항혈전제, 예를 들면 항혈소판제 아세틸살리실산, 티클로피딘, 클로피도그렐, 트롬복산 수용체 및(또는) 신테타제 억제제, 피브리노겐 수용체 길항제, 프로스타시클린 유사제 및 포스포디에스테라제 억제제 및 ADP 수용체(P2T) 길항제와 함께 조합되고 및(또는) 함께 투여될 수 있다.The compounds of the present invention may also contain any antithrombotic agent with various mechanisms of action, such as antiplatelet agents acetylsalicylic acid, ticlopidine, clopidogrel, thromboxane receptor and / or synthetase inhibitors, fibrinogen receptor antagonists, prostacycline analogs And phosphodiesterase inhibitors and ADP receptor (P 2 T) antagonists and / or administered together.

본 발명의 화합물은 또한, 혈전 질병, 특히 심근 경색의 처리에서 조직 프라스미노겐 활성제(천연, 재조합 또는 개질), 스트렙토키나제, 우로키나제, 프로우로키나제, 아니졸화 플라스미노겐-스트렙토키나제 활성제 착물(APSAC), 동물 타액 분비 선 플라스미노겐 활성제 등과 같은 혈전융해제와 조합되고 및(또는) 동시 투여될 수 있다. The compounds of the present invention are also useful for treating tissue plasminogen activators (natural, recombinant or modified), streptokinase, urokinase, prourokinase, anisolated plasminogen-streptokinase activator complexes in the treatment of thrombotic diseases, especially myocardial infarction. APSAC), an animal salivary gland plasminogen activator, and the like, and / or may be co-administered.

본 발명의 다른 측면에 따라, 본 발명의 화합물을 제약상 허용되는 보조제, 희석제 또는 담체와 함께 포함하는 제약 제제가 제공된다. According to another aspect of the invention, there is provided a pharmaceutical formulation comprising a compound of the invention in combination with a pharmaceutically acceptable adjuvant, diluent or carrier.

인간의 치료적 처리에서 본 발명의 화합물의 적합한 일일 투약량은 경구 투여시에 약 0.001-100 mg/kg 체중 그리고 비경구 투여시에 0.001-50 mg/체중이다.Suitable daily dosages of the compounds of the invention in therapeutic treatment of humans are about 0.001-100 mg / kg body weight upon oral administration and 0.001-50 mg / body weight on parenteral administration.

본 발명의 화합물은 당업계에 공지된 화합물에 비해 보다 효능이 있고, 덜 독성이고, 보다 장시간 작용성이고, 활성 범위가 보다 넓고, 보다 강력하고, 부작용이 보다 덜하고, 보다 쉽게 흡수되거나, 또는 기타 유용한 약물 특성을 가질 수 있다는 이점이 있다.Compounds of the present invention are more potent, less toxic, longer acting, have a wider range of activity, are more potent, have fewer side effects, are more easily absorbed than compounds known in the art, or The advantage is that it can have other useful drug properties.

생물학적 시험Biological test

시험 AExam A

트롬빈 응고 시간(TT) 결정Determination of Thrombin Coagulation Time (TT)

pH 7.4인 완충액 100 μl 및 억제제 용액 100 μl 중에 인간 트롬빈(T 6769, Sigma Chem Co. 제품)을 1분 동안 배양하였다. 이어서, 풀화된(pooled) 정상의 시트레이트화 인간 혈장 100 μl를 부가하고 자동화 장치(KC 10, Amelung)로 응고 시각을 측정하였다. Human thrombin (T 6769 from Sigma Chem Co.) was incubated for 1 minute in 100 μl of buffer at pH 7.4 and 100 μl of inhibitor solution. Next, 100 μl of pooled normal citrated human plasma was added and the coagulation time was measured with an automated device (KC 10, Amelung).

응고 시간(초 단위)을 억제제 농도에 대해 플롯하고, IC50TT를 내삽법에 의해 측정하였다.Coagulation time (in seconds) was plotted against inhibitor concentration and IC 50 TT was determined by interpolation.

IC50TT는 인간 혈장에 대한 트롬빈 응고 시간을 2배로 되게하는 시험중 억제제의 농도이다.IC 50 TT is the concentration of inhibitor in the test that doubles thrombin clotting time for human plasma.

시험 BExam B

색소 형성 로봇식 분석에 의한 트롬빈 억제율 결정Determination of Thrombin Inhibition by Pigmentation Robotic Analysis

색소 형성 기질법(chromogenic substrate method)에 따라, 플레토(Plato) 3300 로봇식 미소판 프로세서(스위스 CH-8634 홈브레흐티콘 소재의 Rosys AG)에서, 96 웰의 반부피의 미소적정 플레이트(미국 메사추세츠주 캠브리지 소재의 Costar 제품; Cat No 3690)를 사용하여 트롬빈 억제제 효능을 측정하였다. DMSO(72 μL) 중의 시험 물질의 원료 용액 1 밀리몰/L을 DMSO로 1:3(24 + 48 μL)으로 연속적으로 희석하여 10종의 상이한 농도를 얻었고, 이를 분석 시료로서 분석하였다. 시험 시료 2 μL를 분석 완충액 124 μL, 분석 완충액 중의 색소 형성 기질액(S-2366, 스웨덴 묄른달 소재의 Chromogenix 제품) 12μL 및 최종적으로 분석 완충액 모두에서의 α-트롬빈 용액(인간 α-트롬빈, Sigma Chemical Co. 제품)12μL을 부가하고, 시료를 혼합하였다. 최종 분석 농도는, 시험 물질 0.00068 - 13.3 μ몰/L, S-2366 0.30 밀리몰/L, α-트롬빈 0.020 NIHU/mL였다. 40분 동안 37 ℃에서 배양하는 중에 선형 흡수도 증분을 이용하여, 억제제가 없는 바탕값과 비교하여 본 시험 시료에 대힌 퍼센트 억제율을 계산하였다. 트롬빈 활성 50% 억제율을 유발시키는 억제제 농도에 따른 IC50-로봇 수치를 로그 투약량에 대한 % 억제율 곡선으로부터 계산하였다.A 96-well half-volume microtiter plate (Plato 3300 robotic microplate processor (Rosys AG, CH-8634 Home Brechticon, Switzerland) according to the chromogenic substrate method (US) Thrombin inhibitor efficacy was measured using Costar, Cambridge, Mass .; Cat No 3690). One millimole / L of the stock solution of test substance in DMSO (72 μL) was serially diluted 1: 3 (24 + 48 μL) with DMSO to obtain 10 different concentrations, which were analyzed as analytical samples. 2 μL of the test sample was weighed by 124 μL of assay buffer, 12 μL of pigment-forming substrate solution in assay buffer (S-2366, Chromogenix, Nuremberg, Sweden) and finally α-thrombin solution (human α-thrombin, Sigma in both assay buffers). Chemical Co. 12) was added and the samples were mixed. Final assay concentrations were 0.00068-13.3 μmol / L of test substance, 0.30 mmol / L of S-2366, 0.020 NIHU / mL of α-thrombin. The linear absorbance increments during incubation at 37 ° C. for 40 minutes were used to calculate the percent inhibition for this test sample compared to the background without inhibitor. IC 50 -robot values with inhibitor concentrations that result in a 50% inhibition of thrombin activity were calculated from the% inhibition curve versus log dose.

시험 CExam C

인간 트롬빈에 대한 억제 상수 Ki 결정Determination of Inhibition Constant K i for Human Thrombin

코바스 바이오(Cobas Bio) 원심분리 분석기(스위스 바젤 소재의 Roche 제품) 상에서 37 ℃에서 수행하는 색소 형성 기질법을 사용하여 Ki-결정을 수행하였다. 인간 α-트롬빈을 다양한 농도의 시험 화합물로 배양한 후 3종의 다양한 기질 농도에서 잔류 효소 활성을 결정하고 405 nm에서의 광학 흡수도의 변화를 측정하였다.K i -crystals were carried out using a dye-forming substrate method performed at 37 ° C. on a Cobas Bio centrifuge analyzer (Roche, Basel, Switzerland). Human α-thrombin was incubated with various concentrations of test compound and residual enzyme activity was determined at three different substrate concentrations and the change in optical absorbance at 405 nm was measured.

시험 화합물 용액(100 μL; 보통 BSA 10 g/L를 함유하는 완충액 또는 염수 중)을, BSA(10 g/L)를 함유하는 분석 완충액(0.05 몰/L 트리스-HCl pH 7.4, NaCl로 조절된 이온 강도: 0.15) 중의 인간 α-트롬빈 200 μL(Sigma Chemical Co. 제품)와 혼합하고, 코바스 바이오에서 시료로서 분석하였다. 물 20 μL와 함께 시료 60 μL를 분석 완충액 중의 기질 S-2238(스웨덴 묄른달 소재의 Chromogenix AB 제품) 320 μL에 부가하고, 흡수도 변화(△A/분)를 측정하였다. S-2238의 최종 농도는 16, 24 및 50 μ몰/L이고, 트롬빈의 최종 농도는 0.125 NIH U/ml이었다.Test compound solution (100 μL; usually in buffer or saline containing 10 g / L BSA) was adjusted to assay buffer (0.05 mol / L Tris-HCl pH 7.4, NaCl, containing BSA (10 g / L) 200 μL of human α-thrombin (from Sigma Chemical Co.) in ionic strength: 0.15) and analyzed as a sample in Covas Bio. 60 μL of the sample along with 20 μL of water was added to 320 μL of Substrate S-2238 (Chromogenix AB, Mullendal, Sweden) in assay buffer and the change in absorbance (ΔA / min) was measured. Final concentrations of S-2238 were 16, 24 and 50 μmol / L and final concentrations of thrombin were 0.125 NIH U / ml.

정상 상태 반응 속도를 사용하여 딕손(Dixon) 플롯, 즉 1/(△A/분)에 대한 억제제 농도의 다이아그램을 만들었다. 가역적이고 경쟁적인 억제제에 있어서, 다양한 기질 농도에 대한 데이터 점은 전형적으로 절편이 x= -Ki인 직선을 형성한다.Steady state reaction rates were used to create a Dixon plot, ie a diagram of inhibitor concentration against 1 / (ΔA / min). For reversible and competitive inhibitors, data points for various substrate concentrations typically form a straight line with the segment x = -K i .

시험 DTest D

활성화된 부분 트롬보플라스틴 시간(APTT: Activated Partial Thromboplastin Time)의 결정Determination of Activated Partial Thromboplastin Time (APTT)

풀화된 정상 인간 시트레이트화 혈장에서 스타고(Stago)가 제조한 시약 PTT Automated 5를 사용하여 APTT를 결정하였다. 혈장에 억제제(혈장 90 μl에 억제제 용액 10 μl)를, 이어서 시약 및 염화칼슘 용액을 부가하고, 시약 제조사의 지시 사항에 따라 응고 분석기 KC10(Amelung 제품)을 사용하여 혼합물 중에서 APTT를 결정하였다. 혈장 내의 억제제 농도에 대해 응고 시간(초 단위)을 플롯하였고, IC50APTT를 내삽법으로 결정하였다.APTT was determined using reagent PTT Automated 5 prepared by Stago in pooled normal human citrated plasma. Inhibitors (10 μl of inhibitor solution to 90 μl of plasma) were added to the plasma followed by the reagent and calcium chloride solution, and APTT was determined in the mixture using the coagulation analyzer KC10 (available from Amelung) according to the reagent manufacturer's instructions. Clotting time (in seconds) was plotted against inhibitor concentration in plasma and IC 50 APTT was determined by interpolation.

IC50APTT는 활성화된 부분 트롬보플라스틴 시간을 2배로 하는 인간 혈장 내의 억제제 농도로 정의된다.IC 50 APTT is defined as the inhibitor concentration in human plasma that doubles the activated partial thromboplastin time.

시험 ETest E

트롬빈 시간의 생체외 결정In Vitro Determination of Thrombin Time

에탄올: 솔루톨(Solutol)TM: 물(5:5:90) 중에 용해된 화학식 I 및 Ia의 화합물의 경구 또는 비경구 투여후 트롬빈의 억제율을, 시험 하루 또는 이틀 전에 경동맥 동맥으로부터 혈액 샘플링을 위해 카테테르를 갖추고 있는 의식이 있는 쥐에 대해 시험하였다. 시트르산나트륨 용액(0.13 몰/L) 1부 및 혈액 9부를 함유하는 플라스틱 듀브에 화합물을 투여한 후 실험 일의 지정 시간에 혈액 시료를 회수하였다. 튜브를 원심분리시켜 혈소판의 열등한 혈장을 얻었다. 하기와 같이 트롬빈 시간을 결정하기 위해 이 혈장을 사용하였다.Ethanol: Solutol TM : Inhibition rate of thrombin after oral or parenteral administration of compounds of Formulas I and Ia dissolved in water (5: 5: 90) for blood sampling from the carotid arteries one or two days before the test. Conscious rats with a catheter were tested. Blood samples were collected at the designated time of the experimental day after the compound was administered to a plastic dive containing 1 part sodium citrate solution (0.13 mol / L) and 9 parts blood. Tubes were centrifuged to obtain inferior plasma of platelets. This plasma was used to determine thrombin time as follows.

시트레이트화 쥐 혈장 100 μl를 0.9 % 간수 용액 100 μl로 희석하고, pH 7.4의 완충액 100 μl 중에 인간 트롬빈(T 6769, 미국의 Sigma Chem Co. 제품)을 부가하여 혈장 응고를 개시하였다. 응고 시간을 자동화 장치(KC 10, 독일의 Amelumg)에서 측정하였다.100 μl of citrated rat plasma was diluted with 100 μl of 0.9% liver water solution and plasma coagulation was initiated by adding human thrombin (T 6769, Sigma Chem Co., USA) in 100 μl of pH 7.4 buffer. The solidification time was measured on an automated device (KC 10, Amelumg, Germany).

화학식 Ia의 화합물을 투여하는 경우, 간수에 용해된 상응하는 "활성" 트롬빈 억제제의 공지된 농도에 대한 풀화된 시트레이트화 쥐 혈장 중의 트로빈 시간의 관계를 나타내는 표준 곡선을 사용하여 쥐 혈장 내의 화학식 I의 적합한 활성 트롬빈 억제제 농도를 측정하였다. When administering a compound of Formula (Ia), the formula in rat plasma is used using a standard curve indicating the relationship of the trobin time in pooled citrated rat plasma to a known concentration of the corresponding "active" thrombin inhibitor dissolved in the liver water. A suitable active thrombin inhibitor concentration of I was determined.

쥐 내의 화학식 I의 활성 트롬빈 억제제의 혈장 농도 측정치를 기준으로 하여(트롬빈 시간 연장이 전술한 화합물에 기인한다는 가정하에서), 화학식 Ia의 상응하는 약물 전구체의 경구 및(또는) 비경구 투여후, 데이터의 능형법 및 무한대의 외삽법을 사용하여 곡선 아래의 면적(AUC(Area Under the Curve)pd)을 계산하였다.Based on plasma concentration measurements of the active thrombin inhibitors of formula I in mice (assuming that thrombin time extension is due to the compounds described above), following oral and / or parenteral administration of the corresponding drug precursor of formula Ia, data The area under the curve (AUC) pd was calculated using the rhomboid and infinite extrapolation.

화학식 Ia의 약물 전구체의 경구 또는 비경구 투여후 화학식 I의 활성 트롬빈 억제제의 생체이용률을 다음과 같이 계산하였다:The bioavailability of the active thrombin inhibitor of formula I after oral or parenteral administration of the drug precursor of formula Ia was calculated as follows:

[(AUCpd/투약량)/(AUC활성,비경구/투약량] x 100[(AUCpd / dose) / (AUC active, parenteral / dose] x 100

식 중,In the formula,

"AUC활성,비경구"는 상기한 바와 같이 화학식 I의 상응하는 활성 트롬빈 억제제를 의식이 있는 쥐에 비경구 투여한 후 얻어지는 AUC를 나타낸다."AUC activity, parenteral" refers to an AUC obtained after parenteral administration of a corresponding active thrombin inhibitor of formula (I) to a conscious rat as described above.

시험 FExam F

뇨 중 트롬빈 시간의 생체외 결정In Vitro Determination of Thrombin Time in Urine

에탄올: 솔루톨TM: 물(5:5:90) 중에 용해된 본 발명의 화합물의 경구 또는 비경구 투여후 뇨 내에 분비된 화학식 I의 활성 트롬빈 억제제의 양을, 뇨 중의 트롬빈 시간의 생체외 결정에 의해 측정하였다(트롬빈 시간 연장은 전술한 화합물에 기인한다는 가정하에서).Ethanol: Solutol TM : The amount of active thrombin inhibitor of formula I secreted in urine after oral or parenteral administration of a compound of the invention dissolved in water (5: 5: 90), in vitro determination of thrombin time in urine Was determined (assuming that thrombin time extension is due to the above-mentioned compounds).

의식이 있는 쥐를 신진 대사 케이지(cage)에 위치시키고, 본 발명의 화합물을 경구 투여한 후 24 시간 동안 뇨 및 분변을 각각 수집하였다. 하기와 같이 수집된 뇨에 대한 트롬빈 시간을 결정하였다.Conscious mice were placed in metabolic cages and urine and feces were collected for 24 hours after oral administration of a compound of the invention. The thrombin time for the collected urine was determined as follows.

풀화된 정상 시트레이트화 인간 혈장(100 μl)을 쥐의 농축 뇨, 또는 그의 염수 희석액으로 1 시간 동안 배양하였다. 이어서, 완충액(pH 7.4; 100 μL) 중에서 인간 트롬빈(T 6769, 미국의 Sigma Chem Co. 제품)을 부가하여 혈장 응고를 개시하였다. 응고 시간을 자동화 장치(KC 10, Amelung 제품)에서 측정하였다.Pooled normal citrated human plasma (100 μl) was incubated with rat concentrated urine, or saline dilutions for 1 hour. Plasma coagulation was then initiated by adding human thrombin (T 6769, Sigma Chem Co., USA) in buffer (pH 7.4; 100 μL). Solidification time was measured on an automated device (KC 10, Amelung).

쥐의 농축 뇨(또는 그의 간수 희석액) 중에 용해된 전술한 활성 트롬빈 억제제의 공지된 농도에 대한 풀화된 정상 시트레이트화 인간 혈장 중의 트롬빈 시간 사이의 관계를 나타내는 표준 곡선을 사용하여 쥐 뇨 내의 화학식 I의 활성 트롬빈 억제제 농도를 추정하였다. 24 시간 동안 쥐 뇨 생성량에 전술한 뇨중 활성 억제제의 평균 농도 측정치를 곱하여, 뇨 중에 분비된 활성 억제제의 양(AMOUNTpd)을 계산할 수 있었다.Formula I in rat urine using a standard curve representing the relationship between thrombin time in pooled normal citrated human plasma to known concentrations of the above-described active thrombin inhibitor dissolved in rat concentrated urine (or its liver dilution) The active thrombin inhibitor concentration of was estimated. Rat urine production for 24 hours was multiplied by the above average concentration measurement of urinary activity inhibitors to calculate the amount of active inhibitor secreted in urine (AMOUNTpd).

약물 전구체의 경구 또는 비경구 투여후 화학식 I의 활성 트롬빈 억제제의 생체이용률을 다음과 같이 계산하였다:The bioavailability of the active thrombin inhibitor of formula I after oral or parenteral administration of the drug precursor was calculated as follows:

[(AMOUNTpd/투약량)/(AMOUNT활성,비경구/투약량] x 100[(AMOUNTpd / dose) / (AMOUNT active, parenteral / dose] x 100

식 중,In the formula,

"AMOUNT활성,비경구"는 상기한 바와 같이 화학식 I의 상응하는 활성 트롬빈 억제제를 의식이 있는 쥐에 비경구 투여한 후 뇨 중에 분비된 양을 나타낸다."AMOUNT activity, parenteral" refers to the amount secreted in urine after parenteral administration of the corresponding active thrombin inhibitor of formula (I) as described above.

본 발명은 하기 실시예에 의해 예증된다.The invention is illustrated by the following examples.

일반적인 시험 절차General test procedure

전기분무 계면을 구비한 핀니건(Finnigan) MAT TSQ 700 3중 4극자 질량 분광계(FAB-MS) 및 전기분무 계면을 구비한 VG 플랫폼 II 질량 분광계(LC-MS) 상에서 질량 스펙트럼을 기록하였다. 각각 300.13, 399.96, 499.82 및 599.94 MHz의 1H 주파수 및 각각 75.46, 100.58, 125.69 및 150.88 MHz의 13C 주파수에서 작동하는 브루커(BRUKER) ACP 300 및 베리언 유니티(Varian UNITY)와 400, 500 및 600 분광계 상에서 1H NMR 및 13C NMR 측정을 수행하였다. UV 탐지기(270 내지 290 nm)를 사용하여 10 내지 50 mL/분의 유속으로 역상 칼럼(250 mm, 20 또는 50 mm; 5 내지 7 μM 상 크로마실(Chromasil) C8) 상에서 정제 HPLC를 수행하였다.Mass spectra were recorded on a Finnigan MAT TSQ 700 triple quadrupole mass spectrometer (FAB-MS) with electrospray interface and VG Platform II mass spectrometer (LC-MS) with electrospray interface. BRUKER ACP 300 and Varian UNITY operating at 1 H frequencies of 300.13, 399.96, 499.82 and 599.94 MHz and 13 C frequencies of 75.46, 100.58, 125.69 and 150.88 MHz respectively and 400, 500 and 1 H NMR and 13 C NMR measurements were performed on a 600 spectrometer. Purified HPLC was performed on a reverse phase column (250 mm, 20 or 50 mm; Chromasil C8 on 5-7 μM) using a UV detector (270-290 nm) at a flow rate of 10-50 mL / min.

출발 물질의 제조 Preparation of Starting Material

실시예 AExample A

H-Aze-Pab(Z)H-Aze-Pab (Z)

(i) Boc-Aze-OH(i) Boc-Aze-OH

실온에서 교반하면서 디-tert-부틸 디카르보네이트(13.75 g; 63 밀리몰)을 물(50 mL) 중의 L-아제티딘-2-카르복실산(H-Aze-OH; 5.777 g; 57 밀리몰) 및 Na2CO3(6.04 g; 57 밀리몰)의 혼합물에 부가하였다. 60 시간 후, THF를 진공 상태에서 제거하고 혼합물을 물로 희석하고 2M KHSO4로 산성화시켰다. CH2Cl2로 추출하고 이어서 건조(MgSO4)하고 용매를 증발시켜 잔류물을 얻고, 이를 CH2Cl2 : 헥산으로부터 결정화하여 무색 결정 10.87 g(95%)를 얻었다.Di-tert-butyl dicarbonate (13.75 g; 63 mmol) was stirred at room temperature with L-azetidine-2-carboxylic acid (H-Aze-OH; 5.777 g; 57 mmol) in water (50 mL) and To a mixture of Na 2 CO 3 (6.04 g; 57 mmol). After 60 hours, THF was removed in vacuo and the mixture was diluted with water and acidified with 2M KHSO 4 . Extraction with CH 2 Cl 2 followed by drying (MgSO 4 ) and evaporation of the solvent gave a residue which was crystallized from CH 2 Cl 2 : hexane to give 10.87 g (95%) of colorless crystals.

1H NMR (300 MHz; CDCl3): δ 4.85-4.7(br s, 1H), 4.0-3.75(m, 2H), 2.65-2.35(m, 2H), 1.4(s, 9H) 1 H NMR (300 MHz; CDCl 3 ): δ 4.85-4.7 (br s, 1H), 4.0-3.75 (m, 2H), 2.65-2.35 (m, 2H), 1.4 (s, 9H)

(ii) Boc-Aze-Pab(Z) (ii) Boc-Aze-Pab (Z)

실온에서, 아세토니트릴(270 mL) 중의 Boc-Aze-OH(10.87 g; 54 밀리몰; 상기 단계 (i)로부터의 화합물), H-Pab(Z) x HCl(18.31 g; 57 밀리몰; 국제 특허 출원 WO 제94/29336호에 기재된 방법에 따라 제조함) 및 DMAP(9.9 g; 81 밀리몰)의 혼합물에 EDC(13.5 g; 70 밀리몰)을 부가하였다. 16 시간 후, 용매를 진공하에서 제거하고 에틸 아세테이트로 대체하였다. 혼합물을 물 및 시트르산 수용액으로 세척하였다. 유기층을 건조하고(MgSO4) 용매를 진공하에서 제거하여 잔류물을 얻고, CH2Cl2, 톨루엔, 디이소프로필 에테르 및 석유 에테르의 혼합물로부터 결정화하여 Boc-Aze-Pab(Z) 17.83 g을 얻었다.At room temperature, Boc-Aze-OH (10.87 g; 54 mmol; compound from step (i)), H-Pab (Z) x HCl (18.31 g; 57 mmol; international patent application in acetonitrile (270 mL) EDC (13.5 g; 70 mmol) was added to a mixture of DMAP (9.9 g; 81 mmol) and DMAP (9.9 g) prepared according to the method described in WO 94/29336. After 16 hours, the solvent was removed in vacuo and replaced with ethyl acetate. The mixture was washed with water and citric acid aqueous solution. The organic layer was dried (MgSO 4 ) and the solvent was removed in vacuo to give a residue, crystallized from a mixture of CH 2 Cl 2 , toluene, diisopropyl ether and petroleum ether to give 17.83 g of Boc-Aze-Pab (Z). .

1H NMR (300 MHz; CDCl3): δ 7.85-7.75(d, 1H), 7.45-7.2(m, 7H), 5.2(s, 2H), 4.7(t, l), 4.6-4.4(m, 2H), 3.95-3.8("q", 1H), 3.8-3.7(q, 1H), 2.5-2.3(m, 2H), 1.4(s, 9H) 1 H NMR (300 MHz; CDCl 3 ): δ 7.85-7.75 (d, 1H), 7.45-7.2 (m, 7H), 5.2 (s, 2H), 4.7 (t, l), 4.6-4.4 (m, 2H), 3.95-3.8 ("q", 1H), 3.8-3.7 (q, 1H), 2.5-2.3 (m, 2H), 1.4 (s, 9H)

(iii) H-Aze-Pab(Z) (iii) H-Aze-Pab (Z)

Boc-Aze-Pab(Z)(2.44 g; 5.2 밀리몰)을 트리플루오로아세트산(10 mL) 및 CH2Cl2(10 mL)의 혼합물에 용해하였다. 30분 후, 용매 및 트리플루오로아세트산을 진공하에서 제거하고 잔류물을 CH2Cl2 중에 용해하였다. 유기상을 NaCO3 수용액(10%)로 세척하고 건조하였다(K2CO3). 진공하에서 용매를 제거하여 잔류물을 얻고, CH2Cl2로부터 결정화하여 무색의 결정인 H-Aze-Pab(Z) 1.095 g(57%)를 얻었다.Boc-Aze-Pab (Z) (2.44 g; 5.2 mmol) was dissolved in a mixture of trifluoroacetic acid (10 mL) and CH 2 Cl 2 (10 mL). After 30 minutes, the solvent and trifluoroacetic acid were removed in vacuo and the residue dissolved in CH 2 Cl 2 . The organic phase was washed with aqueous NaCO 3 solution (10%) and dried (K 2 CO 3 ). The solvent was removed in vacuo to afford a residue, which was crystallized from CH 2 Cl 2 to give 1.095 g (57%) of colorless crystals H-Aze-Pab (Z).

1H NMR (300 MHz; CD3OD): δ 7.85-7.75(d, 2H), 7.45-7.25(m, 7H), 5.2 (s, 2H), 4.5(s, 2H), 4.3(d, 1H), 3.65(q, 1H), 3.4-3.3(m, 1H), 2.7-2.5(m, 1H), 2.4-2.2(m, 1H) 1 H NMR (300 MHz; CD 3 OD): δ 7.85-7.75 (d, 2H), 7.45-7.25 (m, 7H), 5.2 (s, 2H), 4.5 (s, 2H), 4.3 (d, 1H ), 3.65 (q, 1H), 3.4-3.3 (m, 1H), 2.7-2.5 (m, 1H), 2.4-2.2 (m, 1H)

실시예 BExample B

H-Pic-Pab(Z) x 2 HClH-Pic-Pab (Z) x 2 HCl

(i) Boc-Pic-OH(i) Boc-Pic-OH

용매로서 디옥산 대신에 THF를 사용하여 엠.보단스즈키(Bodanszky) 및 에이.보단스즈키의 방법("The Practice of Peptide Synthesis")에 따라 제조하였다. THF was used instead of dioxane as the solvent to prepare according to the methods of M. Bodanszky and A. Bodanszuki ("The Practice of Peptide Synthesis").

1H NMR (300 MHz; CDCl3): δ 5.0-4.8(br d, 1H), 4.0(br s, 1h), 3.0(br s, 1H), 2.20(d, 1H), 1.65(m, 2H), 1.5-1.3(s+m, 13H) 1 H NMR (300 MHz; CDCl 3 ): δ 5.0-4.8 (br d, 1H), 4.0 (br s, 1h), 3.0 (br s, 1H), 2.20 (d, 1H), 1.65 (m, 2H ), 1.5-1.3 (s + m, 13H)

(ii) Boc-Pic-Pab(Z)(ii) Boc-Pic-Pab (Z)

Boc-Pic-OH(2.02 g; 8.8 밀리몰; 상기 단계 (i)로부터의 화합물), H-Pab(Z) x 1 HCl(2.36 g; 7.4 밀리몰; 국제 특허 출원 WO 제94/29336호에 기재된 방법에 따라 제조함) 및 DMAP(3.9 g; 32 밀리몰)를 CH2Cl2(40 mL)에 용해하였다. 혼합물을 0 ℃로 냉각하고 EDC 1.99 g(10.4 밀리몰)을 부가하였다. 반응 혼합물을 실온에서 3 일 동안 교반하였다. 혼합물을 0.2 M KHSO4 용액에 붓고 CH2Cl2로 2회 추출하였다. 유기상을 건조하고(Na2SO4) 증발시켰다. 용리액으로 EtOAc:톨루엔 7:3을 사용하여 조생성물을 실리카 겔 상에서 플래시 크로마토그래피하여 생성물 1.59 g(44%)를 얻었다.Boc-Pic-OH (2.02 g; 8.8 mmol; compound from step (i) above), H-Pab (Z) x 1 HCl (2.36 g; 7.4 mmol; method described in international patent application WO 94/29336 Prepared) and DMAP (3.9 g; 32 mmol) were dissolved in CH 2 Cl 2 (40 mL). The mixture was cooled to 0 ° C and 1.99 g (10.4 mmol) EDC were added. The reaction mixture was stirred at rt for 3 days. The mixture was poured into 0.2 M KHSO 4 solution and extracted twice with CH 2 Cl 2 . The organic phase was dried (Na 2 SO 4 ) and evaporated. The crude product was flash chromatographed on silica gel using EtOAc: toluene 7: 3 as eluent to afford 1.59 g (44%) of product.

FAB-MS m/z 495 (M+1)+ FAB-MS m / z 495 (M + 1) +

1H NMR (400 MHz; CDCl3) δ 7.83(d, 2H), 7.43(d, 2H), 7.36-7.11(m, 5H), 6.52(bs, NH), 5.20(s, 2H), 4.81-4.72(m, 1H), 4.61-4.34(m, 2H), 4.10-3.90(m, 1H), 2.79-2.64(m, 1H), 2.36-2.25(m, 1H), 1.7-1.3(m, 14H) 1 H NMR (400 MHz; CDCl 3 ) δ 7.83 (d, 2H), 7.43 (d, 2H), 7.36-7.11 (m, 5H), 6.52 (bs, NH), 5.20 (s, 2H), 4.81- 4.72 (m, 1H), 4.61-4.34 (m, 2H), 4.10-3.90 (m, 1H), 2.79-2.64 (m, 1H), 2.36-2.25 (m, 1H), 1.7-1.3 (m, 14H )

(iii) H-Pic-Pab(Z) x 2 HCl (iii) H-Pic-Pab (Z) x 2 HCl

Boc-Pic-Pab(Z)(1.59 g; 3.25 밀리몰; 상기 단계 (ii)로부터의 화합물)을 HCl로 포화된 EtOAc 100 mL 중에 용해하였다. 반응 혼합물을 30 분 후에 증발시켜 정량적인 수율로 표제 생성물을 얻었다.Boc-Pic-Pab (Z) (1.59 g; 3.25 mmol; compound from step (ii) above) was dissolved in 100 mL of EtOAc saturated with HCl. The reaction mixture was evaporated after 30 minutes to give the title product in quantitative yield.

FAB-MS m/z 395 (M+1)+ FAB-MS m / z 395 (M + 1) +

1H NMR (300 MHz; D2O): δ 7.82(d, 2H), 7.63-7.41(m, 7H), 5.47(s, 2H), 4.69-4.49(δ 4.59에 집중된 AB-계, 2H), 4.03(dd, 1H), 3.52(bd, 1H), 3.10(dt, 1H), 2.29(dd, 1H), 2.08-1.61(m, 5H) 1 H NMR (300 MHz; D 2 O): δ 7.82 (d, 2H), 7.63-7.41 (m, 7H), 5.47 (s, 2H), 4.69-4.49 (AB-based, concentrated at δ 4.59, 2H) , 4.03 (dd, 1H), 3.52 (bd, 1H), 3.10 (dt, 1H), 2.29 (dd, 1H), 2.08-1.61 (m, 5H)

실시예 CExample C

H-Aze-Pig(Z) x 2 HClH-Aze-Pig (Z) x 2 HCl

(i) Boc-Aze-Pig(Z)(i) Boc-Aze-Pig (Z)

실온에서, Boc-Aze-OH(1.03 g; 5.12 밀리몰; 상기 실시예 A (i)로부터의 화합물)를 아세토니트릴(50 mL)에 용해하고 DMAP(1.57 g, 12.8 밀리몰)을 얻어진 용액에 부가하였다. 이어서, DMF(20 mL) 및 EDC(1.47 g; 7.68 밀리몰) 중의 H-Pig(Z) x 2 HCl(1.86 g; 5.12 밀리몰; 국제 특허 출원 WO 제94/29336호에 기재된 방법에 따라 제조함)을 부가하고 반응 혼합물을 실온에서 20 시간 동안 교반하였다. 이어서, 반응 혼합물을 농축하고 CH2Cl2(100 mL)로 희석하고 H2O(2 x 30 mL)로 세척하였다. 유기층을 건조하고(MgSO4) 증발시켰다. CH2Cl2:MeOH(95:5)로 용출된 실리카 겔 칼럼 상의 플래시 크로마토그래피에 의해 조생성물(3.77 g)을 정제하여 표제 화합물 1.24 g(51%)를 얻었다.At room temperature, Boc-Aze-OH (1.03 g; 5.12 mmol; compound from Example A (i) above) was dissolved in acetonitrile (50 mL) and DMAP (1.57 g, 12.8 mmol) was added to the resulting solution. . Subsequently, H-Pig (Z) x 2 HCl (1.86 g; 5.12 mmol; prepared according to the method described in International Patent Application WO 94/29336) in DMF (20 mL) and EDC (1.47 g; 7.68 mmol). Was added and the reaction mixture was stirred at rt for 20 h. The reaction mixture was then concentrated, diluted with CH 2 Cl 2 (100 mL) and washed with H 2 O (2 × 30 mL). The organic layer was dried (MgSO 4 ) and evaporated. The crude product (3.77 g) was purified by flash chromatography on a silica gel column eluted with CH 2 Cl 2 : MeOH (95: 5) to give 1.24 g (51%) of the title compound.

1H NMR (400 MHz; CDCl3): δ7.27-7.43(m, 5H), 5.12(s, 2H), 4.60-4.67(t, 1H), 4.16-4.26(d, 2H), 3.86-3.95(m, 1H), 3.74-3.82(m, 1H), 3.11-3.30(m, 2H), 2.78-2.89(m, 2H), 2.33-2.52(bs, 2H), 1.71-1.83(m, 3H), 1.44(s, 9H), 1.15-1.29(m, 2H) 1 H NMR (400 MHz; CDCl 3 ): δ 7.27-7.43 (m, 5H), 5.12 (s, 2H), 4.60-4.67 (t, 1H), 4.16-4.26 (d, 2H), 3.86-3.95 (m, 1H), 3.74-3.82 (m, 1H), 3.11-3.30 (m, 2H), 2.78-2.89 (m, 2H), 2.33-2.52 (bs, 2H), 1.71-1.83 (m, 3H) , 1.44 (s, 9H), 1.15-1.29 (m, 2H)

(ii) H-Aze-Pig(Z) x 2 HCl (ii) H-Aze-Pig (Z) x 2 HCl

HCl(75 mL)로 포화된 에틸 아세테이트 중의 Boc-Aze-Pig(Z)(1.2 g; 2.53 밀리몰; 상기 단계 (i)로부터의 화합물)을 실온에서 1 시간 동안 교반하였다. 반응 혼합물을 증발시키고, 물로 희석하고 톨루엔으로 추출하였다. 수성층을 동결 건조시켜 표제 화합물 1.085 g(96%)을 얻었다.Boc-Aze-Pig (Z) (1.2 g; 2.53 mmol; compound from step (i) above) in ethyl acetate saturated with HCl (75 mL) was stirred at room temperature for 1 hour. The reaction mixture was evaporated, diluted with water and extracted with toluene. The aqueous layer was lyophilized to give 1.085 g (96%) of the title compound.

1H NMR (500 MHz; CD3OD): δ 7.32-7.46(m, 5H), 5.28(s, 2H), 4.99-5.05(t, 1H), 4.08-4.16(m, 1H), 3.91-3.99(m, 3H), 3.13-3.25(m, 4H), 2.79-2.88(m, 1H), 2.47-2.57(m, 1H), 1.82-1.96(m, 3H), 1.26-1.40(m, 2H) 1 H NMR (500 MHz; CD 3 OD): δ 7.32-7.46 (m, 5H), 5.28 (s, 2H), 4.99-5.05 (t, 1H), 4.08-4.16 (m, 1H), 3.91-3.99 (m, 3H), 3.13-3.25 (m, 4H), 2.79-2.88 (m, 1H), 2.47-2.57 (m, 1H), 1.82-1.96 (m, 3H), 1.26-1.40 (m, 2H)

실시예 DExample D

(R,S)-Ph-CH(CH2OTBDMS)-C(O)-Pro-OH(R, S) -Ph-CH (CH 2 OTBDMS) -C (O) -Pro-OH

(i) (R,S)-Ph-CH(CH2OTBDMS)-C(O)OTBDMS(i) (R, S) -Ph-CH (CH 2 OTBDMS) -C (O) OTBDMS

(R,S)-트로프산(6.6 g; 0.040 몰)을 DMF(20 mL) 중에 용해하였다. 이미다졸(13.0 g; 0.192 몰) 및 TBDMS-Cl(14.4 g; 0.096 몰)을 부가하고 반응 혼합물을 실온에서 4일 동안 교반하였다. H2O(0.5 L)를 부가하고 혼합물을 에테르로 3회 추출하였다. 합한 유기층을 시트르산 수용액(10%), H2O, NaHCO3 수용액 및 H2O로 세척하고, 건조하고(Na2SO4) 증발시켰다. 조 생성물(16 g)을 추가로 정제하지 않고 후속 반응에서 사용하였다.(R, S) -Trophic acid (6.6 g; 0.040 mol) was dissolved in DMF (20 mL). Imidazole (13.0 g; 0.192 mol) and TBDMS-Cl (14.4 g; 0.096 mol) were added and the reaction mixture was stirred at rt for 4 days. H 2 O (0.5 L) was added and the mixture was extracted three times with ether. The combined organic layers were washed with aqueous citric acid solution (10%), H 2 O, aqueous NaHCO 3 and H 2 O, dried (Na 2 SO 4 ) and evaporated. The crude product (16 g) was used in the subsequent reaction without further purification.

1H NMR (500 MHz; CDCl3): δ 7.17-7.40(m, 5H), 4.16-4.23(m, 1H), 3.77-3.87 (m, 2H), 0.88-0.92(m, 18H), 0.02-0.29(m, 12H). 1 H NMR (500 MHz; CDCl 3 ): δ 7.17-7.40 (m, 5H), 4.16-4.23 (m, 1H), 3.77-3.87 (m, 2H), 0.88-0.92 (m, 18H), 0.02- 0.29 (m, 12 H).

(ii) (R,S)-PhCH(CH2OTBDMS)-C(O)OH(ii) (R, S) -PhCH (CH 2 OTBDMS) -C (O) OH

(R,S)-PhCH(CH2OTBDMS)-C(O)OTBDMS(16.0 g; 0.040 몰; 상기 단계 (i)로부터의 화합물), K2CO3(14.0 g; 0.10 몰), MeOH(400 mL) 및 H2O(150 mL)의 혼합물을 실온에서 철야 교반하였다. 농축 후 물 층을 에테르로 추출하였다. pH를 시트르산으로 조절하고 수성층을 다시 에테르로 3회 추출하였다. 합한 유기층을 H2O로 세척하고, 건조하고, 증발시켜 표제 화합물 9.7 g(87%)를 얻었다.(R, S) -PhCH (CH 2 OTBDMS) -C (O) OTBDMS (16.0 g; 0.040 mol; compound from step (i)), K 2 CO 3 (14.0 g; 0.10 mol), MeOH (400 mL) and H 2 O (150 mL) were stirred overnight at room temperature. After concentration the water layer was extracted with ether. The pH was adjusted with citric acid and the aqueous layer was extracted three times with ether again. The combined organic layers were washed with H 2 O, dried and evaporated to give 9.7 g (87%) of the title compound.

1H NMR (300 MHz; CDCl3): δ 7.20-7.40(m, 5H), 4.05-4.20(m, 1H), 3.75-3.90(m, 2H), 0.85(s, 9H), 0.00-0.10(m, 6H) 1 H NMR (300 MHz; CDCl 3 ): δ 7.20-7.40 (m, 5H), 4.05-4.20 (m, 1H), 3.75-3.90 (m, 2H), 0.85 (s, 9H), 0.00-0.10 ( m, 6H)

(iii) (R,S)-PhCH(CH2OTBDMS)-C(O)-Pro-OBn(iii) (R, S) -PhCH (CH 2 OTBDMS) -C (O) -Pro-OBn

아세토니트릴(20 mL) 중의 (R,S)-PhCH(CH2OTBDMS)-C(O)OH(2.01 g; 7.2 밀리몰; 상기 단계 (ii)로부터의 화합물), 프롤린 벤질에스테르 히드로클로라이드(1.85 g; 7.6 밀리몰) 및 DMAP(1.41 g, 11.5 밀리몰)의 혼합물에 EDC(유리 염기; 1.45 mL; 8.4 밀리몰)을 실온에서 부가하였다. 18 시간 후, 용매를 진공하에서 제거하고, 용리액으로 에틸 아세테이트:톨루엔(2:1)을 사용하여 실리카겔 상에서 조생성물을 플래시 크로마토그래피하여 생성물 2.7 g(80%)을 얻었다.(R, S) -PhCH (CH 2 OTBDMS) -C (O) OH (2.01 g; 7.2 mmol; compound from step (ii)), proline benzyl ester hydrochloride (1.85 g) in acetonitrile (20 mL) 7.6 mmol) and DMAP (1.41 g, 11.5 mmol) were added EDC (free base; 1.45 mL; 8.4 mmol) at room temperature. After 18 hours, the solvent was removed in vacuo and the crude product was flash chromatographed on silica gel using ethyl acetate: toluene (2: 1) as eluent to give 2.7 g (80%) of the product.

(iv) (R,S)-PhCH(CH2OTBDMS)-C(O)-Pro-OH(iv) (R, S) -PhCH (CH 2 OTBDMS) -C (O) -Pro-OH

(R,S)-PhCH(CH2OTBDMS)-C(O)-Pro-OBn(2.6 g; 5.56 밀리몰; 상기 단계 (iii)로부터의 화합물)을 에탄올(100 mL) 중에 용해하고 Pd/C(10%; 0.29 g)를 부가하였다. 혼합물을 3시간 동안 대기압에서 수소처리하였다. 여과후 용액을 증발시켰다. 표제 화합물의 수율은 1.7 g(81%)였다.(R, S) -PhCH (CH 2 OTBDMS) -C (O) -Pro-OBn (2.6 g; 5.56 mmol; compound from step (iii)) was dissolved in ethanol (100 mL) and Pd / C ( 10%; 0.29 g) was added. The mixture was hydrotreated at atmospheric pressure for 3 hours. After filtration the solution was evaporated. Yield of the title compound was 1.7 g (81%).

1H NMR (300 MHz; CDCl3): δ 7.15-7.40(m, 5H), 4.45-4.65(m, 1H), 4.15-4.30(m, 1H), 3.85-3.95(m, 1H), 3.55-3.80(m, 2H), 3.25-3.40(m, 1H), 2.30-2.40(m, 1H), 1.75-2.10(m, 3H), 0.75-0.90(m, 9H), -0.20-0.05(m, 6H) 1 H NMR (300 MHz; CDCl 3 ): δ 7.15-7.40 (m, 5H), 4.45-4.65 (m, 1H), 4.15-4.30 (m, 1H), 3.85-3.95 (m, 1H), 3.55- 3.80 (m, 2H), 3.25-3.40 (m, 1H), 2.30-2.40 (m, 1H), 1.75-2.10 (m, 3H), 0.75-0.90 (m, 9H), -0.20-0.05 (m, 6H)

13C NMR (75.5 MHz; CDCl3) 아미딘 및 카르보닐 탄소: 174.00, 172.63 13 C NMR (75.5 MHz; CDCl 3 ) amidine and carbonyl carbon: 174.00, 172.63

실시예 EExample E

(R,S)-3-히드록시-2-(3-메톡시페닐)-프로피온산(R, S) -3-hydroxy-2- (3-methoxyphenyl) -propionic acid

(i) (R,S)-3-히드록시-2-(3-메톡시페닐)-피로피온산 에틸에스테르(i) (R, S) -3-hydroxy-2- (3-methoxyphenyl) -pyrionic acid ethyl ester

에탄올 중의 3-옥소-2-(3-메톡시페닐)-프로피온산 에틸에스테르(0.067 g; 0.3 밀리몰; 문헌[J. Org. Chem. 54, 3831(1989)]에 기재된 방법에 따라 제조)의 용액에 NaBH4(2 당량)을 -70 ℃에서 부가하였다. 2 시간 동안 -70 ℃에서 4 시간 동안 -5 ℃에서 교반한 후, 물을 부가하고 반응 혼합물을 농축하고 에틸 아세테이트로 추출하였다. 유기상을 간수로 세척하고, 건조하고(MgSO4), 농축하여 표제 화합물을 얻었다.Solution of 3-oxo-2- (3-methoxyphenyl) -propionic acid ethyl ester (0.067 g; 0.3 mmol; prepared according to the method described in J. Org. Chem. 54 , 3831 (1989)) in ethanol To NaBH 4 (2 equiv) was added at -70 ° C. After stirring for 2 hours at -70 ° C for 4 hours at -5 ° C, water was added and the reaction mixture was concentrated and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO 4 ) and concentrated to afford the title compound.

(ii) (R,S)-3-히드록시-2-(3-메톡시페닐)-피로피온산(ii) (R, S) -3-hydroxy-2- (3-methoxyphenyl) -pyrionic acid

상기 단계 (i)로부터의 (R,S)-3-히드록시-2-(3-메톡시페닐)-프로피온산 에틸에스테르를 THF:물(1:1) 중에 용해하였다. LiOH x H2O(2 당량)을 부가하고 반응 혼합물을 1 시간 동안 실온에서 교반하였다. 반응 혼합물을 농축하고 CH2Cl2로 추출하였다. 유기상을 건조하고(MgSO4) 농축하여 추가의 정제없이 처리 단계에서 사용되는 3-히드록시-2-(3-메톡시페닐)-프로피온산을 얻었다.(R, S) -3-hydroxy-2- (3-methoxyphenyl) -propionic acid ethyl ester from step (i) was dissolved in THF: water (1: 1). LiOH × H 2 O (2 equiv) was added and the reaction mixture was stirred for 1 h at rt. The reaction mixture was concentrated and extracted with CH 2 Cl 2 . The organic phase was dried (MgSO 4 ) and concentrated to give 3-hydroxy-2- (3-methoxyphenyl) -propionic acid which was used in the treatment step without further purification.

LC-MS m/z 195 (M-1)- LC-MS m / z 195 (M-1) -

1H NMR (400 MHz; CD3OD): δ 6.73-6.79(m, 1H), 6.34-6.46(m, 3H), 3.57-3.66(m, 1H), 3.30(s, 3H), 3.22-3.29(m, 2H) 1 H NMR (400 MHz; CD 3 OD): δ 6.73-6.79 (m, 1H), 6.34-6.46 (m, 3H), 3.57-3.66 (m, 1H), 3.30 (s, 3H), 3.22-3.29 (m, 2H)

실시예 FExample F

(R,S)-3-히드록시-2-(3,4-디메톡시페닐)프로피온산(R, S) -3-hydroxy-2- (3,4-dimethoxyphenyl) propionic acid

3-옥소-2-(3,4-디메톡시페닐)-프로피온산 에틸 에스테르로 출발하여 상기 실시예 E에 기재된 방법으로 제조하였다.Prepared by the method described in Example E above starting with 3-oxo-2- (3,4-dimethoxyphenyl) -propionic acid ethyl ester.

LC-MS m/z 225 (M-1)- LC-MS m / z 225 (M-1) -

1H NMR (400 MHz; CD3OD): δ 6.84-6.95(m, 3H), 4.01-4.10(m, 1H), 3.81(s, 3H), 3.79(s, 3H), 3.65-3.73(m, 2H) 1 H NMR (400 MHz; CD 3 OD): δ 6.84-6.95 (m, 3H), 4.01-4.10 (m, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.65-3.73 (m , 2H)

실시예 GExample G

(R,S)-3-히드록시-2-(2-나프틸)프로피온산(R, S) -3-hydroxy-2- (2-naphthyl) propionic acid

3-옥소-2-(2-나프틸)-프로피온산 에틸 에스테르로 출발하여 상기 실시예 E에 기재된 방법으로 제조하였다.Prepared by the method described in Example E above starting with 3-oxo-2- (2-naphthyl) -propionic acid ethyl ester.

LC-MS m/z 215 (M-1)- LC-MS m / z 215 (M-1) -

1H NMR (400 MHz; CD3OD): δ 7.77-7.85(m, 4H), 7.41-7.50(m, 3H), 4.14-4.22(m, 1H), 3.89-3.95(m, 1H), 3.80-3.87(m, 1H). 1 H NMR (400 MHz; CD 3 OD): δ 7.77-7.85 (m, 4H), 7.41-7.50 (m, 3H), 4.14-4.22 (m, 1H), 3.89-3.95 (m, 1H), 3.80 -3.87 (m, 1 H).

실시예 HExample H

(R,S)-3-히드록시-2-(3,5-디메틸페닐)프로피온산(R, S) -3-hydroxy-2- (3,5-dimethylphenyl) propionic acid

3-옥소-2-(3,5-디메틸페닐)-프로피온산 에틸 에스테르로 출발하여 상기 실시예 E에 기재된 방법으로 제조하였다.Prepared by the method described in Example E above starting with 3-oxo-2- (3,5-dimethylphenyl) -propionic acid ethyl ester.

1H NMR (400 MHz; CDCl3): δ 6.94(s, 1H); 6.89(s, 2H); 4.13(dd, 1H); 3.80(m, 2H); 2.3(s, 6H) 1 H NMR (400 MHz; CDCl 3 ): δ 6.94 (s, 1H); 6.89 (s, 2 H); 4.13 (dd, 1 H); 3.80 (m, 2 H); 2.3 (s, 6H)

실시예 IExample I

(R,S)-3-히드록시-2-(3-트리플루오로메틸페닐)프로피온산(R, S) -3-hydroxy-2- (3-trifluoromethylphenyl) propionic acid

3-옥소-2-(3-트리플루오로메틸페닐)프로피온산 에틸 에스테르로 출발하여 상기 실시예 E에 기재된 방법으로 제조하였다.Prepared by the method described in Example E above starting with 3-oxo-2- (3-trifluoromethylphenyl) propionic acid ethyl ester.

LC-MS m/z 233(M-1)- LC-MS m / z 233 (M-1) -

실시예 JExample J

(R,S)-3-히드록시-2-(3-히드록시페닐)프로피온산(R, S) -3-hydroxy-2- (3-hydroxyphenyl) propionic acid

3-옥소-2-(3-히드록시페닐)프로피온산 에틸 에스테르로 출발하여 상기 실시예 E에 기재된 방법으로 제조하였다.Prepared by the method described in Example E above, starting with 3-oxo-2- (3-hydroxyphenyl) propionic acid ethyl ester.

LC-MS m/z 181(M-1)- LC-MS m / z 181 (M-1) -

실시예 KExample K

(R,S)-3-히드록시-2-(3-플루오로페닐)프로피온산(R, S) -3-hydroxy-2- (3-fluorophenyl) propionic acid

3-옥소-2-(3-플루오로페닐)프로피온산 에틸 에스테르로 출발하여 상기 실시예 E에 기재된 방법으로 제조하였다.Prepared by the method described in Example E above starting with 3-oxo-2- (3-fluorophenyl) propionic acid ethyl ester.

LC-MS m/z 183(M-1)-; FAB-MS m/z 185(M+1)+ LC-MS mlz 183 (M-1) - ; FAB-MS m / z 185 (M + 1) +

실시예 LExample L

(R,S)-3-히드록시-2-(3-클로로페닐)프로피온산(R, S) -3-hydroxy-2- (3-chlorophenyl) propionic acid

3-옥소-2-(3-클로로페닐)프로피온산 에틸 에스테르로 출발하여 상기 실시예 E에 기재된 방법으로 제조하였다.Prepared by the method described in Example E above starting with 3-oxo-2- (3-chlorophenyl) propionic acid ethyl ester.

1H NMR (300 MHz; CDCl3): δ 7.34-7.30(m, 3H); 7.21(dt, 1H); 5.67(b, 2H); 4.15(dd, 1H); 3.87(m, 2H). 1 H NMR (300 MHz; CDCl 3 ): δ 7.34-7.30 (m, 3H); 7.21 (dt, 1 H); 5.67 (b, 2 H); 4.15 (dd, 1 H); 3.87 (m, 2 H).

실시예 MExample M

3-히드록시-2-(3,5-비스(트리플루오로메틸)페닐)프로피온산3-hydroxy-2- (3,5-bis (trifluoromethyl) phenyl) propionic acid

3-옥소-2-(3,5-비스(트리플루오로메틸)페닐)프로피온산 에틸 에스테르로 출발하여 상기 실시예 E에 기재된 방법으로 제조하였다.Prepared by the method described in Example E above starting with 3-oxo-2- (3,5-bis (trifluoromethyl) phenyl) propionic acid ethyl ester.

