KR100372757B1 - Sulfonamide Derivative as a Matrix Metalloproteinase Inhibitor - Google Patents

Abstract

본 발명은 신규한 설폰아미드 유도체에 관한 것이다. 본 발명은 메트릭스 메탈로프로테이나제의 저해제로서 유용한 하기 일반식(Ⅰ)의 신규한 설폰아미드 유도체, 그의 약학적으로 허용되는 염 및 이들의 제조방법을 제공한다. 본 발명의 설폰아미드 유도체 화합물은 시험관내(in vitro) 조건에서 MMP의 활성을 선택적으로 억제하는 바, 전기 설폰아미드 유도체를 유효성분으로 하는 MMP 억제제는 MMP의 과발현 및 과도한 활성화에 의해서 유발되는 각종질병의 예방 및 치료에 유용하게 사용될 수 있을 것이다.The present invention relates to novel sulfonamide derivatives. The present invention provides novel sulfonamide derivatives of the general formula (I), pharmaceutically acceptable salts thereof, and methods for their preparation, which are useful as inhibitors of matrix metalloproteinases. The sulfonamide derivative compounds of the present invention selectively inhibit the activity of MMP under in vitro conditions, and MMP inhibitors comprising the sulfonamide derivative as an active ingredient are various diseases caused by overexpression and excessive activation of MMP. It may be useful for the prevention and treatment of

Description

메트릭스 메탈로프로테이나제의 저해제로서의 설폰아미드 유도체{Sulfonamide Derivative as a Matrix Metalloproteinase Inhibitor}Sulfonamide Derivative as a Matrix Metalloproteinase Inhibitor as Inhibitor of Matrix Metalloproteinases

본 발명은 신규한 설폰아미드 유도체에 관한 것이다. 좀 더 구체적으로, 본 발명은 메트릭스 메탈로프로테이나제의 저해제로서 유용한 하기 일반식(Ⅰ)의 신규한 설폰아미드 유도체, 그의 약학적으로 허용되는 염 및 이들의 제조방법에 관한 것이다.The present invention relates to novel sulfonamide derivatives. More specifically, the present invention relates to novel sulfonamide derivatives of formula (I), pharmaceutically acceptable salts thereof, and methods for their preparation, which are useful as inhibitors of matrix metalloproteinases.

메트릭스 메탈로프로테이나제(matrix metalloproteinase, 이하 'MMP'라 함)는 활성부위에 아연(Zn²⁺)을 함유하고 칼슘(Ca²⁺) 의존적인 프로테이나제로서, 스트로멜리신, 콜라게나제 및 젤라티나제의 페밀리 등 약 18가지가 알려져 있다. 이들MMP 효소들은 생물학적 조건하에서 결합조직의 단백질 성분 즉, 콜라겐, 라미닌, 프로테오글리칸, 피브로넥틴, 엘라스틴, 젤라틴 등을 분해시켜, 관절조직, 골조직, 결합조직의 성장 및 조직의 리모델링을 야기시킨다. 이들 효소들은 공통적으로 활성부위에 아연을 함유하고 칼슘에 따라 활성이 달라지며, 불활성 전효소의 형태로 분비되어 세포의 외부에서 활성화되고, TIMP(tissue inhibitor of metalloproteinase)라는 천연 저해제와 함께 분비된다.Matrix metalloproteinase (MMP) is