LC-MS m/z 301(M-1)- LC-MS m / z 301 (M-1) -

실시예 NExample N

3-히드록시-2-(3-메톡시-5-메틸페닐)-프로피온산3-hydroxy-2- (3-methoxy-5-methylphenyl) -propionic acid

(i) 3-브로모메틸-5-메틸아니졸(i) 3-bromomethyl-5-methylanizol

CCl4 중의 3,5-메틸아니졸(13.6 g; 0.1 몰), NBS(17.8 g, 0.1 몰) 및 AIBN(1.1 g; 6.7 밀리몰)의 혼합물을 2 시간 동안 환류하였다. 얻어진 혼합물을 냉각하고 여과하고 증발시켰다. 약 20%의 출발 물질을 함유한 조생성물을 다음 단계에서 사용하였다.A mixture of 3,5-methylanizol (13.6 g; 0.1 mol), NBS (17.8 g, 0.1 mol) and AIBN (1.1 g; 6.7 mmol) in CCl 4 was refluxed for 2 hours. The resulting mixture was cooled, filtered and evaporated. The crude product containing about 20% of starting material was used in the next step.

1H NMR (400 MHz; CDCl3): δ6.82(s, 1H); 6.77(s, 1H); 6.68(sm, 1H); 4.47(s, 2H); 3.82(s, 3H); 2.37(s, 3H) 1 H NMR (400 MHz; CDCl 3 ): δ6.82 (s, 1H); 6.77 (s, 1 H); 6.68 (sm, 1 H); 4.47 (s, 2 H); 3.82 (s, 3 H); 2.37 (s, 3H)

(ii) 3-메톡시-5-메틸페닐아세토니트릴(ii) 3-methoxy-5-methylphenylacetonitrile

DMSO(25 mL) 중의 3-브로모메틸-5-메틸아니졸(17 g; 0.008 몰; 상기 단계(i)로부터의 생성물) 용액에 NaCN(8.2 g; 0.16 몰)을 부가하였다. 시아나이드의 부가시에 매우 승온되는 혼합물을 방치하여 1 시간에 걸쳐서 실온으로 냉각하였다. 이어서, CH3CN(25 mL)을 부가하고, 혼합물을 1 시간 동안 환류하였다. 반응 혼합물을 농축하고, 물(200 mL)을 부가하고, 얻어진 용액을 에테르로 3회 추출하였다. 합한 유기상을 물로 세척하고, 건조하고(Na2SO4), 농축하여 황색 오일인 부표제 생성물 9 g(70%)을 얻고, 이 생성물을 추가의 정제없이 다음 단계에서 사용하였다.To a solution of 3-bromomethyl-5-methylanizol (17 g; 0.008 moles; product from step (i)) in DMSO (25 mL) was added NaCN (8.2 g; 0.16 moles). The mixture, which was very heated upon addition of cyanide, was left to cool to room temperature over 1 hour. Then CH 3 CN (25 mL) was added and the mixture was refluxed for 1 h. The reaction mixture was concentrated, water (200 mL) was added, and the resulting solution was extracted three times with ether. The combined organic phases were washed with water, dried (Na 2 SO 4 ) and concentrated to give 9 g (70%) of the title product, a yellow oil, which was used in the next step without further purification.

1H NMR (300 MHz; CDCl3): δ 6.74(s, 1H); 6.67(2s, 2H); 3.79(s, 3H); 3.68(s, 2H); 2.33(s, 3H). 1 H NMR (300 MHz; CDCl 3 ): δ 6.74 (s, 1H); 6.67 (2s, 2H); 3.79 (s, 3 H); 3.68 (s, 2 H); 2.33 (s, 3 H).

(iii) 3-메톡시-5-메틸페닐아세트산(iii) 3-methoxy-5-methylphenylacetic acid

물: i-PrOH(2:1) 150 mL 중의 3-메톡시-5-메틸페닐아세토니트릴(9 g; 0.06 몰; 상기 단계 (ii)로부터의 화합물) 및 KOH(17 g; 0.3 몰) 용액을 120℃에서 철야로 이어서 2일 동안 실온에서 고압솥에서 교반하면서 가열하였다. 반응 혼합물을 농축하고 에테르로 추출하였다. 수성상을 산성화하고 에테르로 2회 추출하였다. 합한 유기상을 물로 세척하고, 건조하고(Na2SO4), 증발시켜 잔류물을 얻고, 이를 EtOH 중에 용해하고, 활성탄으로 처리하고, 여과하고, 증발시켜 황색 결정인 부표제 화합물 8.1 g(80%)을 얻었다.Water: A solution of 3-methoxy-5-methylphenylacetonitrile (9 g; 0.06 mol; compound from step (ii)) and KOH (17 g; 0.3 mol) in 150 mL of i-PrOH (2: 1) Heated at 120 ° C. overnight followed by stirring in an autoclave at room temperature for 2 days. The reaction mixture was concentrated and extracted with ether. The aqueous phase was acidified and extracted twice with ether. The combined organic phases were washed with water, dried (Na 2 SO 4 ) and evaporated to give a residue, which was dissolved in EtOH, treated with activated charcoal, filtered and evaporated to give 8.1 g (80%) of a yellow crystal subtitle compound. Got.

1H NMR (300 MHz; CDCl): δ 6.68(s, 1H); 6.63(s, 2H); 3.78(s, 3H); 3.58(s, 2H); 2.31(s, 3H) 1 H NMR (300 MHz; CDCl): δ 6.68 (s, 1H); 6.63 (s, 2 H); 3.78 (s, 3 H); 3.58 (s, 2 H); 2.31 (s, 3H)

(iv) 에틸-3-메톡시-5-메틸페닐아세테이트(iv) ethyl-3-methoxy-5-methylphenylacetate

EtOH(100 mL) 중의 3-메톡시-5-메틸페닐아세트산(8.1 g; 0.045 몰; 상기 단계 (iii)로부터의 화합물)의 용액에 진한 H2SO4를 부가하고, 용액을 40 시간 동안 정치하였다. 반응 혼합물을 농축하고, 조생성물을 물 및 에테르에 분배하였다. 유기층을 NaHCO3 수용액 및 물로 세척하고, 건조하고(Na2SO4), 증발시켜 갈색 오일인 부표제 생성물 8.0 g(85%)을 얻었다.To the solution of 3-methoxy-5-methylphenylacetic acid (8.1 g; 0.045 mol; compound from step (iii)) in EtOH (100 mL) was added concentrated H 2 SO 4 and the solution was left for 40 hours. . The reaction mixture was concentrated and the crude product was partitioned between water and ether. The organic layer was washed with aqueous NaHCO 3 solution and water, dried (Na 2 SO 4 ) and evaporated to afford 8.0 g (85%) of the title product as a brown oil.

1H NMR (400 MHz; CDCl3): δ 6.71(s, 1H); 6.65(s, 1H) 6.64(s, 1H); 4.16(q, 2H); 3.79(s, 3h); 3.55(s, 2H); 2.23(s, 3H); 1.27(t, 3H) 1 H NMR (400 MHz; CDCl 3 ): δ 6.71 (s, 1H); 6.65 (s, 1 H) 6.64 (s, 1 H); 4.16 (q, 2 H); 3.79 (s, 3 h); 3.55 (s, 2 H); 2.23 (s, 3 H); 1.27 (t, 3 H)

(v) 에틸 3-옥소-2-(3-메톡시-5-메틸페닐)프로피오네이트(v) ethyl 3-oxo-2- (3-methoxy-5-methylphenyl) propionate

에테르(75 mL) 중의 에틸 3-메톡시-5-메틸페닐아세테이트(3.0 g; 14 밀리몰; 단계 (iv)로부터의 화합물) 및 에틸 포르메이트(1.9 g; 26 밀리몰)의 용액에 Na(0.39 g; 17 밀리몰)을 작은 덩어리로 부가하였다. 용액을 0 ℃로 냉각하고 이어서 EtOH(무수; 0.24 mL)를 부가하였다. 얻어진 슬러리가 용해될 때까지 이 슬러리에 에테르(100 mL), EtOH(5 mL) 및 물을 부가하였다. 수성상을 수집하고 pH 2로 산성화하고(HCl 수용액) 에테르로 추출하였다. 유기상을 NaHCO3 수용액으로 세척하고, 건조하고(Na2SO4), 증발시켜 부표제 화합물 2 g(59%)을 얻었다.Na (0.39 g) in a solution of ethyl 3-methoxy-5-methylphenylacetate (3.0 g; 14 mmol; compound from step (iv)) and ethyl formate (1.9 g; 26 mmol) in ether (75 mL); 17 mmol) was added in small chunks. The solution was cooled to 0 ° C and then EtOH (anhydrous; 0.24 mL) was added. Ether (100 mL), EtOH (5 mL) and water were added to the slurry until the resulting slurry was dissolved. The aqueous phase was collected, acidified to pH 2 (HCl aqueous solution) and extracted with ether. The organic phase was washed with NaHCO 3 aqueous solution, dried (Na 2 SO 4 ) and evaporated to give 2 g (59%) of the subtitle compound.

1H NMR (300 MHz; CDCl3): δ 12.12(d, 0.5H); 7.31(d, 0.5H); 6.62(bs, 2H); 4.26 (q, 2H); 3.80(s, 3H); 2.35(s, 3H); 1.33(t, 3H) 1 H NMR (300 MHz; CDCl 3 ): δ 12.12 (d, 0.5H); 7.31 (d, 0.5 H); 6.62 (bs, 2 H); 4.26 (q, 2 H); 3.80 (s, 3 H); 2.35 (s, 3 H); 1.33 (t, 3 H)

(vi) 에틸 3-히드록시-2-(3-메톡시-5-메틸페닐)-프로피오네이트(vi) ethyl 3-hydroxy-2- (3-methoxy-5-methylphenyl) -propionate

MeOH(50 mL) 중의 에틸 3-옥소-2-(3-메톡시-5-메틸페닐)프로피오네이트(1.9 g; 8.1 밀리몰; 단계 (v)로부터의 화합물)의 교반액을 -15 ℃로 냉각하였다. 이어서, NaBH4(0.61 g; 16 밀리몰)을 일부분씩 부가하였다. 혼합물을 3 시간 동안 -15 내지 -5 ℃에서 교반하였다. 이어서, 물을 부가하고, 얻어진 혼합물을 농축하였다. 수성상을 EtOAc로 추출하고, 유기상을 물로 세척하고, 건조하고(Na2SO4), 증발시켜 부표제 화합물 2.0 g(59%)을 얻었다.Cool a stirred solution of ethyl 3-oxo-2- (3-methoxy-5-methylphenyl) propionate (1.9 g; 8.1 mmol; compound from step (v)) in MeOH (50 mL) to -15 ° C. It was. Then NaBH 4 (0.61 g; 16 mmol) was added in portions. The mixture was stirred for 3 h at -15 to -5 ° C. Then water was added and the resulting mixture was concentrated. The aqueous phase was extracted with EtOAc, the organic phase was washed with water, dried (Na 2 SO 4 ) and evaporated to give 2.0 g (59%) of the subtitle compound.

1H NMR (300 MHz; CDCl3): δ 6.65(s, 1H); 6.63(s, 1H); 6.58(s, 1H); 4.3-4.05(m, 3H); 3.8(m, 5H); 2.30(s, 3H); 1.32(t, 3H) 1 H NMR (300 MHz; CDCl 3 ): δ 6.65 (s, 1H); 6.63 (s, 1 H); 6.58 (s, 1 H); 4.3-4.05 (m, 3 H); 3.8 (m, 5 H); 2.30 (s, 3 H); 1.32 (t, 3 H)

(vii) 3-히드록시-2-(3-메톡시-5-메틸페닐)-프로피온산(vii) 3-hydroxy-2- (3-methoxy-5-methylphenyl) -propionic acid

MeOH:H2O(1:1) 200 mL 중의 에틸 3-히드록시-2-(3-메톡시-5-메틸페닐)-프로피오네이트(1.7 g; 7.1 밀리몰; 상기 (vi) 단계로부터의 화합물)의 용액을 실온에서 2 시간 동안 교반하였다. 이어서, 반응 혼합물을 농축하고, 에테르로 세척하고 산성화하였다. 얻어진 혼합물을 에테르로 2회 추출하고, 합한 유기층을 물로 세척하고, 건조하고(Na2SO4), 증발시켜 1.47 g(98%)을 얻었다.Ethyl 3-hydroxy-2- (3-methoxy-5-methylphenyl) -propionate (1.7 g; 7.1 mmol; compound from step (vi) above in 200 mL of MeOH: H 2 O (1: 1) ) Solution was stirred at room temperature for 2 hours. The reaction mixture was then concentrated, washed with ether and acidified. The resulting mixture was extracted twice with ether, and the combined organic layers were washed with water, dried (Na 2 SO 4 ) and evaporated to give 1.47 g (98%).

1H NMR (300 MHz; CDCl3): δ 6.70(s, 1H); 6.66(s, 1H); 6.65(s, 1H); 4.12(dd, 1H); 3.85-3.75(m, 2H); 3.75(s, 3H); 2.32(s, 3H) 1 H NMR (300 MHz; CDCl 3 ): δ 6.70 (s, 1H); 6.66 (s, 1 H); 6.65 (s, 1 H); 4.12 (dd, 1 H); 3.85-3.75 (m, 2 H); 3.75 (s, 3 H); 2.32 (s, 3H)

실시예 OExample O

(R,S)-3-히드록시-2-(2,5-디메톡시페닐)-프로피온산(R, S) -3-hydroxy-2- (2,5-dimethoxyphenyl) -propionic acid

3-옥소-2-(2,5-디메톡시페닐)프로피온산 에틸 에스테르로부터 출발하여 상기 실시예 E에 기재된 방법에 따라 제조하였다.Prepared according to the method described in Example E above starting from 3-oxo-2- (2,5-dimethoxyphenyl) propionic acid ethyl ester.

1H NMR (400 MHz; CDCl3): δ 6.89(d, 1H); 6.85(d, 1H); 6.78(dd, 1H); 4.86(넓음, 2H); 4.14(dd, 1H); 3.98(dd, 1H); 3.78(s, 3H); 3.72(s, 3H); 3.67(dd, 1H) 1 H NMR (400 MHz; CDCl 3 ): δ 6.89 (d, 1H); 6.85 (d, 1 H); 6.78 (dd, 1 H); 4.86 (wide, 2H); 4.14 (dd, 1 H); 3.98 (dd, 1 H); 3.78 (s, 3 H); 3.72 (s, 3 H); 3.67 (dd, 1 H)

실시예 PExample P

(R,S)-3-히드록시-2-(3,5-디메톡시페닐)프로피온산(R, S) -3-hydroxy-2- (3,5-dimethoxyphenyl) propionic acid

3-옥소-2-(3,5-디메톡시페닐)프로피온산 에틸 에스테르로부터 출발하여 상기 실시예 E에 기재된 방법에 따라 제조하였다.Prepared according to the method described in Example E above starting from 3-oxo-2- (3,5-dimethoxyphenyl) propionic acid ethyl ester.

1H NMR (400 MHz; CDCl3): δ 6.44(s, 2H); 6.40(s, 1H); 4.13(dd, 1H); 3.85-3.75(m, 2H); 3.75(s, 6H) 1 H NMR (400 MHz; CDCl 3 ): δ 6.44 (s, 2H); 6.40 (s, 1 H); 4.13 (dd, 1 H); 3.85-3.75 (m, 2 H); 3.75 (s, 6H)

실시예 QExample Q

(R,S)-3-히드록시-2-(3,4-메틸렌디옥시페닐)프로피온산(R, S) -3-hydroxy-2- (3,4-methylenedioxyphenyl) propionic acid

3-옥소-2-(3,4-메틸렌디옥시페닐)프로피온산 에틸 에스테르로부터 출발하여 상기 실시예 E에 기재된 방법에 따라 제조하였다.Prepared according to the method described in Example E above starting from 3-oxo-2- (3,4-methylenedioxyphenyl) propionic acid ethyl ester.

1H NMR (400 MHz; CDCl3): δ 6.78(s, 1H); 6.73(s, 2H); 5.95(s, 2H); 4.08(dd, 1H); 3.78(m, 2H) 1 H NMR (400 MHz; CDCl 3 ): δ 6.78 (s, 1H); 6.73 (s, 2 H); 5.95 (s, 2 H); 4.08 (dd, 1 H); 3.78 (m, 2 H)

실시예 RExample R

(R,S)-3-히드록시-2-(1-나프틸)프로피온산(R, S) -3-hydroxy-2- (1-naphthyl) propionic acid

3-옥소-2-(1-나프틸)프로피온산 에틸 에스테르로부터 출발하여 상기 실시예 E에 기재된 방법에 따라 제조하였다.Prepared according to the method described in Example E above starting from 3-oxo-2- (1-naphthyl) propionic acid ethyl ester.

LC-MS m/z 215 (M-1)-1 LC-MS m / z 215 (M-1) -1

실시예 SExample S

(R,S)-3-메톡시페닐-CH(CH2OTBDMS)COOH(R, S) -3-methoxyphenyl-CH (CH 2 OTBDMS) COOH

(i) (R,S)-3-메톡시페닐-CH(CH2OTBDMS)COOTBDMS(i) (R, S) -3-methoxyphenyl-CH (CH 2 OTBDMS) COOTBDMS

이미다졸(6.7 g; 97.8 밀리몰) 및 TBDMS-Cl(7.4 g; 48.9 밀리몰)을 DMF(20 mL) 중의 (R,S)-3-히드록시-2-(3-메톡시페닐)-피로피온산(4 g; 20.4 밀리몰; 상기 실시예 E(ii)로부터의 화합물) 용액에 부가하였다. 반응 혼합물을 실온에서 3일간 교반하였다. 이어서, 물(0.5 L)을 부가하고 혼합물을 에테르로 3회 추출하였다. 합한 유기상을 시트르산(10%), 물, NaHCO3 수용액 및 물로 세척하고, 건조하고(Na2SO4), 증발시켰다. 조생성물(8.53 g; 황색 오일 98%)을 추가의 정제없이 다음 단계에서 사용하였다.Imidazole (6.7 g; 97.8 mmol) and TBDMS-Cl (7.4 g; 48.9 mmol) were added (R, S) -3-hydroxy-2- (3-methoxyphenyl) -pyrropione in DMF (20 mL). Acid (4 g; 20.4 mmol; compound from Example E (ii) above). The reaction mixture was stirred for 3 days at room temperature. Water (0.5 L) was then added and the mixture was extracted three times with ether. The combined organic phases were washed with citric acid (10%), water, aqueous NaHCO 3 and water, dried (Na 2 SO 4 ) and evaporated. The crude product (8.53 g; yellow oil 98%) was used in the next step without further purification.

1H NMR (400 MHz; CDCl3): δ 7.22(t, 1H); 6.90(d, 1H); 6.88(m, 1H); 6.81(m, 1H); 4.16(t, 1H); 3.80(s, 3H); 3.82-3.72(m, 2H); 0.88(s, 6H); 0.87(s, 6H); 0.22(d, 6H); 0.02(d, 6H) 1 H NMR (400 MHz; CDCl 3 ): δ 7.22 (t, 1H); 6.90 (d, 1 H); 6.88 (m, 1 H); 6.81 (m, 1 H); 4.16 (t, 1 H); 3.80 (s, 3 H); 3.82-3.72 (m, 2 H); 0.88 (s, 6 H); 0.87 (s, 6 H); 0.22 (d, 6 H); 0.02 (d, 6H)

(ii) (R,S)-3-메톡시페닐-CH(CH2OTBDMS)COOH(ii) (R, S) -3-methoxyphenyl-CH (CH 2 OTBDMS) COOH

(R,S)-3-메톡시페닐-CH(CH2OTBDMS)COOTBDMS(8.0 g; 18.8 밀리몰), K2CO3(6.25 g; 45.2 밀리몰), MeOH(120 mL) 및 H2O(40 mL)의 혼합물을 실온에서 철야 교반하였다. 농축 후, 수성층을 에테르로 세척하고, 시트르산으로 산성화하고 에테르로 3회 추출하였다. 합한 유기상을 H2O로 세척하고, 건조하고(Na2SO4), 증발시켜 황색 오일인 부표제 생성물 5.0 g(87%)을 얻었다.(R, S) -3-methoxyphenyl-CH (CH 2 OTBDMS) COOTBDMS (8.0 g; 18.8 mmol), K 2 CO 3 (6.25 g; 45.2 mmol), MeOH (120 mL) and H 2 O (40 mL) was stirred overnight at room temperature. After concentration, the aqueous layer was washed with ether, acidified with citric acid and extracted three times with ether. The combined organic phases were washed with H 2 O, dried (Na 2 SO 4 ) and evaporated to give 5.0 g (87%) of the title product as a yellow oil.

1H NMR (400 MHz; CD3OD): δ 7.21(t, 1H); 6.89(s+d, 2H); 6.82(m, 1H); 4.86(b, 2H); 4.13(dd, 1H); 3.76(s, 3H); 3.8-3.7(m, 2H); 0.86(s, 9H); 0.02(d, 6H) 1 H NMR (400 MHz; CD 3 OD): δ 7.21 (t, 1 H); 6.89 (s + d, 2H); 6.82 (m, 1 H); 4.86 (b, 2H); 4.13 (dd, 1 H); 3.76 (s, 3 H); 3.8-3.7 (m, 2 H); 0.86 (s, 9 H); 0.02 (d, 6H)

실시예 TExample T

(R,S)-3-히드록시-2-(3-Boc-아미노페닐)프로피온산(R, S) -3-hydroxy-2- (3-Boc-aminophenyl) propionic acid

(i) 3-아미노페닐아세트산 에틸 에스테르(i) 3-aminophenylacetic acid ethyl ester

무수 EtOH(20 mL) 중의 m-아미노벤조산(3.0 g; 19.8 밀리몰), 및 진한 H2SO4(2 mL) 용액을 3일 동안 75 ℃에서 가열하였다. 용액을 농축하고, Na2CO3 수용액을 부가하고, 혼합물을 에테르(80 mL)로 추출하였다. 유기층을 간수로 세척하고, 건조하고(Na2SO4), 농축하여 부표제 화합물 2.9 g(82%)을 얻었다.A solution of m-aminobenzoic acid (3.0 g; 19.8 mmol), and concentrated H 2 SO 4 (2 mL) in anhydrous EtOH (20 mL) was heated at 75 ° C for 3 days. The solution was concentrated, aqueous Na 2 CO 3 solution was added, and the mixture was extracted with ether (80 mL). The organic layer was washed with brine, dried (Na 2 SO 4 ) and concentrated to give 2.9 g (82%) of the subtitle compound.

1H NMR (400 MHz; CDCl3): δ 7.10(t, 1H); 6.77(d, 1H); 6.62(t, 1H); 6.58(m, 1H); 4.15(q, 2H); 3.65(b, 2H); 3.52(s, 2H), 1.25(t, 3H) 1 H NMR (400 MHz; CDCl 3 ): δ 7.10 (t, 1H); 6.77 (d, 1 H); 6.62 (t, 1 H); 6.58 (m, 1 H); 4.15 (q, 2 H); 3.65 (b, 2 H); 3.52 (s, 2H), 1.25 (t, 3H)

(ii) 3-(Boc-아미노)페닐아세트산 에틸 에스테르(ii) 3- (Boc-amino) phenylacetic acid ethyl ester

THF(50 mL) 중의 3-아미노페닐아세트산 에틸 에스테르(1.9 g; 11 밀리몰; 상기 단계 (i)로부터의 화합물) 및 Boc2O(2.3 g; 11 밀리몰)의 용액을 실온에서 철야 교반하였다. 얻어진 혼합물을 농축하고, HCl 수용액을 부가하였다. 혼합물 수용액을 에테르로 추출하고, 유기층을 물로 세척하고, 건조하고(Na2SO4), 농축하여 부표제 생성물 2.5 g(84%)을 얻었다.A solution of 3-aminophenylacetic acid ethyl ester (1.9 g; 11 mmol; compound from step (i)) and Boc 2 O (2.3 g; 11 mmol) in THF (50 mL) was stirred overnight at room temperature. The resulting mixture was concentrated and HCl aqueous solution was added. The aqueous mixture solution was extracted with ether, the organic layer was washed with water, dried (Na 2 SO 4 ) and concentrated to give 2.5 g (84%) of the subtitle product.

1H NMR (400 MHz; CDCl3): δ 7.33(s, 1H); 7.24(dd, 2H); 6.96(m, 1H), 6.50(b, 1H); 4.15(q, 2H); 3.58(s, 2H); 1.53(s, 9H); 1.26(t, 3H) 1 H NMR (400 MHz; CDCl 3 ): δ 7.33 (s, 1H); 7.24 (dd, 2 H); 6.96 (m, 1 H), 6.50 (b, 1 H); 4.15 (q, 2 H); 3.58 (s, 2 H); 1.53 (s, 9 H); 1.26 (t, 3 H)

(iii) 2-((3-Boc-아미노)페닐)-3-옥소-프로피온산 에틸 에스테르(iii) 2-((3-Boc-amino) phenyl) -3-oxo-propionic acid ethyl ester

무수 에틸 에테르(60 mL) 중의 3-(Boc-아미노)페닐아세트산 에틸 에스테르(2.4 g; 8.6 밀리몰; 상기 단계 (ii)로부터의 화합물) 및 에틸 포르메이트(1.1 g; 15 밀리몰)의 용액에 Na(0.34 g; 15 밀리몰)을 작은 조각으로 부가하였다. 혼합물을 빙조에서 냉각하고, 이후에 무수 EtOH 0.15 mL을 부가하였다. 반응 혼합물을 실온에서 3일 동안 교반하였다. 이와 같이 형성된 회색 슬러리에 에틸 에테르:EtOH(50:5 mL)를 부가하고, 용액을 일정 시간 동안 교반하고 투명한 황색 용액이 형성될 때까지 물을 부가하였다. 상을 분리하고, 유기상을 H2O로 1회 추출하였다. 수성상을 3% HCl 수용액을 사용하여 pH 2로 산성화하는 순간 백색 침전물이 형성되었다. 소량의 간수를 부가하고 혼합물 수용액을 에틸 에테르로 추출하였다. 유기상을 NaHCO3 수용액(10%)으로 세척하고, 건조하고(Na2SO4) 증발시켰다. 부표제 생성물(1.7 g; 64%)를 투명한 갈색 오일로서 단리하였고, 이 생성물은 추가의 정제없이 사용하기에 충분한 정도로 순수하였다.To a solution of 3- (Boc-amino) phenylacetic acid ethyl ester (2.4 g; 8.6 mmol; compound from step (ii)) and ethyl formate (1.1 g; 15 mmol) in anhydrous ethyl ether (60 mL) (0.34 g; 15 mmol) was added in small pieces. The mixture was cooled in an ice bath, after which 0.15 mL of anhydrous EtOH was added. The reaction mixture was stirred at rt for 3 days. Ethyl ether: EtOH (50: 5 mL) was added to the gray slurry thus formed, the solution was stirred for a period of time and water was added until a clear yellow solution formed. The phases were separated and the organic phase was extracted once with H 2 O. A white precipitate formed when the aqueous phase was acidified to pH 2 with 3% aqueous HCl solution. A small amount of brine was added and the mixture aqueous solution was extracted with ethyl ether. The organic phase was washed with aqueous NaHCO 3 (10%), dried (Na 2 SO 4 ) and evaporated. The subtitle product (1.7 g; 64%) was isolated as a clear brown oil which was pure enough to be used without further purification.

1H NMR (300 MHz; CDCl3): δ 7.4(m, 3H); 7.0(m, 1H); 6.6(b, 1H); 4.3(m, 2H); 1.5(s, 9H); 1.3(m, 3H) 1 H NMR (300 MHz; CDCl 3 ): δ 7.4 (m, 3H); 7.0 (m, 1 H); 6.6 (b, 1 H); 4.3 (m, 2 H); 1.5 (s, 9 H); 1.3 (m, 3H)

(iv) (R,S)-3-히드록시-2-(3-Boc-아미노페닐)프로피온산(iv) (R, S) -3-hydroxy-2- (3-Boc-aminophenyl) propionic acid

2-((3-Boc-아미노)페닐)-3-옥소-프로피온산 에틸 에스테르(상기 단계 (iii)로부터의 화합물)으로 출발하여 상기 실시예 E에 기재된 방법으로 제조하였다.Prepared by the method described in Example E above starting with 2-((3-Boc-amino) phenyl) -3-oxo-propionic acid ethyl ester (compound from step (iii) above).

1H NMR (300 MHz; CDCl3): δ7.25(m, 3H); 6.95(d, 1H); 6.55(b, 1H); 4.15(m, 2H); 1.50(s, 9H); 1.20(t, 3H) 1 H NMR (300 MHz; CDCl 3 ): δ 7.25 (m, 3H); 6.95 (d, 1 H); 6.55 (b, 1 H); 4.15 (m, 2 H); 1.50 (s, 9 H); 1.20 (t, 3 H)

실시예 UExample U

(R,S)-3-히드록시-2-(3-(Boc-메틸아미노)페닐)프로피온산(R, S) -3-hydroxy-2- (3- (Boc-methylamino) phenyl) propionic acid

(i) 3-(포르밀아미노)페닐아세트산 에틸 에스테르(i) 3- (formylamino) phenylacetic acid ethyl ester

디이소프로필에테르(150 mL) 중의 3-아미노페닐아세트산 에틸 에스테르(3.0 g; 0.017 몰; 상기 실시예 T(i)로부터의 화합물), 및 포름산(1.5 g; 0.034 몰)의 용액을 딘-스타크 트랩(Dean-Stark trap)으로 철야 환류하였다. 용액을 건조될 정도로 농축하고, 에테르 중에 용해하고 묽은 HCl로 세척하여 잔류하는 출발 물질을 제거하였다. 건조하고(Na2SO4), 농축하여 부표제 화합물 3.1 g(89%)을 얻었다.A solution of 3-aminophenylacetic acid ethyl ester (3.0 g; 0.017 mol; compound from Example T (i) above), and formic acid (1.5 g; 0.034 mol) in diisopropylether (150 mL) was Dean-Stark It was refluxed overnight with a Dean-Stark trap. The solution was concentrated to dryness, dissolved in ether and washed with dilute HCl to remove residual starting material. Dried (Na 2 SO 4 ) and concentrated to give 3.1 g (89%) of the subtitle compound.

1H NMR (300 MHz; CDCl3): δ8.65(d, 1H); 8.40(b, 1H); 7.45(m, 1H); 7.25(m, 1H); 7.05 (m, 2H); 4.15(m, 2H); 3.55(s, 2H), 1.30(m, 3H) 1 H NMR (300 MHz; CDCl 3 ): δ 8.65 (d, 1H); 8.40 (b, 1 H); 7.45 (m, 1 H); 7.25 (m, 1 H); 7.05 (m, 2 H); 4.15 (m, 2 H); 3.55 (s, 2H), 1.30 (m, 3H)

(ii) 3-(메틸아미노)페닐아세트산 에틸 에스테르(ii) 3- (methylamino) phenylacetic acid ethyl ester

보란-디메틸술피드 착물(THF 중의 2M; 20 mL)의 용액을 무수 THF(100 mL) 중의 3-(포르밀아미노)페닐아세트산 에틸 에스테르(4.1 g; 0.02 몰; 상기 단계(i)로부터의 화합물)의 빙냉액에 부가하고 반응 혼합물을 1 시간 동안 교반하였다. 얻어진 용액을 묽은 HCl에 붓고 혼합물을 15 분 동안 정치한 후, 에테르로 세척하여 반응하지 않은 물질을 제거하였다. 수용액을 알칼리성화하고(NaHCO3) 에테르로(3회) 추출하였다. 합한 유기상을 물로 세척하고, 건조하고(Na2SO4), 증발시켜 부표제 화합물 3.0 g(78%)을 얻었다.A solution of borane-dimethylsulfide complex (2M in THF; 20 mL) was added to 3- (formylamino) phenylacetic acid ethyl ester in anhydrous THF (100 mL) (4.1 g; 0.02 moles; compound from step (i) above. ) Was added to the ice cold solution and the reaction mixture was stirred for 1 hour. The resulting solution was poured into dilute HCl and the mixture was left for 15 minutes, then washed with ether to remove unreacted material. The aqueous solution was alkaline (NaHCO 3 ) and extracted with ether (three times). The combined organic phases were washed with water, dried (Na 2 SO 4 ) and evaporated to yield 3.0 g (78%) of the subtitle compound.

1H-NMR(300MHz; CDCl3) δ 7.10(t, 1H); 6.60(d, 1H); 6.50(m, 2H), 4.10(q, 2H); 3.50(s, 2H); 2.80(s, 3H); 1.20(t, 3H) 1 H-NMR (300 MHz; CDCl 3 ) δ 7.10 (t, 1H); 6.60 (d, 1 H); 6.50 (m, 2 H), 4.10 (q, 2 H); 3.50 (s, 2 H); 2.80 (s, 3 H); 1.20 (t, 3 H)

(iii) 3-(N-Boc-메틸아미노)페닐아세트산 에틸 에스테르(iii) 3- (N-Boc-methylamino) phenylacetic acid ethyl ester

THF(100 mL) 중의 3-(메틸아미노)페닐아세트산 에틸 에스테르(3.0 g; 0.016 몰; 상기 단계 (ii)부터의 화합물) 및 Boc2O(3.4 g; 0.016 몰)의 용액을 실온에서 12일 동안 교반하였다. 얻어진 용액을 농축하여 부표제 화합물(4.9 g; 정량적인 양)을 얻었다.A solution of 3- (methylamino) phenylacetic acid ethyl ester (3.0 g; 0.016 mol; compound from step (ii)) and Boc 2 O (3.4 g; 0.016 mol) in THF (100 mL) was 12 days at room temperature. Was stirred. The resulting solution was concentrated to give a subtitle compound (4.9 g; quantitative amount).

1H-NMR(300 MHz; CDCl3): δ 7.25(d, 1H); 7.10(m, 3H); 4.15(q, 2H), 3.60(s, 2H); 3.25(s, 3H); 1.45(s, 9H); 1.25(t, 3H) 1 H-NMR (300 MHz; CDCl 3 ): δ 7.25 (d, 1H); 7.10 (m, 3 H); 4.15 (q, 2 H), 3.60 (s, 2 H); 3.25 (s, 3 H); 1.45 (s, 9 H); 1.25 (t, 3 H)

(iv) 2-((N-Boc-메틸아미노)페닐)-3-옥소-프로피온산 에틸 에스테르(iv) 2-((N-Boc-methylamino) phenyl) -3-oxo-propionic acid ethyl ester

3-(N-Boc-메틸아미노)페닐아세트산 에틸 에스테르(2.0 g; 6.8 밀리몰; 상기 단계 (iii)부터의 화합물)로부터 상기 실시예 T(iii)에 기재된 방법에 따라 제조하여 부표제 생성물 1.6 g(73%)를 얻었다.1.6 g of a subtitle product prepared from the 3- (N-Boc-methylamino) phenylacetic acid ethyl ester (2.0 g; 6.8 mmol; the compound from step (iii)) according to the method described in Example T (iii) above; 73%).

1H-NMR(300 MHz; CDCl3): δ 12.15(d, 0.5H); 7.74(s, 0.5H); 7.25(m, 4H); 4.2(m, 2H); 3.26(s, 3H); 1.46(s, 9H); 1.29(m, 3H) 1 H-NMR (300 MHz; CDCl 3 ): δ 12.15 (d, 0.5H); 7.74 (s, 0.5 H); 7.25 (m, 4 H); 4.2 (m, 2 H); 3.26 (s, 3 H); 1.46 (s, 9 H); 1.29 (m, 3H)

(v) (R,S)-3-히드록시-2-(3-Boc-아미노페닐)프로피온산(v) (R, S) -3-hydroxy-2- (3-Boc-aminophenyl) propionic acid

2-((N-Boc-메틸아미노)페닐)-3-옥소-프로피온산 에틸 에스테르(상기 단계 (iv)부터의 화합물)로 출발하여 상기 실시예 E에 기재된 방법에 따라 제조하였다.Prepared according to the method described in Example E above starting with 2-((N-Boc-methylamino) phenyl) -3-oxo-propionic acid ethyl ester (compound from step (iv) above).

1H-NMR(300 MHz; CDCl3): δ 7.25(m, 1H); 7.15(m, 3H); 7.05(d, 1H); 4.05(m, 1H); 3.80(m, 2H); 1.40(s, 9H) 1 H-NMR (300 MHz; CDCl 3 ): δ 7.25 (m, 1 H); 7.15 (m, 3 H); 7.05 (d, 1 H); 4.05 (m, 1 H); 3.80 (m, 2 H); 1.40 (s, 9H)

실시예 VExample V

(R,S)-3-히드록시-2-(3-클로로-5-메틸페닐)프로피온산(R, S) -3-hydroxy-2- (3-chloro-5-methylphenyl) propionic acid

(i) 3-클로로-5-메틸벤질 브로마이드(i) 3-chloro-5-methylbenzyl bromide

CCl4 중의 5-클로로-m-크실렌(14.06 g; 0.1 몰), NBS(17.8 g; 0.1 몰) 및 AIBN (1.1 g; 6.7 밀리몰)의 용액을 2 시간 동안 환류하였다. 얻어진 혼합물을 냉각하고, 형성된 고체 물질을 여과에 의해 제거하였다. 농축하여 부표제 화합물(17.9 g; 80%)를 얻었다.A solution of 5-chloro-m-xylene (14.06 g; 0.1 mol), NBS (17.8 g; 0.1 mol) and AIBN (1.1 g; 6.7 mmol) in CCl 4 was refluxed for 2 hours. The resulting mixture was cooled and the solid material formed was removed by filtration. Concentration gave a subtitle compound (17.9 g; 80%).

1H-NMR(400 MHz; CDCl3): δ 7.20(s, 1H); 7.11(s, 1H); 7.09(s, 1H); 4.41(s, 2H); 2.34(s, 3H) 1 H-NMR (400 MHz; CDCl 3 ): δ 7.20 (s, 1H); 7.11 (s, 1 H); 7.09 (s, 1 H); 4.41 (s, 2 H); 2.34 (s, 3 H)

(ii) 3-클로로-5-메틸페닐아세토니트릴(ii) 3-chloro-5-methylphenylacetonitrile

DMSO(25 mL) 중의 3-클로로-5-메틸벤질 브로마이드(17.6 g; 0.8 몰; 상기 단계 (i)로부터의 화합물) 및 NaCN (8.2 g; 0.16 몰) 용액을 제조하였다. 얻어진 다소 고온의 혼합물을 조금 냉각하고, 이어서 실온에서 1 시간에 걸쳐 교반하였다. 이어서, CH3CN(25 mL)을 부가하고, 1시간 동안 혼합물을 환류하였다. 냉각 후, 물(200 mL)을 부가하고, 얻어진 용액을 에테르로 3회 추출하였다. 합한 유기상을 물로 3회 세척하고, 건조하고(Na2SO4), 증발시켜 다음 단계에서 추가의 정제없이 사용되는 부표제 조생성물 16.6 g(80%)을 얻었다.A solution of 3-chloro-5-methylbenzyl bromide (17.6 g; 0.8 mol; compound from step (i)) and NaCN (8.2 g; 0.16 mol) in DMSO (25 mL) was prepared. The somewhat hot mixture obtained was slightly cooled and then stirred at room temperature over 1 hour. Then CH 3 CN (25 mL) was added and the mixture was refluxed for 1 h. After cooling, water (200 mL) was added and the resulting solution was extracted three times with ether. The combined organic phases were washed three times with water, dried (Na 2 SO 4 ) and evaporated to give 16.6 g (80%) of the subtitle crude product which was used in the next step without further purification.

1H-NMR(400 MHz; CDCl3): δ 7.14(s, 1H); 7.12(s, 1H); 7.04(s, 1H); 3.69(s, 2H); 2.35(s, 3H) 1 H-NMR (400 MHz; CDCl 3 ): δ 7.14 (s, 1H); 7.12 (s, 1 H); 7.04 (s, 1 H); 3.69 (s, 2 H); 2.35 (s, 3H)

(iii) 3-클로로-5-메틸페닐아세트산(iii) 3-chloro-5-methylphenylacetic acid

물: i-PrOH(2:1) 150 mL 중의 3-클로로-5-메틸페닐아세토니트릴(13.3 g; 상기 단계 (ii)로부터의 화합물) 및 KOH(17 g; 0.3 몰)의 혼합물을 120℃에서 철야로 그리고 이후에 2일 동안 실온에서 고압솥에서 교반하면서 가열하였다. i-PrOH를 증발시키고 잔류물을 pH 2로 산성화시키고(6M HCl) 에테르로 3회 추출하였다. 합한 유기층을 물로 2회 세척하고, 건조하고(Na2SO4), 증발시켜 부표제 화합물 10.4 g(70%)을 얻었다.Water: A mixture of 3-chloro-5-methylphenylacetonitrile (13.3 g; compound from step (ii)) and KOH (17 g; 0.3 mol) in 150 mL of i-PrOH (2: 1) at 120 ° C Heated overnight and then with stirring in autoclave at room temperature for 2 days. i-PrOH was evaporated and the residue acidified to pH 2 (6M HCl) and extracted three times with ether. The combined organic layers were washed twice with water, dried (Na 2 SO 4 ) and evaporated to give 10.4 g (70%) of the subtitle compound.

1H-NMR(400 MHz; CDCl3): δ 7.09(s, 2H); 6.97(s, 1H); 3.57(s, 2H); 2.18(s, 3H) 1 H-NMR (400 MHz; CDCl 3 ): δ 7.09 (s, 2H); 6.97 (s, 1 H); 3.57 (s, 2 H); 2.18 (s, 3H)

FAB-MS m/z 366(M-1)- FAB-MS m / z 366 (M-1) -

(iv) 에틸 3-클로로-5-메틸페닐아세테이트(iv) ethyl 3-chloro-5-methylphenylacetate

EtOH (25 mL) 중의 3-클로로-5-메틸페닐아세트산(5.0 g; 27.09 밀리몰; 상기 단계 (iii)로부터의 화합물) 및 진한 H2SO4(0.1 mL)의 용액을 철야 환류하였다. 용액을 농축하고, 얻어진 혼합물을 Na2CO3 용액(75 mL)에서 처리하였다. 에테르(2 x 75 mL)로 추출한 후, 합한 유기층을 간수로 세척하고, 건조하고(Na2SO4), 증발시켜 부표제 화합물 4.92 g(85%)을 얻었다.A solution of 3-chloro-5-methylphenylacetic acid (5.0 g; 27.09 mmol; compound from step (iii) above) and concentrated H 2 SO 4 (0.1 mL) in EtOH (25 mL) was refluxed overnight. The solution was concentrated and the resulting mixture was treated in Na 2 CO 3 solution (75 mL). After extraction with ether (2 × 75 mL), the combined organic layers were washed with brine, dried (Na 2 SO 4 ) and evaporated to give 4.92 g (85%) of the subtitle compound.

1H-NMR(400 MHz; CDCl3): δ 7.07(s, 1H); 7.08(s, 1H); 6.97(s, 1H); 4.15(q, 2H); 3.54(s, 2H); 2.31(s, 3H); 1.25(t, 3H) 1 H-NMR (400 MHz; CDCl 3 ): δ 7.07 (s, 1H); 7.08 (s, 1 H); 6.97 (s, 1 H); 4.15 (q, 2 H); 3.54 (s, 2 H); 2.31 (s, 3 H); 1.25 (t, 3 H)

(v) 에틸 3-옥소-2-(3-클로로-5-메틸페닐)프로피오네이트(v) ethyl 3-oxo-2- (3-chloro-5-methylphenyl) propionate

무수 에틸 에테르(50 mL) 중에서 에틸 3-클로로-5-메틸페닐아세테이트(4.89 g; 23 밀리몰; 상기 단계 (iv)로부터의 화합물), 에틸 포르메이트(3.3 g; 41.4 밀리몰) 및 Na(0.63 g; 27.6 밀리몰; 작은 덩어리로 부가)로부터 실시예 N(v)에 기재된 방법과 유사하게 제조하여 정치시 천천히 결정화되는 투명한 오일인 부표제 화합물 3.4 g(61%)를 얻었다.Ethyl 3-chloro-5-methylphenylacetate (4.89 g; 23 mmol; compound from step (iv)), ethyl formate (3.3 g; 41.4 mmol) and Na (0.63 g) in anhydrous ethyl ether (50 mL); 27.6 mmol; addition in small mass) yielded 3.4 g (61%) of a subtitle compound which was a transparent oil which crystallized slowly upon standing, analogous to the method described in Example N (v).

1H-NMR(500 MHz; CDCl3): δ 12.2(b, 1H); 7.28(s, 1H); 7.09(s, 1H); 7.07(s, 1H); 6.94(s, 1H); 4.30(q, 2H); 2.33(s, 3H); 1.30(t, 3H) 1 H-NMR (500 MHz; CDCl 3 ): δ 12.2 (b, 1H); 7.28 (s, 1 H); 7.09 (s, 1 H); 7.07 (s, 1 H); 6.94 (s, 1 H); 4.30 (q, 2 H); 2.33 (s, 3 H); 1.30 (t, 3 H)

FAB-MS m/z 238, 240(M-1)- FAB-MS m / z 238, 240 (M-1) -

(vi) (R,S)-3-히드록시-2-(3-클로로-5-메틸페닐)프로피온산(vi) (R, S) -3-hydroxy-2- (3-chloro-5-methylphenyl) propionic acid

에틸 3-옥소-2-(3-클로로-5-메틸페닐)프로피오네이트(상기 단계 (v)로부터의 화합물)로 출발하여 상기 실시예 E에 기재된 방법에 따라 제조하였다.Prepared according to the method described in Example E above starting with ethyl 3-oxo-2- (3-chloro-5-methylphenyl) propionate (compound from step (v) above).

1H-NMR(400 MHz; CDCl3): δ 7.12(s, 1H); 7.10(s, 1H); 6.98(s, 1H); 4.12(m, 1H); 3.82(m, 2H); 2.30(s, 3H) 1 H-NMR (400 MHz; CDCl 3 ): δ 7.12 (s, 1H); 7.10 (s, 1 H); 6.98 (s, 1 H); 4.12 (m, 1 H); 3.82 (m, 2 H); 2.30 (s, 3H)

실시예 WExample W

(R,S)-3-히드록시-2-(3,5-디메톡시페닐)프로피온산(R, S) -3-hydroxy-2- (3,5-dimethoxyphenyl) propionic acid

(i) 에틸 3,5-디메톡시페닐아세테이트(i) ethyl 3,5-dimethoxyphenylacetate

EtOH(50 mL) 중의 3,5-디메톡시페닐아세트산(2.0 g; 10 밀리몰) 및 진한 H2SO4(0.2 mL) 용액을 철야 환류하였다. 용액을 농축하고, 얻어진 물질을 NaOH 수용액(1M) 중에 용해하였다. 에테르(2 x 75 mL)로 추출한 후, 합한 유기상을 간수로 세척하고, 건조하고(Na2SO4) 증발시켜 부표제 화합물(2.0 g; 88%)을 얻었다.A solution of 3,5-dimethoxyphenylacetic acid (2.0 g; 10 mmol) and concentrated H 2 SO 4 (0.2 mL) in EtOH (50 mL) was refluxed overnight. The solution was concentrated and the material obtained was dissolved in aqueous NaOH solution (1M). After extraction with ether (2 × 75 mL), the combined organic phases were washed with brine, dried (Na 2 SO 4 ) and evaporated to afford the subtitle compound (2.0 g; 88%).

1H-NMR(400 MHz; CDCl3): δ 6.46(d, 2H); 6.38(t, 1H); 4.17(q, 2H); 3.71(s, 6H); 3.55(s, 2H); 1.27(t, 3H) 1 H-NMR (400 MHz; CDCl 3 ): δ 6.46 (d, 2H); 6.38 (t, 1 H); 4.17 (q, 2 H); 3.71 (s, 6 H); 3.55 (s, 2 H); 1.27 (t, 3 H)

(ii) 2-(3,5-디메톡시페닐)-3-옥소-프로피온산 에틸에스테르(ii) 2- (3,5-dimethoxyphenyl) -3-oxo-propionic acid ethyl ester

에틸 3,5-디메톡시페닐아세테이트(2.0 g; 8.9 밀리몰; 상기 단계 (i)로부터의 화합물)로부터 문헌 [J. Org. Chem. 54, 3831 (1989)]에 기재된 방법에 따라 제조하여, 정치시 천천히 결정화되는 투명한 오일인 부표제 생성물 3.4 g(61%)를 수득하였다. 생성물은 다음 단계에서 추가의 정제없이 사용할 수 있을 정도로 충분히 순수하였다.From ethyl 3,5-dimethoxyphenylacetate (2.0 g; 8.9 mmol; compound from step (i) above). Org. Chem. 54 , 3831 (1989) to give 3.4 g (61%) of a subtitle product which is a clear oil which crystallizes slowly upon standing. The product was pure enough to be used without further purification in the next step.

1H-NMR(500 MHz; CDCl3): δ 7.25(m, 1H), 6.40(m, 3H); 4.27(q, 2H); 3.75(s, 6H); 1.30(t, 3H) 1 H-NMR (500 MHz; CDCl 3 ): δ 7.25 (m, 1 H), 6.40 (m, 3 H); 4.27 (q, 2 H); 3.75 (s, 6 H); 1.30 (t, 3 H)

(iii) (R,S)-3-히드록시-2-(3,5-디메톡시페닐)프로피온산(iii) (R, S) -3-hydroxy-2- (3,5-dimethoxyphenyl) propionic acid

3-옥소-2-(3,5-디메톡시페닐)프로피온산 에틸 에스테르(상기 단계 (ii)로부터의 화합물)로부터 상기 실시예 E에 기재된 방법에 따라 제조하였다.Prepared from 3-oxo-2- (3,5-dimethoxyphenyl) propionic acid ethyl ester (compound from step (ii) above) according to the method described in Example E above.

1H-NMR(300 MHz; CDCl3): δ 6.44(s, 2H); 6.39(s, 1H); 4.12(m, 1H); 3.76(m, 8H) 1 H-NMR (300 MHz; CDCl 3 ): δ 6.44 (s, 2H); 6.39 (s, 1 H); 4.12 (m, 1 H); 3.76 (m, 8 H)

실시예 XExample X

(R,S)-3-히드록시-2-(2-클로로-5-(Boc-아미노)페닐)프로피온산(R, S) -3-hydroxy-2- (2-chloro-5- (Boc-amino) phenyl) propionic acid

(i) 2-클로로-5-(Boc-아미노)벤질 알코올(i) 2-chloro-5- (Boc-amino) benzyl alcohol

THF:DMF(200 mL; 1:1) 중에 5-아미노-2-클로로벤조산(9.0 g; 33 밀리몰)의 빙냉액에 TEA(4.0 g; 40 밀리몰), 이어서 이소부틸 클로로포르메이트(5.4 g; 40 밀리몰; 적가함)를 부가하였다. 이어서, 혼합물을 30 분간 더 교반하고, 형성된 백색 침전물을 여과에 의해 제거하고, 여과액을 -15 ℃로 냉각하고, NaBH4(3.8 g; 100 밀리몰) 및 물(20 mL)을 부가하였다. 15분 후, 물(200 mL)을 부가하고 용액을 실온에서 1 시간 동안 교반하였다. 증발 후, 잔류물을 MeOH에 용해하였다. 여과 및 농축에 의해 조생성물을 얻고, 이를 플래시 크로마토그래피(Si-겔, CH2Cl2; MeOH(9:1))에 의해 정제하여 부표제 화합물 7.4 g(87%)를 얻었다.To an ice cold solution of 5-amino-2-chlorobenzoic acid (9.0 g; 33 mmol) in THF: DMF (200 mL; 1: 1) was added TEA (4.0 g; 40 mmol) followed by isobutyl chloroformate (5.4 g; 40 mmol; added drop wise). The mixture was then further stirred for 30 min, the white precipitate formed was removed by filtration, the filtrate was cooled to -15 ° C and NaBH 4 (3.8 g; 100 mmol) and water (20 mL) were added. After 15 minutes, water (200 mL) was added and the solution stirred for 1 hour at room temperature. After evaporation, the residue was dissolved in MeOH. The crude product was obtained by filtration and concentration, which was purified by flash chromatography (Si-gel, CH 2 Cl 2 ; MeOH (9: 1)) to give 7.4 g (87%) of the subtitle compound.

1H-NMR(500 MHz; CDCl3): δ 7.48(s, 1H); 7.27(m, 2H); 6.58(s, 1H); 4.74(d, 2H); 1.52(s, 9H) 1 H-NMR (500 MHz; CDCl 3 ): δ 7.48 (s, 1H); 7.27 (m, 2 H); 6.58 (s, 1 H); 4.74 (d, 2 H); 1.52 (s, 9H)

(ii) 2-클로로-5-(Boc-아미노)벤질 메실레이트(ii) 2-chloro-5- (Boc-amino) benzyl mesylate

CH2Cl2(100 mL) 중의 2-클로로-5-(Boc-아미노)벤질 알코올(7.4 g; 29 밀리몰; 상기 단계(i)로부터의 화합물)의 빙냉액에 TEA(2.9 g; 29 밀리몰), 이어서 MsCl(3.3 g, 29 밀리몰; 적가함)을 부가하였다. 2 시간 동안 교반한 후, 얻어진 혼합물을 물에 부었다. 유기층을 분리하고, 물로 세척하고, 건조하고(Na2SO4), 농축하여 부표제 화합물 10 g(100 %)를 얻었다.TEA (2.9 g; 29 mmol) in ice-cold liquid of 2-chloro-5- (Boc-amino) benzyl alcohol (7.4 g; 29 mmol; compound from step (i)) in CH 2 Cl 2 (100 mL) Then MsCl (3.3 g, 29 mmol; added dropwise) was added. After stirring for 2 hours, the resulting mixture was poured into water. The organic layer was separated, washed with water, dried (Na 2 SO 4 ) and concentrated to give 10 g (100%) of the subtitle compound.

1H-NMR(300 MHz; CDCl3): δ 7.50(m, 1H); 7.40(m, 1H); 7.32(s, 1H); 6.55(b, 1H); 5.27(s, 2H); 3.05(s, 3H); 1.50(s, 9H) 1 H-NMR (300 MHz; CDCl 3 ): δ 7.50 (m, 1H); 7.40 (m, 1 H); 7.32 (s, 1 H); 6.55 (b, 1 H); 5.27 (s, 2 H); 3.05 (s, 3 H); 1.50 (s, 9 H)

(iii) (2-클로로-5-(Boc-아미노)페닐)아세토니트릴(iii) (2-chloro-5- (Boc-amino) phenyl) acetonitrile

DMSO 중의 2-클로로-5-(Boc-아미노)벤질 메실레이트(상기 단계(ii)로부터의 화합물)의 교반액에 NaCN(2.9 g; 60 밀리몰)을 부가하고, 용액을 실온에서 철야 교반하였다. 혼합물을 물(300 mL)에 붓고, 수현탁액을 에테르(4 x 50 mL)로 추출하였다. 합한 유기층을 물로 세척하고, 건조하고(Na2SO4), 농축하였다. 플래시 크로마토그래피(Si-겔; 헵탄:EtOAc(8:2))한 후, 부표제 화합물 5.2 g(65 %)을 얻었다.To a stirred solution of 2-chloro-5- (Boc-amino) benzyl mesylate (compound from step (ii) above) in DMSO was added NaCN (2.9 g; 60 mmol) and the solution was stirred overnight at room temperature. The mixture was poured into water (300 mL) and the aqueous suspension was extracted with ether (4 x 50 mL). The combined organic layers were washed with water, dried (Na 2 SO 4 ) and concentrated. After flash chromatography (Si-gel; heptane: EtOAc (8: 2)), 5.2 g (65%) of a subtitle compound were obtained.

1H-NMR(300 MHz; CDCl3): δ 7.52(d, 1H); 7.35(m, 2H); 6.50(b, 1H); 3.80(s, 2H); 1.50(s, 9H) 1 H-NMR (300 MHz; CDCl 3 ): δ 7.52 (d, 1H); 7.35 (m, 2 H); 6.50 (b, 1 H); 3.80 (s, 2 H); 1.50 (s, 9 H)

(iv) (2-클로로-5-(Boc-아미노)페닐)아세트산(iv) (2-chloro-5- (Boc-amino) phenyl) acetic acid

물:i-PrOH(2:1) 37 mL 중의 (2-클로로-5-(Boc-아미노)페닐)아세토니트릴(5.2 g; 20 밀리몰; 상기 단계 (iii)로부터의 화합물) 용액에 KOH(5 g; 89 밀리몰)를 부가하고, 용액을 철야 환류하였다. 이어서, 혼합물을 농축하고, 물:THF(50 mL; 1:1) 및 Boc2O를 부가하고, 혼합물을 철야 교반하였다. THF를 증발시키고, 수성상을 에테르(1 x 50 mL)로 세척하고, 묽은 HCl로 산성화하고 EtOAc(3 x 30 mL)로 추출하였다. 합한 유기층을 물로 세척하고, 건조하고(Na2SO4), 농축하여, 부표제 화합물 2.8 g(50%)을 얻었다.KOH (5) in a solution of (2-chloro-5- (Boc-amino) phenyl) acetonitrile (5.2 g; 20 mmol; compound from step (iii)) in 37 mL of water: i-PrOH (2: 1) g; 89 mmol) was added and the solution was refluxed overnight. The mixture was then concentrated, water: THF (50 mL; 1: 1) and Boc 2 O were added and the mixture was stirred overnight. THF was evaporated and the aqueous phase was washed with ether (1 × 50 mL), acidified with dilute HCl and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water, dried (Na 2 SO 4 ) and concentrated to give 2.8 g (50%) of the subtitle compound.

1H-NMR(300 MHz; CDCl3): δ 7.40(b, 1H); 7.26(s, 1H); 7.21(d, 1H); 6.55(b, 1H); 3.77(s, 2H); 1.50(s, 9H) 1 H-NMR (300 MHz; CDCl 3 ): δ 7.40 (b, 1H); 7.26 (s, 1 H); 7.21 (d, 1 H); 6.55 (b, 1 H); 3.77 (s, 2 H); 1.50 (s, 9 H)

(v) 에틸(2-클로로-5-(Boc-아미노)페닐)아세테이트(v) ethyl (2-chloro-5- (Boc-amino) phenyl) acetate

아세톤 100 mL 중의 (2-클로로-5-(Boc-아미노)페닐)아세트산(2.8 g; 9.8 밀리몰; 상기 단계 (iv)로부터의 화합물) 용액에 K2CO3(2.1 g, 15 밀리몰)를 부가하였다. 이어서, 반응 혼합물을 교반 및 환류하면서 EtI(70.6 g; 150 밀리몰)을 부가하였다. 용액을 농축하고, 얻어진 혼합물을 에테르 및 물(1:1; 60 mL) 사이에 분배시켰다. 유기층을 분리하고, 수성층을 에테르(30 mL)로 1회 추출하였다. 합한 유기상을 물로 세척하고, 건조하고(Na2SO4), 농축하여 부표제 화합물 3.0 g(98%)을 얻었다.To a solution of (2-chloro-5- (Boc-amino) phenyl) acetic acid (2.8 g; 9.8 mmol; compound from step (iv)) in 100 mL acetone was added K 2 CO 3 (2.1 g, 15 mmol) It was. Then the reaction mixture was added EtI (70.6 g; 150 mmol) with stirring and reflux. The solution was concentrated and the resulting mixture was partitioned between ether and water (1: 1; 60 mL). The organic layer was separated and the aqueous layer was extracted once with ether (30 mL). The combined organic phases were washed with water, dried (Na 2 SO 4 ) and concentrated to give 3.0 g (98%) of the subtitle compound.

1H-NMR(300 MHz; CDCl3): δ 7.35(b, 1H); 7.25(s, 1H); 7.20(d, 1H); 6.52(b, 1H); 4.15(q, 2H); 3.70(s, 2H); 1.50(s, 9H); 1.25(t, 3H) 1 H-NMR (300 MHz; CDCl 3 ): δ 7.35 (b, 1H); 7.25 (s, 1 H); 7.20 (d, 1 H); 6.52 (b, 1 H); 4.15 (q, 2 H); 3.70 (s, 2 H); 1.50 (s, 9 H); 1.25 (t, 3 H)

(vi) 2-(2-클로로-5-(Boc-아미노)페닐)-3-옥소-프로피온산 에틸에스테르(vi) 2- (2-chloro-5- (Boc-amino) phenyl) -3-oxo-propionic acid ethyl ester

에틸 (2-클로로-5-(Boc-아미노)페닐)아세테이트(3.0 g; 9.6 밀리몰; 상기 단계 (v)로부터의 화합물)로부터 문헌 [J. Org. Chem. 54, 3831 (1989)]에 기재된 방법에 따라 제조하여, 추가의 정제없이 사용되기에 충분히 순수한 투명한 갈색 오일인 부표제 생성물 1.6 g(49%)를 수득하였다.From ethyl (2-chloro-5- (Boc-amino) phenyl) acetate (3.0 g; 9.6 mmol; compound from step (v) above). Org. Chem. 54 , 3831 (1989) to give 1.6 g (49%) of the subtitle product which is a clear brown oil which is pure enough to be used without further purification.

1H-NMR(300 MHz; MeOD): δ 8.98(b, 0.5H); 7.89(s, 0.5H); 7.25(m, 3H); 4.88(s, 2H); 4.15(q, 2H); 1.45(s, 9H); 1.20(t, 3H) 1 H-NMR (300 MHz; MeOD): δ 8.98 (b, 0.5H); 7.89 (s, 0.5 H); 7.25 (m, 3 H); 4.88 (s, 2 H); 4.15 (q, 2 H); 1.45 (s, 9 H); 1.20 (t, 3 H)

(vii) (R,S)-3-히드록시-2-(2-클로로-5-(Boc-아미노)페닐)프로피온산(vii) (R, S) -3-hydroxy-2- (2-chloro-5- (Boc-amino) phenyl) propionic acid

2-(2-클로로-5-(Boc-아미노)페닐)-3-옥소-프로피온산 에틸에스테르(상기 단계 (vi)로부터의 화합물)로부터 상기 실시예 E에 기재된 방법에 따라 제조하였다.Prepared according to the method described in Example E above from 2- (2-chloro-5- (Boc-amino) phenyl) -3-oxo-propionic acid ethyl ester (compound from step (vi) above).

1H-NMR(300 MHz; CDCl3): δ 7.25(m, 4H); 6.70(b, 1H); 4.37(m, 1H); 4.15(b, 1H); 4.05(t, 1H); 3.90(d, 1H); 1.50(s, 9H) 1 H-NMR (300 MHz; CDCl 3 ): δ 7.25 (m, 4H); 6.70 (b, 1 H); 4.37 (m, 1 H); 4.15 (b, 1 H); 4.05 (t, 1 H); 3.90 (d, 1 H); 1.50 (s, 9 H)

실시예 YExample Y

(R,S)-3-히드록시-2-(3-메틸페닐)프로피온산(R, S) -3-hydroxy-2- (3-methylphenyl) propionic acid

(i) 2-(3-메틸페닐)-3-옥소-프로피온산 에틸에스테르(i) 2- (3-methylphenyl) -3-oxo-propionic acid ethyl ester

에틸 3-메틸페닐아세테이트(3.0 g; 17 밀리몰)로부터 출발하여 문헌 [J. Org. Chem. 54, 3831 (1989)]에 기재된 방법에 따라 제조하여, 다음 단계에서 추가의 정제없이 사용되기에 충분할 정도로 순수한 부표제 화합물 2.5 g(72%)을 수득하였다.Starting from ethyl 3-methylphenylacetate (3.0 g; 17 mmol) J. Org. Chem. 54 , 3831 (1989) to give 2.5 g (72%) of the subtitle compound which is pure enough to be used without further purification in the next step.

1H-NMR(300 MHz; CDCl3): δ 7.25(m, 2H); 7.05(m, 3H); 4.30(q, 2H); 2.40(q, 2H); 1.30(t, 3H) 1 H-NMR (300 MHz; CDCl 3 ): δ 7.25 (m, 2H); 7.05 (m, 3 H); 4.30 (q, 2 H); 2.40 (q, 2 H); 1.30 (t, 3 H)

(ii) (R,S)-3-히드록시-2-(3-메틸페닐)프로피온산(ii) (R, S) -3-hydroxy-2- (3-methylphenyl) propionic acid

3-옥소-2-(3-메틸페닐)프로피온산 에틸 에스테르(상기 단계 (i)로부터의 화합물)로부터 실시예 E에 기재된 방법에 따라 제조하여 표제 화합물 1.6 g(80%)을 얻었다.Prepared according to the method described in Example E from 3-oxo-2- (3-methylphenyl) propionic acid ethyl ester (compound from step (i) above) to give 1.6 g (80%) of the title compound.

1H-NMR(300 MHz; CDCl3): δ 7.20(m, 1H); 7.05(m, 3H); 4.12(t, 1H); 3.80(m, 2H); 2.32(s, 3H) 1 H-NMR (300 MHz; CDCl 3 ): δ 7.20 (m, 1 H); 7.05 (m, 3 H); 4.12 (t, 1 H); 3.80 (m, 2 H); 2.32 (s, 3H)

실시예 ZExample Z

(R,S)-3-히드록시-2-(2,5-디메틸페닐)프로피온산(R, S) -3-hydroxy-2- (2,5-dimethylphenyl) propionic acid

(i) 에틸(2,5-디메틸페닐)아세테이트(i) ethyl (2,5-dimethylphenyl) acetate

EtOH(40 mL) 중에 (2,5-디메틸페닐)아세트산(3.0 g; 18.3 밀리몰) 및 진한 H2SO4(0.1 mL) 용액을 6일에 걸쳐 환류하였다. 용액을 농축하고, 에테르(40 mL)를 부가하고, 얻어진 혼합물을 Na2CO3 용액(2 x 25 mL) 및 물(1 x 25 mL)로 세척하였다. 유기상을 건조하고(MgSO4), 증발시켜 투명한 무색 액체인 부표제 화합물 2.94 g(84%, 순도-97%)를 수득하였다.A solution of (2,5-dimethylphenyl) acetic acid (3.0 g; 18.3 mmol) and concentrated H 2 SO 4 (0.1 mL) in EtOH (40 mL) was refluxed over 6 days. The solution was concentrated, ether (40 mL) was added and the resulting mixture was washed with Na 2 CO 3 solution (2 × 25 mL) and water (1 × 25 mL). The organic phase was dried (MgSO 4 ) and evaporated to yield 2.94 g (84%, purity-97%) of a titleless compound as a clear, colorless liquid.

1H-NMR(400 MHz; CDCl3): δ 7.08(d, 1H); 7.02(d, 1H); 7.00(s, 1H); 4.17(q, 2H); 3.61(s, 2H); 2.33(s, 3H); 2.29(s, 3H); 1.28(t, 3H) 1 H-NMR (400 MHz; CDCl 3 ): δ 7.08 (d, 1H); 7.02 (d, 1 H); 7.00 (s, 1 H); 4.17 (q, 2 H); 3.61 (s, 2 H); 2.33 (s, 3 H); 2.29 (s, 3 H); 1.28 (t, 3 H)

(ii) 2-(2,5-디메틸페닐)-3-옥소-프로피온산 에틸 에스테르(ii) 2- (2,5-dimethylphenyl) -3-oxo-propionic acid ethyl ester

에틸 (2,5-디메틸페닐)아세테이트(2.92 g; 15 밀리몰; 상기 단계(i)로부터의 화합물)로부터 출발하여 문헌 [J. Org. Chem. 54, 3831 (1989)]에 기재된 방법에 따라 제조하여, 갈황색 오일인 부표제 생성물 2.89 g(86%)을 수득하였다.Starting with ethyl (2,5-dimethylphenyl) acetate (2.92 g; 15 mmol; compound from step (i) above), J. Org. Chem. 54 , 3831 (1989), to give 2.89 g (86%) of the title product, which is brownish yellow oil.

1H-NMR(400 MHz; CDCl3): δ 12.00(d, 1H) 7.10(m, 2H); 6.92(s, 1H); 4.25(b, 2H); 2.33(s, 3H); 2.18(s, 3H); 1.25(t, 3H) 1 H-NMR (400 MHz; CDCl 3 ): δ 12.00 (d, 1H) 7.10 (m, 2H); 6.92 (s, 1 H); 4.25 (b, 2 H); 2.33 (s, 3 H); 2.18 (s, 3 H); 1.25 (t, 3 H)

(iii) (R,S)-3-히드록시-2-(2,5-디메틸페닐)프로피온산(iii) (R, S) -3-hydroxy-2- (2,5-dimethylphenyl) propionic acid

3-옥소-2-(2,5-디메틸페닐)프로피온산 에틸 에스테르(2.87 g; 13 밀리몰; 상기 단계 (ii)로부터의 화합물)로부터 실시예 E에 기재된 방법에 따라 백색 분말인 표제 생성물 1.37 g(55%)을 수득하였다. 1.37 g of the title product as a white powder according to the method described in Example E from 3-oxo-2- (2,5-dimethylphenyl) propionic acid ethyl ester (2.87 g; 13 mmol; the compound from step (ii) above) 55%) was obtained.

1H-NMR(400 MHz; CDCl3): δ 7.10(d, 1H); 7.01(d, 1H); 7.00(s, 1H); 4.14(m, 2H); 3.73(q, 1H); 2.37(s, 3H); 2.29(s, 3H) 1 H-NMR (400 MHz; CDCl 3 ): δ 7.10 (d, 1H); 7.01 (d, 1 H); 7.00 (s, 1 H); 4.14 (m, 2 H); 3.73 (q, 1 H); 2.37 (s, 3 H); 2.29 (s, 3H)

실시예 AAExample AA

2-(4-벤질옥시-3-메톡시페닐)-3-히드록시-프로피온산2- (4-Benzyloxy-3-methoxyphenyl) -3-hydroxy-propionic acid

(i) 벤질 4-벤질옥시-3-메톡시페닐아세테이트(i) benzyl 4-benzyloxy-3-methoxyphenylacetate

Cs2CO3(17.88 g; 54.9 밀리몰)을 CH3CN 중의 호모바닐산(2.0 g; 11 밀리몰) 용액에 부가하고, 이후에 BnBr(4.3 g; 24.15 밀리몰)을 10분에 걸쳐 적가하였다. 혼합물을 철야 환류하고, 하이플로(Hyflo)를 통해 여과하고 농축하였다. 얻어진 혼합물을 EtOAc(100 mL)에 용해하고, 물(30 mL)을 부가하고, 수성층을 분리하였다. 유기상을 시트르산 용액(5%, 1 x 20 mL) 및 간수로 세척하고, 건조하고(Na2SO4), 증발시켜 부표제 화합물 4.25 g(정량적인 양)을 얻었다.Cs 2 CO 3 (17.88 g; 54.9 mmol) was added to a solution of homovanic acid (2.0 g; 11 mmol) in CH 3 CN, after which BnBr (4.3 g; 24.15 mmol) was added dropwise over 10 minutes. The mixture was refluxed overnight, filtered through Hyflo and concentrated. The resulting mixture was dissolved in EtOAc (100 mL), water (30 mL) was added, and the aqueous layer was separated. The organic phase was washed with citric acid solution (5%, 1 × 20 mL) and brine, dried (Na 2 SO 4 ) and evaporated to give 4.25 g (quantitative amount) of the subtitle compound.

1H-NMR(300 MHz; CDCl3): δ 7.43(d, 2H); 7.34(m, 8H); 6.82(d, 2H); 6.74(dd, 1H); 5.33(s, 4H); 3.84(s, 3H); 3.59(s, 2H) 1 H-NMR (300 MHz; CDCl 3 ): δ 7.43 (d, 2H); 7.34 (m, 8 H); 6.82 (d, 2 H); 6.74 (dd, 1 H); 5.33 (s, 4 H); 3.84 (s, 3 H); 3.59 (s, 2H)

(ii) 에틸 2-(4-벤질옥시-3-메톡시페닐)-3-옥소-프로피오네이트(ii) ethyl 2- (4-benzyloxy-3-methoxyphenyl) -3-oxo-propionate

벤질 4-벤질옥시-3-메톡시페닐아세테이트(4.12 g; 11.4 밀리몰; 상기 단계(i)로부터의 화합물)로부터 출발하여 문헌 [J. Org. Chem. 54, 3831 (1989)]에 기재된 방법에 따라 제조하여, 부표제 생성물 1.4 g(31.5%)을 수득하였다.Benzyl 4-benzyloxy-3-methoxyphenylacetate (4.12 g; 11.4 mmol; the compound from step (i) above). Org. Chem. 54 , 3831 (1989), to give 1.4 g (31.5%) of the subtitle product.

LC-MS m/z 327(M-1)- LC-MS m / z 327 (M-1) -

1H-NMR(400 MHz; CDCl3): δ 12.03(d, 1H); 7.44(d, 2H); 7.30(m, 5H); 6.85(d, 2H); 6.72(dd, 1H); 5.15(s, 2H); 4.27(q, 2H); 3.88(s, 3H); 1.30(t, 3H) 1 H-NMR (400 MHz; CDCl 3 ): δ 12.03 (d, 1H); 7.44 (d, 2 H); 7.30 (m, 5 H); 6.85 (d, 2 H); 6.72 (dd, 1 H); 5.15 (s, 2 H); 4.27 (q, 2 H); 3.88 (s, 3 H); 1.30 (t, 3 H)

(iii) 에틸 2-(4-벤질옥시-3-메톡시페닐)-3-히드록시-프로피오네이트(iii) ethyl 2- (4-benzyloxy-3-methoxyphenyl) -3-hydroxy-propionate

MeOH:CH2Cl2(3:1, 20 mL) 중의 에틸 2-(4-벤질옥시-3-메톡시페닐)-3-옥소-프로피오네이트 (1.356 g; 3.47 밀리몰; 상기 단계(ii)로부터의 화합물)용액을 -15 내지 -5 ℃로 냉각하고 NaBH4(0.264 g; 6.95 밀리몰)을 일부분씩 부가하였다. 냉각된 반응 혼합물을 교반하고, 이후에 실온이 되도록 하였다. 물을 부가하고, 혼합물을 부분적으로 농축하였다. EtOAc(2 x 25 mL)로 추출하고, 유기상을 간수로 세척하고, 건조하고(Na2SO4), 증발시켜 부표제 화합물 1.32 g(97.1%)을 수득하였다.Ethyl 2- (4-benzyloxy-3-methoxyphenyl) -3-oxo-propionate in MeOH: CH 2 Cl 2 (3: 1, 20 mL) (1.356 g; 3.47 mmol; step (ii) above Solution) was cooled to -15 to -5 ° C and NaBH 4 (0.264 g; 6.95 mmol) was added in portions. The cooled reaction mixture was stirred and then allowed to come to room temperature. Water was added and the mixture was partially concentrated. Extract with EtOAc (2 × 25 mL), wash the organic phase with brine, dry (Na 2 SO 4 ) and evaporate to give 1.32 g (97.1%) of the subtitle compound.

1H-NMR(400 MHz; CDCl3): δ 7.42(d, 2H); 7.32(m, 4H); 6.82(m, 2H); 6.74(dd, 1H); 5.13(s, 2H); 4.15(m, 3H); 3.88(s, 3H); 3.78(m, 2H); 1.23(t, 3H) 1 H-NMR (400 MHz; CDCl 3 ): δ 7.42 (d, 2H); 7.32 (m, 4 H); 6.82 (m, 2 H); 6.74 (dd, 1 H); 5.13 (s, 2 H); 4.15 (m, 3 H); 3.88 (s, 3 H); 3.78 (m, 2 H); 1.23 (t, 3 H)

(iv) 2-(4-벤질옥시-3-메톡시페닐)-3-히드록시-프로피온산(iv) 2- (4-benzyloxy-3-methoxyphenyl) -3-hydroxy-propionic acid

THF(12.5 mL) 중에 에틸 2-(4-벤질옥시-3-메톡시페닐)-3-히드록시-프로피오네이트(1.29 g; 3.29 밀리몰; 상기 단계(iii)로부터의 화합물) 용액에, H2O(5 mL) 중의 LiOH(0.273 g; 6.75 밀리몰) 용액을 부가하고, 혼합물을 실온에서 2.5 시간 동안 교반하였다. 얻어진 혼합물을 부분적으로 농축하고, 물(25 mL)을 부가하고, 혼합물을 2회분의 CH2Cl2로 세척하고, HCl 수용액(2M)으로 산성화하고, 3회분의 CH2Cl2로 추출하였다. 합한 유기층을 간수로 세척하고, 건조하고(Na2SO4), 증발시켜 황색 분말 10.55 g(정량적인 양, 순도 83.2 %)을 수득하였다.To a solution of ethyl 2- (4-benzyloxy-3-methoxyphenyl) -3-hydroxy-propionate (1.29 g; 3.29 mmol; compound from step (iii)) in THF (12.5 mL), H A solution of LiOH (0.273 g; 6.75 mmol) in 2 O (5 mL) was added and the mixture was stirred at rt for 2.5 h. The resulting mixture was partially concentrated, water (25 mL) was added, the mixture was washed with two portions of CH 2 Cl 2 , acidified with aqueous HCl solution (2M) and extracted with three portions of CH 2 Cl 2 . The combined organic layers were washed with brine, dried (Na 2 SO 4 ) and evaporated to give 10.55 g (quantitative amount, purity 83.2%) of yellow powder.

1H-NMR(400 MHz; MeOH): δ 7.41(d, 2H); 7.32(m, 4H); 6.94(d, 2H); 6.82(dd, 1H),; 5.06(s, 2H); 4.04(m, 1H); 3.83(s, 3H), 3.70(m, 2H) 1 H-NMR (400 MHz; MeOH): δ 7.41 (d, 2H); 7.32 (m, 4 H); 6.94 (d, 2 H); 6.82 (dd, 1 H); 5.06 (s, 2 H); 4.04 (m, 1 H); 3.83 (s, 3H), 3.70 (m, 2H)

실시예 ABExample AB

(R,S)-3-히드록시-2-(3,5-디클로로페닐)프로피온산(R, S) -3-hydroxy-2- (3,5-dichlorophenyl) propionic acid

(i) 3,5-디클로로벤질 알코올(i) 3,5-dichlorobenzyl alcohol

3,5-디클로로벤조산(15.3 g; 80 밀리몰), TEA(8.9 g; 88 밀리몰), i-Bu 클로로포르메이트(12 g; 88 밀리몰) 및 NaBH4(9.0 g; 240 밀리몰)로부터 실시예 X(i)에 기재된 방법에 따라 제조하여 부표제 화합물 10.5 g(74%)을 얻었다.Example X from 3,5-dichlorobenzoic acid (15.3 g; 80 mmol), TEA (8.9 g; 88 mmol), i-Bu chloroformate (12 g; 88 mmol) and NaBH 4 (9.0 g; 240 mmol) Prepared according to the method described in (i), to obtain 10.5 g (74%) of a subtitle compound.

1H-NMR(400 MHz; CDCl3): δ 7.27(t, 1H); 7.28(d, 2H); 4.68(s, 2H) 1 H-NMR (400 MHz; CDCl 3 ): δ 7.27 (t, 1H); 7.28 (d, 2 H); 4.68 (s, 2H)

(ii) 3,5-디클로로페닐아세토니트릴(ii) 3,5-dichlorophenylacetonitrile

3,5-디클로로벤질 알코올(10.3 g; 58 밀리몰; 상기 단계 (i)로부터의 화합물), TEA(6.5 g; 64 밀리몰) 및 MsCl(7.0 g, 61 밀리몰)로부터 실시예 X(ii) 및 X(iii)에 기재된 방법에 따라 제조하여 부표제 화합물 9.6 g(89%)을 얻었다.Examples X (ii) and X from 3,5-dichlorobenzyl alcohol (10.3 g; 58 mmol; compound from step (i) above), TEA (6.5 g; 64 mmol) and MsCl (7.0 g, 61 mmol) Prepared according to the method described in (iii), to obtain 9.6 g (89%) of the subtitle compound.

1H-NMR(400 MHz; CDCl3): δ 7.37(m, 3H); 3.74(s, 2H) 1 H-NMR (400 MHz; CDCl 3 ): δ 7.37 (m, 3H); 3.74 (s, 2 H)

(iii) 3,5-디클로로페닐아세트산(iii) 3,5-dichlorophenylacetic acid

3,5-디클로로페닐아세토니트릴(9.6 g; 52 밀리몰; 상기 단계 (ii)로부터의 화합물) 및 KOH(12.3 g; 220 밀리몰)로부터 실시예 X(iv)에 기재된 방법에 따라 제조하여 부표제 화합물 7.6 g(72%)을 얻었다.Subtitled Compound 7.6 prepared according to the method described in Example X (iv) from 3,5-dichlorophenylacetonitrile (9.6 g; 52 mmol; the compound from step (ii) above) and KOH (12.3 g; 220 mmol). g (72%) was obtained.

1H-NMR(400 MHz; CDCl3): δ 7.31(t, 1H); 7.20(d, 2H); 3.63(s, 2H) 1 H-NMR (400 MHz; CDCl 3 ): δ 7.31 (t, 1H); 7.20 (d, 2 H); 3.63 (s, 2 H)

(iv) 에틸 3,5-디클로로페닐아세테이트(iv) ethyl 3,5-dichlorophenyl acetate

3,5-디클로로페닐아세트산(7.5 g, 37 밀리몰; 상기 단계 (iii)로부터의 화합물) 및 진한 H2SO4(0.1 mL)로부터 실시예 T(ii)에 기재된 방법에 따라 제조하여 부표제 화합물 3.0 g(35%)을 얻었다.Subtitled Compound 3.0 prepared according to the method described in Example T (ii) from 3,5-dichlorophenylacetic acid (7.5 g, 37 mmol; the compound from step (iii) above) and concentrated H 2 SO 4 (0.1 mL). g (35%) was obtained.

1H-NMR(400 MHz; CDCl3): δ 7.28(t, 1H); 7.18(d, 2H); 4.17(q, 2H); 3.56(s, 2H); 1.27(t, 3H) 1 H-NMR (400 MHz; CDCl 3 ): δ 7.28 (t, 1H); 7.18 (d, 2 H); 4.17 (q, 2 H); 3.56 (s, 2 H); 1.27 (t, 3 H)

(v) 2-(3,5-(디클로로페닐)-3-옥소-프로피온산 에틸에스테르(v) 2- (3,5- (dichlorophenyl) -3-oxo-propionic acid ethyl ester

에틸 3,5-디클로로페닐아세테이트(3.0 g; 12.9 밀리몰; 상기 단계 (iv)로부터의 화합물)로부터 상기 문헌[J. Org. Chem. 54, 3831(1989)]에 기재된 방법에 따라, 다음 단계에서 추가의 정제없이 사용되기에 충분할 정도로 순수한 투명한 오일인 부표제 생성물 3.0 g(89%)을 얻었다.Ethyl 3,5-dichlorophenylacetate (3.0 g; 12.9 mmol; compound from step (iv)) described above. Org. Chem. 54 , 3831 (1989), yield 3.0 g (89%) of a subtitle product which is a clear oil which is pure enough to be used without further purification in the next step.

1H-NMR(400 MHz; CDCl3): δ 12.20(d, 1H); 7.29(t, 1H); 7.23(d, 2H); 4.32(q, 2H); 1.33(t, 3H) 1 H-NMR (400 MHz; CDCl 3 ): δ 12.20 (d, 1H); 7.29 (t, 1 H); 7.23 (d, 2 H); 4.32 (q, 2 H); 1.33 (t, 3 H)

(vi) (R,S)-3-히드록시-2-(3,5-디클로로페닐)프로피온산(vi) (R, S) -3-hydroxy-2- (3,5-dichlorophenyl) propionic acid

2-(3,5-디클로로페닐)-3-옥소-프로피온산 에틸에스테르(상기 단계(v)로부터의 화합물)로부터 상기 실시예 E에 기재된 방법에 따라 제조하였다.Prepared according to the method described in Example E above from 2- (3,5-dichlorophenyl) -3-oxo-propionic acid ethyl ester (compound from step (v) above).

1H-NMR(400 MHz; CDCl3): δ 7.34(t, 1H); 7.24(d, 2H); 4.12(dd, 1H); 3.91(dd, 1H); 3.84(dd, 1H) 1 H-NMR (400 MHz; CDCl 3 ): δ 7.34 (t, 1H); 7.24 (d, 2 H); 4.12 (dd, 1 H); 3.91 (dd, 1 H); 3.84 (dd, 1 H)

실시예 ACExample AC

(R,S)-3-히드록시-2-(2,3-디메톡시페닐)프로피온산(R, S) -3-hydroxy-2- (2,3-dimethoxyphenyl) propionic acid

(i) 에틸 2,3-디메톡시페닐아세테이트(i) ethyl 2,3-dimethoxyphenylacetate

무수 EtOH 20 mL 중의 2,3-디메톡시페닐아세트산(2.52 g, 12.8 밀리몰)의 용액에 H2SO4(30 μL)을 부가하고, 이 용액을 20 시간 동안 환류하였다. 얻어진 용액을 농축하고, 에테르 중에 용해하고, 에테르 용액을 NaHCO3 수용액(2 x 30 mL) 및 간수로 세척하고, 건조하고(MgSO4) 농축하여 부표제 화합물을 얻었다.To a solution of 2,3-dimethoxyphenylacetic acid (2.52 g, 12.8 mmol) in 20 mL of anhydrous EtOH was added H 2 SO 4 (30 μL) and the solution was refluxed for 20 hours. The resulting solution was concentrated, dissolved in ether, and the ether solution was washed with aqueous NaHCO 3 solution (2 × 30 mL) and brine, dried (MgSO 4 ) and concentrated to give the subtitle compound.

1H-NMR(400 MHz; CDCl3): δ 6.99(m, 1H); 6.83(m, 2H); 4.16(q, 2H); 3.85(s, 3H); 3.82(s, 3H); 3.65(s, 2H); 1.25(t, 3H) 1 H-NMR (400 MHz; CDCl 3 ): δ 6.99 (m, 1H); 6.83 (m, 2 H); 4.16 (q, 2 H); 3.85 (s, 3 H); 3.82 (s, 3 H); 3.65 (s, 2 H); 1.25 (t, 3 H)

(ii) 2-(2,3-디메톡시페닐)-3-옥소-프로피온산 에틸에스테르(ii) 2- (2,3-dimethoxyphenyl) -3-oxo-propionic acid ethyl ester

에틸 2,3-디메톡시페닐아세테이트(2.14 g; 9.5 밀리몰; 상기 단계 (i)로부터의 화합물)로부터 상기 문헌[J. Org. Chem. 54, 3831(1989)]에 기재된 방법에 따라, 다음 단계에서 추가의 정제없이 사용되기에 충분할 정도로 순수한 투명한 녹황색 오일인 부표제 생성물 1.53 g(64%)을 얻었다.Ethyl 2,3-dimethoxyphenylacetate (2.14 g; 9.5 mmol; the compound from step (i)), supra. Org. Chem. 54 , 3831 (1989), yielded 1.53 g (64%) of a subtitle product which was a clear, greenish yellow oil that was pure enough to be used without further purification in the next step.

1H-NMR(400 MHz; CDCl3): δ 12.00(d, 1H); 7.19(d, 1H); 7.05(m, 2H); 6.91(m, 2H); 6.74(dd, 1H); 4.24(q, 2H); 3.87(s, 3H); 3.74(s, 3H); 1.24(t, 3H) 1 H-NMR (400 MHz; CDCl 3 ): δ 12.00 (d, 1H); 7.19 (d, 1 H); 7.05 (m, 2 H); 6.91 (m, 2 H); 6.74 (dd, 1 H); 4.24 (q, 2 H); 3.87 (s, 3 H); 3.74 (s, 3 H); 1.24 (t, 3 H)

(iii) (R,S)-3-히드록시-2-(2,3-디메톡시페닐)프로피온산(iii) (R, S) -3-hydroxy-2- (2,3-dimethoxyphenyl) propionic acid

2-(2,3-디메톡시페닐)-3-옥소-프로피온산 에틸에스테르(상기 단계 (ii)로부터의 화합물)로부터 상기 실시예 E에 기재된 방법에 따라 제조하였다.Prepared according to the method described in Example E above from 2- (2,3-dimethoxyphenyl) -3-oxo-propionic acid ethyl ester (compound from step (ii) above).

LC-MS m/z 225(M-1)- LC-MS m / z 225 (M-1) -

1H-NMR(400 MHz; CDCl3): δ 7.05(t, 1H); 6.87(dd, 1H); 6.82(dd, 1H); 4.15(m, 3H); 3.85(s, 6H); 3.75(m, 1H) 1 H-NMR (400 MHz; CDCl 3 ): δ 7.05 (t, 1H); 6.87 (dd, 1 H); 6.82 (dd, 1 H); 4.15 (m, 3 H); 3.85 (s, 6 H); 3.75 (m, 1 H)

실시예 ADExample AD

(R,S)-3-히드록시-2-(3-메톡시-5-클로로페닐)프로피온산(R, S) -3-hydroxy-2- (3-methoxy-5-chlorophenyl) propionic acid

(i) 3-메톡시-5-클로로벤즈알데히드(i) 3-methoxy-5-chlorobenzaldehyde

무수 THF(20 mL) 중의 마그네슘 칩(0.20 g; 8.2 밀리몰)에 3,5-디클로로아니졸(1.1 g; 6.8 밀리몰)을 일부분씩 부가하였다. 제1 부가 후, EtBr(0.1 mL)을 부가하여 반응을 개시하였다. 완전히 부가한 후 반응 혼합물을 60 ℃에서 철야 교반하고, 그 후 혼합물을 0 ℃로 냉각하고, DMF를 부가하였다. 1 시간 동안 교반한 후, 혼합물을 HCl 수용액에 붓고, 농축하고, 에테르(3 x 50 mL)로 추출하였다. 합한 유기상을 물로 세척하고, 건조하고(Na2SO4), 농축하여 부표제 화합물 2.35 g을 얻었다.To the magnesium chip (0.20 g; 8.2 mmol) in dry THF (20 mL) was added 3,5-dichloroanizol (1.1 g; 6.8 mmol) in portions. After the first addition, EtBr (0.1 mL) was added to initiate the reaction. After complete addition the reaction mixture was stirred overnight at 60 ° C., then the mixture was cooled to 0 ° C. and DMF was added. After stirring for 1 hour, the mixture was poured into aqueous HCl solution, concentrated and extracted with ether (3 × 50 mL). The combined organic phases were washed with water, dried (Na 2 SO 4 ) and concentrated to give 2.35 g of subtitle compound.

1H-NMR(300 MHz; CDCl3): δ 9.91(s, 1H); 7.43(t, 1H); 7.28(t, 1H); 7.15(t, 1H); 3.87(s, 3H) 1 H-NMR (300 MHz; CDCl 3 ): δ 9.91 (s, 1H); 7.43 (t, 1 H); 7.28 (t, 1 H); 7.15 (t, 1 H); 3.87 (s, 3 H)

(ii) 3-메톡시-5-클로로페닐아세트알데히드(ii) 3-methoxy-5-chlorophenylacetaldehyde

3-메톡시-5-클로로벤즈알데히드(2.35 g; 13.8 밀리몰; 상기 단계(i)로부터의 화합물)로부터 출발하여 문헌[P. Weierstahl 등, Liebigs Ann. 1389, (1995)]에 기재된 방법에 따라 제조하여 부표제 화합물 2.0 g(약 54 %)을 얻었다.Starting from 3-methoxy-5-chlorobenzaldehyde (2.35 g; 13.8 mmol; the compound from step (i) above) [P. Weierstahl et al., Liebigs Ann. 1389, (1995)] to give 2.0 g (about 54%) of a subtitle compound.

1H-NMR(400 MHz; CDCl3): δ 9.71(t, 1H); 6.84(t, 1H); 6.81(t, 1H); 6.64(t, 1H); 3.79(s, 3H); 3.62(s, 2H) 1 H-NMR (400 MHz; CDCl 3 ): δ 9.71 (t, 1H); 6.84 (t, 1 H); 6.81 (t, 1 H); 6.64 (t, 1 H); 3.79 (s, 3 H); 3.62 (s, 2 H)

(iii) (3-메톡시-5-클로로페닐)아세트산(iii) (3-methoxy-5-chlorophenyl) acetic acid

3-메톡시-5-클로로페닐아세트알데히드(102 mg; 0.55 밀리몰; 상기 단계(ii)로부터의 화합물) 출발하여 문헌[S. E. de Laszlo 및 P. G. Willard, J. Am. Chem. Soc. 107, 199(1985)]에 기재된 방법에 따라 제조하여 부표제 화합물 37 mg(33.6 %)을 얻었다.3-methoxy-5-chlorophenylacetaldehyde (102 mg; 0.55 mmol; compound from step (ii) above) starting with SE de Laszlo and PG Willard, J. Am. Chem. Soc. 107 , 199 (1985), to obtain 37 mg (33.6%) of the subtitle compound.

LC-MS m/z 199(M-1)- LC-MS m / z 199 (M-1) -

1H-NMR(400 MHz; CDCl3): δ 6.82(t, 1H); 6.75(t, 1H); 6.62(t, 1H); 3.72(s, 3H); 3.50(s, 2H) 1 H-NMR (400 MHz; CDCl 3 ): δ 6.82 (t, 1H); 6.75 (t, 1 H); 6.62 (t, 1 H); 3.72 (s, 3 H); 3.50 (s, 2 H)

(iv) 에틸(3-메톡시-5-클로로페닐)아세테이트(iv) ethyl (3-methoxy-5-chlorophenyl) acetate

EtOH(25 mL) 중의 3-메톡시-5-클로로페닐아세트산(0.938 g; 4.9 밀리몰; 상기 단계(iii)로부터의 화합물) 및 진한 H2SO4(0.1 mL)의 용액을 철야 환류하였다. 얻어진 혼합물을 농축하고, Na2CO3 수용액 75 mL를 부가하였다. 혼합물을 에테르(2 x 75 mL)로 추출하고, 합한 유기층을 간수로 세척하고, 건조하고(Na2SO4), 농축하여 갈색 오일인 부표제 화합물 0.989 g(88.3 %)를 얻었다.A solution of 3-methoxy-5-chlorophenylacetic acid (0.938 g; 4.9 mmol; compound from step (iii) above) and concentrated H 2 SO 4 (0.1 mL) in EtOH (25 mL) was refluxed overnight. The resulting mixture was concentrated and 75 mL of Na 2 CO 3 aqueous solution was added. The mixture was extracted with ether (2 × 75 mL) and the combined organic layers were washed with brine, dried (Na 2 SO 4 ) and concentrated to give 0.989 g (88.3%) of the subtitle compound as a brown oil.

1H-NMR(500 MHz; CDCl3): δ 6.88(t, 1H); 6.81(t, 1H); 6.72(t, 1H); 4.16(q, 2H); 3.79(s, 3H); 3.54(s, 2H); 1.26(t, 4H) 1 H-NMR (500 MHz; CDCl 3 ): δ 6.88 (t, 1H); 6.81 (t, 1 H); 6.72 (t, 1 H); 4.16 (q, 2 H); 3.79 (s, 3 H); 3.54 (s, 2 H); 1.26 (t, 4 H)

(v) 2-(3-메톡시-5-클로로페닐)-3-옥소-프로피온산 에틸에스테르(v) 2- (3-methoxy-5-chlorophenyl) -3-oxo-propionic acid ethyl ester

에틸 (3-메톡시-5-클로로페닐)아세테이트(0.989 g; 4.33 밀리몰; 상기 단계 (iv)로부터의 화합물)로부터 상기 문헌[J. Org. Chem. 54, 3831(1989)]에 기재된 방법에 따라, 다음 단계에서 추가의 정제없이 사용되기에 충분할 정도로 순수한 부표제 생성물 0.347 g(31.3%)을 얻었다.Ethyl (3-methoxy-5-chlorophenyl) acetate (0.989 g; 4.33 mmol; the compound from step (iv)), supra. Org. Chem. 54 , 3831 (1989), yielded 0.347 g (31.3%) of a subtitle product pure enough to be used without further purification in the next step.

1H-NMR(500 MHz; CDCl3): δ 12.15(b, 1H); 7.31(s, 1H); 6.86(t, 1H); 6.82(t, 1H); 6.70(t, 1H); 4.30(q, 2H); 3.80(s, 3H); 1.31(t, 3H) 1 H-NMR (500 MHz; CDCl 3 ): δ 12.15 (b, 1H); 7.31 (s, 1 H); 6.86 (t, 1 H); 6.82 (t, 1 H); 6.70 (t, 1 H); 4.30 (q, 2 H); 3.80 (s, 3 H); 1.31 (t, 3H)

(vi) (R,S)-3-히드록시-2-(3-메톡시-5-클로로페닐)프로피온산(vi) (R, S) -3-hydroxy-2- (3-methoxy-5-chlorophenyl) propionic acid

2-(3-메톡시-5-클로로페닐)-3-옥소-프로피온산 에틸 에스테르(상기 단계 (v)로부터의 화합물)로부터 상기 실시예 E에 기재된 방법에 따라 제조하였다.Prepared according to the method described in Example E above from 2- (3-methoxy-5-chlorophenyl) -3-oxo-propionic acid ethyl ester (compound from step (v) above).

1H-NMR(500 MHz; CDCl3): δ 6.89(t, 1H); 6.84(t, 1H); 6.74(t, 1H); 4.12(dd, 1H); 3.83(m, 2H); 3.79(s, 3H) 1 H-NMR (500 MHz; CDCl 3 ): δ 6.89 (t, 1H); 6.84 (t, 1 H); 6.74 (t, 1 H); 4.12 (dd, 1 H); 3.83 (m, 2 H); 3.79 (s, 3 H)

실시예 AEExample AE

(R,S)-3-히드록시 2-(2-메틸-5-메톡시페닐)프로피온산(R, S) -3-hydroxy 2- (2-methyl-5-methoxyphenyl) propionic acid

(i) 2-(2-브로모-5-메톡시페닐)-1,3-디옥솔란(i) 2- (2-bromo-5-methoxyphenyl) -1,3-dioxolane

톨루엔(300 mL) 중의 2-브로모-5-메톡시벤즈알데히드(5.0 g, 23.2 밀리몰) 용액에 에탄디올(2.16 g, 34.2 밀리몰) 및 p-TsOH(20 mg)을 부가하고, 이후에 혼합물을 12 시간 동안 환류하였다. 얻어진 혼합물을 실온으로 냉각하고, NaHCO3 수용액으로 세척하고, 건조하고(Na2SO4), 농축하여 부표제 화합물 5.918 g(98%)을 얻었다.To a solution of 2-bromo-5-methoxybenzaldehyde (5.0 g, 23.2 mmol) in toluene (300 mL) was added ethanediol (2.16 g, 34.2 mmol) and p-TsOH (20 mg), after which the mixture was Reflux for 12 hours. The resulting mixture was cooled to room temperature, washed with aqueous NaHCO 3 solution, dried (Na 2 SO 4 ) and concentrated to give 5.918 g (98%) of the subtitle compound.

1H-NMR(500 MHz; CDCl3): δ 7.44(d, 1H); 7.16(d, 1H); 6.78(dd, 1H); 6.04(s, 1H); 4.12(m, 4H); 3.80(s, 3H) 1 H-NMR (500 MHz; CDCl 3 ): δ 7.44 (d, 1H); 7.16 (d, 1 H); 6.78 (dd, 1 H); 6.04 (s, 1 H); 4.12 (m, 4 H); 3.80 (s, 3 H)

(ii) 2-(2-메틸-5-메톡시페닐)-1,3-디옥솔란(ii) 2- (2-methyl-5-methoxyphenyl) -1,3-dioxolane

무수 THF(60 mL) 중의 2-(2-브로모-5-메톡시페닐)-1,3-디옥솔란(5.44 g; 21 밀리몰; 상기 단계 (i)로부터의 화합물) 용액을 질소 대기하에서 -78 ℃로 냉각하고, n-BuLi(1.4 M; 19.5 mL)을 시린지를 통해 적가하였다. 부가후, 용액을 -78 ℃에서 35분간 교반한 후, MeI(13.41 g; 94.5 밀리몰)을 부가하였다. 얻어진 혼합물을 실온이 되도록 천천히 교반하고, 이후 NH4Cl 수용액으로 켄칭하고, 에테르로 추출하였다. 유기상을 건조하고(Na2SO4) 농축하여, 갈색 오일인 부표제 화합물 4..25 g(정량적인 양)을 얻었다.A solution of 2- (2-bromo-5-methoxyphenyl) -1,3-dioxolane (5.44 g; 21 mmol; compound from step (i) above) in anhydrous THF (60 mL) under nitrogen atmosphere- Cool to 78 ° C. and n-BuLi (1.4 M; 19.5 mL) was added dropwise via syringe. After addition, the solution was stirred at −78 ° C. for 35 minutes, and then MeI (13.41 g; 94.5 mmol) was added. The resulting mixture was stirred slowly to room temperature, then quenched with aqueous NH 4 Cl solution and extracted with ether. The organic phase was dried (Na 2 SO 4 ) and concentrated to give 4..25 g (quantitative quantity) of the subtitle compound as a brown oil.

1H-NMR (500 MHz; CDCl3): δ 7.12 (d, 1H); 7.08 (d, 1H); 6.81 (dd, 1H); 5.93 (s, 1H); 4.10 (m, 4H); 3.80 (s, 3H); 2.35 (s, 3H) 1 H-NMR (500 MHz; CDCl 3 ): δ 7.12 (d, 1H); 7.08 (d, 1 H); 6.81 (dd, 1 H); 5.93 (s, 1 H); 4.10 (m, 4 H); 3.80 (s, 3 H); 2.35 (s, 3 H)

(iii) 2-메틸-5-메톡시벤즈알데히드(iii) 2-methyl-5-methoxybenzaldehyde

THF(60 mL) 및 HCl 수용액(5%; 30 mL) 혼합물 중의 2-(2-메틸-5-메톡시페닐)-1,3-디옥솔란(4.2 g; 21.6 밀리몰; 상기 단계 (ii)로부터의 화합물) 용액을 실온에서 철야 교반하였다. 용액을 농축하고, 혼합물을 에테르로 추출하였다. 유기상을 건조하고(Na2SO4) 농축하여, 암갈색 액체 2.956 g(91%)을 얻었다.2- (2-methyl-5-methoxyphenyl) -1,3-dioxolane (4.2 g; 21.6 mmol; in step (ii) above in a mixture of THF (60 mL) and aqueous HCl solution (5%; 30 mL) Compound) solution was stirred overnight at room temperature. The solution was concentrated and the mixture was extracted with ether. The organic phase was dried (Na 2 SO 4 ) and concentrated to give 2.956 g (91%) of a dark brown liquid.

1H-NMR (400 MHz; CDCl3): δ 10.28 (s, 1H); 7.33 (d, 1H); 7.16 (d, 1H); 7.04 (dd, 1H); 3.84 (s, 3H); 2.60 (s, 3H). 1 H-NMR (400 MHz; CDCl 3 ): δ 10.28 (s, 1H); 7.33 (d, 1 H); 7.16 (d, 1 H); 7.04 (dd, 1 H); 3.84 (s, 3 H); 2.60 (s, 3 H).

(iv) 에틸 (2-메틸-5-메톡시)아세테이트(iv) ethyl (2-methyl-5-methoxy) acetate

2-메틸-5-메톡시벤즈알데히드(상기 단계 (iii)로부터의 화합물)로부터 실시예 AD(ii) 내지 AD(iv)에 기재된 절차에 따라 제조하여 부표제 생성물 1.18 g(30%, 3 단계에 걸쳐서)을 얻었다.Prepared from 2-methyl-5-methoxybenzaldehyde (compound from step (iii) above) according to the procedure described in Examples AD (ii) to AD (iv) to give 1.18 g (30%, subtitle product over 3 steps). )

1H-NMR (400 MHz; CDCl3): δ 7.08 (d, 1H); 6.77 (d, 1H); 6.73 (dd, 1H); 4.16 (q, 2H); 3.78 (s, 3H); 3.59 (s, 2H); 2.24 (s, 2H); 1.26 (t, 3H) 1 H-NMR (400 MHz; CDCl 3 ): δ 7.08 (d, 1H); 6.77 (d, 1 H); 6.73 (dd, 1 H); 4.16 (q, 2 H); 3.78 (s, 3 H); 3.59 (s, 2 H); 2.24 (s, 2 H); 1.26 (t, 3 H)

(v) 2-(2-메틸-5-메톡시페닐)-3-옥소-프로피온산 에틸에스테르(v) 2- (2-methyl-5-methoxyphenyl) -3-oxo-propionic acid ethyl ester

에틸 2-메틸-5-메톡시아세테이트(1.16 g; 5.57 밀리몰; 상기 단계 (iv)로부터의 화합물)로부터 출발하여 문헌[J. Org. Chem. 54, 3831(1989)]에 기재된 방법으로 제조하여, 추가의 정제없이 사용하기에 충분할 정도로 순수한 부표제 생성물 0.745 g(57%)를 얻었다.Starting with ethyl 2-methyl-5-methoxyacetate (1.16 g; 5.57 mmol; the compound from step (iv) above), J. Org. Chem. 54 , 3831 (1989), to yield 0.745 g (57%) of a subtitle product that is pure enough to be used without further purification.

1H-NMR (500 MHz; CDCl3): δ 11.97 (d, 1H); 7.14 (d, 1H); 7.10 (d, 1H); 6.67 (dd, 1H); 4.24 (q, 2H); 3.78 (s, 3H); 2.14 (s, 2H); 1.23 (t, 3H) 1 H-NMR (500 MHz; CDCl 3 ): δ 11.97 (d, 1H); 7.14 (d, 1 H); 7.10 (d, 1 H); 6.67 (dd, 1 H); 4.24 (q, 2 H); 3.78 (s, 3 H); 2.14 (s, 2 H); 1.23 (t, 3 H)

(vi) (R,S)-3-히드록시 2-(2-메틸-5-메톡시페닐)프로피온산(vi) (R, S) -3-hydroxy 2- (2-methyl-5-methoxyphenyl) propionic acid

2-(2-메틸-5-메톡시페닐)-3-옥소-프로피온산 산 에틸에스테르(상기 단계 (v)로부터의 화합물)로부터 상기 실시예 E에 기재된 방법으로 제조하였다.Prepared by the method described in Example E above from 2- (2-methyl-5-methoxyphenyl) -3-oxo-propionic acid ethyl ester (compound from step (v) above).

1H-NMR (400 MHz; MeOD): δ 7.09 (d, 1H); 6.84 (d, 1H); 6.72 (dd, 1H); 4.03 (m, 2H); 3.73 (s, 3H); 3.64 (dd, 1H); 2.32 (s, 2H) 1 H-NMR (400 MHz; MeOD): δ 7.09 (d, 1 H); 6.84 (d, 1 H); 6.72 (dd, 1 H); 4.03 (m, 2 H); 3.73 (s, 3 H); 3.64 (dd, 1 H); 2.32 (s, 2 H)

실시예 AFExample AF

(i) 트로프산 메틸 에스테르(i) Trophic acid methyl ester

톨루엔 : CH2Cl2(150 mL; 2:1) 중의 트로프산(5.0 g, 30 밀리몰) 중의 용액에 DBU(4.6 g; 30 밀리몰), 이후에 MeI(4.3 g; 30 밀리몰)을 부가하였다. 혼합물을 철야 교반하고, 물을 부가하고 상을 분리시켰다. 수성상을 에테르로 추출하고, 합한 유기상을 NaHCO3 수용액, HCl 수용액 및 물로 세척하고, 건조하고(Na2SO4), 농축하여 부표제 화합물 0.95 g(18%)을 얻었다.Toluene: To a solution in trough acid (5.0 g, 30 mmol) in CH 2 Cl 2 (150 mL; 2: 1) was added DBU (4.6 g; 30 mmol) followed by MeI (4.3 g; 30 mmol). The mixture was stirred overnight, water was added and the phases were separated. The aqueous phase was extracted with ether, and the combined organic phases were washed with aqueous NaHCO 3 solution, aqueous HCl solution and water, dried (Na 2 SO 4 ) and concentrated to give 0.95 g (18%) of the subtitle compound.

1H-NMR (300 MHz; CDCl3): δ 7.25 (m, 5H); 4.25 (m, 1H); 3.88 (m, 2H); 3.73 (s, 3H) 1 H-NMR (300 MHz; CDCl 3 ): δ 7.25 (m, 5H); 4.25 (m, 1 H); 3.88 (m, 2 H); 3.73 (s, 3 H)

(ii) 2-메틸-2-페닐-3-메톡시프로피온산 메틸 에스테르(ii) 2-methyl-2-phenyl-3-methoxypropionic acid methyl ester

DMF(10 mL) 중의 트로프산 메틸 에스테르(0.9 g; 5.0 밀리몰; 상기 단계(i)로부터의 화합물)의 냉 용액에 NaH(0.87 g; 20 밀리몰)을 부가하고, 얻어진 혼합물을 15 분 동안 교반하고, 이후 MeI(2.8 g; 20 밀리몰)을 부가하고, 혼합물을 실온에서 철야 교반하였다. 혼합물을 물(200 mL)에 붓고, 얻어진 현탁액을 에테르(4 x 25 mL)로 추출하였다. 합한 유기상을 물로 세척하고, 건조하고(Na2SO4), 농축하여 다음 단계에서 추가의 정제없이 사용되는 조물질 0.70 g(약 65%)을 얻었다.To the cold solution of trophic acid methyl ester (0.9 g; 5.0 mmol; compound from step (i)) in DMF (10 mL) was added NaH (0.87 g; 20 mmol) and the resulting mixture was stirred for 15 minutes and Then MeI (2.8 g; 20 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was poured into water (200 mL) and the resulting suspension was extracted with ether (4 x 25 mL). The combined organic phases were washed with water, dried (Na 2 SO 4 ) and concentrated to yield 0.70 g (about 65%) of crude which was used without further purification in the next step.

1H-NMR (300 MHz; CDCl3): δ 7.25 (m, 5H); 4.00 (d, 1H); 3.67 (s, 3H); 3.60 (d, 1H); 3.35 (s, 3H); 1.67 (s, 3H) 1 H-NMR (300 MHz; CDCl 3 ): δ 7.25 (m, 5H); 4.00 (d, 1 H); 3.67 (s, 3 H); 3.60 (d, 1 H); 3.35 (s, 3 H); 1.67 (s, 3 H)

(iii) (R,S)-2-메틸-2-페닐-3-메톡시프로피온산(iii) (R, S) -2-methyl-2-phenyl-3-methoxypropionic acid

MeOH(50 mL) 중의 2-메틸-2-페닐-3-메톡시프로피온산 메틸 에스테르(0.7 g; 3.4 밀리몰; 상기 단계(ii)로부터의 화합물)의 용액에 NaOH 수용액(2M; 50 mL)을 부가하고, 혼합물을 2 시간 동안 교반하였다. 혼합물을 HCl 수용액으로 산성화하고 에테르(3 x 50 mL)로 추출하였다. 합한 유기상을 물로 세척하고, 건조하고(Na2SO4), 농축하여 부표제 화합물 0.40 g(약 61%)을 얻었다.To a solution of 2-methyl-2-phenyl-3-methoxypropionic acid methyl ester (0.7 g; 3.4 mmol; compound from step (ii)) in MeOH (50 mL) was added aqueous NaOH solution (2M; 50 mL). And the mixture was stirred for 2 hours. The mixture was acidified with aqueous HCl solution and extracted with ether (3 × 50 mL). The combined organic phases were washed with water, dried (Na 2 SO 4 ) and concentrated to give 0.40 g (about 61%) of the subtitle compound.

1H-NMR (300 MHz; CDCl3): δ 7.35 (m, 5H); 4.00 (d, 1H); 3.60 (d, 1H); 3.40 (s, 3H); 1.66 (s, 3H) 1 H-NMR (300 MHz; CDCl 3 ): δ 7.35 (m, 5H); 4.00 (d, 1 H); 3.60 (d, 1 H); 3.40 (s, 3 H); 1.66 (s, 3 H)

실시예 AGExample AG

(R,S)-3-히드록시-2-(2-클로로-3-메틸페닐)프로피온산(R, S) -3-hydroxy-2- (2-chloro-3-methylphenyl) propionic acid

(i) 2-클로로-3-메틸벤조산(i) 2-chloro-3-methylbenzoic acid

아질산나트륨(14.0 g; 0.2 몰)을 물(200 mL) 및 NaOH 수용액(30%, 24 mL)의 혼합물 중의 2-아미노-3-메틸벤조산(30.2 g; 0.2 몰)의 용액에 부가하였다. 용액을 0 ℃로 냉각하고, 교반하면서 진한 HCl(87.6 mL) 및 얼음(100 g)의 혼합물에 적가하였다. 수분동안 교반한 후, 얻어진 용액을 HCl 수용액(23%; 100 g), CuCl(20 g; 0.2 몰) 및 물(40 mL)의 빙냉 혼합물에 부가하였다. 용액을 실온에서 30분간 그리고 100 ℃에서 30분간 교반하고, 냉각하고, 얻어진 침전물을 여과에 의해 단리하고, 물로 세척하고, 철야 건조하여, 백색의 결정질 물질 27.4 g(80.3%)을 얻었다.Sodium nitrite (14.0 g; 0.2 mol) was added to a solution of 2-amino-3-methylbenzoic acid (30.2 g; 0.2 mol) in a mixture of water (200 mL) and aqueous NaOH solution (30%, 24 mL). The solution was cooled to 0 ° C. and added dropwise to a mixture of concentrated HCl (87.6 mL) and ice (100 g) with stirring. After stirring for a few minutes, the resulting solution was added to an ice cold mixture of aqueous HCl solution (23%; 100 g), CuCl (20 g; 0.2 mol) and water (40 mL). The solution was stirred at room temperature for 30 minutes and at 100 ° C. for 30 minutes, cooled, and the resulting precipitate was isolated by filtration, washed with water and dried overnight to give 27.4 g (80.3%) of white crystalline material.

LC-MS m/z 169, 171 (M - 1)- LC-MS m / z 169, 171 (M-1) -

1H-NMR (500 MHz; CDCl3): δ 7.79 (d, 1H); 7.43 (d, 1H); 7.25 (t, 1H); 2.46 (s, 3H) 1 H-NMR (500 MHz; CDCl 3 ): δ 7.79 (d, 1H); 7.43 (d, 1 H); 7.25 (t, 1 H); 2.46 (s, 3 H)

(ii) 2-클로로-3-메틸벤질 알코올(ii) 2-chloro-3-methylbenzyl alcohol

2-클로로-3-메틸벤조산(13.65 g; 0.08 몰; 상기 단계(i)로부터의 화합물)으로부터 실시예 X(i)에 기재된 방법에 따라 제조하여 백색 결정의 부표제 화합물 11.38 g(90.8%)을 얻었다.11.38 g (90.8%) of a white crystal subtitle compound was prepared according to the method described in Example X (i) from 2-chloro-3-methylbenzoic acid (13.65 g; 0.08 mol; the compound from step (i) above). Got it.

1H-NMR (500 MHz; CDCl3): δ 7.32 (d, 1H); 7.31 (d, 1H); 7.18 (dd, 1H); 4.78 (d, 2H); 2.40 (s, 3H) 1 H-NMR (500 MHz; CDCl 3 ): δ 7.32 (d, 1H); 7.31 (d, 1 H); 7.18 (dd, 1 H); 4.78 (d, 2 H); 2.40 (s, 3 H)

(iii) 2-클로로-3-메틸페닐아세토니트릴(iii) 2-chloro-3-methylphenylacetonitrile

2-클로로-3-메틸벤질 알코올(11.3 g; 72.15 몰; 상기 단계(ii)로부터의 화합물)로부터 실시예 X(ii) 및 X(iii)에 기재된 방법에 따라 제조하여 적갈색 고체인 부표제 화합물 11.4 g(93%)을 얻었다.Subtitle compound 11.4, which is a reddish brown solid prepared according to the method described in Examples X (ii) and X (iii) from 2-chloro-3-methylbenzyl alcohol (11.3 g; 72.15 mol; the compound from step (ii) above). g (93%) was obtained.

1H-NMR (400 MHz; CDCl3): δ 7.35 (d, 1H); 7.24 (t, 1H); 7.21 (d, 1H); 3.84 (s, 2H); 2.41 (s, 3H) 1 H-NMR (400 MHz; CDCl 3 ): δ 7.35 (d, 1H); 7.24 (t, 1 H); 7.21 (d, 1 H); 3.84 (s, 2 H); 2.41 (s, 3 H)

(iv) 에틸 2-클로로-3-메틸페닐아세테이트(iv) ethyl 2-chloro-3-methylphenylacetate

2-클로로-3-메틸페닐아세토니트릴(5.28 g; 32 밀리몰; 상기 단계(iii)로부터의 화합물)으로부터 실시예 T(ii)에 기재된 방법에 따라 제조하여 부표제 화합물 6.3 g (88.2%)을 얻었다.2-Chloro-3-methylphenylacetonitrile (5.28 g; 32 mmol; the compound from step (iii)) was prepared according to the method described in Example T (ii) to give 6.3 g (88.2%) of the subtitle compound.

1H-NMR (400 MHz; CDCl3): δ 7.12 (d, 2H); 7.16 (dd, 1H); 4.17 (q, 2H); 3.77 (s, 2H); 2.39 (s, 3H); 1.26 (t, 3H) 1 H-NMR (400 MHz; CDCl 3 ): δ 7.12 (d, 2H); 7.16 (dd, 1 H); 4.17 (q, 2 H); 3.77 (s, 2 H); 2.39 (s, 3 H); 1.26 (t, 3 H)

(v) 2-(2-클로로-3-메틸페닐)-3-옥소-프로피온산 에틸 에스테르(v) 2- (2-chloro-3-methylphenyl) -3-oxo-propionic acid ethyl ester

2-클로로-3-메틸페닐아세테이트(6.28 g; 29.53 밀리몰; 상기 단계(iv)로부터의 화합물)으로부터 문헌[J. Org. Chem. 54, 3831(1989)]에 기재된 방법에 따라 제조하여 부표제 생성물 5.418 g(76.2%)을 얻었다. 이 생성물은 다음 단계에서 추가의 정제없이 사용될 정도로 충분히 순수했다.2-chloro-3-methylphenylacetate (6.28 g; 29.53 mmol; the compound from step (iv) above); Org. Chem. 54 , 3831 (1989)] to give 5.418 g (76.2%) of the subtitle product. This product was pure enough to be used without further purification in the next step.

LC-MS m/z 239,241 (M - 1)- LC-MS m / z 239,241 (M-1) -

1H-NMR (500 MHz; CDCl3): δ 11.96 (b, 1H); 7.21 (d, 1H); 7.14 (m, 1H); 7.03 (d, 1H); 4.25 (m, 2H); 2.41 (s, 3H); 1.23 (t, 3H) 1 H-NMR (500 MHz; CDCl 3 ): δ 11.96 (b, 1H); 7.21 (d, 1 H); 7.14 (m, 1 H); 7.03 (d, 1 H); 4.25 (m, 2 H); 2.41 (s, 3 H); 1.23 (t, 3 H)

(vi) (R,S)-3-히드록시-2-(2-클로로-3-메틸페닐)프로피온산(vi) (R, S) -3-hydroxy-2- (2-chloro-3-methylphenyl) propionic acid

2-(2-클로로-3-메틸페닐)-3-옥소-프로피온산 에틸 에스테르(5.39 g; 22.39 밀리몰; 상기 단계(v)로부터의 화합물)로부터 상기 실시예 E에 기재된 방법에 따라 제조하여 부표제 화합물 4.03 g(79.8%)을 얻었다.Subtitled Compound 4.03 prepared according to the method described in Example E above from 2- (2-chloro-3-methylphenyl) -3-oxo-propionic acid ethyl ester (5.39 g; 22.39 mmol; the compound from step (v)) g (79.8%) was obtained.

1H-NMR (400 MHz; CDCl3): δ 7.25 (d, 1H); 7.21 (m, 1H); 7.16 (d, 1H); 4.36 (dd, 1H); 4.02 (dd, 1H); 3.74 (dd, 1H); 2.38 (s, 3H) 1 H-NMR (400 MHz; CDCl 3 ): δ 7.25 (d, 1H); 7.21 (m, 1 H); 7.16 (d, 1 H); 4.36 (dd, 1 H); 4.02 (dd, 1 H); 3.74 (dd, 1 H); 2.38 (s, 3 H)

본 발명의 화합물Compound of the Invention

실시예 1Example 1

(R)- 및 (S)-PhCH(CH2OH)-C(O)-Aze-Pab x HCl(R)-and (S) -PhCH (CH 2 OH) -C (O) -Aze-Pab x HCl

(i) (R)- 및 (S)-PhCH(CH2OH)-C(O)-Aze-Pab(Z)(i) (R)-and (S) -PhCH (CH 2 OH) -C (O) -Aze-Pab (Z)

DMF 10 ml 중의 (R,S)-트로프산(0.25 g, 1.5 밀리몰), H-Aze-Pab(Z) x 2HCl(0.73 g; 1.7 밀리몰; 상기 실시예 A로부터의 화합물) 및 TBTU(0.53 g; 1.7 밀리몰)의 혼합물을 빙조에서 냉각하였다. DIPEA(0.78 g; 6.0 밀리몰)을 부가하고 반응 혼합물을 실온에서 48 시간 동안 교반하였다. 이어서, 반응 혼합물을 농축하고, 물 400 mL로 희석하고(NaHCO3를 사용하여 pH를 8로 조절함), 에틸 아세테이트(3 x 75 mL)로 추출하였다. 합한 유기층을 NaHCO3 수용액(3 x 50 mL) 및 물(1 x 50 mL)로 세척하고, 건조하고(Na2SO4) 증발시켰다. 조생성물을 (0.59 g)을 CH2Cl2(300 mL), CH2Cl2 : THF(500 mL; 3:1), 및 THF(1750 mL)로 용출된 실리카겔 칼럼(120 g) 상에서 플래시 크로마토그래피하여 정제하였다. 20 mL 분획물을 수집하였다. 분획물 41-54를 농축하여 > 99:1의 부분입체 이성질체 비로 화합물 1A 150 mg을 얻었다. 분획물 70-90을 농축하여 89 : 11의 부분입체 이성질체 비로 화합물 1B를 얻었다.(R, S) -tropic acid (0.25 g, 1.5 mmol), H-Aze-Pab (Z) x 2HCl (0.73 g; 1.7 mmol; compound from Example A above) and TBTU (0.53 g) in 10 ml DMF 1.7 mmol) was cooled in an ice bath. DIPEA (0.78 g; 6.0 mmol) was added and the reaction mixture was stirred at rt for 48 h. The reaction mixture was then concentrated, diluted with 400 mL of water (adjust the pH to 8 with NaHCO 3 ) and extracted with ethyl acetate (3 × 75 mL). The combined organic layers were washed with aqueous NaHCO 3 solution (3 × 50 mL) and water (1 × 50 mL), dried (Na 2 SO 4 ) and evaporated. The crude product (0.59 g) was flash chromatographed on a silica gel column (120 g) eluted with CH 2 Cl 2 (300 mL), CH 2 Cl 2 : THF (500 mL; 3: 1), and THF (1750 mL). It was purified by chromatography. 20 mL fractions were collected. Fractions 41-54 were concentrated to give 150 mg of compound 1A in a diastereomeric ratio of> 99: 1. Fractions 70-90 were concentrated to give compound 1B with a diastereomeric ratio of 89:11.

화합물 1A:Compound 1A:

1H NMR (400 MHz; CDCl3): δ 8.27 (m, 1H), 7.67 (d, 2H), 7.38 (d, 2H), 7.3-7.1 (m, 10H), 5.49 (d, 1H), 5.15 (s, 2H), 4.73 (m, 1H), 4.4-4.2 (m, 2H), 4.10 (m, 1H), 4.02 (m, 1H), 3.71 (m, 1H), 3.63 (m, 2H), 2.34 (m, 1H), 2.23 (m, 1H). 1 H NMR (400 MHz; CDCl 3 ): δ 8.27 (m, 1H), 7.67 (d, 2H), 7.38 (d, 2H), 7.3-7.1 (m, 10H), 5.49 (d, 1H), 5.15 (s, 2H), 4.73 (m, 1H), 4.4-4.2 (m, 2H), 4.10 (m, 1H), 4.02 (m, 1H), 3.71 (m, 1H), 3.63 (m, 2H), 2.34 (m, 1 H), 2.23 (m, 1 H).

13C NMR(100 MHz; CDCl3) 아미딘 및 카르보닐 탄소: 173.7, 171.0, 168.5, 164.4 13 C NMR (100 MHz; CDCl 3 ) amidine and carbonyl carbon: 173.7, 171.0, 168.5, 164.4

화합물 1B:Compound 1B:

1H NMR (400 MHz; CDCl3): δ 8.27 (m, 1H, 소수의 부분입체 이성질체/회전 이성질체), 8.14 (m, 1H, 다수의 부분입체 이성질체/회전 이성질체), 7.9-7.7 (m, 2H), 7.5-7.1 (m, 12H), 5.56 (d, 1H), 5.22 (s, 2H, 다수의 부분입체 이성질체/회전 이성질체), 5.20 (s, 2H, 소수의 부분입체 이성질체/회전 이성질체), 4.89 (m, 1H, 다수의 부분입체 이성질체/회전 이성질체), 4.82 (m, 1H, 소수의 부분입체 이성질체/회전 이성질체), 4.6-4.3 (m, 2H), 4.2-4.0 (m, 2H), 3.8-3.6 (m, 3H), 2.48 (m, 1H), 2.38 (m, 1H) 1 H NMR (400 MHz; CDCl 3 ): δ 8.27 (m, 1H, few diastereoisomers / rotary isomers), 8.14 (m, 1H, multiple diastereomers / rotary isomers), 7.9-7.7 (m, 2H), 7.5-7.1 (m, 12H), 5.56 (d, 1H), 5.22 (s, 2H, multiple diastereomers / rotary isomers), 5.20 (s, 2H, few diastereomers / rotary isomers) , 4.89 (m, 1H, multiple diastereomers / rotary isomers), 4.82 (m, 1H, few diastereomers / rotary isomers), 4.6-4.3 (m, 2H), 4.2-4.0 (m, 2H) , 3.8-3.6 (m, 3H), 2.48 (m, 1H), 2.38 (m, 1H)

13C NMR(100 MHz; CDCl3), 아미딘 및 카르보닐 탄소: 174.8, 170.8, 168.0, 164.7 13 C NMR (100 MHz; CDCl 3 ), amidine and carbonyl carbon: 174.8, 170.8, 168.0, 164.7

(ii) (R)- 또는 (S)-PhCH(CH2OH)-C(O)-Aze-Pab x HCl(ii) (R)-or (S) -PhCH (CH 2 OH) -C (O) -Aze-Pab x HCl

에탄올 10 mL에 화합물 1A(100 mg; 0.19 밀리몰; 상기 단계 (i)로부터의 화합물)을 용해하고, 5% Pd/C(52 mg)을 부가하였다. 혼합물을 대기압에서 5 시간 동안 수소처리하였다. 여과 및 증발후, 생성물을 물 5 mL에 용해하고 HCl(1 M) 190 μL를 부가하였다. 동결 건조 후, 백색 분말인 표제 생성물을 얻었다. 수율은 60 mg(74%)이고, 부분입체 이성질체 비는 99:1이었다.Compound 1A (100 mg; 0.19 mmol; compound from step (i)) was dissolved in 10 mL of ethanol and 5% Pd / C (52 mg) was added. The mixture was hydrotreated at atmospheric pressure for 5 hours. After filtration and evaporation, the product was dissolved in 5 mL of water and 190 μL of HCl (1 M) was added. After freeze drying, the title product was obtained as a white powder. The yield was 60 mg (74%) and the diastereomeric ratio was 99: 1.

1H-NMR (400 MHz; D2O): δ 8.75 (m, 1H, 다수의 회전 이성질체), 8.59 (m, 1H, 소수의 회전 이성질체), 7.69 (d, 2H, 다수의 회전 이성질체), 7.63 (d, 2H, 소수의 회전 이성질체), 7.5-7.0 (m, 7 H), 5.10 (m, 1H; HDO-시그널과 중첩되는 동일한 양성자로부터의 다른 시그널), 4.47 (bs, 1H), 4.27 (m, 1H, 다수의 회전 이성질체), 4.17 (1H, 소수의 회전 이성질체), 4.1-3.6 (m, 5H), 2.67 (m, 1H, 소수의 회전 이성질체), 2.40 (m, 1H, 다수의 회전 이성질체), 2.3-2.1 (m, 1H). 1 H-NMR (400 MHz; D 2 O): δ 8.75 (m, 1H, multiple isomers), 8.59 (m, 1H, few rotational isomers), 7.69 (d, 2H, multiple rotational isomers), 7.63 (d, 2H, few rotational isomers), 7.5-7.0 (m, 7H), 5.10 (m, 1H; other signals from the same protons that overlap with HDO-signal), 4.47 (bs, 1H), 4.27 (m, 1H, many isomers), 4.17 (1H, few isomers), 4.1-3.6 (m, 5H), 2.67 (m, 1H, few isomers), 2.40 (m, 1H, many Rotamers), 2.3-2.1 (m, 1H).

13C NMR(75 MHz; D2O), 아미딘 및 카르보닐 탄소 (회전 이성질체): 177.4, 176.4, 175.3, 174.8, 160.0, 157.6. 13 C NMR (75 MHz; D 2 O), amidine and carbonyl carbon (rotary isomers): 177.4, 176.4, 175.3, 174.8, 160.0, 157.6.

(iii) (S)- 또는 (R)-PhCHCH2OH-C(O)-Aze-Pab x HCl(iii) (S)-or (R) -PhCHCH 2 OH-C (O) -Aze-Pab x HCl

화학식 1B의 화합물(상기 단계 (i)로부터의 화합물) 50 mg(0.097 밀리몰)로부터 실시예 1(ii)의 방법에 따라 표제 화합물을 제조하였다. 수율은 32 mg(79%)이고, 부분입체 이성질체 비는 83:17이었다.The title compound was prepared according to the method of Example 1 (ii) from 50 mg (0.097 mmol) of the compound of Formula 1B (compound from step (i) above). The yield was 32 mg (79%) and the diastereomeric ratio was 83:17.

1H-NMR (400 MHz; D2O): δ 7.8-7.0 (m, 9H), 5.10 (m, 1H, 소수의 부분입체 이성질체/회전 이성질체), 4.83 (m, 1H, 다수의 부분입체 이성질체/회전 이성질체), 4.6-4.2 (m, 3H), 4.1-3.4 (m, 4H), 2.54 (m, 1H, 다수의 부분입체 이성질체/회전 이성질체), 2.39 (m, 1H, 소수의 부분입체 이성질체/회전 이성질체), 2.2-2.1 (m, 1H) 1 H-NMR (400 MHz; D 2 O): δ 7.8-7.0 (m, 9H), 5.10 (m, 1H, few diastereomers / rotary isomers), 4.83 (m, 1H, multiple diastereomers / Rotate isomers), 4.6-4.2 (m, 3H), 4.1-3.4 (m, 4H), 2.54 (m, 1H, multiple diastereomers / rotary isomers), 2.39 (m, 1H, few diastereomers Rotational isomer), 2.2-2.1 (m, 1H)

13C NMR(75 MHz; D2O) 아미딘 및 카르보닐 탄소: 176.6, 174.9, 168.9 13 C NMR (75 MHz; D 2 O) amidine and carbonyl carbon: 176.6, 174.9, 168.9

실시예 2Example 2

(R)- 및 (S)-3-메톡시페닐-CH(CH2OH)-C(O)-Aze-Pab x HOAc(R)-and (S) -3-methoxyphenyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

(i) (R)- 및 (S)-3-메톡시페닐-CH(CH2OH)-C(O)-Aze-Pab(Z)(i) (R)-and (S) -3-methoxyphenyl-CH (CH 2 OH) -C (O) -Aze-Pab (Z)

DMF 10 ml 중의 (R,S)-3-히드록시-2-(3-메톡시페닐)-프로피온산(0.157 g; 0.8 밀리몰; 상기 실시예 E로부터의 수득물)의 용액에 H-Aze-Pab(Z) x 2HCl(0.387 g; 0.88 밀리몰; 상기 실시예 A로부터의 화합물)을 부가하고 혼합물을 빙조에서 냉각하였다. TBTU(0.283 g; 0.88 밀리몰) 및 DIPEA(0.414 g; 3.20 밀리몰)을 부가하고 반응 혼합물을 실온에서 48 시간 동안 교반하였다. 이어서, 반응 혼합물을 증발시키고, 잔류물을 H2O(100 mL)에 용해하고, 이어서 에틸 아세테이트(3 x 25 mL)로 추출하였다. 합한 유기층을 NaHCO3 수용액(3 x 25 mL) 및 H2O(25 mL)로 세척하고, 건조하고(Na2SO4) 증발시켰다. 조생성물을 CH2Cl2:MeOH(98:2), 에틸 아세테이트, 에틸 아세테이트:EtOH(95:5), 에틸 아세테이트:EtOH(9:1) 및 에틸 아세테이트:EtOH(85:15)로 용출된 실리카겔 칼럼에서 플래시 크로마토그래피하여 정제하였다. 일부 분획물을 농축하여 88:12의 부분입체 이성질체 비로 화학식 2A 177 mg을 얻었다. 다른 분획물을 농축하여 88 : 12의 부분입체 이성질체 비로 화합물 2B 164 mg을 얻었다.H-Aze-Pab in a solution of (R, S) -3-hydroxy-2- (3-methoxyphenyl) -propionic acid (0.157 g; 0.8 mmol; the product from Example E above) in 10 ml of DMF. (Z) x 2HCl (0.387 g; 0.88 mmol; compound from Example A) was added and the mixture was cooled in an ice bath. TBTU (0.283 g; 0.88 mmol) and DIPEA (0.414 g; 3.20 mmol) were added and the reaction mixture was stirred at rt for 48 h. The reaction mixture was then evaporated and the residue was dissolved in H 2 O (100 mL) and then extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with aqueous NaHCO 3 solution (3 × 25 mL) and H 2 O (25 mL), dried (Na 2 SO 4 ) and evaporated. The crude product was eluted with CH 2 Cl 2 : MeOH (98: 2), ethyl acetate, ethyl acetate: EtOH (95: 5), ethyl acetate: EtOH (9: 1) and ethyl acetate: EtOH (85:15). Purification by flash chromatography on a silica gel column. Some fractions were concentrated to give 177 mg of formula 2A in a diastereomeric ratio of 88:12. The other fractions were concentrated to give 164 mg of compound 2B in a diastereomeric ratio of 88:12.

화합물 2A:Compound 2A:

1H NMR (500 MHz; CDCl3): δ 8.20-8.27 (m, NH), 7.79-7.85 (m, 2H), 7.18-7.48 (m, 8H), 6.70-6.88 (m, 3H), 5.20-5.24 (m, 2H), 4.84-4.99 (m, 1H), 4.34-4.64 (m, 2H), 3.98-4.16 (m, 2H), 3.56-3.82 (m, 6 H), 2.26-2.70 (m, 2H). 1 H NMR (500 MHz; CDCl 3 ): δ 8.20-8.27 (m, NH), 7.79-7.85 (m, 2H), 7.18-7.48 (m, 8H), 6.70-6.88 (m, 3H), 5.20- 5.24 (m, 2H), 4.84-4.99 (m, 1H), 4.34-4.64 (m, 2H), 3.98-4.16 (m, 2H), 3.56-3.82 (m, 6H), 2.26-2.70 (m, 2H).

화합물 2B:Compound 2B:

1H NMR (500 MHz; CDCl3): δ 8.14-8.21 (m, NH), 7.78-7.88 (m, 2H), 7.18-7.48 (m, 8H), 6.70-6.87 (m, 3H), 5.20-5.24 (m, 2H), 4.86-5.00 (m, 1H), 4.34-4.64 (m, 2H), 4.00-4.16 (m, 2H), 3.58-3.82 (m, 6H), 2.39-2.69 (m, 2H). 1 H NMR (500 MHz; CDCl 3 ): δ 8.14-8.21 (m, NH), 7.78-7.88 (m, 2H), 7.18-7.48 (m, 8H), 6.70-6.87 (m, 3H), 5.20- 5.24 (m, 2H), 4.86-5.00 (m, 1H), 4.34-4.64 (m, 2H), 4.00-4.16 (m, 2H), 3.58-3.82 (m, 6H), 2.39-2.69 (m, 2H ).

(ii) (R)- 또는 (S)-3-메톡시페닐-CH(CH2OH)-C(O)-Aze-Pab x HOAc(ii) (R)-or (S) -3-methoxyphenyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

에탄올 7 mL 중의 화합물 2A(0.164 g; 0.30 밀리몰; 상기 단계 (i)로부터의 화합물)의 용액에 아세트산(0.018 g; 0.30 밀리몰) 및 Pd/C(5%; 0.08 g)을 부가하였다. 반응 혼합물을 대기압에서 4 시간 동안 수소처리하였다. 반응 혼합물을 셀라이트(celite)를 통해 여과하고 여과액을 농축하였다. 조생성물을 H2O 중에 용해하고 동결 건조시켜 부분입체 이성질체 비가 88:12인 표제 화합물 128 mg(91%)를 얻었다.To a solution of compound 2A (0.164 g; 0.30 mmol; compound from step (i) above) in 7 mL of ethanol was added acetic acid (0.018 g; 0.30 mmol) and Pd / C (5%; 0.08 g). The reaction mixture was hydrotreated at atmospheric pressure for 4 hours. The reaction mixture was filtered through celite and the filtrate was concentrated. The crude product was dissolved in H 2 O and lyophilized to give 128 mg (91%) of the title compound with a diastereomeric ratio of 88:12.

LC-MS m/z 411 (M + 1)+ LC-MS m / z 411 (M + 1) +

1H NMR (500 MHz; D2O): δ 7.67-7.85 (m, 2H), 7.25-7.62 (m, 3H), 6.89-7.04 (m, 2H), 6.74-6.83 (m, 1H), 5.16-5.22 (m, 1H), 4.24-4.66 (m, 2H), 3.97-4.19 (m, 3H), 3.64-3.94 (m, 5H), 2.18-2.82 (m, 2H). 1 H NMR (500 MHz; D 2 O): δ 7.67-7.85 (m, 2H), 7.25-7.62 (m, 3H), 6.89-7.04 (m, 2H), 6.74-6.83 (m, 1H), 5.16 -5.22 (m, 1H), 4.24-4.66 (m, 2H), 3.97-4.19 (m, 3H), 3.64-3.94 (m, 5H), 2.18-2.82 (m, 2H).

(iii) (S)- 또는 (R)-3-메톡시페닐-CH(CH2OH)-C(O)-Aze-Pab x HOAc(iii) (S)-or (R) -3-methoxyphenyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

에탄올(7 mL) 중의 화합물 2B(0.142 g; 0.26 밀리몰; 상기 단계 (i)로부터의 화합물)의 용액에 아세트산(0.016 g; 0.26 밀리몰) 및 Pd/C(5%; 0.07 g)을 부가하였다. 반응 혼합물을 대기압에서 4 시간 동안 수소처리하였다. 반응 혼합물을 셀라이트(celite)를 통해 여과하고 여과액을 농축하였다. 조생성물을 H2O 중에 용해하고 동결 건조시켜, 부분입체 이성질체 비가 88:12인 표제 화합물 113 mg(92%)을 얻었다.To a solution of compound 2B (0.142 g; 0.26 mmol; compound from step (i) above) in ethanol (7 mL) was added acetic acid (0.016 g; 0.26 mmol) and Pd / C (5%; 0.07 g). The reaction mixture was hydrotreated at atmospheric pressure for 4 hours. The reaction mixture was filtered through celite and the filtrate was concentrated. The crude product was dissolved in H 2 O and lyophilized to give 113 mg (92%) of the title compound having a diastereomeric ratio of 88:12.

LC-MS m/z 411 (M + 1)+ LC-MS m / z 411 (M + 1) +

1H NMR (500 MHz; D2O): δ 7.26-7.86 (m, 5H), 6.88-7.04 (m, 2H), 6.75-6.83 (m, 1H), 4.91-4.96 (m, 1H), 4.26-4.68 (m, 3H), 3.96-4.18 (m, 2H), 3.64-3.94 (m, 5H), 2.18-2.70 (m, 2H). 1 H NMR (500 MHz; D 2 O): δ 7.26-7.86 (m, 5H), 6.88-7.04 (m, 2H), 6.75-6.83 (m, 1H), 4.91-4.96 (m, 1H), 4.26 -4.68 (m, 3H), 3.96-4.18 (m, 2H), 3.64-3.94 (m, 5H), 2.18-2.70 (m, 2H).

실시예 3Example 3

(R,S)-3,4-디메톡시페닐-CH(CH2OH)-C(O)-Aze-Pab x HOAc(R, S) -3,4-dimethoxyphenyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

(i) (R,S)-3,4-디메톡시페닐-CH(CH2OH)-C(O)-Aze-Pab(Z)(i) (R, S) -3,4-dimethoxyphenyl-CH (CH 2 OH) -C (O) -Aze-Pab (Z)

DMF 10 ml 중의 (R,S)-3-히드록시-2-(3,4-디메톡시페닐)-프로피온산(0.23 g; 1.0 밀리몰; 상기 실시예 F로부터의 화합물), H-Aze-Pab(Z) x 2HCl(0.48 g; 1.1 밀리몰; 상기 실시예 A로부터의 화합물) 및 TBTU(0.35 g, 1.1 밀리몰)의 혼합물을 빙조에서 냉각하였다. DIPEA(0.52 g; 4.0 밀리몰)을 부가하고 반응 혼합물을 실온에서 4 일 동안 교반하였다. 이어서, 반응 혼합물을 농축하였다. 잔류물을 에틸 아세테이트:H2O(1:2; 300 mL)로 희석하고, NaHCO3 수용액으로 pH를 9로 조절하고, 이어서 에틸 아세테이트(3 x 100 mL)로 추출하였다. 합한 유기층을 NaHCO3 수용액(3 x 100 mL) 및 물(3 x 125 mL)로 세척하고, 건조하고(Na2SO4) 증발시켰다. 조생성물(0.43 g)을 에틸 아세테이트(200 mL), 에틸 아세테이트:EtOH(95:5; 200 mL), 에틸 아세테이트:EtOH(9:1; 200 mL) 및 에틸 아세테이트:EtOH(85:15; 200 mL)로 용출되는 실리카겔 칼럼(50g)에서 플래시 크로마토그래피하여 정제하였다. 52 : 48의 부분입체 이성질체 비로 표제 화합물 244 mg(42%)을 얻었다.(R, S) -3-hydroxy-2- (3,4-dimethoxyphenyl) -propionic acid (0.23 g; 1.0 mmol; compound from Example F above), H-Aze-Pab (in 10 ml of DMF) Z) A mixture of x 2 HCl (0.48 g; 1.1 mmol; compound from Example A) and TBTU (0.35 g, 1.1 mmol) was cooled in an ice bath. DIPEA (0.52 g; 4.0 mmol) was added and the reaction mixture was stirred at rt for 4 days. Then the reaction mixture was concentrated. The residue was diluted with ethyl acetate: H 2 O (1: 2; 300 mL), the pH was adjusted to 9 with aqueous NaHCO 3 solution and then extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with aqueous NaHCO 3 solution (3 × 100 mL) and water (3 × 125 mL), dried (Na 2 SO 4 ) and evaporated. The crude product (0.43 g) was diluted with ethyl acetate (200 mL), ethyl acetate: EtOH (95: 5; 200 mL), ethyl acetate: EtOH (9: 1; 200 mL) and ethyl acetate: EtOH (85:15; 200 purified by flash chromatography on a silica gel column (50 g) eluting with mL). A diastereomeric ratio of 52:48 gave 244 mg (42%) of the title compound.

FAB-MS m/z 575 (M + 1)+ FAB-MS m / z 575 (M + 1) +

1H NMR (400 MHz; CDCl3): δ 8.18-8.26 (m, 1H), 8.00-8.08 (m, 1H), 7.76-7.84 (d, 1H), 7.63-7.68 (d, 1H), 7.25-7.47 (m, 6H), 7.02-7.07 (d, 1H), 6.64-6.84 (m, 3H), 5.20 (s, 2H), 4.82-5.00 (m, 1H), 4.40-4.79 (m, 2H), 3.98-4.24 (m, 2H), 3.84-3.87 (m, 6H), 3.53-3.82 (m, 3H), 2.26-2.69 (m, 2H). 1 H NMR (400 MHz; CDCl 3 ): δ 8.18-8.26 (m, 1H), 8.00-8.08 (m, 1H), 7.76-7.84 (d, 1H), 7.63-7.68 (d, 1H), 7.25- 7.47 (m, 6H), 7.02-7.07 (d, 1H), 6.64-6.84 (m, 3H), 5.20 (s, 2H), 4.82-5.00 (m, 1H), 4.40-4.79 (m, 2H), 3.98-4.24 (m, 2H), 3.84-3.87 (m, 6H), 3.53-3.82 (m, 3H), 2.26-2.69 (m, 2H).

(ii) (R,S)-3,4-디메톡시페닐-CH(CH2OH)-C(O)-Aze-Pab x HOAc(ii) (R, S) -3,4-dimethoxyphenyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

(R,S)-3,4-디메톡시페닐-CH(CH2OH)-C(O)-Aze-Pab(Z) (0.095 g; 0.17 밀리몰; 상기 단계 (i)로부터의 화합물), 아세트산(0.010 g, 0.17 밀리몰) 및 Pd/C(5%, 0.087 g)을 에탄올(10 mL)에 부가하였고, 얻어진 혼합물을 대기압에서 5 시간 동안 수소처리하였다. 반응 혼합물을 여과하고 여과액을 증발시켰다. 잔류물을 H2O에서 용해하고 동결 건조하여 52:48의 부분입체 이성질체 비로 백색 분말인 표제 화합물 70 mg(85%)을 얻었다.(R, S) -3,4-dimethoxyphenyl-CH (CH 2 OH) -C (O) -Aze-Pab (Z) (0.095 g; 0.17 mmol; compound from step (i) above), acetic acid (0.010 g, 0.17 mmol) and Pd / C (5%, 0.087 g) were added to ethanol (10 mL) and the resulting mixture was hydrotreated at atmospheric pressure for 5 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was dissolved in H 2 O and lyophilized to give 70 mg (85%) of the title compound as a white powder in a diastereomeric ratio of 52:48.

LC-MS m/z 441 (M + 1)+ LC-MS m / z 441 (M + 1) +

1H NMR (400 MHz; D2O): δ 7.29-7.85 (m, 4H), 6.85-7.09 (m, 2H), 6.71-6.81 (m, 1H), 4.90-5.19 (m, 1H), 4.31-4.65 (m, 2H), 3.95-4.28 (m, 3H), 3.62-3.90 (m, 8H), 2.15-2.84 (m, 2H). 1 H NMR (400 MHz; D 2 O): δ 7.29-7.85 (m, 4H), 6.85-7.09 (m, 2H), 6.71-6.81 (m, 1H), 4.90-5.19 (m, 1H), 4.31 -4.65 (m, 2H), 3.95-4.28 (m, 3H), 3.62-3.90 (m, 8H), 2.15-2.84 (m, 2H).

실시예 4Example 4

(R)- 및 (S)-2-나프틸-CH(CH2OH)-C(O)-Aze-Pab x HOAc(R)-and (S) -2-naphthyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

(i) (R)- 및 (S)-2-나프틸-CH(CH2OH)-C(O)-Aze-Pab(Z)(i) (R)-and (S) -2-naphthyl-CH (CH 2 OH) -C (O) -Aze-Pab (Z)

DMF 10 ml 중의 H-Aze-Pab(Z) x 2HCl(0.483 g; 1.1 밀리몰; 상기 실시예 A로부터의 화합물)의 용액을 빙조에서 냉각하였다. (R,S)-3-히드록시-2-(2-나프틸)-프로피온산(0.216 g; 1.0 밀리몰; 상기 실시예 G로부터의 화합물), TBTU(0.353 g; 1.1 밀리몰) 및 DIPEA(0.517 g; 4.0 밀리몰)을 부가하고 혼합물을 실온에서 3 일 동안 교반하였다. 이어서, 반응 혼합물을 증발시키고 잔류물을 에틸 아세테이트:H2O의 혼합물에 용해하고, 이어서 에틸 아세테이트(2 x 75 mL)로 추출하였다. 합한 유기층을 NaHCO3 수용액(3 x 30 mL) 및 H2O(25 mL)로 세척하고, 건조하고(Na2SO4) 증발시켰다. 조생성물을 에틸 아세테이트, 에틸 아세테이트:EtOH(95:5) 및 에틸 아세테이트:EtOH(9:1)로 용출되는 실리카 겔 칼럼 상에서 플래시 크로마토그래피하여 정제하였다. 일부 분획물을 농축하여 95 : 5의 부분입체 이성질체 비로 화합물 4A 204 mg(36%)을 얻었다. 다른 분획물을 농축하여 90 : 10의 부분입체 이성질체 비로 화합물 4B 219 mg(39%)을 얻었다.A solution of H-Aze-Pab (Z) x 2HCl (0.483 g; 1.1 mmol; compound from Example A) in 10 ml of DMF was cooled in an ice bath. (R, S) -3-hydroxy-2- (2-naphthyl) -propionic acid (0.216 g; 1.0 mmol; compound from Example G above), TBTU (0.353 g; 1.1 mmol) and DIPEA (0.517 g) 4.0 mmol) was added and the mixture was stirred at rt for 3 days. The reaction mixture was then evaporated and the residue was dissolved in a mixture of ethyl acetate: H 2 O and then extracted with ethyl acetate (2 × 75 mL). The combined organic layers were washed with aqueous NaHCO 3 solution (3 × 30 mL) and H 2 O (25 mL), dried (Na 2 SO 4 ) and evaporated. The crude product was purified by flash chromatography on a silica gel column eluting with ethyl acetate, ethyl acetate: EtOH (95: 5) and ethyl acetate: EtOH (9: 1). Some fractions were concentrated to give 204 mg (36%) of compound 4A in a diastereomeric ratio of 95: 5. The other fractions were concentrated to give 219 mg (39%) of compound 4B in a diastereomeric ratio of 90:10.

화합물 4A:Compound 4A:

LC-MS m/z 565 (M + 1)+ LC-MS m / z 565 (M + 1) +

1H NMR (500 MHz; CDCl3): δ 8.23-8.31 (t, NH), 7.20-7.88 (m, 16H), 5.22 (s, 2H), 4.85-4.92 (m, 1H), 4.44-4.64 (m, 2H), 4.07-4.24 (m, 2H), 3.64-3.92 (m, 3H), 2.21-2.70 (m, 2H). 1 H NMR (500 MHz; CDCl 3 ): δ 8.23-8.31 (t, NH), 7.20-7.88 (m, 16H), 5.22 (s, 2H), 4.85-4.92 (m, 1H), 4.44-4.64 ( m, 2H), 4.07-4.24 (m, 2H), 3.64-3.92 (m, 3H), 2.21-2.70 (m, 2H).

화합물 4B:Compound 4B:

LC-MS m/z 565 (M + 1)+, 587 (M + Na)+ LC-MS mlz 565 (M + 1) + , 587 (M + Na) +

1H NMR (500 MHz; CDCl3): δ 8.13-8.21 (t, NH), 7.20-7.90 (m, 16H), 5.24 (s, 2H), 4.95-5.02 (m, 1H), 4.31-4.65 (m, 2H), 4.09-4.24 (m, 2H), 3.62-3.92 (m, 3H), 2.38-2.76 (m, 2H). 1 H NMR (500 MHz; CDCl 3 ): δ 8.13-8.21 (t, NH), 7.20-7.90 (m, 16H), 5.24 (s, 2H), 4.95-5.02 (m, 1H), 4.31-4.65 ( m, 2H), 4.09-4.24 (m, 2H), 3.62-3.92 (m, 3H), 2.38-2.76 (m, 2H).

(ii) (R)- 또는 (S)-2-나프틸-CH(CH2OH)-C(O)-Aze-Pab x HOAc(ii) (R)-or (S) -2-naphthyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

에탄올(7 mL) 중의 화합물 4A(0.175 g; 0.31 밀리몰; 상기 단계 (i)로부터의 화합물)의 용액에 아세트산(0.019 g, 0.31 밀리몰) 및 Pd/C(5%, 0.09 g)을 부가하였다. 반응 혼합물을 대기압하에서 4 시간 동안 수소처리하고, 이어서 셀라이트를 통해 여과하고 여과액을 농축하였다. 조생성물을 H2O에 용해하고 동결 건조하여 부분입체 이성질체 비가 95:5인 표제 화합물 136 mg(89%)을 얻었다.To a solution of compound 4A (0.175 g; 0.31 mmol; compound from step (i) above) in ethanol (7 mL) was added acetic acid (0.019 g, 0.31 mmol) and Pd / C (5%, 0.09 g). The reaction mixture was hydrotreated at atmospheric pressure for 4 hours, then filtered through celite and the filtrate was concentrated. The crude product was dissolved in H 2 O and lyophilized to give 136 mg (89%) of the title compound with a diastereomeric ratio of 95: 5.

LC-MS m/z 431 (M + 1)+ LC-MS m / z 431 (M + 1) +

1H NMR (500 MHz; D2O): δ 7.05-8.00 (m, 11H), 5.14-5.22 (m, 1H), 3.60-4.58 (m, 8H), 2.12-2.81 (m, 2H). 1 H NMR (500 MHz; D 2 O): δ 7.05-8.00 (m, 11H), 5.14-5.22 (m, 1H), 3.60-4.58 (m, 8H), 2.12-2.81 (m, 2H).

(iii) (S)- 또는 (R)-2-나프틸-CH(CH2OH)-C(O)-Aze-Pab x HOAc(iii) (S)-or (R) -2-naphthyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

에탄올(7 mL) 중의 화합물 4B(0.194 g; 0.34 밀리몰; 상기 단계 (i)로부터의 화합물) 용액에 아세트산(0.021 g; 0.34 밀리몰) 및 Pd/C(5%, 0.09 g)을 부가하였다. 반응 혼합물을 대기압하에서 4 시간 동안 수소처리하였다. 반응 혼합물을 셀라이트를 통해 여과하고 여과액을 농축하였다. 조생성물을 H2O에서 용해하고 동결 건조하여 부분입체 이성질체 비가 90:10인 표제 화합물 151 mg(90%)을 얻었다.To a solution of compound 4B (0.194 g; 0.34 mmol; compound from step (i)) in ethanol (7 mL) was added acetic acid (0.021 g; 0.34 mmol) and Pd / C (5%, 0.09 g). The reaction mixture was hydrotreated at atmospheric pressure for 4 hours. The reaction mixture was filtered through celite and the filtrate was concentrated. The crude product was dissolved in H 2 O and lyophilized to give 151 mg (90%) of the title compound having a diastereomeric ratio of 90:10.

LC-MS m/z 431 (M + 1)+ LC-MS m / z 431 (M + 1) +

1H NMR (500 MHz; D2O): δ 7.00-8.00 (m, 11H), 4.92-4.99 (m, 1H), 3.60-4.62 (m, 8H), 2.12-2.83 (m, 2H). 1 H NMR (500 MHz; D 2 O): δ 7.00-8.00 (m, 11H), 4.92-4.99 (m, 1H), 3.60-4.62 (m, 8H), 2.12-2.83 (m, 2H).

실시예 5Example 5

(R)- 및 (S)-PhCH(CH2OH)-C(O)-Aze-Pig x HOAc(R)-and (S) -PhCH (CH 2 OH) -C (O) -Aze-Pig x HOAc

(i) (R)- 및 (S)-PhCH(CH2OH)-C(O)-Aze-Pig(Z)(i) (R)-and (S) -PhCH (CH 2 OH) -C (O) -Aze-Pig (Z)

DMF 10 ml 중의 (R,S)-트로프산(0.132 g; 0.8 밀리몰), H-Aze-Pig(Z) x 2HCl(0.393 g; 0.88 밀리몰; 상기 실시예 C로부터의 화합물) 및 TBTU(0.283 g; 0.88 밀리몰)의 혼합물을 빙냉조에서 냉각하였다. DIPEA(0.414 g; 3.20 밀리몰)을 부가하고 반응 혼합물을 실온에서 48 시간 동안 교반하였다. 이어서, 반응 혼합물을 농축하고, 물로 희석하고(175 mL, NaHCO3에 의해 pH가 8로 조절됨), 에틸 아세테이트(3 x 50 mL)로 추출하였다. 합한 유기층을 NaHCO3 수용액(3 x 25 mL) 및 H2O(25 mL)로 세척하고, 건조하고(Na2SO4) 증발시켰다. 조생성물(0.895 g)을 CH2Cl2, CH2Cl2:THF(4:1, 1:1, 1:4) 및 CH2Cl2:MeOH(95:5, 9:1)로 용출되는 실리카 겔 칼럼 상에서 플래시 크로마토그래피하여 정제하였다. 일부 분획물을 농축하여 >99 : 1의 부분입체 이성질체 비로 화합물 117 mg을 얻었다.(R, S) -tropic acid (0.132 g; 0.8 mmol), H-Aze-Pig (Z) x 2HCl (0.393 g; 0.88 mmol; compound from Example C above) and TBTU (0.283 g) in 10 ml DMF ; 0.88 mmol) was cooled in an ice cold bath. DIPEA (0.414 g; 3.20 mmol) was added and the reaction mixture was stirred at rt for 48 h. The reaction mixture was then concentrated, diluted with water (175 mL, pH adjusted to 8 by NaHCO 3 ) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with aqueous NaHCO 3 solution (3 × 25 mL) and H 2 O (25 mL), dried (Na 2 SO 4 ) and evaporated. Crude product (0.895 g) is eluted with CH 2 Cl 2 , CH 2 Cl 2 : THF (4: 1, 1: 1, 1: 4) and CH 2 Cl 2 : MeOH (95: 5, 9: 1) Purification by flash chromatography on a silica gel column. Some fractions were concentrated to give 117 mg of compound in a diastereomeric ratio of> 99: 1.

1H NMR (400 MHz; CDCl3): δ 7.88-7.95 (bt, NH), 7.21-7.41 (m, 10H), 7.09 (bs, NH), 5.11 (s, 2H), 4.78-4.80 (m, 1H), 4.00-4.38 (m, 4H), 3.58-3.76 (m, 3H), 3.12-3.34 (m, 2H), 2.76-2.97 (m, 3H), 2.46-2.66 (m, 1H), 2.22-2.35 (m, 1H), 1.66-1.78 (m, 2H), 1.22-1.38 (m, 2H). 1 H NMR (400 MHz; CDCl 3 ): δ 7.88-7.95 (bt, NH), 7.21-7.41 (m, 10H), 7.09 (bs, NH), 5.11 (s, 2H), 4.78-4.80 (m, 1H), 4.00-4.38 (m, 4H), 3.58-3.76 (m, 3H), 3.12-3.34 (m, 2H), 2.76-2.97 (m, 3H), 2.46-2.66 (m, 1H), 2.22- 2.35 (m, 1 H), 1.66-1.78 (m, 2H), 1.22-1.38 (m, 2H).

(나중 분획물을 농축하여 87:13의 부분입체 이성질체 비로 상기 화합물의 에피머 156 mg을 얻었다) (Later fractions were concentrated to give 156 mg of epimer of this compound in a diastereomeric ratio of 87:13).

(ii) (S)- 및 (R)-PhCH(CH2OH)-C(O)-Aze-Pig x HOAc(ii) (S)-and (R) -PhCH (CH 2 OH) -C (O) -Aze-Pig x HOAc

(R)- 또는 (S)-PhCH(CH2OH)-C(O)-Aze-Pig(Z)(0.117 g; 0.22 밀리몰; 상기 단계 (i)로부터의 특징적인 화합물), 아세트산(0.013 g; 0.22 밀리몰) 및 Pd/C(5%; 0.06 g)을 에탄올(5 mL)에 부가하고 혼합물을 2.5 시간 동안 대기압에서 수소 처리하였다. 반응 혼합물을 셀라이트를 통해 여과하고 여과액을 증발시켰다. 잔류물을 H2O에 용해하고 동결 건조하여 >99 : 1의 부분입체 이성질체 비로 표제 화합물 92 mg(93%)을 얻었다.(R)-or (S) -PhCH (CH 2 OH) -C (O) -Aze-Pig (Z) (0.117 g; 0.22 mmol; characteristic compound from step (i)), acetic acid (0.013 g 0.22 mmol) and Pd / C (5%; 0.06 g) were added to ethanol (5 mL) and the mixture was hydrogenated at atmospheric pressure for 2.5 hours. The reaction mixture was filtered through celite and the filtrate was evaporated. The residue was dissolved in H 2 O and lyophilized to give 92 mg (93%) of the title compound in a diastereomeric ratio of> 99: 1.

1H NMR (400 MHz; D2O; 부분입체 이성질체/회전 이성질체의 존재로 인해 복합화됨): δ 7.14-7.41 (m, 5H), 4.60-5.06 (m, 1H), 3.64-4.09 (m, 7H), 2.78-3.19 (m, 4H), 2.58-2.71 (m, 1H), 2.34-2.45 (m, 1H), 2.03-2.20 (m, 1H), 0.98-1.77 (m, 4H). 1 H NMR (400 MHz; D 2 O; complexed due to the presence of diastereomers / rotary isomers): δ 7.14-7.41 (m, 5H), 4.60-5.06 (m, 1H), 3.64-4.09 (m, 7H), 2.78-3.19 (m, 4H), 2.58-2.71 (m, 1H), 2.34-2.45 (m, 1H), 2.03-2.20 (m, 1H), 0.98-1.77 (m, 4H).

13C NMR (100.5 MHz; D2O) 아미딘 및 카르보닐 시그널 175.95, 172.69, 155.85. 13 C NMR (100.5 MHz; D 2 O) amidine and carbonyl signals 175.95, 172.69, 155.85.

실시예 6Example 6

(R,S)-PhCH(CH2OH)-C(O)-Pro-(R,S)-Hig x HOAc(R, S) -PhCH (CH 2 OH) -C (O) -Pro- (R, S) -Hig x HOAc

(i) (R,S)-PhCH(CH2OTBDMS)-C(O)-Pro-(R,S)-Hig(Z)(i) (R, S) -PhCH (CH 2 OTBDMS) -C (O) -Pro- (R, S) -Hig (Z)

아세토니트릴 10 mL 중의 (R,S)-PhCH(CH2OTBDMS)-C(O)-Pro-OH(0.38 g; 1.0 밀리몰; 상기 실시예 D로부터의 화합물), (R,S)-H-Hig-Z x 2HCl(0.36 g; 1.0 밀리몰; Boc-(R,S)-Hig(Z)(국제 특허 출원 WO 제94/29336호 참조)을 EtOAc 중의 가스상 HCl(g)과 반응시킨 후 증발 건조하여 제조함) 및 DMAP(0.49 g; 4.0 밀리몰)의 혼합물에 EDC x HCl(0.24 g; 1.25 밀리몰)을 부가하고, 반응 혼합물을 실온에서 4 시간 동안 교반하였다. 반응 혼합물을 증발시키고 잔류물을 H2O(300 mL, pH가 9로 조절됨)에 용해하였다. 수성상을 에틸 아세테이트(3 x 150 mL)로 추출하였다. 합한 유기층을 NaHCO3 수용액(2 x 150 mL) 및 H2O(3 x 150 mL)로 세척하고, 건조하고(Na2SO4), 증발시켜 진행 단계에서 추가의 정제없이 사용되는 부표제 화합물 0.48 g을 얻었다.(R, S) -PhCH (CH 2 OTBDMS) -C (O) -Pro-OH (0.38 g; 1.0 mmol; compound from Example D), (R, S) -H- in 10 mL acetonitrile. Hig-Z × 2HCl (0.36 g; 1.0 mmol; Boc- (R, S) -Hig (Z) (see international patent application WO 94/29336) To a mixture of DMAP (0.49 g; 4.0 mmol) and EDC x HCl (0.24 g; 1.25 mmol) was added and the reaction mixture was stirred at room temperature for 4 hours. Stirred. The reaction mixture was evaporated and the residue was dissolved in H 2 O (300 mL, pH adjusted to 9). The aqueous phase was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with aqueous NaHCO 3 solution (2 × 150 mL) and H 2 O (3 × 150 mL), dried (Na 2 SO 4 ) and evaporated to 0.48 g of the subtitle compound used without further purification in the progress step. Got.

(ii) (R,S)-PhCH(CH2OH)-C(O)-Pro-(R,S)-Hig(Z)(ii) (R, S) -PhCH (CH 2 OH) -C (O) -Pro- (R, S) -Hig (Z)

TFA (6.5 mL; CH2Cl2 중의 10%) 중의 (R,S)-PhCH(CH2OTBDMS)-C(O)-Pro-(R,S)-Hig(Z)(0.265 g; 0.41 밀리몰; 상기 단계 (i)로부터의 화합물)을 0 ℃에서 30분 간 교반하였다. K2CO3 수용액을 사용하여 혼합물의 pH를 9로 조절하고, 이어서 CH2Cl2(3 x 75 mL)로 추출하였다. 합한 유기층을 H2O로 세척하고, 건조하고(Na2SO4) 증발시켰다. CH2Cl2(200 mL), CH2Cl2:EtOH(95:5; 200 mL) 및 CH2Cl2:EtOH(9:1; 400 mL)로 용출된 실리카 겔 칼럼(50 g) 상에서 플래시 크로마토그래피하여 조생성물(0.24 g)을 정제하였다. 수율은 표제 화합물 109 mg(50%)이었다.(R, S) -PhCH (CH 2 OTBDMS) -C (O) -Pro- (R, S) -Hig (Z) (0.265 g; 0.41 mmol) in TFA (6.5 mL; 10% in CH 2 Cl 2 ) The compound from step (i) was stirred at 0 ° C. for 30 minutes. The pH of the mixture was adjusted to 9 using K 2 CO 3 aqueous solution and then extracted with CH 2 Cl 2 (3 × 75 mL). The combined organic layers were washed with H 2 O, dried (Na 2 SO 4 ) and evaporated. Flash on silica gel column (50 g) eluted with CH 2 Cl 2 (200 mL), CH 2 Cl 2 : EtOH (95: 5; 200 mL) and CH 2 Cl 2 : EtOH (9: 1; 400 mL). Chromatography purified the crude product (0.24 g). Yield was 109 mg (50%) of the title compound.

LC-MS m/z 536 (M + 1)+ LC-MS m / z 536 (M + 1) +

1H NMR (400 MHz; CDCl3): δ 7.17-7.45 (m, 10H), 5.06-5.15 (m, 2H), 4.46-4.62 (m, 1H), 3.97-4.21 (m, 2H), 3.08-3.91 (m, 8H), 2.80-2.98 (m, 1H), 1.35-2.30 (m, 9H). 1 H NMR (400 MHz; CDCl 3 ): δ 7.17-7.45 (m, 10H), 5.06-5.15 (m, 2H), 4.46-4.62 (m, 1H), 3.97-4.21 (m, 2H), 3.08- 3.91 (m, 8H), 2.80-2.98 (m, 1H), 1.35-2.30 (m, 9H).

13C NMR (100.5 MHz; CDCl3) 아미딘 및 카르보닐 시그널: 172.72, 171.74, 163.77, 159.14. 13 C NMR (100.5 MHz; CDCl 3 ) amidine and carbonyl signals: 172.72, 171.74, 163.77, 159.14.

(iii) (R,S)-PhCH(CH2OH)-C(O)-Pro-(R,S)-Hig x HOAc(iii) (R, S) -PhCH (CH 2 OH) -C (O) -Pro- (R, S) -Hig x HOAc

EtOH(10 mL) 중의 (R,S)-PhCH(CH2OH)-C(O)-Pro-Hig-(Z)(0.11 g; 0.21 밀리몰; 상기 단계 (ii)로부터의 화합물), Pd/C(5%; 0.06 g) 및 아세트산(0.012 g, 0.21 밀리몰)의 혼합물을 대기압하에서 4 시간 동안 수소처리하였다. 반응 혼합물을 여과하고 여과액을 증발시켰다. 조생성물을 H2O에 용해하고 동결 건조하여 표제 화합물 78 mg(82%)을 얻었다.(R, S) -PhCH (CH 2 OH) -C (O) -Pro-Hig- (Z) (0.11 g; 0.21 mmol; compound from step (ii) above) in EtOH (10 mL), Pd / A mixture of C (5%; 0.06 g) and acetic acid (0.012 g, 0.21 mmol) was hydrotreated under atmospheric pressure for 4 hours. The reaction mixture was filtered and the filtrate was evaporated. The crude product was dissolved in H 2 O and lyophilized to give 78 mg (82%) of the title compound.

LC-MS m/z 402 (M + 1)+ LC-MS m / z 402 (M + 1) +

1H NMR (400 MHz; D2O): δ 7.15-7.45 (m, 5H), 4.20-4.38 (m, 1H), 3.89-4.14 (m, 2H), 3.67-3.81 (m, 2H), 2.70-3.64 (m, 7H), 1.40-2.37 (m, 9H) 1 H NMR (400 MHz; D 2 O): δ 7.15-7.45 (m, 5H), 4.20-4.38 (m, 1H), 3.89-4.14 (m, 2H), 3.67-3.81 (m, 2H), 2.70 -3.64 (m, 7H), 1.40-2.37 (m, 9H)

13C NMR (75.5 MHz; D2O) 아미딘 및 카르보닐 시그널: 174.90, 173.48, 154.84. 13 C NMR (75.5 MHz; D 2 O) amidine and carbonyl signals: 174.90, 173.48, 154.84.

실시예 7Example 7

(R)- 및 (S)-2,5-디메톡시페닐-CH(CH2OH)-C(O)-Aze-Pab x HOAc(R)-and (S) -2,5-dimethoxyphenyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

(i) (R)- 및 (S)-2,5-디메톡시페닐-CH(CH2OH)-C(O)-Aze-Pab(Z)(i) (R)-and (S) -2,5-dimethoxyphenyl-CH (CH 2 OH) -C (O) -Aze-Pab (Z)

DMF(10 mL) 중의 H-Aze-Pab(Z) x 2HCl(0.387 g; 0.88 밀리몰)을 빙조에서 냉각하였다. 3-히드록시-2-(2,5-디메톡시페닐)-프로피온산(0.181 g; 0.8 밀리몰), TBTU(0.283 g; 0.88 밀리몰) 및 DIPEA(0.414 g; 3.20 밀리몰)을 부가하고 반응 혼합물을 실온에서 4 시간 동안 교반하였다. 이어서, 반응 혼합물을 증발시키고 잔류물의 H2O:에틸 아세테이트(2:1; 150 mL) 혼합물에 용해하고, 이어서 에틸 아세테이트(3 x 25 mL)로 추출하였다. 합한 유기층을 NaHCO3 수용액(3 x 25 mL) 및 H2O(25 mL)로 세척하고, 건조하고(Na2SO4), 증발시켰다. 에틸 아세테이트, 에틸 아세테이트:EtOH(99:1), 에틸 아세테이트:EtOH(97:3) 및 에틸 아세테이트:EtOH(95:5)로 용출되는 실리카겔 칼럼 상에서 플래시 크로마토그래피에 의해 조생성물(0.43 g)을 정제하였다. 일부의 분획물을 농축하여 > 99:1의 부분입체 이성질체 비로 화합물 7A 165 mg을 얻었다. 다른 분획물을 농축하여 93:7의 부분입체 이성질체 비로 화합물 7B 185 mg을 얻었다.H-Aze-Pab (Z) x 2HCl (0.387 g; 0.88 mmol) in DMF (10 mL) was cooled in an ice bath. 3-hydroxy-2- (2,5-dimethoxyphenyl) -propionic acid (0.181 g; 0.8 mmol), TBTU (0.283 g; 0.88 mmol) and DIPEA (0.414 g; 3.20 mmol) were added and the reaction mixture was allowed to room temperature. Stirred for 4 h. The reaction mixture was then evaporated and dissolved in a residue mixture of H 2 O: ethyl acetate (2: 1; 150 mL), then extracted with ethyl acetate (3 × 25 mL). The combined organic layers were washed with aqueous NaHCO 3 solution (3 × 25 mL) and H 2 O (25 mL), dried (Na 2 SO 4 ) and evaporated. The crude product (0.43 g) was purified by flash chromatography on a silica gel column eluting with ethyl acetate, ethyl acetate: EtOH (99: 1), ethyl acetate: EtOH (97: 3) and ethyl acetate: EtOH (95: 5). Purified. Some fractions were concentrated to give 165 mg of compound 7A in a diastereomeric ratio of> 99: 1. The other fractions were concentrated to give 185 mg of compound 7B in a diastereomeric ratio of 93: 7.

화합물 7A:Compound 7A:

LC-MS m/z 575 (M + 1)+, 597 (M + Na)+ LC-MS mlz 575 (M + 1) + , 597 (M + Na) +

1H NMR (500 MHz; CDCl3): δ 8.26-8.36 (m, NH), 7.80-7.87 (d, 2H), 7.24-7.48 (m, 7H), 6.76-6.85 (m, 3H), 5.22 (s, 2H), 4.83-4.90 (m, 1H), 4.43-4.59 (m, 2H), 3.92-4.18 (m, 3H), 3.80 (s, 3H), 3.75 (s, 3H), 3.58-3.72 (m, 2H), 2.25-2.72 (m, 2H). 1 H NMR (500 MHz; CDCl 3 ): δ 8.26-8.36 (m, NH), 7.80-7.87 (d, 2H), 7.24-7.48 (m, 7H), 6.76-6.85 (m, 3H), 5.22 ( s, 2H), 4.83-4.90 (m, 1H), 4.43-4.59 (m, 2H), 3.92-4.18 (m, 3H), 3.80 (s, 3H), 3.75 (s, 3H), 3.58-3.72 ( m, 2H), 2.25-2.72 (m, 2H).

화합물 7B:Compound 7B:

LC-MS m/z 575 (M + 1)+, 597 (M + Na)+ LC-MS mlz 575 (M + 1) + , 597 (M + Na) +

1H NMR (500 MHz; CDCl3): δ 8.11-8.19 (m, NH), 7.79-7.88 (m, 2H), 7.24-7.48 (m, 7H), 6.68-6.84 (m, 3H), 5.22 (s, 2H), 4.91-4.98 (m, 1H), 4.36-4.67 (m, 2H), 3.99-4.22 (m, 3H), 3.48-3.82 (m, 8H), 2.38-2.95 (m, 2H). 1 H NMR (500 MHz; CDCl 3 ): δ 8.11-8.19 (m, NH), 7.79-7.88 (m, 2H), 7.24-7.48 (m, 7H), 6.68-6.84 (m, 3H), 5.22 ( s, 2H), 4.91-4.98 (m, 1H), 4.36-4.67 (m, 2H), 3.99-4.22 (m, 3H), 3.48-3.82 (m, 8H), 2.38-2.95 (m, 2H).

(ii) (R)- 또는 (S)-2,5-디메톡시페닐-CH(CH2OH)-C(O)-Aze-Pab x HOAc(ii) (R)-or (S) -2,5-dimethoxyphenyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

화합물 7A(0.141 g; 0.25 밀리몰; 상기 단계 (i)으로부터의 화합물)을 EtOH(7 mL)에 용해하였다. 아세트산(0.015 g; 0.25 밀리몰) 및 Pd/C(5%; 0.07 g)을 부가하고 혼합물을 대기압에서 3 시간 동안 수소 처리하였다. 반응 혼합물을 셀라이트를 통해 여과하고 여과액을 증발시켰다. 잔류물을 H2O에 용해하고 동결 건조하여 >99:1의 부분입체 이성질체 비로 표제 화합물 113 mg(90%)을 얻었다.Compound 7A (0.141 g; 0.25 mmol; compound from step (i) above) was dissolved in EtOH (7 mL). Acetic acid (0.015 g; 0.25 mmol) and Pd / C (5%; 0.07 g) were added and the mixture was hydrogenated at atmospheric pressure for 3 hours. The reaction mixture was filtered through celite and the filtrate was evaporated. The residue was dissolved in H 2 O and lyophilized to give 113 mg (90%) of the title compound in a diastereomeric ratio of> 99: 1.

LC-MS m/z 441 (M + 1)+ LC-MS m / z 441 (M + 1) +

1H NMR (400 MHz; D2O): δ 7.34-7.84 (m, 4H), 6.82-7.14 (m, 3H), 5.06-5.13 (m, 1H), 3.72-4.37 (m, 13H), 2.11-2.86 (m, 2H). 1 H NMR (400 MHz; D 2 O): δ 7.34-7.84 (m, 4H), 6.82-7.14 (m, 3H), 5.06-5.13 (m, 1H), 3.72-4.37 (m, 13H), 2.11 -2.86 (m, 2 H).

(iii) (R)- 또는 (S)-2,5-디메톡시페닐-CH(CH2OH)-C(O)-Aze-Pab x HOAc(iii) (R)-or (S) -2,5-dimethoxyphenyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

화합물 5B(0.164 g; 0.286 밀리몰; 상기 단계 (i)으로부터의 화합물)을 EtOH(7 mL)에 용해하였다. 아세트산(0.017 g; 0.286 밀리몰) 및 Pd/C(5%; 0.08 g)을 부가하고 혼합물을 대기압에서 3 시간 동안 수소 처리하였다. 반응 혼합물을 셀라이트를 통해 여과하고 여과액을 증발시켰다. 잔류물을 H2O에 용해하고 동결 건조하여 93:7의 부분입체 이성질체 비로 표제 화합물 130 mg(91%)을 얻었다.Compound 5B (0.164 g; 0.286 mmol; compound from step (i) above) was dissolved in EtOH (7 mL). Acetic acid (0.017 g; 0.286 mmol) and Pd / C (5%; 0.08 g) were added and the mixture was hydrogenated at atmospheric pressure for 3 hours. The reaction mixture was filtered through celite and the filtrate was evaporated. The residue was dissolved in H 2 O and lyophilized to give 130 mg (91%) of the title compound in a diastereomeric ratio of 93: 7.

LC-MS m/z 441 (M + 1)+ LC-MS m / z 441 (M + 1) +

1H NMR (400 MHz; D2O): δ 7.34-7.86 (m, 4H), 6.78-7.10 (m, 3H), 4.89-4.96 (m, 1H), 3.70-4.68 (m, 13H), 2.16-2.73 (m, 2H). 1 H NMR (400 MHz; D 2 O): δ 7.34-7.86 (m, 4H), 6.78-7.10 (m, 3H), 4.89-4.96 (m, 1H), 3.70-4.68 (m, 13H), 2.16 -2.73 (m, 2 H).

실시예 8Example 8

(R,S)-Ph-CH(CH2OH)-C(O)-Pro-Pab-OH(R, S) -Ph-CH (CH 2 OH) -C (O) -Pro-Pab-OH

(i) (R,S)-Ph-CH(CH2OTBDMS)-C(O)-Pro-Pab(Z)(i) (R, S) -Ph-CH (CH 2 OTBDMS) -C (O) -Pro-Pab (Z)

아세토니트릴(7 mL) 중의 (R,S)-Ph-CH(CH2OTBDMS)-C(O)-Pro-OH(0.753 g; 2.0 밀리몰, 상기 실시예 D 참조), H-Pab(Z) x HCl(0.681 g; 2.1 밀리몰), DMAP(0.366 g; 3.0 밀리몰) 및 EDC(500 μL; 2.7 밀리몰)의 혼합물을 실온에서 3 일 동안 교반하였다. 반응 혼합물을 증발시키고 잔류물을 에틸 아세테이트:톨루엔(2:1) 및 THF:톨루엔(3:7)으로 용출되는 실리카 겔 칼럼 상에서 플래시 크로마토그래피에 의해 정제하였다. 부포제 화합물의 수율은 345mg (27%)였다. FAB-MS m/z 643 (M + 1)+ (R, S) -Ph-CH (CH 2 OTBDMS) -C (O) -Pro-OH (0.753 g; 2.0 mmol, see Example D above), H-Pab (Z) in acetonitrile (7 mL) A mixture of x HCl (0.681 g; 2.1 mmol), DMAP (0.366 g; 3.0 mmol) and EDC (500 μL; 2.7 mmol) was stirred at room temperature for 3 days. The reaction mixture was evaporated and the residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate: toluene (2: 1) and THF: toluene (3: 7). The yield of the buoyant compound was 345 mg (27%). FAB-MS m / z 643 (M + 1) +

1H NMR (300 MHz; CDCl3): δ 6.85-7.85 (m, 14H), 5.15 (s, 2H), 3.15-4.80 (m, 8H), 1.60-2.30 (m, 4H), 0.65-0.90 (m, 9H), -0.80-0.05 (m, 6H). 1 H NMR (300 MHz; CDCl 3 ): δ 6.85-7.85 (m, 14H), 5.15 (s, 2H), 3.15-4.80 (m, 8H), 1.60-2.30 (m, 4H), 0.65-0.90 ( m, 9H), -0.80-0.05 (m, 6H).

(ii) (R,S)-Ph-CH(CH2OH)-C(O)-Pro-Pab(Z)(ii) (R, S) -Ph-CH (CH 2 OH) -C (O) -Pro-Pab (Z)

CH2Cl2 (8 mL) 중의 트리플루오로아세트산 2 mL의 혼합물에 (R,S)-PhCH(CH2OTBDMS)-C(O)-Pro-Pab(Z)(0.345 g; 0.54 밀리몰, 상기 단계 (i) 로부터의 화합물)을 부가하고 반응 혼합물을 실온에서 4 시간 동안 교반하였다. 혼합물을 CH2Cl2로 희석하고 Na2CO3 수용액을 사용하여 pH를 7로 조절하였다. 유기층을 건조하고(Mg2SO4) 증발시켰다. 정제 RPLC로 잔류물을 처리하여 부표제 화합물 111 mg(39 %)를 얻었다.To a mixture of 2 mL trifluoroacetic acid in CH 2 Cl 2 (8 mL) (R, S) -PhCH (CH 2 OTBDMS) -C (O) -Pro-Pab (Z) (0.345 g; 0.54 mmol, above Compound from step (i)) was added and the reaction mixture was stirred at rt for 4 h. The mixture was diluted with CH 2 Cl 2 and the pH adjusted to 7 using aqueous Na 2 CO 3 solution. The organic layer was dried (Mg 2 SO 4 ) and evaporated. The residue was treated with purified RPLC to give 111 mg (39%) of the subtitle compound.

FAB-MS m/z 529 (M+1)+; LC-MS m/z 527 (M-1)-, 529(M + 1)+, 551 (M+Na)+ FAB-MS m / z 529 (M + l) + ; LC-MS mlz 527 (M-1) - , 529 (M + 1) + , 551 (M + Na) +

1H NMR (400 MHz; CDCl3):δ 7.10-7.86 (m, 14 H), 5.18-5.25 (m, 2 H), 3.05-4.69 (m, 8 H), 1.66-2.28 (m, 4 H). 1 H NMR (400 MHz; CDCl 3 ): δ 7.10-7.86 (m, 14H), 5.18-5.25 (m, 2H), 3.05-4.69 (m, 8H), 1.66-2.28 (m, 4H ).

(iii) (R,S)-Ph-CH(CH2OH)-C(O)-Pro-Pab-OH(iii) (R, S) -Ph-CH (CH 2 OH) -C (O) -Pro-Pab-OH

EtOH (4 mL) 중의 히드록시아민 히드로클로라이드(0.206 g; 3.0 밀리몰) 및 트리에틸아민(1.3 mL; 9.3 밀리몰)의 혼합물에 (R,S)-Ph-CH(CH2OH)-C(O)-Pro-Pab(Z)(0.111 g; 0.21 밀리몰, 상기 단계 (ii) 로부터의 화합물)을 부가하였다. 반응 혼합물을 실온에서 4 시간 동안 교반하였다. 조생성물을 정제 RPLC로 처리하여 표제 화합물 50 mg(23 %)을 얻었다.To a mixture of hydroxyamine hydrochloride (0.206 g; 3.0 mmol) and triethylamine (1.3 mL; 9.3 mmol) in EtOH (4 mL) was added (R, S) -Ph-CH (CH 2 OH) -C (O ) -Pro-Pab (Z) (0.111 g; 0.21 mmol, compound from step (ii) above) was added. The reaction mixture was stirred at rt for 4 h. The crude product was treated with purified RPLC to give 50 mg (23%) of the title compound.

LC-MS m/z 411(M + 1)+, 433 (M + Na)+ LC-MS mlz 411 (M + 1) + , 433 (M + Na) +

실시예 9Example 9

(R)- 또는 (S)-3-메톡시페닐-CH(CH2OH)-C(O)-Aze-Pab-OH(R)-or (S) -3-methoxyphenyl-CH (CH 2 OH) -C (O) -Aze-Pab-OH

THF 11 mL 중의 히드록시아민 히드로클로라이드(0.083 g; 1.2 밀리몰) 및 TEA(0.405 g; 4.0 밀리몰)의 용액을 35분 동안 초음파처리하였다. (R)- 또는 (S)-3-메톡시페닐-CH(CH2OH)-C(O)-Aze-Pab(Z)(상기 실시예 2(i)로부터의 화합물 2A; 0.109 g; 0.2 밀리몰)의 용액을 부가하고, 혼합물을 40 ℃에서 철야 교반하였다. 용매를 증발시키고 조물질을 CH2Cl2:IPA:HOAc(100:0:0 --> 90:10:0 --> 80:20:2)의 기울기로 용출되는 실리카 겔 칼럼 상의 플래시 크로마토그래피, 이어서 HPLC(CH3CN:NH4OAc(0.1 M)(32.5:67.5)에 의해 정제하였다. 동결 건조 후, 백색 분말 38 mg(44%)을 얻었다.A solution of hydroxyamine hydrochloride (0.083 g; 1.2 mmol) and TEA (0.405 g; 4.0 mmol) in 11 mL of THF was sonicated for 35 minutes. (R)-or (S) -3-methoxyphenyl-CH (CH 2 OH) -C (O) -Aze-Pab (Z) (Compound 2A from Example 2 (i); 0.109 g; 0.2 Mmol) was added and the mixture was stirred overnight at 40 ° C. Flash chromatography on silica gel column eluting the solvent and eluting the crude with a gradient of CH 2 Cl 2 : IPA: HOAc (100: 0: 0-> 90: 10: 0-> 80: 20: 2) Then purified by HPLC (CH 3 CN: NH 4 OAc (0.1 M) (32.5: 67.5) After freeze drying, 38 mg (44%) of a white powder were obtained.

LC-MS m/z 427 (M + 1)+ LC-MS m / z 427 (M + 1) +

실시예 10Example 10

(S)- 또는 (R)-3-메톡시페닐-CH(CH2OH)CO-Pro-Pab(Z)(S)-or (R) -3-methoxyphenyl-CH (CH 2 OH) CO-Pro-Pab (Z)

H-Pro-Pab(Z)(0.5 g; 1.1 밀리몰; 국제 특허 출원 WO 제97/02284호에 기재된 방법에 따라 제조함), 이어서 TBTU(0.353 g; 1.1 밀리몰), 이어서 DIPEA(0.517 g; 4.0 밀리몰)을 DMF 10 mL 중의 (R,S)-3-히드록시-2-(3-메톡시페닐)-프로피온산(0.196 g; 1 밀리몰; 상기 실시예 E(ii)로부터의 화합물)의 용액에 0 ℃에서 부가하였다. 실온에서 4일 동안 교반한 후, 반응 혼합물을 농축하고 RPLC(CH3CN:H4NOAc(1M)(40:60))에 의해 정제하였다. 분획물을 농축하고 EtOAc로 4회 추출하였다. 이어서, 합한 유기상을 건조하고(Na2SO4), 증발시켜 부분입체 이성질체의 조혼합물을 얻었다. 혼합물(0.84 g)을 RPLC(CH3CN: H4NOAc (1M) (34:66))로 크로마토그래피하여, 2개의 부분입체 이성질체, 화합물 10A(0.352 g; 83%; 보다 빠르게 움직이는 부분입체 이성질체; 순도 - HPLC에 의해 90.5%) 및 화합물 10B(0.311 g; 74%; 보다 느리게 움직이는 부분입체 이성질체; 순도 - HPLC에 의해 96.9%)를 분리하였다.H-Pro-Pab (Z) (0.5 g; 1.1 mmol; prepared according to the method described in international patent application WO 97/02284), followed by TBTU (0.353 g; 1.1 mmol), then DIPEA (0.517 g; 4.0 Mmol) was added to a solution of (R, S) -3-hydroxy-2- (3-methoxyphenyl) -propionic acid (0.196 g; 1 mmol; compound from Example E (ii) above) in 10 mL of DMF. Add at 0 ° C. After stirring for 4 days at room temperature, the reaction mixture was concentrated and purified by RPLC (CH 3 CN: H 4 NOAc (1M) (40:60)). Fractions were concentrated and extracted four times with EtOAc. The combined organic phases were then dried (Na 2 SO 4 ) and evaporated to afford a crude mixture of diastereomers. The mixture (0.84 g) was chromatographed with RPLC (CH 3 CN: H 4 NOAc (1M) (34:66)) to give two diastereomers, Compound 10A (0.352 g; 83%; faster moving diastereomers. Purity-90.5% by HPLC) and Compound 10B (0.311 g; 74%; slower moving diastereomer; purity-96.9% by HPLC).

화합물 10B:Compound 10B:

1H NMR (400 MHz; CDCl3):δ 7.83 (d, 2H); 7.46 (dd, 2H); 7.4-7.3 (m, 8H); 6.84 (dd+s, 3H); 5.23 (s, 2H); 4.62 (dd, 1H); 4.49 (ddd, 2H); 4.03 (dd, 1H); 3.88 (dd, 1H); 3.80(s, 2H); 3.73(dd, 2H); 3.63(m, 1H); 3.2 (m, 1H); 2.3 (m, 1H); 2.1-2.0 (m, 2H); 1.82 (m, 3H); 1.74 (b, 3H) 1 H NMR (400 MHz; CDCl 3 ): δ 7.83 (d, 2H); 7.46 (dd, 2 H); 7.4-7.3 (m, 8 H); 6.84 (dd + s, 3H); 5.23 (s, 2 H); 4.62 (dd, 1 H); 4.49 (ddd, 2 H); 4.03 (dd, 1 H); 3.88 (dd, 1 H); 3.80 (s, 2 H); 3.73 (dd, 2 H); 3.63 (m, 1 H); 3.2 (m, 1 H); 2.3 (m, 1 H); 2.1-2.0 (m, 2 H); 1.82 (m, 3 H); 1.74 (b, 3 H)

실시예 11Example 11

(S)- 또는 (R)-3-메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab x HOAc(S)-or (R) -3-methoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HOAc

EtOH 10 mL 중의 (S)- 또는 (R)-3-메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab(Z)(상기 실시예 10으로부터의 화합물 10B; 10 mg; 0.018 밀리몰)의 산성화된(HOAc; 2.7 mg; 0.045 밀리몰) 용액에 Pd/C (5%; 10 mg)을 부가하였다. 반응 혼합물을 3.5 시간 동안 실온에서 수소처리하였다(1 atm). 용액을 여과하고, 증발시키고 CH3CN:H2O(50:50) 20 mL에 용해하였다. 이 용액을 동결 건조하여 백색 분말인 표제 화합물 10 mg(100%)를 얻었다.(S)-or (R) -3-methoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab (Z) in 10 mL EtOH (Compound 10B from Example 10 above; 10 mg; Pd / C (5%; 10 mg) was added to 0.018 mmol) of acidified (HOAc; 2.7 mg; 0.045 mmol) solution. The reaction mixture was hydrotreated at room temperature for 3.5 hours (1 atm). The solution was filtered, evaporated and dissolved in 20 mL of CH 3 CN: H 2 O (50:50). The solution was lyophilized to give 10 mg (100%) of the title compound as a white powder.

LC-MS m/z 425 (M + 1)+ LC-MS m / z 425 (M + 1) +

실시예 12Example 12

(R,S)-3-아미노페닐-CH(CH2OH)-C(O)-Pro-Pab x HOAc(R, S) -3-Aminophenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HOAc

(i) (R,S)-(3-Boc-아미노페닐)-CH(CH2OH)-C(O)-Pro-Pab(Z)(i) (R, S)-(3-Boc-aminophenyl) -CH (CH 2 OH) -C (O) -Pro-Pab (Z)

DMF 10 mL 중의 (R,S)-3-히드록시-2-(3-Boc-아미노페닐)프로피온산(0.146 g; 0.8 밀리몰; 상기 실시예 T로부터의 화합물) 용액을 0 ℃로 냉각하였다. H-Pro-Pab(Z) x HCl(0.339; 0.88 밀리몰), TBTU(0.283 g; 0.88 밀리몰) 및 DIPEA(0.414 g; 3.20 밀리몰)을 순서대로 부가하고 반응 혼합물을 실온에서 4 일 동안 교반하였다. 이어서, DMF를 증발시키고 잔류물을 정제 HPLC(CH3CN; NH4OAc(10%); 42:58)에 의해 정제하였다. CH3CN을 증발시키고 수용액을 동결 건조하여 표제 화합물(187 mg; 43%)을 얻었다.A solution of (R, S) -3-hydroxy-2- (3-Boc-aminophenyl) propionic acid (0.146 g; 0.8 mmol; compound from Example T above) in 10 mL of DMF was cooled to 0 ° C. H-Pro-Pab (Z) x HCl (0.339; 0.88 mmol), TBTU (0.283 g; 0.88 mmol) and DIPEA (0.414 g; 3.20 mmol) were added in sequence and the reaction mixture was stirred at rt for 4 days. DMF was then evaporated and the residue was purified by purified HPLC (CH 3 CN; NH 4 OAc (10%); 42:58). CH 3 CN was evaporated and the aqueous solution was lyophilized to give the title compound (187 mg; 43%).

1H NMR (500 MHz; CDCl3):δ 9.48 (b, 1H); 7.73 (d, 1H); 7.43 (t, 1H); 7.34 (m, 5H); 7.20 (d, 1H); 6.85 (d, 1H); 6.80 (d, 1H); 5.21 (d, 2H); 4.62 (m, 1H); 4.40 (m, 2H); 4.02 (m, 1H); 3.87 (m, 1H); 3.75 (m, 1H); 3.70 (dd, 1H); 3.65 (m, 1H); 3.50 (m, 1H); 3.23 (m, 1H); 2.25 (m, 1H); 1.87 (m, 4H); 1.79 (m, 1H); 1.47 (d, 9H) 1 H NMR (500 MHz; CDCl 3 ): δ 9.48 (b, 1H); 7.73 (d, 1 H); 7.43 (t, 1 H); 7.34 (m, 5 H); 7.20 (d, 1 H); 6.85 (d, 1 H); 6.80 (d, 1 H); 5.21 (d, 2 H); 4.62 (m, 1 H); 4.40 (m, 2 H); 4.02 (m, 1 H); 3.87 (m, 1 H); 3.75 (m, 1 H); 3.70 (dd, 1 H); 3.65 (m, 1 H); 3.50 (m, 1 H); 3.23 (m, 1 H); 2.25 (m, 1 H); 1.87 (m, 4 H); 1.79 (m, 1 H); 1.47 (d, 9 H)

(ii) (R,S)-(3-Boc-아미노페닐)-CH(CH2OH)-C(O)-Pro-Pab x HOAc(ii) (R, S)-(3-Boc-aminophenyl) -CH (CH 2 OH) -C (O) -Pro-Pab x HOAc

EtOH 10 mL 및 HOAc(10 방울) 중의 (R,S)-(3-Boc-아미노페닐)-CH(CH2OH)-C(O)-Pro-Pab(Z)(270 mg; 0.42 밀리몰; 상기 단계(i)로부터의 화합물) 용액에 Pd/C(10%; 10 mg)를 부가하였다. 반응 혼합물을 실온에서 2 시간 동안 수소처리하였다(1atm). 얻어진 혼합물을 하이플로(Hyflo)를 통해 여과하였다. 용액을 증발시키고, 물을 부가하고, 용액을 동결 건조하여 백색 발포성 물질인 부표제 화합물 214 mg(100%)을 얻었다.(R, S)-(3-Boc-aminophenyl) -CH (CH 2 OH) -C (O) -Pro-Pab (Z) (270 mg; 0.42 mmol) in 10 mL EtOH and HOAc (10 drops); To the solution of the compound from step (i) was added Pd / C (10%; 10 mg). The reaction mixture was hydrotreated for 2 hours at room temperature (1 atm). The resulting mixture was filtered through Hyflo. The solution was evaporated, water was added, and the solution was lyophilized to give 214 mg (100%) of a buoyant compound, a white foam.

1H NMR (400 MHz; D2O):δ 7.75 (d, 1H); 7.70 (d, 1H); 7.50 (d, 1H); 7.35 (d, 2H); 7.25 (m, 2H); 7.05 (m, 1H); 4.50 (m, 2H); 4.10 (m, 2H); 3.90 (m, 2H); 1.45 (d, 9H) 1 H NMR (400 MHz; D 2 O): δ 7.75 (d, 1 H); 7.70 (d, 1 H); 7.50 (d, 1 H); 7.35 (d, 2 H); 7.25 (m, 2 H); 7.05 (m, 1 H); 4.50 (m, 2 H); 4.10 (m, 2 H); 3.90 (m, 2 H); 1.45 (d, 9H)

(iii) (R,S)-3-아미노페닐-CH(CH2OH)-C(O)-Pro-Pab x HOAc(iii) (R, S) -3-Aminophenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HOAc

HCl(6M, 10ml) 중의 (R,S)-(3-Boc-아미노페닐)-CH(CH2OH)-C(O)-Pro-Pab(172 mg; 0.42 밀리몰) 용액을 실온에서 2 시간 동안 교반하고 생성물을 동결 건조하여 백색 물질인 표제 화합물 153 mg(76%; 순도 94.2%)을 얻었다.A solution of (R, S)-(3-Boc-aminophenyl) -CH (CH 2 OH) -C (O) -Pro-Pab (172 mg; 0.42 mmol) in HCl (6M, 10 ml) at room temperature for 2 hours. Was stirred and the product was lyophilized to give 153 mg (76%; purity 94.2%) of the title compound as a white substance.

1H NMR (500 MHz; D2O):δ 7.33 (m, 2H); 7.16 (t, 1H); 7.02 (m, 5H); 4.07 (m, 3H); 3.84 (q, 1H); 3.68 (m, 1H); 3.44 (m, 1H); 3.24 (m, 1H); 2.96 (m, 1H); 1.83 (m, 1H); 1.50 (m, 3H) 1 H NMR (500 MHz; D 2 O): δ 7.33 (m, 2H); 7.16 (t, 1 H); 7.02 (m, 5 H); 4.07 (m, 3 H); 3.84 (q, 1 H); 3.68 (m, 1 H); 3.44 (m, 1 H); 3.24 (m, 1 H); 2.96 (m, 1 H); 1.83 (m, 1 H); 1.50 (m, 3H)

13C NMR (100 MHz; D2O) 174.6, 174.3 (회전 이성질체 및(또는) 부분입체 이성질체); 172.1, 171.9 (회전 이성질체 및(또는) 부분입체 이성질체); 166.1 13 C NMR (100 MHz; D 2 O) 174.6, 174.3 (rotary isomers and / or diastereomers); 172.1, 171.9 (rotary isomers and / or diastereomers); 166.1

실시예 13Example 13

(S)- 또는 (R)-3-메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab-OH(S)-or (R) -3-methoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab-OH

THF 11 mL 중의 히드록시아민 히드로클로라이드(149 mg; 2.15 밀리몰) 및 TEA(725 mg; 7,16 밀리몰)의 용액을 35분 동안 초음파처리하였다. (S)- 또는 (R)-3-메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab(Z)(상기 실시예 10으로부터의 화합물 10B; 200 mg, 0.36 밀리몰)을 부가하고, 혼합물을 40 ℃에서 철야 가열하였다. 용매를 증발시키고, 우선 CH2Cl2:IPA:HOAc(100:0:0 -> 90:10:0 -> 80:20:2)의 기울기로 용출되는 실리카 겔 칼럼 상에서 크로마토그래피하고, 이어서 RPLC(CH3CN:NH4OAc(0.1 M)(32.5:67.5))에 의해 조생성물을 정제하였다. 동결 건조하여 포제 화합물 119mg (75%)을 백색 분말로서 얻었다. LC-MS m/z 441 (M + 1)+ A solution of hydroxyamine hydrochloride (149 mg; 2.15 mmol) and TEA (725 mg; 7,16 mmol) in 11 mL of THF was sonicated for 35 minutes. (S)-or (R) -3-methoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab (Z) (Compound 10B from Example 10; 200 mg, 0.36 mmol) And the mixture was heated at 40 ° C. overnight. The solvent was evaporated and first chromatographed on a silica gel column eluted with a gradient of CH 2 Cl 2 : IPA: HOAc (100: 0: 0-> 90: 10: 0-> 80: 20: 2), followed by RPLC The crude product was purified by (CH 3 CN: NH 4 OAc (0.1 M) (32.5: 67.5)). Lyophilization gave 119 mg (75%) of a foam compound as a white powder. LC-MS m / z 441 (M + 1) +

1H NMR (400 MHz; CD3OD):δ 7.64 (d, 2H); 7.38 (d, 2H); 7.27 (t, 1H); 6.93 (m, 2H); 6.87 (m, 1H); 4.47 (s, 3H); 4.14 (dd, 1H); 4.03 (dd, 1H); 3.80 (s, 1H); 3.72 (dd, 1H); 3.38 (dt, 1H); 2.12 (m, 1H); 2.00 (m, 3H); 1.48 (m, 1H) 1 H NMR (400 MHz; CD 3 OD): δ 7.64 (d, 2H); 7.38 (d, 2 H); 7.27 (t, 1 H); 6.93 (m, 2 H); 6.87 (m, 1 H); 4.47 (s, 3 H); 4.14 (dd, 1 H); 4.03 (dd, 1 H); 3.80 (s, 1 H); 3.72 (dd, 1 H); 3.38 (dt, 1 H); 2.12 (m, 1 H); 2.00 (m, 3 H); 1.48 (m, 1 H)

13C NMR (CD3OD) 아미딘 및 카르보닐 탄소: 174.7; 173.4; 161.5 13 C NMR (CD 3 OD) amidine and carbonyl carbon: 174.7; 173.4; 161.5

실시예 14Example 14

(S)- 또는 (R)-3-메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab-OC(O)Et(S)-or (R) -3-methoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab-OC (O) Et

(i) (R)- 및 (S)-3-메톡시페닐-CH(CH2OTBTMS)-C(O)-Pro-Pab(Z)(i) (R)-and (S) -3-methoxyphenyl-CH (CH 2 OTBTMS) -C (O) -Pro-Pab (Z)

DMF(100 mL) 중의 (R,S)-3-메톡시페닐-CH(CH2OTBDMS)COOH(3 g; 9.66 밀리몰; 상기 실시예 S로부터의 수득물)의 용액을 빙수에서 냉각하고, H-Pro-Pab(Z)(4.8 g; 10.63 밀리몰; 국제특허출원 WO 제97/02284호에 기재된 방법에 따라 제조함), TBTU(3.4 g; 10.63 mg), 이어서 DIPEA(5.0 g; 38.65 밀리몰)을 부가하였다. 혼합물을 실온에서 5일 동안 교반하고, 용액을 농축하고, 잔류물을 H2O 400 mL 및 EtOAc 200 mL의 혼합물에 용해하였다. 유기층을 분리하고, 수성상을 EtOAc(3 x 50 mL)로 추출하였다. 합한 유기상을 NaHCO3 수용액(10%)으로 2회, 물로 1회 세척하고, 건조하고(Na2SO4), 증발시켰다. 조생성물(갈색 고체 6.25 g)을 실리카겔 상의 플래시 크로마토그래피(EtOAc : EtOH (95:5))에 의해 정제하여 진갈색 오일 4.27 g을 얻었다. 이 물질을 RPLC(CH3CN:NH4OAc(10%) (70:30))에 의해 추가로 정제하여 2개의 부분입체 이성질체, 화합물 14A(1.49 g; 보다 빠르게 이동하는 이성질체) 및 화합물 14B(1.0 g; 보다 느리게 이동하는 이성질체)를 얻었다.A solution of (R, S) -3-methoxyphenyl-CH (CH 2 OTBDMS) COOH (3 g; 9.66 mmol; the yield from Example S) in DMF (100 mL) was cooled in ice water and H Pro-Pab (Z) (4.8 g; 10.63 mmol; prepared according to the method described in International Patent Application WO 97/02284), TBTU (3.4 g; 10.63 mg), followed by DIPEA (5.0 g; 38.65 mmol) Was added. The mixture was stirred at rt for 5 days, the solution was concentrated and the residue was dissolved in a mixture of 400 mL H 2 O and 200 mL EtOAc. The organic layer was separated and the aqueous phase extracted with EtOAc (3 x 50 mL). The combined organic phases were washed twice with aqueous NaHCO 3 (10%), once with water, dried (Na 2 SO 4 ) and evaporated. The crude product (6.25 g of a brown solid) was purified by flash chromatography on silica gel (EtOAc: EtOH (95: 5)) to give 4.27 g of a dark brown oil. This material was further purified by RPLC (CH 3 CN: NH 4 OAc (10%) (70:30)) to give two diastereomers, Compound 14A (1.49 g; faster moving isomers) and Compound 14B ( 1.0 g; slower moving isomers).

LC-MS m/z 672.6 (M+1)+ (라세미체)LC-MS mlz 672.6 (M + 1) + (racemate)

(ii) (S)- 또는 (R)-3-메톡시페닐-CH(CH2OTBTMS)-C(O)-Pro-Pab-OH(ii) (S)-or (R) -3-methoxyphenyl-CH (CH 2 OTBTMS) -C (O) -Pro-Pab-OH

THF(50 mL) 중의 히드록시아민 x HCl(0.43 g; 6.2 밀리몰) 및 TEA(2.1 g; 20.8 밀리몰)의 용액을 2 시간 동안 초음파처리하고, 이후에 화합물 14B(0.70 g; 1.04 밀리몰; 상기 단계(ii)로부터의 수득물)을 부가하였다. 용액을 56 ℃에서 철야 교반하였다. 증발 후, 생성물을 RPLC(CH3CN:NH4OAc(10%)(65:35))로 정제하여 백색 분말인 부표제 화합물 0.396 g(69 %)을 얻었다.A solution of hydroxyamine x HCl (0.43 g; 6.2 mmol) and TEA (2.1 g; 20.8 mmol) in THF (50 mL) was sonicated for 2 hours, followed by Compound 14B (0.70 g; 1.04 mmol; above steps from (ii)) was added. The solution was stirred overnight at 56 ° C. After evaporation, the product was purified by RPLC (CH 3 CN: NH 4 OAc (10%) (65:35)) to give 0.396 g (69%) of a subtitle compound as a white powder.

1H NMR (400 MHz; CDCl3): δ 7.89 (bt, 1H); 7.49 (d, 2H); 7.25 (d, 2H); 6.90 (s+d, 2H); 6.83 (m, 1H); 4.93 (b, 2H); 4.66 (m, 2H); 4.24 (t, 1H); 4.20 (d, 1H); 3.88 (dd, 1H); 3.81 (s, 3H); 3.74 (m, 2H); 3.34 (m, 1H); 2.38 (m, 1H); 2.10 (m, 1H); 1.82 (m, 2H); 0.83 (s, 9H), -0.05 (d, 6H). 1 H NMR (400 MHz; CDCl 3 ): δ 7.89 (bt, 1H); 7.49 (d, 2 H); 7.25 (d, 2 H); 6.90 (s + d, 2H); 6.83 (m, 1 H); 4.93 (b, 2 H); 4.66 (m, 2 H); 4.24 (t, 1 H); 4.20 (d, 1 H); 3.88 (dd, 1 H); 3.81 (s, 3 H); 3.74 (m, 2 H); 3.34 (m, 1 H); 2.38 (m, 1 H); 2.10 (m, 1 H); 1.82 (m, 2 H); 0.83 (s, 9 H), -0.05 (d, 6 H).

(iii) (S)- 또는 (R)-3-메톡시페닐-CH(CH2OTBTMS)-C(O)-Pro-Pab-OC(O)(iii) (S)-or (R) -3-methoxyphenyl-CH (CH 2 OTBTMS) -C (O) -Pro-Pab-OC (O)

EtEt

(S)- 또는 (R)-3-메톡시페닐-CH(CH2OTBTMS)-C(O)-Pro-Pab-OH(130 mg; 0.23 밀리몰; 상기 단계(ii)로부터의 수득물), 피로피온산 무수물(1 g; 7.7 밀리몰) 및 DMAP(9 mg; 0.07 밀리몰)의 혼합물을 실온에서 35 분 동안 교반하였다. 이어서, 얻어진 혼합물을 증발시켜 황색 오일을 얻고, RPLC(CH3CN:NH4OAc(10%)(70:30))로 정제하여 부표제 생성물 75 mg(52 %)(순도: 99.6 %)을 얻었다.(S)-or (R) -3-methoxyphenyl-CH (CH 2 OTBTMS) -C (O) -Pro-Pab-OH (130 mg; 0.23 mmol; the obtained from step (ii) above), A mixture of pyridonic anhydride (1 g; 7.7 mmol) and DMAP (9 mg; 0.07 mmol) was stirred at room temperature for 35 minutes. The resulting mixture was then evaporated to a yellow oil which was purified by RPLC (CH 3 CN: NH 4 OAc (10%) (70:30)) to give 75 mg (52%) of subtitle product (purity: 99.6%). .

1H NMR (400 MHz; CDCl3): δ 7.66 (d, 2H); 7.62 (t, 1H); 7.33 (d, 2H); 6.90 (d+s, 3H); 6.82 (m, 1H); 5.04 (b, 2H); 4.63 (t, 1H); 4.59 (d, 1H); 4.30 (dd, 1H); 4.23 (t, 1H); 3.88 (dd, 1H); 3.80 (s, 3H); 3.7 (m, 2H); 3.32 (m, 1H); 2.55 (q, 2H); 2.43 (m, 1H); 2.02 (m, 1H); 1.85 (m, 1H); 1.75 (m, 1H); 1.26 (t, 3H); 0.82 (s, 9H); -0.05 (d, 6H) 1 H NMR (400 MHz; CDCl 3 ): δ 7.66 (d, 2H); 7.62 (t, 1 H); 7.33 (d, 2 H); 6.90 (d + s, 3 H); 6.82 (m, 1 H); 5.04 (b, 2 H); 4.63 (t, 1 H); 4.59 (d, 1 H); 4.30 (dd, 1 H); 4.23 (t, 1 H); 3.88 (dd, 1 H); 3.80 (s, 3 H); 3.7 (m, 2 H); 3.32 (m, 1 H); 2.55 (q, 2 H); 2.43 (m, 1 H); 2.02 (m, 1 H); 1.85 (m, 1 H); 1.75 (m, 1 H); 1.26 (t, 3 H); 0.82 (s, 9 H); -0.05 (d, 6H)

(iv) (S)- 또는 (R)-3-메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab-OC(O)Et(iv) (S)-or (R) -3-methoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab-OC (O) Et

CH2Cl2 중의 (S)- 또는 (R)-3-메톡시페닐-CH(CH2OTBTMS)-C(O)-Pro-Pab-OC(O)Et(75 mg; 0.12 밀리몰; 상기 단계(iii)로부터의 화합물)의 빙냉액에 TFA(0.2 mL)을 부가하였다. 용액을 0 ℃에서 35분간 교반하고, 이후에 고상 Na2CO3를 이용하여 용액을 알칼리성으로 하고, CH2Cl2로 추출하였다. 유기상을 수집하고, 세척하고(물), 건조하고(Na2SO4), 증발시켜 조생성물 60 mg을 얻었다. RPLC(CH3CN:NH4OAc(10%)(42:58))로 정제하고 동결 건조한 후, 백색 분말의 표제 생성물 41 mg(67 %)을 얻었다.(S)-or (R) -3-methoxyphenyl-CH (CH 2 OTBTMS) -C (O) -Pro-Pab-OC (O) Et (75 mg; 0.12 mmol) in CH 2 Cl 2 ; To the ice cold solution of (iii) from) was added TFA (0.2 mL). The solution was stirred at 0 ° C. for 35 minutes, after which the solution was made alkaline using solid Na 2 CO 3 and extracted with CH 2 Cl 2 . The organic phase was collected, washed (water), dried (Na 2 SO 4 ) and evaporated to give 60 mg of crude product. Purification by RPLC (CH 3 CN: NH 4 OAc (10%) (42:58)) and lyophilization gave 41 mg (67%) of the title product as a white powder.

LC-MS m/z 497 (M + 1)+ LC-MS m / z 497 (M + 1) +

1H NMR (500 MHz; CDCl3): δ 7.66 (d, 2H); 7.34 (d, 2H); 6.83 (dd, 3H); 5.11 (b, 2H); 4.63 (dd, 1H); 4.48 (ddd, 2H); 4.03 (dd, 1H); 3.88 (dd, 1H); 3.80 (s, 3H); 3.73 (dd, 1H); 3.64 (m, 1H); 3.19 (m, 1H); 2.54 (q, 2H); 2.35 (m, 1H); 2.06 (m, 1H); 1.82 (m, 2H); 1.27 (t, 3H) 1 H NMR (500 MHz; CDCl 3 ): δ 7.66 (d, 2H); 7.34 (d, 2 H); 6.83 (dd, 3 H); 5.11 (b, 2 H); 4.63 (dd, 1 H); 4.48 (ddd, 2 H); 4.03 (dd, 1 H); 3.88 (dd, 1 H); 3.80 (s, 3 H); 3.73 (dd, 1 H); 3.64 (m, 1 H); 3.19 (m, 1 H); 2.54 (q, 2 H); 2.35 (m, 1 H); 2.06 (m, 1 H); 1.82 (m, 2 H); 1.27 (t, 3 H)

실시예 15Example 15

(S)- 또는 (R)-3-메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab-OC(O)CH3 (S)-or (R) -3-methoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab-OC (O) CH 3

(i) (S)- 또는 (R)-3-메톡시페닐-CH(CH2OTBTMS)-C(O)-Pro-Pab-OC(O)CH3 (i) (S)-or (R) -3-methoxyphenyl-CH (CH 2 OTBTMS) -C (O) -Pro-Pab-OC (O) CH 3

(S)- 또는 (R)-3-메톡시페닐-CH(CH2OTBTMS)-C(O)-Pro-Pab-OH(130 mg; 0.23 밀리몰; 상기 실시예 14(ii)로부터의 화합물), 아세트산 무수물(1 mL; 10 밀리몰), 및 DMAP(9 mg; 0.07 밀리몰)의 혼합물을 실온에서 90분간 교반하였다. 증발후, 조생성물을 RPLC(CH3CN:NH4OAc(10%)(60:40))로 정제하여, 표제 생성물 78 mg(57 %)을 얻었다.(S)-or (R) -3-methoxyphenyl-CH (CH 2 OTBTMS) -C (O) -Pro-Pab-OH (130 mg; 0.23 mmol; compound from Example 14 (ii) above) , A mixture of acetic anhydride (1 mL; 10 mmol), and DMAP (9 mg; 0.07 mmol) was stirred at room temperature for 90 minutes. After evaporation, the crude product was purified by RPLC (CH 3 CN: NH 4 OAc (10%) (60:40)) to give 78 mg (57%) of the title product.

LC-MS m/z 598(M + 1)+ LC-MS m / z 598 (M + 1) +

(ii) (S)- 및 (R)-3-메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab-OC(O)CH3 (ii) (S)-and (R) -3-methoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab-OC (O) CH 3

CH2Cl2(2.5 mL) 중의 (S)- 또는 (R)-3-메톡시페닐-CH(CH2OTBTMS)-C(O)-Pro-Pab-(OC(O)CH3)(125 mg; 0.21 밀리몰; 상기 단계(i)로부터의 화합물)의 용액에 TFA 0.2 mL를 가하고 혼합물을 실온에서 40분간 교반하고, 이후 용액을 Na2CO3 수용액으로 알칼리화하고 CH2Cl2로 추출하였다. 유기층을 물로 1회 세척하고, 건조하고(Na2SO4), 중발하여, 조생성물 60 mg을 얻었다. RPLC(CH3CN:NH4OAc(10%)(60:40))로 정제하고 동결 건조한 후, 백색 분말인 표제 생성물 36 mg(36 %)을 얻었다.(S)-or (R) -3-methoxyphenyl-CH (CH 2 OTBTMS) -C (O) -Pro-Pab- (OC (O) CH 3 ) (125) in CH 2 Cl 2 (2.5 mL) mg; 0.21 mmol; compound from step (i) 0.2 mL of TFA was added and the mixture was stirred at room temperature for 40 minutes, after which the solution was alkalized with Na 2 CO 3 aqueous solution and extracted with CH 2 Cl 2 . The organic layer was washed once with water, dried (Na 2 SO 4 ) and heavy to afford 60 mg of crude product. Purification by RPLC (CH 3 CN: NH 4 OAc (10%) (60:40)) and lyophilization gave 36 mg (36%) of the title product as a white powder.

LC-MS m/z 484 (M + 1)+ LC-MS m / z 484 (M + 1) +

실시예 16Example 16

(R)- 또는 (S)-3-(메틸아미노)페닐-CH(CH2OH)-C(O)-Pro-Pab x 2 HCl(R)-or (S) -3- (methylamino) phenyl-CH (CH 2 OH) -C (O) -Pro-Pab x 2 HCl

(i) (R,S)-((3-Boc-메틸아미노)페닐)-CH(CH2OH)-C(O)-Pro-Pab(Z)(i) (R, S)-((3-Boc-methylamino) phenyl) -CH (CH 2 OH) -C (O) -Pro-Pab (Z)

DMF(10 mL) 중의 (R,S)-3-히드록시-2-(3-Boc-아미노페닐)프로피온산(0.28 g; 0.95 밀리몰; 상기 실시예 U로부터의 화합물)의 용액을 0 ℃로 냉각하였다. H-Pro-Pab(Z) x HCl(0.46; 0.88 밀리몰), TBTU(0.32 g; 1.0 밀리몰) 및 DIPEA(0.44 g; 3.4 밀리몰)을 순서대로 부가하고 반응 혼합물을 실온에서 4 일 동안 교반하였다. 이어서, DMF를 증발시키고 잔류물을 정제 HPLC(CH3CN:NH4OAc(10%); (42:58))로 정제하였다. CH3CN을 증발시키고 수용액을 동결 건조하여 부표제 화합물 220 mg(43 %)을 얻었다.Cool a solution of (R, S) -3-hydroxy-2- (3-Boc-aminophenyl) propionic acid (0.28 g; 0.95 mmol; compound from Example U above) in DMF (10 mL) to 0 ° C. It was. H-Pro-Pab (Z) x HCl (0.46; 0.88 mmol), TBTU (0.32 g; 1.0 mmol) and DIPEA (0.44 g; 3.4 mmol) were added in sequence and the reaction mixture was stirred at rt for 4 days. DMF was then evaporated and the residue was purified by purified HPLC (CH 3 CN: NH 4 OAc (10%); (42:58)). CH 3 CN was evaporated and the aqueous solution was lyophilized to give 220 mg (43%) of the subtitle compound.

1H NMR (500 MHz; CDCl3): δ 7.28 (d, 1H); 7.75 (d, 1H); 7.42 (m, 2H); 7.33 (m, 3H); 7.28 (m, 3H); 7.23 (m, 1H); 7.12 (d, 2H); 5.20 (d, 2H); 4.60 (m, 1H); 4.40 (m, 2H); 4.03 (m, 1H); 3.90 (m, 1H); 3.72 (m, 1H); 3.50 (m, 1H); 3.14 (s, 3H); 2.25 (m, 1H); 1.85 (m, 4H); 1.43 (s, 9H) 1 H NMR (500 MHz; CDCl 3 ): δ 7.28 (d, 1H); 7.75 (d, 1 H); 7.42 (m, 2 H); 7.33 (m, 3 H); 7.28 (m, 3 H); 7.23 (m, 1 H); 7.12 (d, 2 H); 5.20 (d, 2 H); 4.60 (m, 1 H); 4.40 (m, 2 H); 4.03 (m, 1 H); 3.90 (m, 1 H); 3.72 (m, 1 H); 3.50 (m, 1 H); 3.14 (s, 3 H); 2.25 (m, 1 H); 1.85 (m, 4 H); 1.43 (s, 9 H)

(ii) (R)- 및 (S)-((3-Boc-메틸아미노)페닐)-CH(CH2OH)-C(O)-Pro-Pab(ii) (R)-and (S)-((3-Boc-methylamino) phenyl) -CH (CH 2 OH) -C (O) -Pro-Pab

EtOH 10 mL 및 HOAc(10 방울) 중의 (R,S)-((3-Boc-메틸아미노)페닐)-CH(CH2OH)-C(O)-Pro-Pab(Z)(270 mg; 0.42 밀리몰; 상기 단계(i)로부터의 화합물) 용액에 Pd/C(10%; 10 mg)을 부가하였다. 반응 혼합물을 실온에서 2 시간 동안 수소처리하고(1atm), 얻어진 혼합물을 하이플로(Hyflo)를 통해 여과하였다. 용액을 증발시키고, 물을 부가하고, 용액을 동결 건조하여 백색 발포성 물질인 부표제의 조화합물 214 mg(100%)를 얻었다. 조생성물을 RPLC(CH3CN: NH4OAc (0.1M); (32:68))로 정제하여 부분입체 이성질체를 분리하였다. CH3CN을 증발시키고 수용액을 동결 건조하여 화합물 16A(보다 빠르게 움직이는 부분입체 이성질체) 및 화합물 16B(보다 느리게 움직이는 부분입체 이성질체)를 수득하였다.(R, S)-((3-Boc-methylamino) phenyl) -CH (CH 2 OH) -C (O) -Pro-Pab (Z) (270 mg) in 10 mL EtOH and HOAc (10 drops); 0.42 mmol; compound from step (i) above was added Pd / C (10%; 10 mg). The reaction mixture was hydrotreated for 2 hours at room temperature (1 atm) and the resulting mixture was filtered through Hyflo. The solution was evaporated, water was added, and the solution was lyophilized to give 214 mg (100%) of crude compound as a white foam, subtitle. The crude product was purified by RPLC (CH 3 CN: NH 4 OAc (0.1M); (32:68)) to separate diastereomers. CH 3 CN was evaporated and the aqueous solution was lyophilized to afford Compound 16A (faster moving diastereomers) and Compound 16B (slower moving diastereomers).

화합물 16ACompound 16A

1H NMR (300 MHz; D2O): δ 7.8 (d, 2H); 7.4 (d, 2H); 7.2 (m, 4H); 4.6 (m, 2H); 4.3 (d, 1H); 4.15 (m, 2H); 3.85 (m, 2H); 3.55 (m, 1H); 2.95 (s, 2H); 2.3 (m, 1H); 2.0 (d, 5H); 1.4 (d, 9H) 1 H NMR (300 MHz; D 2 O): δ 7.8 (d, 2H); 7.4 (d, 2 H); 7.2 (m, 4 H); 4.6 (m, 2 H); 4.3 (d, 1 H); 4.15 (m, 2 H); 3.85 (m, 2 H); 3.55 (m, 1 H); 2.95 (s, 2 H); 2.3 (m, 1 H); 2.0 (d, 5 H); 1.4 (d, 9H)

화합물 16BCompound 16b

1H NMR (300 MHz; D2O): δ 7.8 (d, 2H); 7.5 (d, 2H); 7.3 (m, 4H); 4.5 (m, 2H); 4.4 (d, 1H); 4.1 (m, 2H); 3.8 (m, 2H); 3.4 (m, 1H); 3.2 (s, 2H); 2.2 (m, 1H); 2.0 (d, 5H); 1.4 (d, 9H) 1 H NMR (300 MHz; D 2 O): δ 7.8 (d, 2H); 7.5 (d, 2 H); 7.3 (m, 4 H); 4.5 (m, 2 H); 4.4 (d, 1 H); 4.1 (m, 2 H); 3.8 (m, 2 H); 3.4 (m, 1 H); 3.2 (s, 2 H); 2.2 (m, 1 H); 2.0 (d, 5 H); 1.4 (d, 9H)

(iii) (R)- 및 (S)-3-(메틸아미노)페닐-CH(CH2OH)-C(O)-Pro-Pab x HCl(iii) (R)-and (S) -3- (methylamino) phenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HCl

HCl(6 M; 10 mL) 중의 (R)- 또는 (S)-((3-Boc-메틸아미노)페닐)-CH(CH2OH)-C(O)-Pro-Pab(172 mg; 0.42 밀리몰; 상기 단계(ii)로부터의 화합물 16B) 용액을 실온에서 2 시간 동안 교반하고 생성물을 동결 건조하여 백색 물질인 표제 화합물 153 mg(76%; 순도 94.2 %)을 얻었다.(R)-or (S)-((3-Boc-methylamino) phenyl) -CH (CH 2 OH) -C (O) -Pro-Pab (172 mg; 0.42 in HCl (6M; 10 mL)) Millimoles; The compound 16B) solution from step (ii) was stirred for 2 hours at room temperature and the product was lyophilized to give 153 mg (76%; purity 94.2%) of the title compound as a white substance.

FAB-MS m/z 424 (M+1)+ FAB-MS m / z 424 (M + 1) +

1H NMR (400 MHz; D2O): δ 8.77 (t, 1H); 7.80(d, 2H); 7.72 (d, 1H); 7.63 (t, 1H); 7.54 (d, 2H); 7.50 (m, 2H); 4.55 (m, 2H); 4.46 (m, 2H); 4.46 (dd, 1H); 4.27 (t, 1H); 4.12 (m, 2H); 3.88 (m, 2H); 3.66 (dd 1H); 3.42 (m, 1H); 3.13 (s, 3H); 2.22 (m, 1H); 2.00 (m, 2H); 1.90 (m, 1H) 1 H NMR (400 MHz; D 2 O): δ 8.77 (t, 1 H); 7.80 (d, 2 H); 7.72 (d, 1 H); 7.63 (t, 1 H); 7.54 (d, 2 H); 7.50 (m, 2 H); 4.55 (m, 2 H); 4.46 (m, 2 H); 4.46 (dd, 1 H); 4.27 (t, 1 H); 4.12 (m, 2 H); 3.88 (m, 2 H); 3.66 (dd 1 H); 3.42 (m, 1 H); 3.13 (s, 3 H); 2.22 (m, 1 H); 2.00 (m, 2 H); 1.90 (m, 1 H)

13C NMR (100 MHz; D2O) 174.6, 171.9, 166.6 13 C NMR (100 MHz; D 2 O) 174.6, 171.9, 166.6

실시예 17Example 17

(S)-PhCH(CH2OH)-C(O)-Pro-Pab x HCl(S) -PhCH (CH 2 OH) -C (O) -Pro-Pab x HCl

(i) (S)-트로프산(i) (S) -tropic acid

포더(G Fodor) 등의 문헌 [Acta Chem. Hung, 28, 407 (1961)]에 기재된 절차에 따라 (1R:2R)-(-)-1-p-니트로페닐-2-아미노프로판-1,3-디올(7.85 g; 47 밀리몰)을 사용하여 라세믹 트로프산(10 g; 47 밀리몰)을 용해하여, 표제 화합물 0.25 g(5%)를 얻었다.G Fodor et al., Acta Chem. Hung, 28 , 407 (1961) using (1R: 2R)-(-)-1-p-nitrophenyl-2-aminopropane-1,3-diol (7.85 g; 47 mmol) Was dissolved to 10 g (47 mmol) to give 0.25 g (5%) of the title compound.

〔α〕D 20 = -77。; c = 0.5(H2O) (Lit: -72。)[Α] D 20 = −77 °; c = 0.5 (H 2 O) (Lit: -72 °)

(ii) (S)-PhCH(CH2OH)-C(O)-Pro-Pab(Z)(ii) (S) -PhCH (CH 2 OH) -C (O) -Pro-Pab (Z)

CH2Cl2(30 mL) 중의 (S)-트로프산(234 mg; 1.4 밀리몰; 상기 단계 (i)으로부터의 화합물), H-Pro-Pab(Z)(884 mg; 1.95 밀리몰; 국제특허출원 WO 제97/02284호에 기재된 방법에 따라 제조함) 및 TEA(1 mL; 7 밀리몰)의 용액을 제조하고 0 ℃로 냉각하였다. 이어서, HBTU(570 mg; 1.5 밀리몰)을 부가하고 용액을 철야 교반하였다. 이후에, 용매를 증발시키고 조생성물을 RPLC에 의해 정제하여 부표제 생성물 0.50 g(68%)을 얻었다.(S) -tropic acid (234 mg; 1.4 mmol; compound from step (i)), H-Pro-Pab (Z) (884 mg; 1.95 mmol; international patent application in CH 2 Cl 2 (30 mL) Prepared according to the method described in WO 97/02284) and a solution of TEA (1 mL; 7 mmol) and cooled to 0 ° C. HBTU (570 mg; 1.5 mmol) was then added and the solution stirred overnight. Thereafter, the solvent was evaporated and the crude product was purified by RPLC to give 0.50 g (68%) of the subtitle product.

LC-MS m/z 527(M-1)- LC-MS m / z 527 (M-1) -

(iii) (S)-PhCH(CH2OH)-C(O)-Pro-Pab x HCl(iii) (S) -PhCH (CH 2 OH) -C (O) -Pro-Pab x HCl

Pd/C(10%; 161 mg)와 함께 EtOH(25 mL) 중의 (S)-PhCH(CH2OH)-C(O)-Pro-Pab(Z)(220 mg; 0.42 밀리몰; 상기 단계 (i)으로부터의 화합물)의 용액을 대기압하에서 실온에서 18시간 동안 수소처리하였다. 얻어진 용액을 하이플로를 통해 여과하고 증발시켰다. 형성된 고체를 H2O에 용해하고, 2M HCl 수용액 1 mL를 부가하고, 용액을 동결 건조하였다. 백색 고체인 표제 생성물(132 mg, 80 %)을 수득하였다.(S) -PhCH (CH 2 OH) -C (O) -Pro-Pab (Z) (220 mg; 0.42 mmol) in Pt / C (10%; 161 mg) in EtOH (25 mL); The solution of compound from i) was hydrotreated for 18 h at room temperature under atmospheric pressure. The resulting solution was filtered through hyflo and evaporated. The solid formed was dissolved in H 2 O, 1 mL of 2M aqueous HCl solution was added and the solution was lyophilized. The title product (132 mg, 80%) was obtained as a white solid.

LC-MS m/z 394.5(M+1)+ LC-MS m / z 394.5 (M + 1) +

실시예 18Example 18

(R,S)-3,5-디메틸페닐-CH(CH2OH)-C(O)-Aze-Pab x HOAc(R, S) -3,5-Dimethylphenyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

(i) (R,S)-3,5-디메틸페닐-CH(CH2OH)-C(O)-Aze-Pab(Z)(i) (R, S) -3,5-Dimethylphenyl-CH (CH 2 OH) -C (O) -Aze-Pab (Z)

DMF(10 mL) 중의 (R,S)-3-히드록시-2-(3,5-디메틸페닐)프로피온산(0.155g; 0.8 밀리몰; 상기 실시예 H로부터의 화합물)의 용액을 0 ℃로 냉각하였다. H-Aze-Pab(Z) x 2HCl(0.387 g; 0.88 밀리몰; 상기 실시예 A로부터의 화합물), 이어서 TBTU(0.283 g; 0.88 밀리몰), 이어서 DIPEA(0.414 g; 3.2 밀리몰)을 부가하고, 용액을 실온에서 4일간 교반하였다. 용액을 농축하고, 얻어진 혼합물을 RPLC(CH3CN:NH4OAc(10%)(40:60))에 의해 정제하였다. CH3CN을 증발시키고, 수성상을 EtOAc로 추출하였다. 유기상을 건조하고(Na2SO4) 증발 건조시켰다. 백색 고체의 부표제 생성물(270 mg; 62%)을 단리하였다.Cool a solution of (R, S) -3-hydroxy-2- (3,5-dimethylphenyl) propionic acid (0.155 g; 0.8 mmol; compound from Example H above) in DMF (10 mL) to 0 ° C. It was. H-Aze-Pab (Z) x 2HCl (0.387 g; 0.88 mmol; compound from Example A above), followed by TBTU (0.283 g; 0.88 mmol), followed by DIPEA (0.414 g; 3.2 mmol) and solution Was stirred at room temperature for 4 days. The solution was concentrated and the resulting mixture was purified by RPLC (CH 3 CN: NH 4 OAc (10%) (40:60)). CH 3 CN was evaporated and the aqueous phase was extracted with EtOAc. The organic phase was dried (Na 2 SO 4 ) and evaporated to dryness. A white solid subtitle product (270 mg; 62%) was isolated.

1H NMR (500 MHz; CDCl3): δ 8.27 (bt, 0.5H); 8.15 (bt, 0.5H); 7.80 (d, 2H); 7.44 (m, 2H); 7.34 (d, 2H); 7.30 (d, 2H); 6.91 (d, 1H); 6.85 (s, 1H); 6.65 (s, 1H); 5.20 (d, 2H); 4.90 (m, 1H); 4.6-4.4 (m, 2H); 4.1-4.0 (m, 2H); 3.8-3.5 (m, 3H); 2.58 (m, 1H); 2.29 (s, 3H); 2.21 (s, 3H) 1 H NMR (500 MHz; CDCl 3 ): δ 8.27 (bt, 0.5H); 8.15 (bt, 0.5 H); 7.80 (d, 2 H); 7.44 (m, 2 H); 7.34 (d, 2 H); 7.30 (d, 2 H); 6.91 (d, 1 H); 6.85 (s, 1 H); 6.65 (s, 1 H); 5.20 (d, 2 H); 4.90 (m, 1 H); 4.6-4.4 (m, 2 H); 4.1-4.0 (m, 2 H); 3.8-3.5 (m, 3 H); 2.58 (m, 1 H); 2.29 (s, 3 H); 2.21 (s, 3 H)

(ii) (R,S)-3,5-디메틸페닐-CH(CH2OH)-C(O)-Aze-Pab x HOAc(ii) (R, S) -3,5-dimethylphenyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

EtOH(10 mL) 중의 (R,S)-3,5-디메틸페닐-CH(CH2OH)-C(O)-Aze-Pab(Z)(0.229 g; 0.42 밀리몰; 상기 단계(i)로부터의 화합물)의 용액에 아세트산(24 μl) 및 Pd/C(5%, 0.115 g)을 부가하였다. 대기압 및 실온에서 2.5 시간 동안 용액을 수소처리하였다. 혼합물을 하이플로를 통해 여과하고, 얻어진 용액을 농축하고, 최소량의 물에 용해하고 동결 건조하여 백색 고체의 표제 화합물 0.174 g(88%; 순도 93.6%)을 얻었다.(R, S) -3,5-Dimethylphenyl-CH (CH 2 OH) -C (O) -Aze-Pab (Z) (0.229 g; 0.42 mmol; in step (i) above in EtOH (10 mL) Acetic acid (24 μl) and Pd / C (5%, 0.115 g) were added to the solution. The solution was hydrotreated for 2.5 hours at atmospheric pressure and room temperature. The mixture was filtered through hyflo and the resulting solution was concentrated, dissolved in a minimum amount of water and lyophilized to give 0.174 g (88%; purity 93.6%) of the title compound as a white solid.

LC-MS m/z 409(M+1)+ LC-MS m / z 409 (M + 1) +

실시예 19Example 19

(S)- 또는 (R)-3-(트리플루오로메틸)페닐-CH(CH2OH)-C(O)-Pro-Pab x HCl(S)-or (R) -3- (trifluoromethyl) phenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HCl

(i) (R)- 및 (S)-3-(트리플루오로메틸)페닐-CH(CH2OH)-C(O)-Pro-Pab(Z)(i) (R)-and (S) -3- (trifluoromethyl) phenyl-CH (CH 2 OH) -C (O) -Pro-Pab (Z)

DMF(10 mL) 중의 (R,S)-3-히드록시-2-(3-트리플루오로메틸페닐)프로피온산(0.25g; 1.07 밀리몰; 상기 실시예 I로부터의 화합물), H-Pro-Pab(Z)(0.532 g; 1.17 밀리몰; 국제특허출원 WO 제97/02284호에 기재된 방법에 따라 제조함) 및 TBTU(0.377 g; 1.7 밀리몰)용액을 0℃에서 냉각하고, DIPEA(0.72 g; 4.27 밀리몰)를 부가하였다. 얻어진 용액을 실온에서 40 시간 동안 교반하였다. 반응 혼합물을 농축하고, 물(400 mL)을 부가하고, pH를 9로 설정하였다(NaHCO3 수용액). 얻어진 혼합물을 EtOAc(3 x 100 mL)로 추출하였다. 합한 유기상을 간수로 세척하고, 건조하고(Na2SO4), 증발시켰다. 정제 HPLC(CH3CN:NH4OAc(0.1 M) (45:55))에 의해 2종의 부분입체 이성질체, 화합물 19A(87 mg; 0.15 mg; 순도 HPLC에 의해 94.4 %); 보다 빠르게 움직이는 부분입체 이성질체) 및 화합물 19B(120 mg; 0.20 mg; 순도 HPLC에 의해 91 %); 보다 느리게 움직이는 부분입체 이성질체)를 얻었다.(R, S) -3-hydroxy-2- (3-trifluoromethylphenyl) propionic acid (0.25 g; 1.07 mmol; compound from Example I above), H-Pro-Pab ( Z) (0.532 g; 1.17 mmol; prepared according to the method described in International Patent Application WO 97/02284) and TBTU (0.377 g; 1.7 mmol) solution are cooled at 0 ° C. and DIPEA (0.72 g; 4.27 mmol) ) Was added. The resulting solution was stirred at rt for 40 h. The reaction mixture was concentrated, water (400 mL) was added and the pH was set to 9 (NaHCO 3 aqueous solution). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine, dried (Na 2 SO 4 ) and evaporated. Two diastereoisomers, Compound 19A (87 mg; 0.15 mg; 94.4% by purity HPLC) by purified HPLC (CH 3 CN: NH 4 OAc (0.1 M) (45:55)); Faster moving diastereomers) and Compound 19B (120 mg; 0.20 mg; 91% by purity HPLC); Slower moving diastereomers).

LC-MS m/z 597(M + 1)+ (2개의 부분입체 이성질체 모두)LC-MS m / z 597 (M + 1) + (both diastereoisomers)

(ii) (S)- 또는 (R)-3-(트리플루오로메틸)페닐-CH(CH2OH)C(O)-Pro-Pab x HCl(ii) (S)-or (R) -3- (trifluoromethyl) phenyl-CH (CH 2 OH) C (O) -Pro-Pab x HCl

EtOH(10 mL) 및 수성 HCl (1M; 0.4 mL) 중의 (R) 또는 (S)-3-(트리플루오로메틸)페닐-CH(CH2OH)-C(O)-Pro-Pab(Z)(118 mg; 0.20 밀리몰; 상기 단계(i)로부터의 화합물 19B)의 용액에 Pd/C(10%)를 부가하였다. 혼합물을 3 시간 동안 실온에서 대기압하에서 수소처리하였다. 얻어진 혼합물을 하이플로를 통해 여과하고 용액을 증발시켰다. 물을 부가하고 용액을 동결 건조하여 백색 고체인 표제 화합물 66 mg(66.9 %)(순도 94.5%(HPLC))을 얻었다.(R) or (S) -3- (trifluoromethyl) phenyl-CH (CH 2 OH) -C (O) -Pro-Pab (Z) in EtOH (10 mL) and aqueous HCl (1M; 0.4 mL) ) (118 mg; 0.20 mmol; Pd / C (10%) was added to the solution of compound 19B from step (i) above. The mixture was hydrotreated under atmospheric pressure for 3 hours at room temperature. The resulting mixture was filtered through hyflo and the solution was evaporated. Water was added and the solution was lyophilized to give 66 mg (66.9%) of the title compound (purity 94.5% (HPLC)) as a white solid.

LC-MS m/z 463(M + 1)+ LC-MS m / z 463 (M + 1) +

실시예 20Example 20

(R,S)-3-히드록시페닐-CH(CH2OH)-C(O)-Pro-Pab x HOAc(R, S) -3-hydroxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HOAc

(i) (R,S)-3-히드록시페닐-CH(CH2OH)-C(O)-Pro-Pab(Z)(i) (R, S) -3-hydroxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab (Z)

DMF(10 mL) 중의 (R,S)-3-히드록시-2-(3-히드록시페닐)프로피온산(0.146g; 0.8 밀리몰; 상기 실시예 J로부터의 화합물)의 용액을 0℃로 냉각하였다. H-Aze-Pab(Z) x HCl(0.399 g; 0.88 밀리몰; 상기 실시예 A로부터의 화합물), TBTU(0.283 g; 0.88 밀리몰), 및 DIPEA(0.414 g; 3.2 밀리몰)을 부가하고, 용액을 실온에서 4일 동안 교반하였다. 반응 혼합물을 농축하고, 얻어진 혼합물을 RPLC(CH3CN:NH4OAc(10%) (42:58))에 의해 정제하였다. CH3CN을 증발시키고, 수용액을 동결 건조하였다. 백색 고체인 부표제 생성물(187 mg; 43%)을 단리하였다.A solution of (R, S) -3-hydroxy-2- (3-hydroxyphenyl) propionic acid (0.146 g; 0.8 mmol; compound from Example J) in DMF (10 mL) was cooled to 0 ° C. . H-Aze-Pab (Z) x HCl (0.399 g; 0.88 mmol; compound from Example A above), TBTU (0.283 g; 0.88 mmol), and DIPEA (0.414 g; 3.2 mmol) were added and the solution was added. Stir at room temperature for 4 days. The reaction mixture was concentrated and the resulting mixture was purified by RPLC (CH 3 CN: NH 4 OAc (10%) (42:58)). CH 3 CN was evaporated and the aqueous solution was lyophilized. A white solid subtitle product (187 mg; 43%) was isolated.

1H NMR (500 MHz; CD3OD):δ 7.82 (d, 2H); 7.41 (m, 3H); 7.34 (m, 2H); 7.25 (d, 1H); 7.13 (t, 1H); 6.78 (s+d, 2H); 6.66 (d, 1H); 5.18 (b, 2H); 4.5 (m, 2H); 4.07 (m, 1H); 3.93 (m, 1H); 3.79 (m, 1H); 3.65 (m, 1H); 3.5-3.3 (m, 2H); 3.30 (s, 1H); 2.2-2.0 (m, 2H); 1.95 (m, 3H); 1.81 (m, 1H) 1 H NMR (500 MHz; CD 3 OD): δ 7.82 (d, 2H); 7.41 (m, 3 H); 7.34 (m, 2 H); 7.25 (d, 1 H); 7.13 (t, 1 H); 6.78 (s + d, 2H); 6.66 (d, 1 H); 5.18 (b, 2 H); 4.5 (m, 2 H); 4.07 (m, 1 H); 3.93 (m, 1 H); 3.79 (m, 1 H); 3.65 (m, 1 H); 3.5-3.3 (m, 2 H); 3.30 (s, 1 H); 2.2-2.0 (m, 2 H); 1.95 (m, 3 H); 1.81 (m, 1 H)

(ii) (R,S)-3-히드록시페닐-CH(CH2OH)-C(O)-Pro-Pab x HOAc(ii) (R, S) -3-hydroxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HOAc

EtOH(10 mL) 중의 (R,S)-3-히드록시페닐-CH(CH2OH)-C(O)-Pro-Pab(Z)(0.173 g; 0.32 밀리몰; 상기 단계(i)로부터의 화합물 )의 용액에 아세트산(18 μl) 및 Pd/C(5%)를 부가하였다. 용액을 3 시간 동안 실온에서 대기압하에서 수소처리하였다. 혼합물을 하이플로를 통해 여과하고, 얻어진 용액을 농축하고, 최소량의 물에서 용해하고, 동결 건조하여 플러피(fluffy) 백색 결정 0.133 g(89 %, 순도 94.2%)을 수득하였다.(R, S) -3-hydroxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab (Z) in EtOH (10 mL) (0.173 g; 0.32 mmol; from step (i) above To the solution of compound) acetic acid (18 μl) and Pd / C (5%) were added. The solution was hydrotreated under atmospheric pressure for 3 hours at room temperature. The mixture was filtered through hyflo and the resulting solution was concentrated, dissolved in a minimum amount of water and lyophilized to yield 0.133 g (89%, 94.2% purity) of fluffy white crystals.

LC-MS m/z 411(M + 1)+ LC-MS m / z 411 (M + 1) +

실시예 21Example 21

(R)- 또는 (S)-((3-클로로-5-메틸페닐)-CH(CH2OH)-C(O)-Pro-Pab x HCl(R)-or (S)-((3-chloro-5-methylphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab x HCl

(i) (R)- 및 (S)-((3-클로로-5-메틸페닐)-CH(CH2OH)-C(O)-Pro-Pab(Z)(i) (R)-and (S)-((3-chloro-5-methylphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab (Z)

DMF(10 mL) 중의 (R,S)-3-히드록시-2-(3-클로로-5-메틸페닐)프로피온산(0.30g; 1.4 밀리몰; 상기 실시예 V로부터의 화합물)의 용액을 0℃로 냉각하였다. H-Pro-Pab(Z) x HCl(0.70 g; 1.54 밀리몰), TBTU(0.99 g; 1.5 밀리몰) 및 DIPEA(0.94 g; 5.5 밀리몰)을 순서대로 부가하고 반응 혼합물을 실온에서 4일 동안 교반하였다. 이어서, DMF를 증발시키고, 얻어진 혼합물을 물(400 mL)에 붓고, NaHCO3 10% 수용액으로 pH를 9로 설정하였다. 혼합물 수용액을 EtOAc(3 x 100 mL)로 추출하고, 합한 유기상을 NaHCO3 10% 수용액, 물, 간수로 세척하고, 건조하고(Na2SO4) 농축하였다. 조생성물(0.674 g)을 RPLC(CH3CN:NH4OAc(10 %) ;45:55)에 의해 정제하고, 부분입체 이성질체를 분리하였다. CH3CN을 분리하고 수용액을 EtOAc로 추출하였다. 유기층을 물로 세척하고, 건조하고(Na2SO4), 농축하여, 화합물 21A(125 mg; 31%; 보다 빠르게 움직이는 부분입체 이성질체) 및 화합물 21B(102 mg; 25%; 보다 느리게 움직이는 부분입체 이성질체)를 얻었다.A solution of (R, S) -3-hydroxy-2- (3-chloro-5-methylphenyl) propionic acid (0.30 g; 1.4 mmol; compound from Example V above) in DMF (10 mL) was brought to 0 ° C. Cooled. H-Pro-Pab (Z) x HCl (0.70 g; 1.54 mmol), TBTU (0.99 g; 1.5 mmol) and DIPEA (0.94 g; 5.5 mmol) were added in this order and the reaction mixture was stirred at room temperature for 4 days. . The DMF was then evaporated and the resulting mixture was poured into water (400 mL) and the pH was set to 9 with a 10% aqueous NaHCO 3 solution. The aqueous mixture solution was extracted with EtOAc (3 × 100 mL) and the combined organic phases were washed with 10% aqueous NaHCO 3 , water, brine, dried (Na 2 SO 4 ) and concentrated. The crude product (0.674 g) was purified by RPLC (CH 3 CN: NH 4 OAc (10%); 45:55) and diastereomers were separated. CH 3 CN was separated and the aqueous solution was extracted with EtOAc. The organic layer was washed with water, dried (Na 2 SO 4 ) and concentrated to give Compound 21A (125 mg; 31%; faster moving diastereomer) and Compound 21B (102 mg; 25%; slower moving diastereomer )

화합물 21BCompound 21B

FAB-MS m/z 577, 579 (M+1)+ FAB-MS m / z 577, 579 (M + 1) +

1H NMR (400 MHz; CDCl3):δ 7.76 (d, 2H); 7.43 (m, 2H); 7.30 (m, 5H); 7.07 (d, 2H); 6.95 (s, 1H); 5.20 (s, 2H); 4.58 (dd, 1H); 4.42 (m, 2H); 3.97 (t, 1H); 3.85 (dd, 1H); 3.68 (m, 2H); 3.23 (m, 1H); 2.30 (s, 3H); 2.25 (m, 1H); 2.03 (m, 1H); 1.85 (m, 4H) 1 H NMR (400 MHz; CDCl 3 ): δ 7.76 (d, 2H); 7.43 (m, 2 H); 7.30 (m, 5 H); 7.07 (d, 2 H); 6.95 (s, 1 H); 5.20 (s, 2 H); 4.58 (dd, 1 H); 4.42 (m, 2 H); 3.97 (t, 1 H); 3.85 (dd, 1 H); 3.68 (m, 2 H); 3.23 (m, 1 H); 2.30 (s, 3 H); 2.25 (m, 1 H); 2.03 (m, 1 H); 1.85 (m, 4H)

(ii) (R)- 또는 (S)-(3-클로로-5-메틸페닐)-CH(CH2OH)-C(O)-Pro-Pab x HCl(ii) (R)-or (S)-(3-chloro-5-methylphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab x HCl

TFA 3.7 mL 중의 (R)- 또는 (S)-((3-클로로-5-메틸페닐)-CH(CH2OH)-C(O)-Pro-Pab(Z)(상기 단계(i)로부터의 화합물 21B; 0.102 g; 0.18 밀리몰)의 용액에 티오아니졸(1.04 g; 8.83 밀리몰)을 부가하였다. 반응 혼합물을 실온에서 3 시간 동안 교반하였다. 얻어진 혼합물을 물에 용해하고, 수용액을 에테르로 2회 세척하고, 얻어진 용액을 동결 건조하였다. 조생성물을 정제 HPLC(CH3CN:NH4OAc(0.1 M); 35:65)로 정제하였다. CH3CN을 증발시키고 수용액을 동결 건조하여 백색 분말인 표제 화합물 50 mg(59 %)을 수득하였다.(R)-or (S)-((3-chloro-5-methylphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab (Z) in 3.7 mL of TFA (from step (i) Thianiazole (1.04 g; 8.83 mmol) was added to a solution of compound 21B; 0.102 g; 0.18 mmol) The reaction mixture was stirred at rt for 3 h The resulting mixture was dissolved in water and the aqueous solution was washed with ether 2 Washed several times and the resulting solution was lyophilized The crude product was purified by purified HPLC (CH 3 CN: NH 4 OAc (0.1 M); 35:65) CH 3 CN was evaporated and the aqueous solution was lyophilized to white powder. 50 mg (59%) of the title compound were obtained.

1H NMR (400 MHz; CDCl3):δ 9.23 (b, 2H); 8.74 (b, 2H); 7.78 (d, 2H); 7.57 (d, 2H); 7.18 (s, 1H); 7.12 (m, 2H); 4.52 (s, 2H); 4.52 (s, 2H); 4.46 (dd, 1H); 4.06 (m, 2H); 3.89 (m, 1H); 3.72 (m, 1H); 3.39 (m, 1H); 2.32 (s, 3H); 2.15 (m, 1H); 1.98 (m, 2H); 1.87 (m, 1H) 1 H NMR (400 MHz; CDCl 3 ): δ 9.23 (b, 2H); 8.74 (b, 2 H); 7.78 (d, 2 H); 7.57 (d, 2 H); 7.18 (s, 1 H); 7.12 (m, 2 H); 4.52 (s, 2 H); 4.52 (s, 2 H); 4.46 (dd, 1 H); 4.06 (m, 2 H); 3.89 (m, 1 H); 3.72 (m, 1 H); 3.39 (m, 1 H); 2.32 (s, 3 H); 2.15 (m, 1 H); 1.98 (m, 2 H); 1.87 (m, 1 H)

13C NMR (100 MHz; CD3OD) 174.9, 173.1, 168.3 13 C NMR (100 MHz; CD 3 OD) 174.9, 173.1, 168.3

실시예 22Example 22

(S)- 또는 (R)-3-플루오로페닐-CH(CH2OH)-C(O)-Pro-Pab x HCl(S)-or (R) -3-fluorophenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HCl

(i) (R)- 및 (S)-3-플루오로페닐-CH(CH2OH)-C(O)-Pro-Pab(Z)(i) (R)-and (S) -3-fluorophenyl-CH (CH 2 OH) -C (O) -Pro-Pab (Z)

DMF(10 mL) 중의 (R,S)-3-히드록시-2-(3-플루오로페닐)프로피온산(0.2g; 1.09 밀리몰; 상기 실시예 K로부터의 화합물), H-Pro-Pab(Z)(0.542 g; 1.19 밀리몰; 국제특허출원 WO 제97/02284호에 기재된 방법에 따라 제조함) 및 TBTU(0.383 g; 1.19 밀리몰)을 0℃에서 냉각하고, DIPEA(0.73 g; 4.34 밀리몰)을 부가하였다. 얻어진 혼합물을 실온에서 22 시간 동안 교반하였다. 반응 혼합물을 농축하고, 물(400 mL)을 부가하고, pH를 9로 설정하였다(NaHCO3 수용액). 합한 유기상을 NaHCO3 수용액, 물, 이어서 간수로 세척하고, 건조하고(Na2SO4) 증발시켰다. 이어서, 얻어진 혼합물을 EtOAc(3 x 100 mL)로 추출하였다. RPLC(CH3CN:NH4OAc(0.1 M) (45:55))에 의해 2종의 부분입체 이성질체, 화합물 22A(85 mg; 0.16 밀리몰; 순도 - HPLC에 의해 90 %; 보다 빠르게 움직이는 부분입체 이성질체) 및 화합물 22B(95 mg; 0.17 밀리몰; 순도 - HPLC에 의해 91 %; 보다 느리게 움직이는 부분입체 이성질체)를 분리하였다.(R, S) -3-hydroxy-2- (3-fluorophenyl) propionic acid (0.2 g; 1.09 mmol; compound from Example K above), H-Pro-Pab (Z in DMF (10 mL) ) (0.542 g; 1.19 mmol; prepared according to the method described in International Patent Application WO 97/02284) and TBTU (0.383 g; 1.19 mmol) were cooled at 0 ° C. and DIPEA (0.73 g; 4.34 mmol) Added. The resulting mixture was stirred at rt for 22 h. The reaction mixture was concentrated, water (400 mL) was added and the pH was set to 9 (NaHCO 3 aqueous solution). The combined organic phases were washed with aqueous NaHCO 3 solution, water then brine, dried (Na 2 SO 4 ) and evaporated. The resulting mixture was then extracted with EtOAc (3 x 100 mL). 2 diastereoisomers, compound 22A (85 mg; 0.16 mmol; purity-90% by HPLC; faster moving diastereomers) by RPLC (CH 3 CN: NH 4 OAc (0.1 M) (45:55)) Isomers) and Compound 22B (95 mg; 0.17 mmol; purity-91% by HPLC; slower moving diastereomers).

LC-MS m/z 547(M + 1)+ (2개의 부분입체 이성질체 모두)LC-MS m / z 547 (M + 1) + (both diastereoisomers)

(ii) (S)- 또는 (R)-3-플루오로페닐-CH(CH2OH)-C(O)-Pro-Pab x HCl(ii) (S)-or (R) -3-fluorophenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HCl

EtOH(10 mL) 및 HCl 수용액(1M; 0.4 mL) 중의 화합물 22B(85 mg; 0.16 밀리몰; 상기 단계(i)로부터의 화합물)의 용액에 Pd/C(10%)를 부가하고, 혼합물을 3 시간 동안 실온에서 대기압에서 수소처리하였다. 얻어진 혼합물을 하이플로를 통해 여과하고 용액을 증발시켰다. 물을 부가하고 용액을 동결 건조하여 백색 고체 62.9 mg(90.1 %)(순도 93.3%(HPLC))를 얻었다.To the solution of compound 22B (85 mg; 0.16 mmol; compound from step (i) above) in EtOH (10 mL) and aqueous HCl solution (1M; 0.4 mL) was added Pd / C (10%) and the mixture was 3 Hydrogenated at atmospheric pressure at room temperature for hours. The resulting mixture was filtered through hyflo and the solution was evaporated. Water was added and the solution was lyophilized to give 62.9 mg (90.1%) (purity 93.3% (HPLC)) of a white solid.

LC-MS m/z 413(M + 1)+ LC-MS m / z 413 (M + 1) +

실시예 23Example 23

(S)- 또는 (R)-3-클로로페닐-CH(CH2OH)-C(O)-Pro-Pab x HOAc(S)-or (R) -3-chlorophenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HOAc

(i) (R,S)-3-클로로페닐-CH(CH2OH)-C(O)-Pro-Pab(Z)(i) (R, S) -3-Chlorophenyl-CH (CH 2 OH) -C (O) -Pro-Pab (Z)

DMF(20 mL) 중의 (R,S)-3-히드록시-2-(3-클로로페닐)-프로피온산(0.30g; 1.5 밀리몰; 상기 실시예 L로부터의 화합물), H-Pro-Pab(Z)(0.77 g; 1.7 밀리몰; 국제특허출원 WO 제97/02284호에 기재된 방법에 따라 제조함), TBTU(0.55 g; 1.7 밀리몰), 및 DIPEA(0.41 g; 3.2 밀리몰)의 용액을 2일 동안 교반하였다. 얻어진 혼합물을 톨루엔:EtOAc(1:1, 300 mL)으로 추출하고, 유기상을 모으고, NaHCO3 수용액 및 물로 세척하고, 건조하고(Na2SO4) 증발시켰다. 플래시 크로마토그래피하여(Si 겔, CH2Cl2:THF(7:3)) 부표제 화합물 0.50 g(59%)을 얻었다.(R, S) -3-hydroxy-2- (3-chlorophenyl) -propionic acid (0.30 g; 1.5 mmol; compound from Example L above), H-Pro-Pab (Z in DMF (20 mL) ) (0.77 g; 1.7 mmol; prepared according to the method described in International Patent Application WO 97/02284), TBTU (0.55 g; 1.7 mmol), and DIPEA (0.41 g; 3.2 mmol) for 2 days Stirred. The resulting mixture was extracted with toluene: EtOAc (1: 1, 300 mL), the organic phases were combined, washed with aqueous NaHCO 3 and water, dried (Na 2 SO 4 ) and evaporated. Flash chromatography (Si gel, CH 2 Cl 2 : THF (7: 3)) gave 0.50 g (59%) of the subtitle compound.

FAB-MS m/z 562.4, 564.5(M + 1)+ FAB-MS m / z 562.4, 564.5 (M + 1) +

(ii) (R)- 또는 (S)-(3-클로로페닐)-CH(CH2OH)-C(O)-Pro-Pab x HOAc(ii) (R)-or (S)-(3-chlorophenyl) -CH (CH 2 OH) -C (O) -Pro-Pab x HOAc

CH2Cl2 및 아니졸(43 mg; 0.40 밀리몰) 중의 (R,S)-3-클로로페닐-CH(CH2OH)-C(O)-Pro-Pab(Z)(0.15 g; 0.27 밀리몰; 상기 단계(i)로부터의 화합물)의 용액에 트리플루오로메탄술폰산(0.2 g; 1.3 밀리몰)을 부가하였다. 얻어진 혼합물을 1 시간 동안 교반하고, 이어서 농축하였다. 이어서, 물을 부가하고 NaHCO3 수용액을 사용하여 수용액의 pH를 약 9로 조절하였다. 수성상을 에테르로 세척하고 동결 건조하여 조생성물을 얻었다. RPLC에 의해 2종의 부분입체 이성질체, 화합물 23A(11 mg; 19%; 순도 HPLC에 의해 81.7 %; 보다 빠르게 움직이는 부분입체 이성질체) 및 화합물 23B(11 mg; 19%, 순도 HPLC에 의해 90.0%; 보다 느리게 움직이는 부분입체 이성질체)를 얻었다.(R, S) -3-Chlorophenyl-CH (CH 2 OH) -C (O) -Pro-Pab (Z) (0.15 g; 0.27 mmol) in CH 2 Cl 2 and anisol (43 mg; 0.40 mmol) Trifluoromethanesulfonic acid (0.2 g; 1.3 mmol) was added to the solution of step (i). The resulting mixture was stirred for 1 hour and then concentrated. Water was then added and the pH of the aqueous solution was adjusted to about 9 using NaHCO 3 aqueous solution. The aqueous phase was washed with ether and lyophilized to afford crude product. Two diastereomers by RPLC, Compound 23A (11 mg; 19%; 81.7% by purity HPLC; faster moving diastereomers) and Compound 23B (11 mg; 19%, 90.0% by purity HPLC; Slower moving diastereomers).

화합물 23A:Compound 23A:

LC-MS m/z 428.4 (M + 1)+ LC-MS mlz 428.4 (M + 1) +

화합물 23B:Compound 23B:

FAB-MS m/z 431 (M + 1)+ FAB-MS m / z 431 (M + 1) +

실시예 24Example 24

(R,S)-3,5-디메틸페닐-CH(CH2OH)-C(O)-Pro-Pab x HOAc(R, S) -3,5-Dimethylphenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HOAc

(i) (R,S)-(3,5-디메틸페닐)-CH(CH2OH)-C(O)-Pro-Pab(Z)(i) (R, S)-(3,5-Dimethylphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab (Z)

DMF(10 mL) 중의 (R,S)-3-히드록시-2-(3,5-디메틸페닐)프로피온산(0.155g; 0.8 밀리몰; 상기 실시예 H로부터의 화합물) 용액을 0 ℃로 냉각하였다. H-Pro-Pab(Z) x 2HCl(0.399 g; 0.88 밀리몰; 국제특허출원 WO 제97/02284호에 기재된 방법에 따라 제조함), TBTU(0.283 g; 0.88 밀리몰), 및 DIPEA(0.414 g; 3.2 밀리몰)을 순서대로 부가하고, 용액을 실온에서 5일 동안 교반하였다. 반응 혼합물을 농축하고, 잔류물을 RPLC(CH3CN:NH4OAc(10%)(40:60))에 의해 정제하였다. CH3CN을 증발시키고, 수성상을 EtOAc로 추출하였다. 유기상을 건조하고(Na2SO4) 증발 건조하였다. 담황색 고체인 부표제 생성물(300 mg; 67%)을 단리하였다.A solution of (R, S) -3-hydroxy-2- (3,5-dimethylphenyl) propionic acid (0.155 g; 0.8 mmol; compound from Example H above) in DMF (10 mL) was cooled to 0 ° C. . H-Pro-Pab (Z) x 2HCl (0.399 g; 0.88 mmol; prepared according to the method described in International Patent Application WO 97/02284), TBTU (0.283 g; 0.88 mmol), and DIPEA (0.414 g; 3.2 mmol) was added in order and the solution was stirred at room temperature for 5 days. The reaction mixture was concentrated and the residue was purified by RPLC (CH 3 CN: NH 4 OAc (10%) (40:60)). CH 3 CN was evaporated and the aqueous phase was extracted with EtOAc. The organic phase was dried (Na 2 SO 4 ) and evaporated to dryness. The subtitle product (300 mg; 67%) as a light yellow solid was isolated.

1H NMR (500 MHz; CDCl3):δ 7.83 (d, 2H); 7.45 (m, 2H); 7.32 (m, 6H); 6.88 (s, 1H); 6.84 (s, 1H); 6.78 (s, 1H); 5.21 (d, 2H); 4.75-4.30 (m, 3H); 4.04 (m, 1H); 3.83 (m, 1H); 3.74 (dt, 1H); 3.63 (m, 1H); 3.47 (m, 1H); 3.19 (m, 1H); 2.28 (s, 3H); 2.16 (s, 3H); 1.95-1.75 (m, 3H) 1 H NMR (500 MHz; CDCl 3 ): δ 7.83 (d, 2H); 7.45 (m, 2 H); 7.32 (m, 6 H); 6.88 (s, 1 H); 6.84 (s, 1 H); 6.78 (s, 1 H); 5.21 (d, 2 H); 4.75-4.30 (m, 3 H); 4.04 (m, 1 H); 3.83 (m, 1 H); 3.74 (dt, 1 H); 3.63 (m, 1 H); 3.47 (m, 1 H); 3.19 (m, 1 H); 2.28 (s, 3 H); 2.16 (s, 3 H); 1.95-1.75 (m, 3H)

(ii) (R,S)-(3,5-디메틸페닐)-CH(CH2OH)-C(O)-Pro-Pab x HOAc(ii) (R, S)-(3,5-dimethylphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab x HOAc

EtOH(10 mL) 중의 (R,S)-(3,5-디메틸페닐)-CH(CH2OH)-C(O)-Pro-Pab(Z)(0.280 g; 0.50 밀리몰; 상기 단계(i)로부터의 화합물)의 용액에 아세트산(29 μl) 및 Pd/C(5%; 0.140g)를 부가하였다. 용액을 대기압에서 실온으로 2.5 시간 동안 수소처리하였다. 이어서, 혼합물을 하이플로에서 여과하고, 얻어진 용액을 농축하고, 최소량의 물로 용해하고, 동결 건조하여, 백색 결정 0.174 g(88%, 순도 92.1%)을 얻었다.(R, S)-(3,5-dimethylphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab (Z) (0.280 g; 0.50 mmol) in EtOH (10 mL); To acetic acid (29 μl) and Pd / C (5%; 0.140 g) were added to a solution of compound). The solution was hydrotreated at atmospheric pressure for room temperature for 2.5 hours. The mixture was then filtered over Hyflo, and the resulting solution was concentrated, dissolved with a minimum amount of water and lyophilized to give 0.174 g (88%, purity 92.1%) of white crystals.

LS-MS m/z 423 (M + 1)+ LS-MS m / z 423 (M + 1) +

13C NMR (100 MHz; D2O) 카르보닐 및 아미딘 탄소, 부분입체 이성질체 및(또는) 회전 이성질체 174.93, 173.17, 173.02, 166.55, 166.40 13 C NMR (100 MHz; D 2 O) carbonyl and amidine carbon, diastereomers and / or rotamers 174.93, 173.17, 173.02, 166.55, 166.40

실시예 25Example 25

(S)- 또는 (R)-3,5-비스(트리플루오로메틸)페닐-CH(CH2OH)-C(O)-Pro-Pab x HCl(S)-or (R) -3,5-bis (trifluoromethyl) phenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HCl

(i) (R) 및 (S)-2-(3,5-비스(트리플루오로페닐)페닐)-CH(CH2OH)-C(O)-Pro(i) (R) and (S) -2- (3,5-bis (trifluorophenyl) phenyl) -CH (CH 2 OH) -C (O) -Pro

-Pab(Z)-Pab (Z)

DMF(10 mL) 중의 3-히드록시-2-(3,5-비스(트리플루오로메틸)페닐)-프로피온산(284 mg; 0.94 밀리몰; 상기 실시예 M으로부터의 화합물), H-Pro-Pab(Z) x 2HCl(468 mg; 1.03 밀리몰; 국제특허출원 WO 제97/02284호에 기재된 방법에 따라 제조함) 및 TBTU(332 mg; 1.03 밀리몰)의 용액을 0℃로 냉각하고, DIPEA(485 mg; 3.76 밀리몰)을 부가하였다. 반응 혼합물을 실온에서 60 시간 동안 교반하였다. 용액을 물 400 mL에 붓고, pH를 9로 조절하고(NaHCO3 수용액), 용액을 EtOAc 3 x 100 mL로 추출하였다. 합한 유기상을 NaHCO3 수용액, 물, 및 간수로 세척하고, 건조하고(Na2SO4), 증발시켰다. 정제 HPLC(CH3CN:NH4OAc(0.1 M) (55:45))에 의해 2종의 부분입체 이성질체, 화합물 25A(161 mg; 0.24 밀리몰; 순도 HPLC에 의해 86.9 %; 보다 빠르게 움직이는 부분입체 이성질체) 및 화합물 25B(241 mg; 0.36 밀리몰; 순도 HPLC에 의해 90.9 %; 보다 느리게 움직이는 부분입체 이성질체)를 얻었다.3-hydroxy-2- (3,5-bis (trifluoromethyl) phenyl) -propionic acid (284 mg; 0.94 mmol; compound from Example M above), H-Pro-Pab in DMF (10 mL) A solution of (Z) x 2HCl (468 mg; 1.03 mmol; prepared according to the method described in International Patent Application WO 97/02284) and TBTU (332 mg; 1.03 mmol) was cooled to 0 ° C. and DIPEA (485 mg; 3.76 mmol) was added. The reaction mixture was stirred at rt for 60 h. The solution was poured into 400 mL of water, the pH was adjusted to 9 (NaHCO 3 aqueous solution) and the solution was extracted with 3 × 100 mL of EtOAc. The combined organic phases were washed with aqueous NaHCO 3 solution, water, and brine, dried (Na 2 SO 4 ) and evaporated. 2 diastereoisomers, Compound 25A (161 mg; 0.24 mmol; 86.9% by purity HPLC; faster moving diastereomers by purified HPLC (CH 3 CN: NH 4 OAc (0.1 M) (55:45)) Isomer) and compound 25B (241 mg; 0.36 mmol; 90.9% by purity HPLC; slower moving diastereomer).

화합물 25BCompound 25b

1H NMR (500 MHz; CDCl3): 7.80 (s, 3H); 7.67 (d, 2H); 7.56 (t, 1H); 7.41 (dd, 2H); 7.39-7.28 (m, 3H); 7.21 (d, 1H); 5.19 (s, 2H); 4.57 (dd, 1H); 4.33 (m, 2H); 4.12 (m, 1H); 3.96 (t, 1H); 3.84 (m, 1H); 3.77 (dd, 1H); 3.36 (dd, 1H); 2.17 (m, 1H); 2.10-1.87 (m, 4H). 1 H NMR (500 MHz; CDCl 3 ): 7.80 (s, 3H); 7.67 (d, 2 H); 7.56 (t, 1 H); 7.41 (dd, 2 H); 7.39-7.28 (m, 3 H); 7.21 (d, 1 H); 5.19 (s, 2 H); 4.57 (dd, 1 H); 4.33 (m, 2 H); 4.12 (m, 1 H); 3.96 (t, 1 H); 3.84 (m, 1 H); 3.77 (dd, 1 H); 3.36 (dd, 1 H); 2.17 (m, 1 H); 2.10-1.87 (m, 4 H).

(ii) (S)- 또는 (R)-3,5-비스(트리플루오로메틸)페닐-CH(CH2OH)-C(O)-Pro-(ii) (S)-or (R) -3,5-bis (trifluoromethyl) phenyl-CH (CH 2 OH) -C (O) -Pro-

PabPab

EtOH(10 mL) 및 HCl 수용액(1M; 0.7 mL) 중의 화합물 25B(235 mg; 0.35 밀리몰; 상기 단계(i)로부터의 화합물)의 용액에 Pd/C(10%)를 부가하였다. 혼합물을 3 시간 동안 주변 온도 및 대기압하에서 수소처리하였다. 반응 혼합물을 여과하고 농축하고, 물을 부가하고, 얻어진 용액을 동결 건조하여, 백색의 발포성 물질인 표제 화합물 174 mg(83.3 %)(순도 92.7%(HPLC))을 얻었다.Pd / C (10%) was added to a solution of compound 25B (235 mg; 0.35 mmol; compound from step (i) above) in EtOH (10 mL) and aqueous HCl solution (1M; 0.7 mL). The mixture was hydrotreated at ambient temperature and atmospheric pressure for 3 hours. The reaction mixture was filtered and concentrated, water was added, and the resulting solution was lyophilized to give 174 mg (83.3%) of the title compound (purity 92.7% (HPLC)) as a white foam.

LC-MS m/z 531(M + 1)+ LC-MS m / z 531 (M + 1) +

실시예 26Example 26

(R,S)-3-메톡시-5-메틸페닐-CH(CH2OH)-C(O)-Pro-Pab x HCl(R, S) -3-methoxy-5-methylphenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HCl

(i) (R,S)-(3-메톡시-5-메틸페닐)-CH(CH2OH)-C(O)-Pro-Pab(Z)(i) (R, S)-(3-methoxy-5-methylphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab (Z)

CH2Cl2 중의 3-히드록시-2-(3-메톡시-5-메틸페닐)-프로피온산(0.19 g; 0.9 밀리몰; 상기 실시예 N으로부터의 화합물), H-Aze-Pab(Z) x 2HCl(0.35 g; 0.99 밀리몰; 상기 실시예 A로부터의 화합물) 및 TBTU(0.32 g; 0.99 밀리몰)의 혼합물을 빙조에서 냉각하고, DIPEA(0.47 g, 3.7 밀리몰)를 부가하였다. 혼합물을 실온에서 철야 교반하고, 이후에 CH2Cl2를 증발시키고, 조 혼합물을 플래시 크로마토그래피하였다(CH2Cl2:THF:MeOH(11:2:1); Si-겔). 모은 분획물을 H2O에 용해하고, 다소 탁한 수용액을 EtOAc로 추출하였다. 유기층을 건조하고(Na2SO4) 증발시켜 부표제 화합물 0.18 g(35%)을 얻었다.3-hydroxy-2- (3-methoxy-5-methylphenyl) -propionic acid (0.19 g; 0.9 mmol; compound from Example N above), H-Aze-Pab (Z) x 2HCl in CH 2 Cl 2 (0.35 g; 0.99 mmol; compound from Example A above) and TBTU (0.32 g; 0.99 mmol) were cooled in an ice bath and DIPEA (0.47 g, 3.7 mmol) was added. The mixture was stirred overnight at room temperature, after which time CH 2 Cl 2 was evaporated and the crude mixture was flash chromatographed (CH 2 Cl 2 : THF: MeOH (11: 2: 1); Si-gel). The combined fractions were dissolved in H 2 O and the rather turbid aqueous solution was extracted with EtOAc. The organic layer was dried (Na 2 SO 4 ) and evaporated to yield 0.18 g (35%) of the subtitle compound.

1H NMR (500 MHz; CDCl3); δ 9.5 (b, 1H); 7.77 (dd, 2H); 7.43 (m, 2H); 7.37-7.21 (m, 6H); 6.63 (d, 1H); 6.59 (m, 1H); 5.20 (d, 2H); 4.67 (d, 0.5H); 4.58 (dd, 0.5H); 4.40 (m, 2H); 4.07 (dd, 0.5H); 4.00 (dd, 0.5H); 3.82 (m, 1H); 3.75 (s, 3H); 3.69 (m, 2H); 3.48 (m, 1H); 3.21 (m, 1H); 2.28 (s, 3H); 2.05-1.94 (m, 1H); 1.95-1.75 (m, 3H). 1 H NMR (500 MHz; CDCl 3 ); δ 9.5 (b, 1 H); 7.77 (dd, 2 H); 7.43 (m, 2 H); 7.37-7.21 (m, 6 H); 6.63 (d, 1 H); 6.59 (m, 1 H); 5.20 (d, 2 H); 4.67 (d, 0.5 H); 4.58 (dd, 0.5 H); 4.40 (m, 2 H); 4.07 (dd, 0.5 H); 4.00 (dd, 0.5 H); 3.82 (m, 1 H); 3.75 (s, 3 H); 3.69 (m, 2 H); 3.48 (m, 1 H); 3.21 (m, 1 H); 2.28 (s, 3 H); 2.05-1.94 (m, 1 H); 1.95-1.75 (m, 3 H).

(ii) (R,S)-(3-메톡시-5-메틸페닐)-CH(CH2OH)-C(O)-Pro-Pab x HCl(ii) (R, S)-(3-methoxy-5-methylphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab x HCl

EtOH(10 mL) 중의 (R,S)-(3-메톡시-5-메틸페닐)-CH(CH2OH)-C(O)-Pro-Pab(Z)(100 mg; 0.17 밀리몰; 상기 단계(i)로부터의 화합물), 진한 HCl 수용액(10방울) 및 Pd/C(10%)의 혼합물을 실온 및 대기압에서 2 시간 동안 수소처리하였다. 얻어진 혼합물을 하이플로를 통해 여과하고, 농축하고 최소량의 물에 용해하였다. 동결 건조하여 표제 화합물 75 mg(90%)을 얻었다(순도- HPLC에 의해 92%).(R, S)-(3-methoxy-5-methylphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab (Z) (100 mg; 0.17 mmol) in EtOH (10 mL); compound from (i)), concentrated aqueous HCl solution (10 drops) and Pd / C (10%) were hydrotreated for 2 hours at room temperature and atmospheric pressure. The resulting mixture was filtered through hyflo, concentrated and dissolved in a minimum amount of water. Lyophilization gave 75 mg (90%) of the title compound (Purity-92% by HPLC).

LC-LM m/z 440 (M + 1)+ LC-LM m / z 440 (M + 1) +

실시예 27Example 27

(R,S)-(2,5-디메톡시페닐)-CH(CH2OH)-C(O)-Pro-Pab x HOAc(R, S)-(2,5-Dimethoxyphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab x HOAc

(i) (R,S)-(2,5-디메톡시페닐)-CH(CH2OH)-C(O)-Pro-Pab(Z)(i) (R, S)-(2,5-dimethoxyphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab (Z)

DMF(10 mL) 중의 (R,S)-3-히드록시-2-(2,5-디메톡시페닐)-프로피온산(0.23 g; 1.0 밀리몰; 상기 실시예 O로부터의 화합물)의 용액을 0 ℃로 냉각하였다. H-Pro-Pab(Z) x 2HCl(0.500 g; 1.1 밀리몰; 국제특허출원 WO 제97/02284호에 기재된 방법에 따라 제조함), TBTU(0.353 g; 1.1 밀리몰), 및 DIPEA(0.517 g; 4.0 밀리몰)을 (순서대로) 부가하고, 용액을 실온에서 3 일 동안 교반하였다. DMF를 증발시키고, 얻어진 혼합물을 RPLC(CH3CN:NH4OAc(10%)(40:60))에 의해 정제하였다. CH3CN을 증발시키고, 수성상을 EtOAc로 추출하였다. 유기상을 건조하고(Na2SO4) 증발 건조하였다. 연분홍색 고체인 부표제 생성물(400 mg; 68 %)을 단리하였다.A solution of (R, S) -3-hydroxy-2- (2,5-dimethoxyphenyl) -propionic acid (0.23 g; 1.0 mmol; compound from Example O above) in DMF (10 mL) was brought to 0 ° C. Cooled to. H-Pro-Pab (Z) x 2HCl (0.500 g; 1.1 mmol; prepared according to the method described in International Patent Application WO97 / 02284), TBTU (0.353 g; 1.1 mmol), and DIPEA (0.517 g; 4.0 mmol) was added (in order) and the solution was stirred at room temperature for 3 days. DMF was evaporated and the resulting mixture was purified by RPLC (CH 3 CN: NH 4 OAc (10%) (40:60)). CH 3 CN was evaporated and the aqueous phase was extracted with EtOAc. The organic phase was dried (Na 2 SO 4 ) and evaporated to dryness. The subtitle product (400 mg; 68%), which is a pale pink solid, was isolated.

1H NMR (500 MHz; CDCl3); δ 7.19 (d, 3H); 7.43 (dd, 1H); 7.43 (dt, 1H); 7.30 (d, 1H); 6.82-6.72 (m, 4H); 6.68 (d, 1H); 5.20 (d, 3H); 4.70-4.57 (m, 1H); 4.52-4.30 (m, 5H); 3.96 (m, 1H); 3.72 (s, 3H); 3.70 (m, 1H); 3.60 (s, 3H); 3.65-3.45 (m, 2H); 3.18-3.02 (m, 1H); 2.29 (m, 1H); 2.04-1.96 (m, 1H); 1.95-1.74 (m, 4H). 1 H NMR (500 MHz; CDCl 3 ); δ 7.19 (d, 3H); 7.43 (dd, 1 H); 7.43 (dt, 1 H); 7.30 (d, 1 H); 6.82-6.72 (m, 4 H); 6.68 (d, 1 H); 5.20 (d, 3 H); 4.70-4.57 (m, 1 H); 4.52-4.30 (m, 5 H); 3.96 (m, 1 H); 3.72 (s, 3 H); 3.70 (m, 1 H); 3.60 (s, 3 H); 3.65-3.45 (m, 2 H); 3.18-3.02 (m, 1 H); 2.29 (m, 1 H); 2.04-1.96 (m, 1 H); 1.95-1.74 (m, 4 H).

(ii) (R,S)-(2,5-디메톡시페닐)-CH(CH2OH)-C(O)-Pro-Pab x HOAc(ii) (R, S)-(2,5-dimethoxyphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab x HOAc

EtOH(10 mL) 중의 (R,S)-(2,5-디메톡시페닐)-CH(CH2OH)-C(O)-Pro-Pab(Z)(0.375 g; 0.64 밀리몰; 상기 단계(i)로부터의 화합물)의 용액에 아세트산(36 μL) 및 Pd/C(5%; 0.190 g)을 부가하였다. 용액을 3.5 시간 동안 실온 및 대기압하에서 수소처리하였다. 혼합물을 하이플로를 통해 여과하고, 얻어진 용액을 농축하고, 최소량의 물에 용해하고, 동결 건조하여, 백색의 결정0.174 g(88 %; 순도 92.1%)을 얻었다.(R, S)-(2,5-dimethoxyphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab (Z) (0.375 g; 0.64 mmol) in EtOH (10 mL); To a solution of compound from i)) acetic acid (36 μL) and Pd / C (5%; 0.190 g) were added. The solution was hydrotreated at room temperature and atmospheric pressure for 3.5 hours. The mixture was filtered through hyflo and the resulting solution was concentrated, dissolved in a minimum amount of water and lyophilized to give 0.174 g (88%; purity 92.1%) of white crystals.

LC-MS m/z 455(M + 1)+ LC-MS m / z 455 (M + 1) +

실시예 28Example 28

(R,S)-(3,5-디메톡시페닐)-CH(CH2OH)-C(O)-Pro-Pab x HCl(R, S)-(3,5-Dimethoxyphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab x HCl

(i) (R,S)-(3,5-디메톡시페닐)-CH(CH2OH)-C(O)-Pro-Pab(Z)(i) (R, S)-(3,5-dimethoxyphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab (Z)

DMF(10 mL) 중의 (R,S)-3-히드록시-2-(3,5-디메톡시페닐)-프로피온산(0.18 g; 0.8 밀리몰; 상기 실시예 P로부터의 화합물), H-Pro-Pab(Z) x 2HCl(0.40 g; 0.88 밀리몰; 국제특허출원 WO 제97/02284호에 기재된 방법에 따라 제조함) 및 TBTU(0.28 g; 0.88 밀리몰)의 혼합물을 빙조에서 냉각하고, DIPEA(0.39 g, 3.0 밀리몰)을 부가하였다. 혼합물을 실온에서 철야 교반하고, 이후에 얻어진 혼합물을 농축하였다. 조생성물을 플래시 크로마토그래피하였다(CH2Cl2:THF:MeOH(10:3:1); Si-겔). 모아진 분획물에 물을 부가하고, 얻어진 혼합물을 EtOAc로 추출하였다. 유기층을 건조하고(Na2SO4) 증발시켜 부표제 화합물 0.32 g(68 %)을 얻었다.(R, S) -3-hydroxy-2- (3,5-dimethoxyphenyl) -propionic acid (0.18 g; 0.8 mmol; compound from Example P above), H-Pro- in DMF (10 mL) A mixture of Pab (Z) x 2HCl (0.40 g; 0.88 mmol; prepared according to the method described in International Patent Application WO 97/02284) and TBTU (0.28 g; 0.88 mmol) was cooled in an ice bath and DIPEA (0.39 g, 3.0 mmol) was added. The mixture was stirred overnight at room temperature, after which the resulting mixture was concentrated. The crude product was flash chromatographed (CH 2 Cl 2 : THF: MeOH (10: 3: 1); Si-gel). Water was added to the collected fractions and the resulting mixture was extracted with EtOAc. The organic layer was dried (Na 2 SO 4 ) and evaporated to yield 0.32 g (68%) of the subtitle compound.

1H NMR (500 MHz; CDCl3); δ 7.76 (t, 1H); 7.43 (dd, 1H); 7.37-7.20 (m, 6H); 6.40 (d, 2H); 5.20 (d, 2H); 4.65-4.56 (m, 2H); 4.48-4.32 (m, 2H); 4.09-3.98 (m, 4H); 3.82 (m, 2H); 3.75 (s, 3H); 3.66 (s, 3H); 3.52-3.45 (m, 1H); 3.28-3.21 (m, 1H); 2.30-2.18 (m, 1H); 2.04-1.76 (m, 5H). 1 H NMR (500 MHz; CDCl 3 ); δ 7.76 (t, 1 H); 7.43 (dd, 1 H); 7.37-7.20 (m, 6 H); 6.40 (d, 2 H); 5.20 (d, 2 H); 4.65-4.56 (m, 2 H); 4.48-4.32 (m, 2 H); 4.09-3.98 (m, 4 H); 3.82 (m, 2 H); 3.75 (s, 3 H); 3.66 (s, 3 H); 3.52-3.45 (m, 1 H); 3.28-3.21 (m, 1 H); 2.30-2.18 (m, 1 H); 2.04-1.76 (m, 5 H).

(ii) (R,S)-3,5-디메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab x HCl(ii) (R, S) -3,5-dimethoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HCl

EtOH(10 mL) 중의 (R,S)-(3,5-디메톡시페닐)-CH(CH2OH)-C(O)-Pro-Pab(Z)(0.16 g; 0.27 밀리몰; 상기 단계(i)로부터의 화합물)의 용액에 진한 HCl 10 방울 및 Pd/C(10%)를 부가하였다. 혼합물을 2 시간 동안 실온 및 대기압하에서 수소처리하였다. 얻어진 혼합물을 하이플로를 통해 여과하고 증발 건조하여 표제 화합물 0.14 g(100 %, 순도 HPLC에 의해 94.2%)을 얻었다.(R, S)-(3,5-dimethoxyphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab (Z) (0.16 g; 0.27 mmol) in EtOH (10 mL); To the solution of compound from i) 10 drops of concentrated HCl and Pd / C (10%) were added. The mixture was hydrotreated for 2 hours at room temperature and atmospheric pressure. The resulting mixture was filtered through hyflo and evaporated to dryness to afford 0.14 g (100%, 94.2% by purity HPLC) of the title compound.

FAB-MS m/z 455(M + 1)+ FAB-MS m / z 455 (M + 1) +

실시예 29Example 29

(R,S)-3,4-(메틸렌디옥시페닐)-CH(CH2OH)-C(O)-Pro-Pab x HCl(R, S) -3,4- (Methylenedioxyphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab x HCl

(i) (R,S)-(3,4-메틸렌디옥시페닐)-CH(CH2OH)-C(O)-Pro-Pab(Z)(i) (R, S)-(3,4-Methylenedioxyphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab (Z)

CH2Cl2(10 mL) 중의 (R,S)-3-히드록시-2-(3,4-메틸렌디옥시페닐)-프로피온산(0.21 g; 1.0 밀리몰; 상기 실시예 Q로부터의 화합물), H-Pro-Pab(Z) x 2HCl(0.50 g; 1.1 밀리몰; 국제특허출원 WO 제97/02284호에 기재된 방법에 따라 제조함), TBTU(0.35 g; 1.1 밀리몰) 및 DIPEA(0.47 g; 3.7 밀리몰)을 7일 동안 교반하였다. 얻어진 혼합물을 증발시키고, 조생성물을 플래시 크로마토그래피(CH2Cl2:THF(7:3))에 의해 정제하였다. 관심 대상인 합한 분획물을 농축하고 조생성물을 EtOAc 중에 용해하였다. 용액을 물로 세척하고, 건조하고(Na2SO4), 농축하여 부표제 화합물(0.28 g; 49 %)을 얻었다.(R, S) -3-hydroxy-2- (3,4-methylenedioxyphenyl) -propionic acid (0.21 g; 1.0 mmol; compound from Example Q above) in CH 2 Cl 2 (10 mL), H-Pro-Pab (Z) x 2HCl (0.50 g; 1.1 mmol; prepared according to the method described in International Patent Application WO 97/02284), TBTU (0.35 g; 1.1 mmol) and DIPEA (0.47 g; 3.7 Mmol) was stirred for 7 days. The resulting mixture was evaporated and the crude product was purified by flash chromatography (CH 2 Cl 2 : THF (7: 3)). The combined fractions of interest were concentrated and the crude product was dissolved in EtOAc. The solution was washed with water, dried (Na 2 SO 4 ) and concentrated to give a subtitle compound (0.28 g; 49%).

1H NMR (300 MHz; CDCl3); δ 7.79 (d, 1H); 7.72 (d, 1H); 7.42 (m, 2H); 7.36-7.25 (m, 4H); 7.22 (dd, 2H); 6.76-7.57 (m, 3H); 5.91 (s, 2H); 5.87 (dd, 1H); 5.19 (d, 2H); 4.62-4.52 (m, 1H); 4.45-4.30 (m, 1H); 4.00-3.90 (m, 1H); 3.84-3.74 (m, 1H); 3.64 (m, 1H); 3.22 (m, 1H); 2.28-2.23 (m, 1H); 2.23-2.15 (m, 1H); 2.03-1.75 (m, 4H). 1 H NMR (300 MHz; CDCl 3 ); δ 7.79 (d, 1 H); 7.72 (d, 1 H); 7.42 (m, 2 H); 7.36-7.25 (m, 4 H); 7.22 (dd, 2 H); 6.76-7.57 (m, 3 H); 5.91 (s, 2 H); 5.87 (dd, 1 H); 5.19 (d, 2 H); 4.62-4.52 (m, 1 H); 4.45-4.30 (m, 1 H); 4.00-3.90 (m, 1 H); 3.84-3.74 (m, 1 H); 3.64 (m, 1 H); 3.22 (m, 1 H); 2.28-2.23 (m, 1 H); 2.23-2.15 (m, 1 H); 2.03-1.75 (m, 4 H).

(ii) (R,S)-3,4-메틸렌디옥시페닐-CH(CH2OH)-C(O)-Pro-Pab x HCl(ii) (R, S) -3,4-methylenedioxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HCl

EtOH(10 mL) 중의 (R,S)-(3,4-메틸렌디옥시페닐)-CH(CH2OH)-C(O)-Pro-Pab(Z)(90 mg; 0.16 밀리몰; 상기 단계(i)로부터의 화합물)의 용액에 진한 HCl 6 방울 및 Pd/C(10%)를 부가하였다. 혼합물을 2 시간 동안 실온 및 대기압하에서 수소처리하였다. 얻어진 혼합물을 하이플로를 통해 여과하고 증발 건조하여 표제 화합물 69 mg(92 %)을 얻었다.(R, S)-(3,4-Methylenedioxyphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab (Z) (90 mg; 0.16 mmol) in EtOH (10 mL); To the solution of (compound from (i)) was added 6 drops of concentrated HCl and Pd / C (10%). The mixture was hydrotreated for 2 hours at room temperature and atmospheric pressure. The resulting mixture was filtered through hyflo and evaporated to dryness to give 69 mg (92%) of the title compound.

FAB-MS 439 (M + 1)+ FAB-MS 439 (M + 1) +

13C NMR (100 MHz; CDCl3)(카르보닐 및 아미딘 탄소; 회전 이성질체 및(또는) 부분입체 이성질체에 기인하는 복합화) 174.96, 174.79, 173.04, 166.58, 172.99, 166.45 13 C NMR (100 MHz; CDCl 3 ) (carbonyl and amidine carbon; complex due to rotamers and / or diastereomers) 174.96, 174.79, 173.04, 166.58, 172.99, 166.45

실시예 30Example 30

(S)- 또는 (R)-3-(1-나프틸)-CH(CH2OH)-C(O)-Pro-Pab(S)-or (R) -3- (1-naphthyl) -CH (CH 2 OH) -C (O) -Pro-Pab

(i) (R)- 및 (S)-3-(1-나프틸)-CH(CH2OH)-C(O)-Pro-Pab(Z)(i) (R)-and (S) -3- (1-naphthyl) -CH (CH 2 OH) -C (O) -Pro-Pab (Z)

DMF(10 mL) 중의 (R,S)-3-히드록시-2-(1-나프틸)-프로피온산(0.3 g; 1.39 밀리몰; 상기 실시예 R로부터의 화합물), H-Pro-Pab(Z)(0.692 g; 1.53 밀리몰; 국제특허출원 WO 제97/02284호에 기재된 방법에 따라 제조함) 및 TBTU(0.490 g; 1.53 밀리몰)의 용액을 0 ℃로 냉각하고, DIPEA(0.93 g; 5.55 밀리몰)를 부가하였다. 얻어진 혼합물을 실온에서 60 시간 동안 교반하였다. DMF를 부분 증발시키고, 잔류물을 물 400 mL에 부었다. pH를 9로 조절하고(NaHCO3 수용액), 용액을 EtOAc 3 x 100 mL로 추출하였다. 합한 유기상을 NaHCO 수용액, 물 및 간수로 세척하고, 건조하고(Na2SO4), 증발시켰다. 정제 HPLC(CH3CN: H4NOAc (0.1M) (45:55))에 의해 2개의 부분입체 이성질체, 화합물 30A(262 mg; 0.45 밀리몰; 순도-HPLC에 의해 92.4%; 보다 빠르게 움직이는 부분입체 이성질체) 및 화합물 30B(199 mg; 0.34 밀리몰; 순도-HPLC에 의해 99.9%; 보다 느리게 움직이는 부분입체 이성질체)를 분리하였다.(R, S) -3-hydroxy-2- (1-naphthyl) -propionic acid (0.3 g; 1.39 mmol; compound from Example R above), H-Pro-Pab (Z in DMF (10 mL) ) (0.692 g; 1.53 mmol; prepared according to the method described in international patent application WO 97/02284) and a solution of TBTU (0.490 g; 1.53 mmol) was cooled to 0 ° C. and DIPEA (0.93 g; 5.55 mmol). ) Was added. The resulting mixture was stirred at rt for 60 h. DMF was partially evaporated and the residue was poured into 400 mL of water. The pH was adjusted to 9 (NaHCO 3 aqueous solution) and the solution extracted with EtOAc 3 × 100 mL. The combined organic phases were washed with aqueous NaHCO solution, water and brine, dried (Na 2 SO 4 ) and evaporated. Two diastereomers, Compound 30A (262 mg; 0.45 mmol; 92.4% by purity-HPLC; faster moving diastereomers by purified HPLC (CH 3 CN: H 4 NOAc (0.1M) (45:55)) Isomer) and Compound 30B (199 mg; 0.34 mmol; 99.9% by purity-HPLC; slower moving diastereomer).

LC-MC m/z 580 (M + 1)+ (2개의 부분입체 이성질체 모두)LC-MC m / z 580 (M + 1) + (both diastereoisomers)

(ii) (S)- 또는 (R)-3-(1-나프틸)-CH(CH2OH)-C(O)-Pro-Pab x HCl(ii) (S)-or (R) -3- (1-naphthyl) -CH (CH 2 OH) -C (O) -Pro-Pab x HCl

EtOH(10 mL) 및 HCl 수용액(1M; 0.66 mL) 중의 화학식 30B(190 mg; 0.16 밀리몰; 상기 단계(i)로부터의 화합물)의 용액에 Pd/C(10%)을 부가하고, 혼합물을 실온 및 대기압에서 3 시간 동안 수소처리하였다. 얻어진 혼합물을 하이플로를 통해 여과하고 용액을 증발시켰다. 물을 부가하고 용액을 동결 건조하여 백색 발포성 물질 157 mg(99.4%, 순도-HPLC에 의해 99.8%)를 얻었다.To the solution of formula 30B (190 mg; 0.16 mmol; compound from step (i) above) in EtOH (10 mL) and aqueous HCl solution (1M; 0.66 mL) was added Pd / C (10%) and the mixture was allowed to come to room temperature. And hydrotreated at atmospheric pressure for 3 hours. The resulting mixture was filtered through hyflo and the solution was evaporated. Water was added and the solution was lyophilized to yield 157 mg (99.4%, 99.8% by purity-HPLC) of white foam.

LC-MS m/z 445 (M + 1)+ LC-MS m / z 445 (M + 1) +

실시예 31Example 31

(R,S)-3,5-디메톡시페닐-CH(CH2OH)-C(O)-Aze-Pab x HOAc(R, S) -3,5-dimethoxyphenyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

(i) (R,S)-3,5-디메톡시페닐-CH(CH2OH)-C(O)-Aze-Pab(Z)(i) (R, S) -3,5-dimethoxyphenyl-CH (CH 2 OH) -C (O) -Aze-Pab (Z)

DMF(10 mL) 중의 (R,S)-3-히드록시-2-(3,5-디메톡시페닐)-프로피온산(0.27 g; 1.2 밀리몰; 상기 실시예 W로부터의 화합물)의 용액을 0 ℃로 냉각하였다. H-Aze-Pab(Z) x 2HCl(0.57 g; 1.3 밀리몰; 상기 실시예 A로부터의 화합물), TBTU(0.42 g; 1.3 밀리몰), 및 DIPEA(0.54 g; 4.2 밀리몰)을 순서대로 부가하고, 용액을 실온에서 2 일 동안 교반하였다. DMF를 증발시키고, 조생성물을 CH2Cl2:THF:MeOH(80:30:5)로 용출되는 실리카 겔 칼럼 상에서 플래시 크로마토그래피에 의해 정제하여 부표제 생성물 230 mg(34%)를 수득하였다.A solution of (R, S) -3-hydroxy-2- (3,5-dimethoxyphenyl) -propionic acid (0.27 g; 1.2 mmol; compound from Example W above) in DMF (10 mL) was brought to 0 ° C. Cooled to. H-Aze-Pab (Z) × 2HCl (0.57 g; 1.3 mmol; compound from Example A), TBTU (0.42 g; 1.3 mmol), and DIPEA (0.54 g; 4.2 mmol) were added in this order, The solution was stirred at rt for 2 days. DMF was evaporated and the crude product was purified by flash chromatography on a silica gel column eluting with CH 2 Cl 2 : THF: MeOH (80: 30: 5) to give 230 mg (34%) of the title product.

1H NMR (400 MHz; CDCl3); δ 8.20 (d, 1H); 7.75 (t, 2H); 7.40 (t, 2H); 7.30 (m, 5H); 6.40 (s, 1H); 6.37 (m, 1H); 6.30 (s, 1H); 5.20 (d, 2H); 4.85 (m, 1H); 4.40 (m, 2H); 4.05 (m, 2H); 3.75 (s, 6H); 3.65 (s, 3H); 2.55 (m, 1H); 2.35 (m, 1H). 1 H NMR (400 MHz; CDCl 3 ); δ 8.20 (d, 1 H); 7.75 (t, 2 H); 7.40 (t, 2 H); 7.30 (m, 5 H); 6.40 (s, 1 H); 6.37 (m, 1 H); 6.30 (s, 1 H); 5.20 (d, 2 H); 4.85 (m, 1 H); 4.40 (m, 2 H); 4.05 (m, 2 H); 3.75 (s, 6 H); 3.65 (s, 3 H); 2.55 (m, 1 H); 2.35 (m, 1 H).

(ii) (R,S)-3,5-디메톡시페닐-CH(CH2OH)-C(O)-Aze-Pab x HOAc(ii) (R, S) -3,5-dimethoxyphenyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

EtOH(10 mL) 및 HOAc(10 방울) 중의 (R,S)-3,5-디메톡시페닐-CH(CH2OH)-C(O)-Aze-Pab(Z)(270 g; 0.42 밀리몰; 상기 단계(i)로부터의 화합물)의 용액에 Pd/C(10%)을 부가하고, 혼합물을 2 시간 동안 실온 및 대기압하에서 수소처리하였다. 얻어진 혼합물을 하이플로를 통해 여과하였다. 용액을 증발시키고, 물을 부가하고 용액을 동결 건조하여, 표제 화합물 170 mg(89 %)을 얻었다.(R, S) -3,5-dimethoxyphenyl-CH (CH 2 OH) -C (O) -Aze-Pab (Z) (270 g; 0.42 mmol) in EtOH (10 mL) and HOAc (10 drops) Pd / C (10%) was added to the solution of the compound from step (i) above and the mixture was hydrotreated for 2 hours at room temperature and atmospheric pressure. The resulting mixture was filtered through hyflo. The solution was evaporated, water was added and the solution was lyophilized to give 170 mg (89%) of the title compound.

FAB-MS m/z 441 (M + 1)+ FAB-MS m / z 441 (M + 1) +

1H NMR (400 MHz; D2O): δ 7.8 (m, 1H); 7.68 (d, 1H); 7.57 (m, 1H); 7.39 (d, 1H); 6.60 (m, 1H); 6.54 (m, 1H); 6.45 (m, 1H); 5.00 (m, 1H); 4.50 (m, 3H); 4.10 (m, 3H); 3.80 (m, 9H); 2.60 (m, 1H); 2.28 (m, 1H); 1.95 (s, 3H). 1 H NMR (400 MHz; D 2 O): δ 7.8 (m, 1H); 7.68 (d, 1 H); 7.57 (m, 1 H); 7.39 (d, 1 H); 6.60 (m, 1 H); 6.54 (m, 1 H); 6.45 (m, 1 H); 5.00 (m, 1 H); 4.50 (m, 3 H); 4.10 (m, 3 H); 3.80 (m, 9 H); 2.60 (m, 1 H); 2.28 (m, 1 H); 1.95 (s, 3 H).

13C NMR (100 MHz; D2O) 카르보닐 및 아미딘 탄소; δ 182.0; 174.4; 174.0; (회전 이성질체 및(또는) 부분입체 이성질체에); 173.2; 172.9; 172.8 (회전 이성질체 및(또는) 부분입체 이성질체) 13 C NMR (100 MHz; D 2 O) carbonyl and amidine carbon; δ 182.0; 174.4; 174.0; (In rotational isomers and / or diastereomers); 173.2; 172.9; 172.8 (rotary isomers and / or diastereomers)

실시예 32Example 32

(R,S)-2-클로로-5-아미노페닐-CH(CH2OH)-C(O)-Aze-Pab x HOAc(R, S) -2-Chloro-5-aminophenyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

(i) (R,S)-2-클로로-5-(Boc-아미노)페닐-CH(CH2OH)-C(O)-Aze-Pab(Z)(i) (R, S) -2-Chloro-5- (Boc-amino) phenyl-CH (CH 2 OH) -C (O) -Aze-Pab (Z)

DMF(10 mL) 중의 (R,S)-3-히드록시-2-(2-클로로-5-(Boc-아미노)페닐)프로피온산(0.22 g; 0.7 밀리몰; 상기 실시예 X로부터의 화합물)의 용액을 0 ℃로 냉각하였다. H-Aze-Pab(Z) x 2HCl(0.32 g; 0.75 밀리몰; 상기 실시예 A로부터의 화합물), TBTU(0.24 g, 0.75 밀리몰), 및 DIPEA(0.32 g; 2.5 밀리몰)을 순서대로 부가하고, 용액을 실온에서 2 일 동안 교반하였다. DMF를 증발시키고, 조생성물을 CH2Cl2:THF:MeOH(85:15:5)로 용출되는 실리카 겔 칼럼 상에서 플래시 크로마토그래피에 의해 정제하여 부표제 생성물 180 mg(39%)을 얻었다.Of (R, S) -3-hydroxy-2- (2-chloro-5- (Boc-amino) phenyl) propionic acid (0.22 g; 0.7 mmol; compound from Example X above) in DMF (10 mL) The solution was cooled to 0 ° C. H-Aze-Pab (Z) x 2HCl (0.32 g; 0.75 mmol; compound from Example A), TBTU (0.24 g, 0.75 mmol), and DIPEA (0.32 g; 2.5 mmol) were added in this order, The solution was stirred at rt for 2 days. DMF was evaporated and the crude product was purified by flash chromatography on a silica gel column eluting with CH 2 Cl 2 : THF: MeOH (85: 15: 5) to give 180 mg (39%) of the title product.

1H NMR (300 MHz; CDCl3); δ 9.45 (b, 1H); 8.23 (m, 0.5H); 7.95 (m, 0.5H); 7.65 (m, 3H); 7.20 (m, 10H); 5.15 (d, 2H); 4.85 (m, 1H); 4.5-3.6 (m, 9H); 2.40 (m, 2H); 1.45 (s, 9H). 1 H NMR (300 MHz; CDCl 3 ); δ 9.45 (b, 1 H); 8.23 (m, 0.5 H); 7.95 (m, 0.5 H); 7.65 (m, 3 H); 7.20 (m, 10 H); 5.15 (d, 2 H); 4.85 (m, 1 H); 4.5-3.6 (m, 9 H); 2.40 (m, 2 H); 1.45 (s, 9 H).

(ii) (R,S)-2-클로로-5-아미노페닐-CH(CH2OH)-C(O)-Aze-Pab x HOAc(ii) (R, S) -2-Chloro-5-aminophenyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

(R,S)-2-클로로-5-(Boc-아미노)페닐-CH(CH2OH)-C(O)-Aze-Pab(Z)(170 mg; 0.26 밀리몰; 상기 단계(i)로부터의 화합물), TFA(5.3 mL; 69 밀리몰) 및 티오아니졸(1.6 g; 13 밀리몰)로부터 상기 실시예 23(ii)에 기재된 방법에 따라 제조하여 표제 생성물 40 mg(32 %)을 얻었다.(R, S) -2-Chloro-5- (Boc-amino) phenyl-CH (CH 2 OH) -C (O) -Aze-Pab (Z) (170 mg; 0.26 mmol; from step (i) above Compound), TFA (5.3 mL; 69 mmol) and thianiazole (1.6 g; 13 mmol) according to the method described in Example 23 (ii) above to give 40 mg (32%) of the title product.

1H NMR (400 MHz; D2O); δ 7.62 (m, 1H); 7.60 (d, 1H); 7.40 (m, 1H); 7.30 (m, 1H); 7.05 (t, 1H); 6.60 (m, 2H); 4.90 (m, 1H); 4.41 (s, 1H); 3.90 (m, 3H); 3.65 (m, 1H); 3.60 (m, 1H); 2.40 (m, 1H); 2.05 (m, 1H); 1.80 (s, 3H) 1 H NMR (400 MHz; D 2 O); δ 7.62 (m, 1 H); 7.60 (d, 1 H); 7.40 (m, 1 H); 7.30 (m, 1 H); 7.05 (t, 1 H); 6.60 (m, 2 H); 4.90 (m, 1 H); 4.41 (s, 1 H); 3.90 (m, 3 H); 3.65 (m, 1 H); 3.60 (m, 1 H); 2.40 (m, 1 H); 2.05 (m, 1 H); 1.80 (s, 3 H)

실시예 33Example 33

(S)- 또는 (R)-3-메틸페닐-CH(CH2OH)-C(O)-Aze-Pab x HOAc(S)-or (R) -3-methylphenyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

(i) (R,S)-3-메틸페닐-CH(CH2OH)-C(O)-Aze-Pab(Z)(i) (R, S) -3-methylphenyl-CH (CH 2 OH) -C (O) -Aze-Pab (Z)

DMF(10 mL) 중의 (R,S)-3-히드록시-2-(3-메틸페닐)프로피온산(0.18 g; 1 밀리몰; 상기 실시예 Y로부터의 화합물)용액을 0 ℃로 냉각하였다. H-Aze-Pab(Z) x 2 HCl(0.48 g; 1.1 밀리몰; 상기 실시예 A로부터의 화합물), TBTU(0.35 g; 1.1 밀리몰), 및 DIPEA(0.52 g; 4 밀리몰)을 순서대로 부가하고, 용액을 실온에서 2 일 동안 교반하였다. DMF를 증발시키고, 얻어진 물질은 NaHCO3 수용액(300 mL)에 용해하고 EtOAc(100 mL)를 부가하였다. 상들을 분리하고 수성상을 EtOAc(4 x 75 mL)로 추출하였다. 합한 유기상을 NaHCO 수용액(1 x 75 mL)로 세척하고, 건조하고(Na2SO4), 증발시켰다. RPLC(CH3CN: H4NOAc (10 %) (40:60))에 의해 조생성물(0.3 g)을 정제하여 부표제 생성물(118 mg; 20%)을 얻었다.The (R, S) -3-hydroxy-2- (3-methylphenyl) propionic acid (0.18 g; 1 mmol; compound from Example Y above) solution in DMF (10 mL) was cooled to 0 ° C. H-Aze-Pab (Z) x 2 HCl (0.48 g; 1.1 mmol; compound from Example A), TBTU (0.35 g; 1.1 mmol), and DIPEA (0.52 g; 4 mmol) were added in this order The solution was stirred for 2 days at room temperature. DMF was evaporated and the resulting material was dissolved in aqueous NaHCO 3 (300 mL) and EtOAc (100 mL) was added. The phases were separated and the aqueous phase was extracted with EtOAc (4 x 75 mL). The combined organic phases were washed with aqueous NaHCO (1 × 75 mL), dried (Na 2 SO 4 ) and evaporated. The crude product (0.3 g) was purified by RPLC (CH 3 CN: H 4 NOAc (10%) (40:60)) to give the subtitle product (118 mg; 20%).

LC-MS m/z 528 (M + 1)+ LC-MS m / z 528 (M + 1) +

1H NMR (500 MHz; CDCl3); δ 8.25 (m, 1H); 7.77 (d, 1H); 7.40 (m, 8H); 7.12 (m, 4H); 5.25 (s, 2H); 4.93 (m, 1H); 4.50 (m, 2H); 4.10 (m, 2H); 3.70 (m, 2H); 3.60 (m, 1H); 2.60 (m, 1H); 2.35 (s, 3H). 1 H NMR (500 MHz; CDCl 3 ); δ 8.25 (m, 1 H); 7.77 (d, 1 H); 7.40 (m, 8 H); 7.12 (m, 4 H); 5.25 (s, 2 H); 4.93 (m, 1 H); 4.50 (m, 2 H); 4.10 (m, 2 H); 3.70 (m, 2 H); 3.60 (m, 1 H); 2.60 (m, 1 H); 2.35 (s, 3 H).

(ii) (S)- 또는 (R)-3-메틸페닐-CH(CH2OH)-C(O)-Aze-Pab x HOAc(ii) (S)-or (R) -3-methylphenyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

EtOH(10 mL) 및 HOAc(17 μL) 중의 (R,S)-3-메틸페닐-CH(CH2OH)-C(O)-Aze-Pab(Z)(114 mg; 0.22 밀리몰; 상기 단계(i)로부터의 화합물) 용액에 Pd/C(5%; 0.13 g)를 부가하고, 혼합물을 실온 및 대기압에서 3 시간 동안 수소처리하였다. 얻어진 혼합물을 하이플로를 통해 여과하였다. 용액을 증발시키고 물을 부가하고, 혼합물을 EtOAc로 세척하고, 용액을 동결 건조하여, 조생성물 48 mg을 수득하였다. RPLC(CH3CN: NH4OAc (10 %) (20:80))에 의해 부분입체 이성질체, 화합물 33A(보다 빠르게 움직이는 부분입체 이성질체; 17 mg) 및 화합물 33B(보다 느리게 움직이는 부분입체 이성질체; 15 mg; 순도 99.1%)를 분리하였다.(R, S) -3-methylphenyl-CH (CH 2 OH) -C (O) -Aze-Pab (Z) (114 mg; 0.22 mmol) in EtOH (10 mL) and HOAc (17 μL); Pd / C (5%; 0.13 g) was added to the solution from i) and the mixture was hydrotreated for 3 hours at room temperature and atmospheric pressure. The resulting mixture was filtered through hyflo. The solution was evaporated and water was added, the mixture was washed with EtOAc and the solution was lyophilized to give 48 mg of crude product. Diastereomers, Compound 33A (faster moving diastereomers; 17 mg) and Compound 33B (slower moving diastereomers) by RPLC (CH 3 CN: NH 4 OAc (10%) (20:80)) mg; purity 99.1%).

화합물 33A:Compound 33A:

LC-MS m/z 395 (M + 1)+ LC-MS m / z 395 (M + 1) +

1H NMR (400 MHz; D2O); δ 7.80 (d, 1H); 7.71 (d, 1H); 7.54 (d, 1H); 7.39 (d, 1H); 7.35 (d, 1H); 7.24 (m, 2H); 7.17 (d, 1H); 5.17 (m, 0.5H); 4.80 (m, 0.5H); 4.60 (s, 2H); 4.2-3.6 (m, 5H); 2.60 (m, 1H); 2.36 (s, 2H); 2.30 (s, 2H); 2.22 (m, 1H); 1.93 (s, 3H) 1 H NMR (400 MHz; D 2 O); δ 7.80 (d, 1 H); 7.71 (d, 1 H); 7.54 (d, 1 H); 7.39 (d, 1 H); 7.35 (d, 1 H); 7.24 (m, 2 H); 7.17 (d, 1 H); 5.17 (m, 0.5 H); 4.80 (m, 0.5 H); 4.60 (s, 2 H); 4.2-3.6 (m, 5 H); 2.60 (m, 1 H); 2.36 (s, 2 H); 2.30 (s, 2 H); 2.22 (m, 1 H); 1.93 (s, 3 H)

13C NMR (75 MHz; D2O) 카르보닐 및 아미딘 탄소: δ 175.7; 174.6; (회전 이성질체); 173.5; 173.0(회전 이성질체) 13 C NMR (75 MHz; D 2 O) carbonyl and amidine carbon: δ 175.7; 174.6; (Rotary isomers); 173.5; 173.0 (rotary isomer)

실시예 34Example 34

(S)- 또는 (R)-2,5-디메틸페닐-CH-(CH2OH)-C(O)-Pro-Pab x HOAc(S)-or (R) -2,5-dimethylphenyl-CH- (CH 2 OH) -C (O) -Pro-Pab x HOAc

(i) (R)- 및 (S)-2,5-디메틸페닐-CH-(CH2OH)-C(O)-Pro-Pab(Z)(i) (R)-and (S) -2,5-dimethylphenyl-CH- (CH 2 OH) -C (O) -Pro-Pab (Z)

DMF(10 mL) 중의 (R,S)-3-히드록시-2-(2,5-디메틸페닐)프로피온산(0.27 g; 1.2 밀리몰; 상기 실시예 Z로부터의 화합물) 용액을 0 ℃로 냉각하였다. H-Pro-Pab(Z) x 2 HCl(0.75 g; 1.65 밀리몰; 국제특허출원 WO 제97/02284호에 기재된 방법에 따라 제조함), TBTU(0.53 g; 1.65 밀리몰), 및 DIPEA(0.78 g; 6 밀리몰)을 순서대로 부가하고, 용액을 실온에서 2 일 동안 교반하였다. DMF를 증발시키고, NaHCO3 수용액을 부가하고, 수용액을 EtOAc(3 x 30 mL)로 추출하였다. 합한 유기상을 NaHCO 수용액(2 x 20 mL), H2O로 세척하고, 건조하고(Na2SO4), 증발시켜 조생성물 0.35 g(42%)를 얻었다. 정제 HPLC(CH3CN: H4NOAc (10 %) ; (45:55 내지 80:20))에 의해 부분입체 이성질체, 화합물 34A(보다 빠르게 움직이는 부분입체 이성질체; 136 mg; 32%, 순도 97.6%) 및 화합물 34B(보다 느리게 움직이는 부분입체 이성질체; 197 mg; 47%; 순도 98.4%)를 분리하였다.A solution of (R, S) -3-hydroxy-2- (2,5-dimethylphenyl) propionic acid (0.27 g; 1.2 mmol; compound from Example Z) in DMF (10 mL) was cooled to 0 ° C. . H-Pro-Pab (Z) x 2 HCl (0.75 g; 1.65 mmol; prepared according to the method described in International Patent Application WO 97/02284), TBTU (0.53 g; 1.65 mmol), and DIPEA (0.78 g) 6 mmol) was added sequentially, and the solution was stirred at room temperature for 2 days. DMF was evaporated, NaHCO 3 aqueous solution was added and the aqueous solution was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with aqueous NaHCO solution (2 × 20 mL), H 2 O, dried (Na 2 SO 4 ) and evaporated to afford 0.35 g (42%) of crude product. Diastereomer, Compound 34A (faster moving diastereomer; 136 mg; 32%, purity 97.6%) by purified HPLC (CH 3 CN: H 4 NOAc (10%); (45:55 to 80:20)) ) And Compound 34B (slower moving diastereomers; 197 mg; 47%; purity 98.4%).

화합물 34B:Compound 34B:

1H NMR (500 MHz; CDCl3); δ 7.83 (d, 2H); 7.45 (d, 2H); 7.40 (m, 1H); 7.35 (m, 4H); 7.08 (d, 1H); 6.99 (d, 1H); 5.22 (s, 2H); 4.63 (d, 1H); 4.49 (m, 2H); 4.04 (dd, 1H); 3.95 (dd, 1H); 3.61 (dd, 1H); 3.53 (dt, 1H); 2.92 (m, 1H); 2.34 (3H); 2.32 (m, 1H); 2.26 (s, 3H); 1.73 (m, 3H). 1 H NMR (500 MHz; CDCl 3 ); δ 7.83 (d, 2 H); 7.45 (d, 2 H); 7.40 (m, 1 H); 7.35 (m, 4 H); 7.08 (d, 1 H); 6.99 (d, 1 H); 5.22 (s, 2 H); 4.63 (d, 1 H); 4.49 (m, 2 H); 4.04 (dd, 1 H); 3.95 (dd, 1 H); 3.61 (dd, 1 H); 3.53 (dt, 1 H); 2.92 (m, 1 H); 2.34 (3 H); 2.32 (m, 1 H); 2.26 (s, 3 H); 1.73 (m, 3 H).

(ii) (S)- 또는 (R)-2,5-디메틸페닐-CH-(CH2OH)-C(O)-Pro-Pab x HOAc(ii) (S)-or (R) -2, 5-dimethylphenyl-CH- (CH 2 OH) -C (O) -Pro-Pab x HOAc

EtOH(10 mL) 및 HOAc(10 방울) 중의 (R)- 또는 (S)-2,5-디메틸페닐-CH-(CH2OH)-C(O)-Pro-Pab(Z)(61 mg; 0.11 밀리몰; 상기 단계(i)로부터의 화합물 34 B) 용액에 Pd/C(5%; 45 mg)를 부가하고, 혼합물을 실온 및 대기압에서 5 시간 동안 수소처리하였다. 얻어진 혼합물을 하이플로를 통해 여과하고, 용액을 농축하고, 물을 부가하고 용액을 동결 건조하여, 백색 분말인 표제 화합물 45 mg(89%, 순도 97.8%)을 얻었다.(R)-or (S) -2,5-dimethylphenyl-CH- (CH 2 OH) -C (O) -Pro-Pab (Z) (61 mg) in EtOH (10 mL) and HOAc (10 drops) 0.11 mmol; Pd / C (5%; 45 mg) was added to the solution of compound 34 B) from step (i) and the mixture was hydrotreated at room temperature and atmospheric pressure for 5 hours. The resulting mixture was filtered through hyflo, the solution was concentrated, water was added and the solution was lyophilized to give 45 mg (89%, purity 97.8%) of the title compound as a white powder.

LC-MS m/z 423 (M + 1)+ LC-MS m / z 423 (M + 1) +

1H NMR (500 MHz; D2O): δ 7.65 (d, 2H); 7.56 (d, 1H); 7.40 (d, 2H); 7.10 (m, 2H); 7.00 (m, 2H); 4.41 (s, 2H); 4.32 (dd, 1H); 4.11 (dd, 1H); 3.91 (m, 1H); 3.64 (m, 1H); 3.55 (m, 2H); 2.98 (m, 1H); 2.26 (s, 3H); 2.18 (s, 3H); 2.05 (m, 1H); 1.80 (m, 6H); 1.65 (m, 2H). 1 H NMR (500 MHz; D 2 O): δ 7.65 (d, 2H); 7.56 (d, 1 H); 7.40 (d, 2 H); 7.10 (m, 2 H); 7.00 (m, 2 H); 4.41 (s, 2 H); 4.32 (dd, 1 H); 4.11 (dd, 1 H); 3.91 (m, 1 H); 3.64 (m, 1 H); 3.55 (m, 2 H); 2.98 (m, 1 H); 2.26 (s, 3 H); 2.18 (s, 3 H); 2.05 (m, 1 H); 1.80 (m, 6 H); 1.65 (m, 2 H).

실시예 35Example 35

(S)- 또는 (R)-4-히드록시-3-메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab x HCl(S)-or (R) -4-hydroxy-3-methoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HCl

(i) (R)- 및 (S)-4-벤질옥시-3-메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab(Z)(i) (R)-and (S) -4-benzyloxy-3-methoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab (Z)

DMF(10 mL) 중의 (R,S)-3-히드록시-2-(4-벤질옥시-3-메톡시페닐)프로피온산(0.27 g; 1.2 밀리몰; 상기 실시예 AA로부터의 화합물) 용액을 0 ℃로 냉각하였다. H-Pro-Pab(Z) x 2 HCl(0.66 g; 1.46 밀리몰; 국제특허출원 WO 제97/02284호에 기재된 방법에 따라 제조함), TBTU(0.467 g; 1.46 밀리몰), 및 DIPEA(0.69 mL; 5.29 밀리몰)을 순서대로 부가하고, 용액을 실온에서 3 일 동안 교반하였다. DMF를 증발시키고, NaHCO3 수용액을 부가하고, 이 수용액을 EtOAc(3 x 100 mL)로 추출하였다. 합한 유기상을 NaHCO3 수용액(1 x 20 mL), H2O 및 간수로 세척하고, 건조하고(Na2SO4), 증발시켜 조생성물 0.983 g(정량적인 양)를 수득하였다. 정제 HPLC(CH3CN: NH4OAc (10 %) (50:50))에 의해 부분입체 이성질체, 화합물 35A(보다 빠르게 움직이는 부분입체 이성질체; 136 mg; 32%, 순도 98.5%) 및 화합물 34B(보다 느리게 움직이는 부분입체 이성질체; 163 mg; 47%; 순도 99.2%)를 분리하였다.A solution of (R, S) -3-hydroxy-2- (4-benzyloxy-3-methoxyphenyl) propionic acid (0.27 g; 1.2 mmol; compound from Example AA above) in DMF (10 mL) Cooled to C. H-Pro-Pab (Z) x 2 HCl (0.66 g; 1.46 mmol; prepared according to the method described in International Patent Application WO 97/02284), TBTU (0.467 g; 1.46 mmol), and DIPEA (0.69 mL) 5.29 mmol) were added in order and the solution was stirred at room temperature for 3 days. DMF was evaporated and aqueous NaHCO 3 solution was added and the aqueous solution was extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with aqueous NaHCO 3 solution (1 × 20 mL), H 2 O and brine, dried (Na 2 SO 4 ) and evaporated to yield 0.983 g (quant.) Of crude product. Diastereomer, Compound 35A (faster moving diastereomer; 136 mg; 32%, purity 98.5%) and Compound 34B (by purified HPLC (CH 3 CN: NH 4 OAc (10%) (50:50))) Slower moving diastereomers: 163 mg; 47%; purity 99.2%).

화합물 35B:Compound 35B:

1H NMR (400 MHz; CDCl3); δ 7.77 (d, 2H); 7.42 (m, 4H); 7.34 (m, 9H); 6.81 (m, 2H); 6.70 (dd, 1H); 5.20 (s, 2H); 5.11 (s, 2H); 4.59 (m, 1H); 4.44 (m, 2H); 4.00 (m, 1H); 3.83 (m, 1H); 3.66 (m, 2H); 3.23 (m, 1H); 2.28 (m, 1H); 2.01 (m, 2H); 1.81 (m, 3H). 1 H NMR (400 MHz; CDCl 3 ); δ 7.77 (d, 2 H); 7.42 (m, 4 H); 7.34 (m, 9 H); 6.81 (m, 2 H); 6.70 (dd, 1 H); 5.20 (s, 2 H); 5.11 (s, 2 H); 4.59 (m, 1 H); 4.44 (m, 2 H); 4.00 (m, 1 H); 3.83 (m, 1 H); 3.66 (m, 2 H); 3.23 (m, 1 H); 2.28 (m, 1 H); 2.01 (m, 2 H); 1.81 (m, 3 H).

(ii) (S)- 또는 (R)-4-히드록시-3-메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab x HCl(ii) (S)-or (R) -4-hydroxy-3-methoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HCl

EtOH(10 mL) 및 HCl 수용액(1M; 0.5 mL) 중의 (R)- 또는 (S)-4-벤질옥시-3-메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab(Z)(157 mg; 0.24 밀리몰; 상기 단계(i)로부터의 화합물 35 B) 용액에 Pd/C(10%)를 부가하고, 혼합물을 실온 및 대기압에서 4.5 시간 동안 수소처리하였다. 얻어진 혼합물을 하이플로를 통해 여과하고, 용액을 농축하고, 물을 부가하고 용액을 동결 건조하여, 백색 분말인 표제 화합물 104 mg(90.9%, 순도 97.4%)을 수득하였다.(R)-or (S) -4-benzyloxy-3-methoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab in EtOH (10 mL) and aqueous HCl solution (1M; 0.5 mL) (Z) (157 mg; 0.24 mmol; Pd / C (10%) was added to the solution of compound 35 B from step (i) above and the mixture was hydrotreated at room temperature and atmospheric pressure for 4.5 hours. The resulting mixture was filtered through hyflo, the solution was concentrated, water was added and the solution was lyophilized to yield 104 mg (90.9%, purity 97.4%) of the title compound as a white powder.

LC-MS m/z 441 (M + 1)+ LC-MS m / z 441 (M + 1) +

1H NMR (400 MHz; D2O); δ 7.70 (d, 2H); 7.57 (d, 2H); 6.90 (s, 1H); 6.75 (s, 2H); 4.51 (s, 2H); 4.44 (dd, 1H); 4.07 (m, 1H); 3.95 (dd, 2H); 3.83 (s, 3H); 3.67 (dd, 2H); 3.40 (m, 1H); 3.30 (m, 1H); 2.11 (m, 1H); 1.97 (m, 2H); 1.82 (m, 1H) 1 H NMR (400 MHz; D 2 O); delta 7.70 (d, 2H); 7.57 (d, 2 H); 6.90 (s, 1 H); 6.75 (s, 2 H); 4.51 (s, 2 H); 4.44 (dd, 1 H); 4.07 (m, 1 H); 3.95 (dd, 2 H); 3.83 (s, 3 H); 3.67 (dd, 2 H); 3.40 (m, 1 H); 3.30 (m, 1 H); 2.11 (m, 1 H); 1.97 (m, 2 H); 1.82 (m, 1 H)

13C-NMR (100 MHz; D2O) 카르보닐 및 아미딘 탄소: δ 174.8; 173.9; 173.1; 166.3 (회전 이성질체) 13 C-NMR (100 MHz; D 2 O) carbonyl and amidine carbon: δ 174.8; 173.9; 173.1; 166.3 (rotary isomers)

실시예 36Example 36

(S)- 또는 (R)-3,5-디클로로페닐-CH(CH2OH)-C(O)-Pro-Pab x HOAc(S)-or (R) -3,5-dichlorophenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HOAc

(i) (R)- 및 (S)-3,5-디클로로페닐-CH(CH2OH)-C(O)-Pro-Pab(Z)(i) (R)-and (S) -3,5-dichlorophenyl-CH (CH 2 OH) -C (O) -Pro-Pab (Z)

DMF(10 mL) 중의 (R,S)-3-히드록시-2-(3,5-디클로로페닐)프로피온산(0.35 g; 1.5 밀리몰; 상기 실시예 AB로부터의 화합물) 용액을 0 ℃로 냉각하였다. H-Pro-Pab(Z) x 2 HCl(0.75 g; 1.65 밀리몰; 국제특허출원 WO 제97/02284호에 기재된 방법에 따라 제조함), TBTU(0.53 g; 1.65 밀리몰), 및 DIPEA(0.78 g; 6 밀리몰)을 순서대로 부가하고, 용액을 실온에서 철야 교반하였다. DMF를 증발시키고, H2O를 부가하고, 수용액을 EtOAc(3 x 30 mL)로 추출하였다. 합한 유기상을 NaHCO 수용액(2 x 20 mL), H2O로 세척하고, 건조하고(Na2SO4), 증발시켜 조생성물 0.32 g(36%)을 수득하였다. 100% EtOAc 내지 EtOAc:EtOH(100:5)의 기울기를 사용하는 실리카 겔(110 g) 상의 플래시 크로마토그래피에 의해 부분입체 이성질체, 화합물 36A(보다 빠르게 움직이는 부분입체 이성질체; 153 mg; 34%, 순도 89.2%) 및 화합물 36B(보다 느리게 움직이는 부분입체 이성질체; 166 mg; 37%; 순도 85.2%)를 분리하였다.A solution of (R, S) -3-hydroxy-2- (3,5-dichlorophenyl) propionic acid (0.35 g; 1.5 mmol; compound from Example AB above) in DMF (10 mL) was cooled to 0 ° C. . H-Pro-Pab (Z) x 2 HCl (0.75 g; 1.65 mmol; prepared according to the method described in International Patent Application WO 97/02284), TBTU (0.53 g; 1.65 mmol), and DIPEA (0.78 g) 6 mmol) was added sequentially, and the solution was stirred overnight at room temperature. DMF was evaporated, H 2 O was added and the aqueous solution was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with aqueous NaHCO solution (2 × 20 mL), H 2 O, dried (Na 2 SO 4 ) and evaporated to afford 0.32 g (36%) of crude product. Diastereomer, Compound 36A (faster moving diastereomer; 153 mg; 34%, purity) by flash chromatography on silica gel (110 g) using a gradient of 100% EtOAc to EtOAc: EtOH (100: 5). 89.2%) and Compound 36B (slower moving diastereoisomers; 166 mg; 37%; purity 85.2%).

화합물 36B:Compound 36B:

1H NMR (500 MHz; CDCl3); δ 7.73 (d, 2H); 7.43 (d, 2H); 7.34 (m, 2H); 7.26 (m, 2H); 7.19 (d, 2H); 5.20 (s, 2H); 4.56 (dd, 1H); 4.40 (m, 2H); 3.91 (m, 2H); 3.72 (m, 2H); 3.60 (b, 1H); 3.27 (q, 1H); 2.22 (m, 1H); 2.03 (m, 1H); 1.94 (m, 1H); 1.89 (m, 1H); 1.75 (b, 1H). 1 H NMR (500 MHz; CDCl 3 ); δ 7.73 (d, 2 H); 7.43 (d, 2 H); 7.34 (m, 2 H); 7.26 (m, 2 H); 7.19 (d, 2 H); 5.20 (s, 2 H); 4.56 (dd, 1 H); 4.40 (m, 2 H); 3.91 (m, 2 H); 3.72 (m, 2 H); 3.60 (b, 1 H); 3.27 (q, 1 H); 2.22 (m, 1 H); 2.03 (m, 1 H); 1.94 (m, 1 H); 1.89 (m, 1 H); 1.75 (b, 1 H).

(ii) (S)- 또는 (R)-3,5-디클로로페닐-CH(CH2OH)-C(O)-Pro-Pab x HOAc(ii) (S)-or (R) -3, 5-dichlorophenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HOAc

(R)- 또는 (S)-3,5-디클로로페닐-CH(CH2OH)-C(O)-Pro-Pab(Z)(130 mg; 0.22 밀리몰; 상기 단계(i)로부터의 화합물 26 B), 아니졸(35 mg, 0.33 밀리몰) 및 트리플루오로메탄 술폰산(0.16 g; 1.1 밀리몰)로부터 실시예 23(ii)에 기재된 방법에 따라 제조하여 표제 화합물 15 mg(13%)을 얻었다.(R)-or (S) -3,5-dichlorophenyl-CH (CH 2 OH) -C (O) -Pro-Pab (Z) (130 mg; 0.22 mmol; compound 26 from step (i) 26 B), anisol (35 mg, 0.33 mmol) and trifluoromethane sulfonic acid (0.16 g; 1.1 mmol) were prepared according to the method described in Example 23 (ii) to give 15 mg (13%) of the title compound.

LC-MS m/z 463, 465 (M + 1)+ LC-MS mlz 463, 465 (M + 1) +

1H NMR (500 MHz; D2O); δ 7.64 (d, 2H); 7.56 (d, 1H); 7.38 (t, 1H); 7.34 (t, 1H); 7.21 (d, 2H); 7.07 (s, 1H); 4.39 (d, 1H); 4.30 (dd, 1H); 4.00 (m, 3H); 3.68 (m, 2H); 3.50 (m, 1H); 3.26 (m, 1H); 2.10 (m, 1H); 2.08 (m, 1H); 1.81 (m, 3H); 1.73 (m, 1H). 1 H NMR (500 MHz; D 2 O); δ 7.64 (d, 2 H); 7.56 (d, 1 H); 7.38 (t, 1 H); 7.34 (t, 1 H); 7.21 (d, 2 H); 7.07 (s, 1 H); 4.39 (d, 1 H); 4.30 (dd, 1 H); 4.00 (m, 3 H); 3.68 (m, 2 H); 3.50 (m, 1 H); 3.26 (m, 1 H); 2.10 (m, 1 H); 2.08 (m, 1 H); 1.81 (m, 3 H); 1.73 (m, 1 H).

실시예 37Example 37

(S)- 또는 (R)-2,3-디메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab x HOAc(S)-or (R) -2,3-dimethoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HOAc

(i) (R)- 및 (S)-2,3-디메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab(Z)(i) (R)-and (S) -2,3-dimethoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab (Z)

DMF(10 mL) 중의 (R,S)-3-히드록시-2-(2,3-디메톡시페닐)프로피온산(0.21 g; 0.93 밀리몰; 상기 실시예 AC로부터의 화합물) 용액을 0 ℃로 냉각하였다. H-Pro-Pab(Z) x 2 HCl(0.46 g; 1.02 밀리몰; 국제특허출원 WO 제97/02284호에 기재된 방법에 따라 제조함), TBTU(0.32 g; 1.0 밀리몰), 및 DIPEA(0.48 g; 3.7 밀리몰)을 순서대로 부가하고, 용액을 실온에서 철야 교반하였다. DMF를 증발시키고, NaHCO3 수용액을 부가하고, 수용액을 EtOAc(4 x 50 mL)로 추출하였다. 합한 유기상을 NaHCO3 수용액(2 x 20 mL), H2O로 세척하고, 건조하고(Na2SO4), 증발시켜 조생성물 0.34 g(62%)을 수득하였다. 정제 HPLC(CH3CN:NH4OAc(10%) (40:60))에 의해 부분입체 이성질체, 화합물 37A(보다 빠르게 움직이는 부분입체 이성질체; 70 mg; 24%) 및 화합물 37B(보다 느리게 움직이는 부분입체 이성질체; 57 mg; 21%)를 분리하였다.Cool a solution of (R, S) -3-hydroxy-2- (2,3-dimethoxyphenyl) propionic acid (0.21 g; 0.93 mmol; compound from Example AC above) in DMF (10 mL) to 0 ° C. It was. H-Pro-Pab (Z) x 2 HCl (0.46 g; 1.02 mmol; prepared according to the method described in International Patent Application WO 97/02284), TBTU (0.32 g; 1.0 mmol), and DIPEA (0.48 g) 3.7 mmol) was added sequentially, and the solution was stirred overnight at room temperature. DMF was evaporated, NaHCO 3 aqueous solution was added and the aqueous solution was extracted with EtOAc (4 × 50 mL). The combined organic phases were washed with aqueous NaHCO 3 solution (2 × 20 mL), H 2 O, dried (Na 2 SO 4 ) and evaporated to afford 0.34 g (62%) of crude product. Diastereomers, Compound 37A (faster moving diastereomers; 70 mg; 24%) and Compound 37B (slower moving parts) by purified HPLC (CH 3 CN: NH 4 OAc (10%) (40:60)) Stereoisomer; 57 mg; 21%).

화합물 37B:Compound 37B:

LC-MS m/z 590 (M + 1)+ LC-MS m / z 590 (M + 1) +

(ii) (S)- 또는 (R)-2,3-디메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab x HOAc(ii) (S)-or (R) -2,3-dimethoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HOAc

EtOH(10 mL) 및 HOAc(15 mg) 중의 (R)- 또는 (S)-2,3-디메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab(Z)(57 mg; 0.097 밀리몰; 상기 단계(i)로부터의 화합물 37 B) 용액에 Pd/C(5%; 44 mg)를 부가하고, 혼합물을 4.5 시간 동안 실온 및 대기압에서 수소처리하였다. 얻어진 혼합물을 하이플로를 통해 여과하고, 용액을 농축하고, 물을 부가하고, 용액을 동결 건조하여 백색 분말인 표제 화합물 44 mg(88%, 순도 97.2 %)을 얻었다.(R)-or (S) -2,3-dimethoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab (Z) (57 mg) in EtOH (10 mL) and HOAc (15 mg) 0.0d mmol; Pd / C (5%; 44 mg) was added to the solution of compound 37 B) from step (i) and the mixture was hydrotreated at room temperature and atmospheric pressure for 4.5 h. The resulting mixture was filtered through hyflo, the solution was concentrated, water was added and the solution was lyophilized to give 44 mg (88%, purity 97.2%) of the title compound as a white powder.

LC-MS m/z 455 (M + 1)+ LC-MS m / z 455 (M + 1) +

1H NMR (300 MHz; D2O); δ 7.78 (d, 2H); 7.50 (d, 2H); 7.20 (m, 2H); 6.90 (d, 1H); 4.50 (s, 2H); 4.40 (m, 4H);4.08 (m, 2H); 3.90 (s, 3H); 3.87 (s, 3H); 3.80 (m, 6H); 3.32 (m, 1H); 2.18 (m, 1H); 1.92 (m, 3H). 1 H NMR (300 MHz; D 2 O); δ 7.78 (d, 2 H); 7.50 (d, 2 H); 7.20 (m, 2 H); 6.90 (d, 1 H); 4.50 (s, 2 H); 4.40 (m, 4 H); 4.08 (m, 2 H); 3.90 (s, 3 H); 3.87 (s, 3 H); 3.80 (m, 6 H); 3.32 (m, 1 H); 2.18 (m, 1 H); 1.92 (m, 3 H).

실시예 38Example 38

(S)- 또는 (R)-3-메톡시-5-클로로페닐-CH(CH2OH)-C(O)-Pro-Pab x HCl(S)-or (R) -3-methoxy-5-chlorophenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HCl

(i) (R)- 및 (S)-3-메톡시-5-클로로페닐-CH(CH2OH)-C(O)-Pro-Pab(Z)(i) (R)-and (S) -3-methoxy-5-chlorophenyl-CH (CH 2 OH) -C (O) -Pro-Pab (Z)

DMF(4 mL) 중의 (R,S)-3-히드록시-2-(3-메톡시-5-클로로페닐)프로피온산(0.112 g; 0.49 밀리몰; 상기 실시예 AD로부터의 화합물) 용액을 0 ℃로 냉각하였다. H-Pro-Pab(Z) x 2 HCl(0.242 g; 0.53 밀리몰; 국제특허출원 WO 제97/02284호에 기재된 방법에 따라 제조함), TBTU(0.171 g; 0.53 밀리몰), 및 DIPEA(0.33 mL; 2.12 밀리몰)을 이 순서로 부가하고, 용액을 실온에서 5일 동안 교반하였다. DMF를 증발시키고, H2O를 부가하고, 용액의 pH를 9로 조절하고(NaHCO3 수용액), 수용액을EtOAc(3 x 30 mL)로 추출하였다. 합한 유기상을 NaHCO3 수용액(2 x 20 mL), H2O 및 간수로 세척하고, 건조하고(Na2SO4), 증발시켜 조생성물 0.242 g(83%)을 얻었다. 정제 HPLC(CH3CN:10% NH4OAc (45:55))에 의해 부분입체 이성질체, 화합물 38A(보다 빠르게 움직이는 부분입체 이성질체; 50 mg; 33%) 및 화합물 38B(보다 느리게 움직이는 부분입체 이성질체; 44.8 mg; 31%)를 분리하였다.A solution of (R, S) -3-hydroxy-2- (3-methoxy-5-chlorophenyl) propionic acid (0.112 g; 0.49 mmol; compound from Example AD above) in DMF (4 mL) was stirred at 0 ° C. Cooled to. H-Pro-Pab (Z) x 2 HCl (0.242 g; 0.53 mmol; prepared according to the method described in WO 97/02284), TBTU (0.171 g; 0.53 mmol), and DIPEA (0.33 mL) 2.12 mmol) was added in this order and the solution was stirred at room temperature for 5 days. DMF was evaporated, H 2 O was added, the pH of the solution was adjusted to 9 (NaHCO 3 aqueous solution), and the aqueous solution was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with aqueous NaHCO 3 solution (2 × 20 mL), H 2 O and brine, dried (Na 2 SO 4 ) and evaporated to afford 0.242 g (83%) of crude product. Diastereomers, Compound 38A (faster moving diastereomers; 50 mg; 33%) and Compound 38B (slower moving diastereomers) by purified HPLC (CH 3 CN: 10% NH 4 OAc (45:55)) 44.8 mg; 31%).

화합물 38B:Compound 38B:

LC-MS m/z 592, 594 (M + 1)+ LC-MS m / z 592, 594 (M + 1) +

(ii) (S)- 또는 (R)-3-메톡시-5-클로로페닐-CH(CH2OH)-C(O)-Pro-Pab x HCl(ii) (S)-or (R) -3-methoxy-5-chlorophenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HCl

(R)- 또는 (S)-3-메톡시-5-클로로페닐-CH(CH2OH)-C(O)-Pro-Pab(Z)(상기 단계(i)로부터의 화합물 38 B; 44 mg; 0.074 밀리몰), TFA(1.53 mL; 20 밀리몰) 및 티오아니졸(0.44 mL; 3.7 밀리몰)로부터 상기 실시예 23(ii)에 기재된 방법에 따라 표제 생성물 18 mg(49%, 순도 93.5 %)을 얻었다.(R)-or (S) -3-methoxy-5-chlorophenyl-CH (CH 2 OH) -C (O) -Pro-Pab (Z) (compound 38 B from step (i) above; 44 mg; 0.074 mmol), TFA (1.53 mL; 20 mmol) and thioaniazole (0.44 mL; 3.7 mmol) according to the method described in Example 23 (ii) above 18 mg (49%, purity 93.5%) Got.

1H NMR (500 MHz; CD3OD): δ 9.24 (b, 1H); 8.73 (b, 1H); 7.77 (d, 2H); 7.57 (d, 2H); 6.96 (t, 1H); 6.86 (m, 2H); 4.51 (s, 2H); 4.45 (dd, 1H); 4.04 (m, 2H); 3.86 (m, 1H); 3.71 (m, 1H); 3.40 (m, 1H); 2.15 (m, 1H); 1.99 (m, 2H); 1.87 (m, 1H). 1 H NMR (500 MHz; CD 3 OD): δ 9.24 (b, 1 H); 8.73 (b, 1 H); 7.77 (d, 2 H); 7.57 (d, 2 H); 6.96 (t, 1 H); 6.86 (m, 2 H); 4.51 (s, 2 H); 4.45 (dd, 1 H); 4.04 (m, 2 H); 3.86 (m, 1 H); 3.71 (m, 1 H); 3.40 (m, 1 H); 2.15 (m, 1 H); 1.99 (m, 2 H); 1.87 (m, 1 H).

실시예 39Example 39

(S)- 또는 (R)-2-메톡시-5-메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab x HOAc(S)-or (R) -2-methoxy-5-methoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HOAc

(i) (R)- 및 (S)-2-메틸-5-메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab(Z)(i) (R)-and (S) -2-methyl-5-methoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab (Z)

DMF(10 mL) 중의 (R,S)-3-히드록시-2-(2-메틸-5-메톡시페닐)프로피온산(0.168 g; 0.8 밀리몰; 상기 실시예 AE로부터의 화합물) 용액을 0 ℃로 냉각하였다. H-Pro-Pab(Z) x 2 HCl(0.399 g; 0.88 밀리몰; 국제특허출원 WO 제97/02284호에 기재된 방법에 따라 제조함), TBTU(0.283 g; 0.88 밀리몰), 및 DIPEA(0.414 mL; 3.2 밀리몰)을 순서대로 부가하고, 용액을 실온에서 3일 동안 교반하였다. DMF를 증발시키고, 물을 부가하고, 수용액을 EtOAc(3 x 30 mL)로 추출하였다. 합한 유기상을 건조하고(Na2SO4) 증발시켰다. 정제 HPLC(CH3CN/10% NH4OAc (40:60))에 의해 부분입체 이성질체, 화합물 39A(보다 빠르게 움직이는 부분입체 이성질체; 147 mg; 64%; 순도 92.8%) 및 화합물 39B(보다 느리게 움직이는 부분입체 이성질체; 147 mg; 64%, 순도 99.1%)를 분리하였다.A solution of (R, S) -3-hydroxy-2- (2-methyl-5-methoxyphenyl) propionic acid (0.168 g; 0.8 mmol; compound from Example AE above) in DMF (10 mL) was stirred at 0 ° C. Cooled to. H-Pro-Pab (Z) x 2 HCl (0.399 g; 0.88 mmol; prepared according to the method described in WO 97/02284), TBTU (0.283 g; 0.88 mmol), and DIPEA (0.414 mL) 3.2 mmol) was added in order and the solution was stirred at room temperature for 3 days. DMF was evaporated, water was added, and the aqueous solution was extracted with EtOAc (3 × 30 mL). The combined organic phases were dried (Na 2 SO 4 ) and evaporated. Diastereomer, Compound 39A (faster moving diastereomer; 147 mg; 64%; Purity 92.8%) and Compound 39B (slower) by purified HPLC (CH 3 CN / 10% NH 4 OAc (40:60)) Moving diastereomers; 147 mg; 64%, purity 99.1%).

화합물 39BCompound 39b

LC-MS m/z 573 (M + 1)+ LC-MS m / z 573 (M + 1) +

1H NMR (400 MHz; CDCl3); δ 7.76 (d, 2H); 7.50 (t, 1H); 7.42 (d, 2H); 7.33 (t, 1H); 7.27 (m, 3H); 7.08 (d, 1H); 6.71 (m, 2H); 5.19 (s, 1H); 4.58 (d, 1H); 4.40 (m, 2H); 4.03 (dd, 1H); 3.97 (t, 1H); 3.70 (s, 3H); 3.58 (m, 2H); 2.95 (q, 2H); 2.28 (s, 2H); 2.22 (m, 1H); 1.99 (m, 1H); 1.78 (m, 2H) 1 H NMR (400 MHz; CDCl 3 ); δ 7.76 (d, 2 H); 7.50 (t, 1 H); 7.42 (d, 2 H); 7.33 (t, 1 H); 7.27 (m, 3 H); 7.08 (d, 1 H); 6.71 (m, 2 H); 5.19 (s, 1 H); 4.58 (d, 1 H); 4.40 (m, 2 H); 4.03 (dd, 1 H); 3.97 (t, 1 H); 3.70 (s, 3 H); 3.58 (m, 2 H); 2.95 (q, 2 H); 2.28 (s, 2 H); 2.22 (m, 1 H); 1.99 (m, 1 H); 1.78 (m, 2 H)

(ii) (S)- 또는 (R)-2-메틸-5-메톡시페닐-CH(CH2OH)-C(O)-Pro-Pab x HOAc(ii) (S)-or (R) -2-methyl-5-methoxyphenyl-CH (CH 2 OH) -C (O) -Pro-Pab x HOAc

EtOH(10 mL) 및 HOAc(13 mL) 중의 화합물 39 B(131 mg; 0.23 밀리몰) 용액에 Pd/C(5%; 70 mg)을 부가하고, 혼합물을 3시간 동안 실온 및 대기압하에서 수소처리하였다. 얻어진 혼합물을 하이플로를 통해 여과하고, 용액을 농축하고, 물을 부가하고, 용액을 동결 건조하여, 표제 화합물 96 mg(84%, 순도 95.9 %)을 얻었다. Pd / C (5%; 70 mg) was added to a solution of Compound 39 B (131 mg; 0.23 mmol) in EtOH (10 mL) and HOAc (13 mL), and the mixture was hydrotreated for 3 hours at room temperature and atmospheric pressure. . The resulting mixture was filtered through hyflo, the solution was concentrated, water was added and the solution was lyophilized to give 96 mg (84%, purity 95.9%) of the title compound.

1H NMR (400 MHz; D2O): δ 7.78 (d, 2H); 7.54 (d, 2H); 6.86 (m, 2H); 6.75 (d, 1H); 4.72 (d, 1H); 4.54 (s, 1H); 4.46 (dd, 2H); 4.25 (m, 4.05(t, 1H); 3.77 (s, 3H); 3.70 (dd, 1H); 3.64 (m, 1H); 3.10 (m, 1H); 2.36 (s, 2H); 2.15 (m, 1H); 1.95 (m, 4H); 1.76 (m, 1H). 1 H NMR (400 MHz; D 2 O): δ 7.78 (d, 2H); 7.54 (d, 2 H); 6.86 (m, 2 H); 6.75 (d, 1 H); 4.72 (d, 1 H); 4.54 (s, 1 H); 4.46 (dd, 2 H); 4.25 (m, 4.05 (t, 1H); 3.77 (s, 3H); 3.70 (dd, 1H); 3.64 (m, 1H); 3.10 (m, 1H); 2.36 (s, 2H); 2.15 (m, 1H); 1.95 (m, 4H); 1.76 (m, 1H).

13C-NMR (100 MHz; D2O) 카르보닐 및 아미딘 탄소: δ 176.0; 174.3; 167.6 13 C-NMR (100 MHz; D 2 O) carbonyl and amidine carbon: δ 176.0; 174.3; 167.6

LC-MS m/z 439 (M + 1)+ LC-MS m / z 439 (M + 1) +

실시예 40Example 40

(R,S)-Ph-C(Me)(CH2OMe)-C(O)-Pro-Pab(Z)(R, S) -Ph-C (Me) (CH 2 OMe) -C (O) -Pro-Pab (Z)

DMF(10 mL) 중의 (R,S)-2-메틸-2-페닐-3-메톡시프로피온산(0.40 g; 2.1 밀리몰; 상기 실시예 AF로부터의 화합물) 용액을 0 ℃로 냉각하였다. H-Pro-Pab(Z) x 2 HCl(0.93 g; 2.1 밀리몰; 국제특허출원 WO 제97/02284호에 기재된 방법에 따라 제조함), TBTU(0.64 g; 2.1 밀리몰), 및 DIPEA(0.90 g; 7 밀리몰)을 순서대로 부가하고, 용액을 실온에서 2일 동안 교반하였다. DMF를 증발시키고, NaHCO3 수용액을 부가하고, 수용액을 EtOAc(3 x 30 mL)로 추출하였다. 합한 유기상을 NaHCO3 수용액(2 x 20 mL), H2O로 세척하고, 건조하고(Na2SO4) 증발시켜서, 조 생성물을 얻고, 이를 CH2Cl2:THF:MeOH(90:10:2)를 사용하여 용출되는 실리카 겔 상의 플래시 크로마토그래피에 의해 추가로 정제하여 생성물 0.50 g(최종 3 단계를 거쳐서 44%)를 얻었다.A solution of (R, S) -2-methyl-2-phenyl-3-methoxypropionic acid (0.40 g; 2.1 mmol; compound from Example AF) in DMF (10 mL) was cooled to 0 ° C. H-Pro-Pab (Z) x 2 HCl (0.93 g; 2.1 mmol; prepared according to the method described in International Patent Application WO 97/02284), TBTU (0.64 g; 2.1 mmol), and DIPEA (0.90 g) 7 mmol) was added sequentially, and the solution was stirred at room temperature for 2 days. DMF was evaporated, NaHCO 3 aqueous solution was added and the aqueous solution was extracted with EtOAc (3 × 30 mL). The combined organic phases were washed with aqueous NaHCO 3 solution (2 × 20 mL), H 2 O, dried (Na 2 SO 4 ) and evaporated to afford the crude product, which was CH 2 Cl 2 : THF: MeOH (90:10: Further purification by flash chromatography on silica gel eluting with 2) gave 0.50 g (44% through 3 final steps) of the product.

1H NMR (500 MHz; CDCl3); δ 7.83 (m, 2H); 7.41 (d, 2H); 7.30 (m, 9H); 7.11 (d, 1H); 5.21 (s, 2H); 4.77 (m, 1H); 4.70 (m, 1H); 4.53 (m, 1H); 4.43 (m, 1H); 4.12 (d, 1H); 3.90 (d, 1H); 3.62 (t, 1H); 3.23 (s, 3H); 2.90 (m, 2H); 2.18 (m, 1H); 2.03 (m, 1H); 1.8-1.4 (m, 9H) 1 H NMR (500 MHz; CDCl 3 ); δ 7.83 (m, 2 H); 7.41 (d, 2 H); 7.30 (m, 9 H); 7.11 (d, 1 H); 5.21 (s, 2 H); 4.77 (m, 1 H); 4.70 (m, 1 H); 4.53 (m, 1 H); 4.43 (m, 1 H); 4.12 (d, 1 H); 3.90 (d, 1 H); 3.62 (t, 1 H); 3.23 (s, 3 H); 2.90 (m, 2 H); 2.18 (m, 1 H); 2.03 (m, 1 H); 1.8-1.4 (m, 9H)

13C-NMR (100 MHz; CDCl3) 카르보닐 및 아미딘 탄소: δ 174.6; 173.1; 172.2; 172.0; 167.9; 164.4 (부분입체 이성질체 및(또는) 회전 이성질체) 13 C-NMR (100 MHz; CDCl 3 ) carbonyl and amidine carbon: δ 174.6; 173.1; 172.2; 172.0; 167.9; 164.4 (diastereomers and / or rotational isomers)

실시예 41Example 41

(R,S)-Ph-C(Me)(CH2OMe)-C(O)-Pro-Pab x HCl(R, S) -Ph-C (Me) (CH 2 OMe) -C (O) -Pro-Pab x HCl

EtOH(10 mL) 및 진한 HCl 수용액(10 방울) 중의 (R,S)-Ph-C(Me)(CH2OMe)-C(O)-Pro-Pab(Z)(190 mg; 0.34 밀리몰; 상기 실시예 40으로부터의 화합물) 용액에 Pd/C(10%, 20 mg)을 부가하고, 혼합물을 실온 및 대기압에서 2 시간 동안 수소처리하였다. 얻어진 혼합물을 하이플로를 통해 여과하고, 용액을 농축하고, 물을 부가하고, 용액을 동결 건조하여 표제 화합물 160 mg(100%; 순도 77%)를 얻었다.(R, S) -Ph-C (Me) (CH 2 OMe) -C (O) -Pro-Pab (Z) (190 mg; 0.34 mmol) in EtOH (10 mL) and concentrated aqueous HCl solution (10 drops); To the solution from the compound from Example 40) was added Pd / C (10%, 20 mg) and the mixture was hydrotreated at room temperature and atmospheric pressure for 2 hours. The resulting mixture was filtered through hyflo, the solution was concentrated, water was added and the solution was lyophilized to give 160 mg (100%; purity 77%) of the title compound.

LC-MS m/z 423 (M + 1)+ LC-MS m / z 423 (M + 1) +

1H NMR (500 MHz; D2O): δ 7.80 (m, 2H); 7.55 (m, 2H); 7.35 (m, 5H); 4.50 (m, 3H); 3.88 (d, 0.5H); 3.78 (m, 1H); 3.76 (d, 0.5H); 3.21 (d, 3H); 3.15 (m, 1H); 2.78 (m, 1H); 2.18 (m, 1H); 1.70 (m, 3H); 1.63 (d, 3H) 1 H NMR (500 MHz; D 2 O): δ 7.80 (m, 2H); 7.55 (m, 2 H); 7.35 (m, 5 H); 4.50 (m, 3 H); 3.88 (d, 0.5 H); 3.78 (m, 1 H); 3.76 (d, 0.5 H); 3.21 (d, 3 H); 3.15 (m, 1 H); 2.78 (m, 1 H); 2.18 (m, 1 H); 1.70 (m, 3 H); 1.63 (d, 3 H)

13C NMR (100 MHz; D2O) 카르보닐 및 아미딘 탄소: δ 176.4; 176.3; 176.1; 175.9; 167.2; 167.1(부분입체 이성질체 및(또는) 회전 이성질체) 13 C NMR (100 MHz; D 2 O) carbonyl and amidine carbon: δ 176.4; 176.3; 176.1; 175.9; 167.2; 167.1 (diastereomers and / or rotational isomers)

실시예 42Example 42

(S)- 또는 (R)-2-클로로-3-메틸페닐-CH(CH2OH)-C(O)-Aze-Pab x HOAc(S)-or (R) -2-chloro-3-methylphenyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

(i) (R)- 및 (S)-2-클로로-3-메틸페닐-CH(CH2OH)-C(O)-Aze-Pab(Z)(i) (R)-and (S) -2-chloro-3-methylphenyl-CH (CH 2 OH) -C (O) -Aze-Pab (Z)

DMF(10 mL) 중의 (R,S)-3-히드록시-2-(2-클로로-3-메틸페닐)프로피온산(0.3 g; 1.4 밀리몰; 상기 실시예 AG로부터의 화합물) 용액을 0 ℃로 냉각하였다. H-Aze-Pab(Z) x 2 HCl(0.739 g; 1.68 밀리몰; 상기 실시예 A로부터의 화합물), TBTU(0.495 g; 1.54 밀리몰), 및 DIPEA(0.94 g; 5.6 밀리몰)을 순서대로 부가하고, 용액을 실온에서 5일 동안 교반하였다. 반응 혼합물을 농축하고, 물(400 mL)에 용해하고, 이후에 NaHCO3 수용액으로 pH를 9로 조절하였다. 얻어진 혼합물을 EtOAc(3 x 100 mL)로 추출하였다. 합한 유기상을 NaHCO3 수용액, 물 및 간수로 세척하고, 건조하고(Na2SO4), 농축하였다. 조생성물(0.636 g)을 RPLC(CH3CN:10% NH4OAc (40:60))에 의해 정제하여, 부분입체 이성질체, 화합물 42A(보다 빠르게 움직이는 부분입체 이성질체; 127 mg; 32%; 순도 95%) 및 화합물 42B(보다 느리게 움직이는 부분입체 이성질체; 131 mg; 33%, 순도 85%)를 분리하였다.Cool a solution of (R, S) -3-hydroxy-2- (2-chloro-3-methylphenyl) propionic acid (0.3 g; 1.4 mmol; compound from Example AG) above in DMF (10 mL) to 0 ° C. It was. H-Aze-Pab (Z) x 2 HCl (0.739 g; 1.68 mmol; compound from Example A), TBTU (0.495 g; 1.54 mmol), and DIPEA (0.94 g; 5.6 mmol) were added in this order and The solution was stirred for 5 days at room temperature. The reaction mixture was concentrated, dissolved in water (400 mL), and then the pH was adjusted to 9 with aqueous NaHCO 3 solution. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with aqueous NaHCO 3 solution, water and brine, dried (Na 2 SO 4 ) and concentrated. The crude product (0.636 g) was purified by RPLC (CH 3 CN: 10% NH 4 OAc (40:60)) to give diastereomer, Compound 42A (faster moving diastereomer; 127 mg; 32%; purity 95%) and Compound 42B (slower moving diastereoisomers; 131 mg; 33%, purity 85%).

화합물 42B:Compound 42B:

LC-MS m/z 563, 564 (M + 1)+ LC-MS m / z 563, 564 (M + 1) +

1H NMR (400 MHz; CDCl3); δ 8.23 (t, 1H); 7.80 (d, 2H); 7.44 (d, 2H); 7.33 (m, 4H); 7.18 (m, 3H); 5.21 (s, 2H); 4.86 (dd, 1H); 4.50 (m, 2H); 4.28 (dd, 1H); 4.13 (m, 1H); 3.96 (dd, 1H); 3.75 (dd,1H); 3.62 (q, 1H); 2.60 (m, 1H); 2.41 (s, 3H); 2.31 (m, 1H). 1 H NMR (400 MHz; CDCl 3 ); δ 8.23 (t, 1 H); 7.80 (d, 2 H); 7.44 (d, 2 H); 7.33 (m, 4 H); 7.18 (m, 3 H); 5.21 (s, 2 H); 4.86 (dd, 1 H); 4.50 (m, 2 H); 4.28 (dd, 1 H); 4.13 (m, 1 H); 3.96 (dd, 1 H); 3.75 (dd, 1 H); 3.62 (q, 1 H); 2.60 (m, 1 H); 2.41 (s, 3 H); 2.31 (m, 1 H).

(ii) (R)- 또는 (S)-2-클로로-3-메틸페닐-CH(CH2OH)-C(O)-Aze-Pab x HOAc(ii) (R)-or (S) -2-chloro-3-methylphenyl-CH (CH 2 OH) -C (O) -Aze-Pab x HOAc

(R)- 또는 (S)-2-클로로-3-메틸페닐-CH(CH2OH)-C(O)-Aze-Pab(Z)(상기 단계(i)로부터의 화합물 42 B; 129 mg; 0.23 밀리몰), TFA(4.7 mL; 62밀리몰) 및 티오아니졸(1.35 mL; 11.5 밀리몰)로부터 상기 실시예 23(ii)에 기재된 방법에 따라 제조하여 표제 생성물 45 mg(40.2%, 순도 90.4 %)을 수득하였다.(R)-or (S) -2-chloro-3-methylphenyl-CH (CH 2 OH) -C (O) -Aze-Pab (Z) (compound 42 B from step (i) above; 129 mg; 0.23 mmol), TFA (4.7 mL; 62 mmol) and thioanizole (1.35 mL; 11.5 mmol), prepared according to the method described in Example 23 (ii) above, 45 mg (40.2%, 90.4%) of the title product. Obtained.

LC-MS m/z 429, 431 (M + 1)+ LC-MS m / z 429, 431 (M + 1) +

1H NMR (400 MHz; CDCl3); δ 7.77 (d, 2H); 7.55 (d, 2H); 7.26 (m, 2H); 7.19 (d, 1H); 4.75 (dd, 1H); 4.55 (s, 2H); 4.34 (m, 2H); 4.04 (dd, 1H); 3.88 (m, 1H); 3.70 (dd, 1H); 2.48 (m, 1H); 2.40 (s, 3H); 2.27 (m, 1H); 1.89 (s, 3H) 1 H NMR (400 MHz; CDCl 3 ); δ 7.77 (d, 2 H); 7.55 (d, 2 H); 7.26 (m, 2 H); 7.19 (d, 1 H); 4.75 (dd, 1 H); 4.55 (s, 2 H); 4.34 (m, 2 H); 4.04 (dd, 1 H); 3.88 (m, 1 H); 3.70 (dd, 1 H); 2.48 (m, 1 H); 2.40 (s, 3 H); 2.27 (m, 1 H); 1.89 (s, 3 H)

13C NMR (100 MHz; CD3OD) 카르보닐 및 아미딘 탄소: δ 174.0, 172.9, 167.9 13 C NMR (100 MHz; CD 3 OD) carbonyl and amidine carbon: δ 174.0, 172.9, 167.9

실시예 43Example 43

(S)- 또는 (R)-2,3-(메틸렌디옥시페닐)-CH(CH2OH)-C(O)-Pro-Pab x HOAc(S)-or (R) -2,3- (methylenedioxyphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab x HOAc

상기 실시예 29에 기재된 방법에 따라 (R,S)-3-히드록시-2-(2,3-메틸렌디옥시페닐)프로피온산(0.26 g)으로부터 (2,3-메틸렌디옥시페닐)-CH(CH2OH)-C(O)-Pro-Pab(Z)를 얻고, 이를 RPLC로 분리하여 2종의 부분입체 이성질체, 화합물 43A(보다 빠르게 움직이는 부분입체 이성질체; 0.27 g; 40%) 및 화합물 43B(보다 느리게 움직이는 부분입체 이성질체; 0.18 g; 26%)를 얻었다. (R)- 또는 (S)-(2,3-메틸렌디옥시페닐)-CH(CH2OH)-C(O)-Pro-Pab(Z)(화합물 43B; 130 mg)를 탈보호시켜 표제 화합물 81 mg(72%)을 제조하였다.(2,3-methylenedioxyphenyl) -CH from (R, S) -3-hydroxy-2- (2,3-methylenedioxyphenyl) propionic acid (0.26 g) according to the method described in Example 29 above. (CH 2 OH) -C (O) -Pro-Pab (Z) was obtained and separated by RPLC to form two diastereomers, Compound 43A (faster moving diastereomer; 0.27 g; 40%) and compound 43B (slower moving diastereomer; 0.18 g; 26%) was obtained. Deprotection of (R)-or (S)-(2,3-methylenedioxyphenyl) -CH (CH 2 OH) -C (O) -Pro-Pab (Z) (Compound 43B; 130 mg) to give the title 81 mg (72%) were prepared.

LC-MS m/z 439 (M + 1)+ LC-MS m / z 439 (M + 1) +

실시예 44Example 44

실시예 1 내지 7, 11, 12, 16 내지 39, 41, 42 및 43의 화합물(모두 화학식 I의 화합물)을 상기 시험 A에서 시험하였고 모두 0.3 μM 미만의 IC50TT 수치를 나타내는 것으로 밝혀졌다.The compounds of Examples 1-7, 11, 12, 16-39, 41, 42 and 43 (all of Formula I) were tested in Test A above and were found to all exhibit IC 50 TT values of less than 0.3 μM.

실시예 45Example 45

실시예 8, 9, 10, 13, 14, 15 및 40의 화합물(모두 화학식 Ia의 화합물)을 상기 시험 A에서 시험하였고 모두 1 μM 초과의 IC50TT 수치를 나타내는 것으로 밝혀졌다.Compounds of Examples 8, 9, 10, 13, 14, 15 and 40 (all of Formula Ia) were tested in Test A above and were found to all exhibit IC 50 TT values greater than 1 μM.

실시예 46Example 46

실시예 8, 9, 10, 13, 14, 15 및 40의 화합물(모두 화학식 Ia의 화합물)을 상기 시험 C에서 시험하였고, 모두 쥐에서 화학식 I의 상응하는 활성 억제제로서 경구 및(또는) 비경구 생체이용율을 나타내는 것으로 밝혀졌다.The compounds of Examples 8, 9, 10, 13, 14, 15 and 40 (all of the compounds of formula (Ia)) were tested in Test C above, all orally and / or parenterally as corresponding activity inhibitors of formula (I) in rats. It was found to exhibit bioavailability.

약자Abbreviation

AIBN = 아조비스이소부티로니트릴AIBN = azobisisobutyronitrile

aq = 수용액aq = aqueous solution

Aze = 아제티딘-2-카르복실산Aze = Azetidine-2-carboxylic acid

Boc = tert-부틸옥시카르보닐Boc = tert-butyloxycarbonyl

Bn = 벤질Bn = benzyl

Bu = 부틸Bu = Butyl

Ch = 시클로헥실Ch = cyclohexyl

DBU = 1,8-디아자비시클로[5.4.0]운데크-7-엔DBU = 1,8-diazabicyclo [5.4.0] undec-7-ene

DCC = 디시클로헥실카르보디이미드DCC = dicyclohexylcarbodiimide

DIPEA = 디이소프로필에틸아민DIPEA = diisopropylethylamine

DMAP = N,N-디메틸 아미노 피리딘DMAP = N, N-dimethyl amino pyridine

DMF = 디메틸포름아미드DMF = dimethylformamide

DMSO = 디메틸술폭시드DMSO = dimethyl sulfoxide

EDC = 1-(3-디메틸아미노프로필)-3-에틸카르보디이미드 히드로클로라이드EDC = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

Et = 에틸Et = ethyl

EtOH = 에탄올EtOH = ethanol

h = 시간h = hours

HBTU = [N,N,N',N'-테트라메틸-O-(벤조트리아졸-1-일)우로늄헥사플루오로포스페이트]HBTU = [N, N, N ', N'-tetramethyl-O- (benzotriazol-1-yl) uronium hexafluorophosphate]

HCl = 염산HCl = hydrochloric acid

H-Hig = 1-아미디노-3-아미노에틸 피롤리딘H-Hig = 1-amidino-3-aminoethyl pyrrolidine

H-Hig(Z) = 3-아미노에틸-1-(N-벤질옥시카르보닐아미디노)피롤리딘H-Hig (Z) = 3-aminoethyl-1- (N-benzyloxycarbonylamidino) pyrrolidine

HOAc = 아세트산HOAc = acetic acid

H-Pab = 1-아미디노-4-아미노메틸 벤젠H-Pab = 1-amidino-4-aminomethyl benzene

H-Pab(Z) = 4-아미노메틸-1-(N-벤질옥시카르보닐아미디노)벤젠H-Pab (Z) = 4-aminomethyl-1- (N-benzyloxycarbonylamidino) benzene

H-Pig = 1-아미디노-3-아미노메틸 피페리딘H-Pig = 1-amidino-3-aminomethyl piperidine

H-Pig(Z) = 3-아미노메틸-1-(N-벤질옥시카르보닐아미디노)피페리딘H-Pig (Z) = 3-aminomethyl-1- (N-benzyloxycarbonylamidino) piperidine

HPLC = 고성능 액체 크로마토그래피HPLC = high performance liquid chromatography

Me = 메틸Me = methyl

MeOH = 메탄올MeOH = Methanol

MsCl = 메탄술포닐 클로라이드MsCl = methanesulfonyl chloride

NBS = N-브로모숙신이미드NBS = N-bromosuccinimide

Ph = 페닐Ph = phenyl

Pr = 프로필Pr = profile

i-PrOH = i-프로판올 i-PrOH = i-propanol

RPLC = 정제 역상 고성능 액체 크로마토그래피RPLC = purified reverse phase high performance liquid chromatography

TBDMS = tert-부틸디메틸실릴TBDMS = tert-butyldimethylsilyl

TBTU = [N,N,N',N'-테트라메틸-O-(벤조트리아졸-1-일)우로늄 테트라플루오로보레이트]TBTU = [N, N, N ', N'-tetramethyl-O- (benzotriazol-1-yl) uronium tetrafluoroborate]

TEA = 트리에틸아민TEA = triethylamine

THF = 테트라히드로푸란THF = tetrahydrofuran

THP = 테트라히드로피라닐THP = tetrahydropyranyl

TMS = 트리메틸실릴TMS = trimethylsilyl

p-TsOH = p-톨루엔술폰산p-TsOH = p-toluenesulfonic acid

WSCI = 수용성 카르보디이미드WSCI = Water Soluble Carbodiimide

Z = 벤질옥시 카르보닐Z = benzyloxy carbonyl

접두사 n, s, i 및 t는 일반적인 의미, 즉 노르말, 이소, sec 및 tert의 의미를 갖는다. 달리 언급되지 않는 한 아미노산에 대한 입체 화학은 디폴트(S)이다.The prefixes n, s, i and t have the general meaning ie normal, iso, sec and tert. Unless otherwise stated, the stereochemistry for amino acids is the default (S).

Claims (15)

하기 화학식 I의 화합물 또는 그의 제약상 허용되는 염. A compound of formula (I) or a pharmaceutically acceptable salt thereof. <화학식 I><Formula I> 식 중, R1은 H 또는 C1-6 알킬을 나타내고,Wherein R 1 represents H or C 1-6 alkyl, Rx는 하기 화학식 IIa의 구조 프레그먼트를 나타내고R x represents a structural fragment of the formula <화학식 IIa><Formula IIa> [여기서, k 및 l은 독립적으로 0을 나타내고,[Wherein k and l independently represent 0, R4 및 R5는 독립적으로 H, 1- 또는 2-나프틸, 페닐 또는 메틸렌디옥시페닐(페닐 또는 메틸렌디옥시 기들은 C1-4 알킬(이 기는 1개 이상의 할로 치환체로 치환될 수 있다), C1-4 알콕시, 할로, 히드록시 또는 N(H)R43 중 1개 이상으로 치환될 수 있다)을 나타내고,R 4 and R 5 are independently H, 1- or 2-naphthyl, phenyl or methylenedioxyphenyl (phenyl or methylenedioxy groups are C 1-4 alkyl (this group may be substituted with one or more halo substituents) ), C 1-4 alkoxy, halo, hydroxy or N (H) R 43 may be substituted). R43은 H를 나타낸다];R 43 represents H; Y는 CH2 또는 (CH2)2를 나타내고;Y represents CH 2 or (CH 2 ) 2 ; n은 1 또는 2를 나타내고;n represents 1 or 2; B는 하기 화학식 IVa 또는 IVb의 구조 프레그먼트를 나타낸다B represents a structural fragment of formula IVa or IVb <화학식 IVa><Formula IVa> <화학식 IVb><Formula IVb> (여기서, X1 및 X2는 독립적으로 단일 결합 또는 CH2를 나타낸다).Wherein X 1 and X 2 independently represent a single bond or CH 2 . 제1항에 있어서, n이 2를 나타내고, B가 화학식 IVb의 구조 프레그먼트를 나타내고, X1 및 X2가 동시에 CH2를 나타내지 않는 화학식 I의 화합물.The compound of claim 1, wherein n represents 2, B represents a structural fragment of Formula IVb, and X 1 And compounds of formula I, wherein X 2 does not represent CH 2 at the same time. 제1항에 있어서, n이 1인 화학식 I의 화합물.2. Compounds of formula I according to claim 1, wherein n is 1. 제1항에 있어서, B가 화학식 IVa의 구조 프레그먼트를 나타내는 화학식 I의 화합물.The compound of formula I according to claim 1, wherein B represents a structural fragment of formula IVa. 제1항 또는 제2항에 있어서, 하기 프레그먼트The fragment according to claim 1 or 2, wherein 가 S 배위인 화학식 I의 화합물.Is a S configuration. 제1항에 있어서, R4 및 R5 중 하나 또는 둘 다가 할로 치환된 C1-6 알킬로 치환된 페닐을 나타내지 않는 화학식 I의 화합물.2. Compounds of formula I according to claim 1, wherein one or both of R 4 and R 5 do not represent phenyl substituted with halo substituted C 1-6 alkyl. 제1항에 있어서, R4 및 R5 중 하나 또는 둘 다가 메틸렌디옥시페닐을 나타내지 않는 화학식 I의 화합물.The compound of formula I according to claim 1, wherein one or both of R 4 and R 5 do not represent methylenedioxyphenyl. 제1항에 있어서, R4 및 R5 중 하나 또는 둘 다가 할로 치환된 C1-6 알킬로 치환된 페닐을 나타내는 화학식 I의 화합물.2. Compounds of formula I according to claim 1, wherein one or both of R 4 and R 5 represent phenyl substituted with halo substituted C 1-6 alkyl. 제1항에 있어서, R4 및 R5 중 하나 또는 둘 다가 메틸렌디옥시페닐을 나타내는 화학식 I의 화합물.The compound of formula I according to claim 1, wherein one or both of R 4 and R 5 represent methylenedioxyphenyl. 하기 화학식 Ia의 화합물 또는 그의 제약상 허용되는 염.A compound of formula la or a pharmaceutically acceptable salt thereof. <화학식 Ia><Formula Ia> 식 중, B1은 하기 화학식 IVd 또는 IVe의 구조 프레그먼트를 나타내고In the formula, B 1 represents the structural fragment of the formula (IVd) or (IVe) <화학식 IVd><Formula IVd> <화학식 IVe><Formula IVe> (여기서, D1 및 D2는 독립적으로 H, OH, OC(O)Rb 또는 C(O)ORd를 나타내고, Rb, 및 Rd는 독립적으로 벤질 또는 C1-6 알킬(이 기는 산소 원자가 개재될 수 있다)을 나타내고, 단 D1 및 D2가 동시에 H를 나타내지 않는다);Wherein D 1 and D 2 independently represent H, OH, OC (O) R b or C (O) OR d , and R b , and R d independently represent benzyl or C 1-6 alkyl Oxygen atoms may be interrupted), provided that D 1 and D 2 do not simultaneously represent H); R1, Rx, Y, n, X1 및 X2는 제1항에서 정의한 바와 같다.R 1 , R x , Y, n, X 1 and X 2 are as defined in claim 1. 제10항에 있어서, D1이 H를 나타내고, D2가 OH, OC(O)Rb 또는 C(O)ORd를 나타내고, Rb 및 Rd가 제10항에서 정의한 바와 같은 화학식 Ia의 화합물.The compound of formula Ia according to claim 10, wherein D 1 represents H, D 2 represents OH, OC (O) R b or C (O) OR d , and R b and R d are of formula (Ia) as defined in claim 10. compound. 제약상 허용되는 보조제, 희석제 또는 담체와 함께 제1항 내지 제4항 중 어느 한 항에서 정의된 화학식 I의 화합물 또는 그의 제약상 허용되는 염을 포함하는, 트롬빈 억제가 필요한 증상(이 트롬빈 억제가 필요한 증상은 혈전증; 혈액 및 조직에서의 과응고능; 활성화된 단백질 C 저항증; 인자 V-돌연변이(인자 V 라이덴(Leiden)); 안티트롬빈 III, 단백질 C, 단백질 S 또는 헤파린 조인자 II의 선천성 또는 후천성 결핍증; 순환 항인지질 항체(낭창 항응고제); 호모시스테인혈증; 헤파린 유도 혈소판감소증 및 섬유소용해소 결핍증; 알츠하이머병; 정맥 혈전증; 폐 색전증; 동맥 혈전증; 전신 색전증; 박테리아, 다수의 외상, 중독 또는 기타 메카니즘에 기인하는 분산성 혈관내 응고; 신체 내의 이종 면에 혈액이 접할 경우의 항응고 처리; 신체 외부의 의료 장치와 혈액이 접할 때의 항응고 처리; 특발성 및 성인 호흡 곤란 증후군; 방사선 또는 화학요법에 의한 처리 이후의 폐 섬유증; 폐혈성 쇼크증; 폐혈증; 염증성 반응; 부종; 급성 또는 만성 아테롬성 경화증; 대뇌 동맥 질병; 말초 동맥 질병; 재환류 손상; 경피경관혈관성형술 이후의 협착증; 및 췌장염으로 이루어진 군으로부터 선택된다)의 치료를 위한 제약 제제.A condition requiring thrombin inhibition, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 4 together with a pharmaceutically acceptable adjuvant, diluent or carrier, Symptoms required are thrombosis; hypercoagulability in blood and tissues; activated protein C resistance; factor V-mutation (factor V Leiden); congenital or antithrombin III, protein C, protein S or heparin factor II Acquired deficiency; circulating antiphospholipid antibody (anti-coagulant anti-coagulant); homocysteinemia; heparin-induced thrombocytopenia and fibrinolytic deficiency; Alzheimer's disease; venous thrombosis; pulmonary embolism; arterial thrombosis; systemic embolism; bacteria, multiple traumas, poisoning or other mechanisms Disperse intravascular coagulation caused by: Anticoagulant treatment when blood is in contact with heterogeneous surfaces in the body; Medical devices and blood outside the body Anticoagulant treatment in contact with fluid; idiopathic and adult respiratory distress syndrome; pulmonary fibrosis after treatment by radiation or chemotherapy; pulmonary shock; pulmonary disease; inflammatory response; edema; acute or chronic atherosclerosis; cerebral artery disease; Pharmaceutical preparations for the treatment of peripheral arterial disease; recurrent injuries; stenosis after percutaneous angioplasty; and pancreatitis). 제12항에 있어서, 상기 증상이 혈전증인 제약 제제.13. The pharmaceutical formulation of claim 12, wherein said condition is thrombosis. 제12항에 있어서, 상기 증상이 혈액 및 조직에서의 과응고능인 제약 제제.13. The pharmaceutical formulation of claim 12, wherein said condition is hypercoagulant in blood and tissue. (a) 하기 화학식 V의 화합물과 하기 화학식 VI의 화합물을 커플링시키거나; 또는(a) coupling a compound of Formula V to a compound of Formula VI: or (b) 하기 화학식 VII의 화합물과 하기 화학식 VIII의 화합물을 커플링시키는 것을 포함하는 제1항에 따른 화학식 I의 화합물의 제조 방법.(b) A process for preparing a compound of formula I according to claim 1 comprising coupling a compound of formula VII to a compound of formula VIII. <화학식 V><Formula V> <화학식 VI><Formula VI> <화학식 VII><Formula VII> <화학식 VIII><Formula VIII> H2N-(CH2)n-BH 2 N- (CH 2 ) n -B 식 중, R1, Rx, Y, n 및 B는 제1항에서 정의한 바와 같다.Wherein R 1 , R x , Y, n and B are as defined in claim 1.
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* Cited by examiner, † Cited by third party
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WO1995035309A1 (en) * 1994-06-17 1995-12-28 Basf Aktiengesellschaft New thrombin inhibitors, their preparation and use

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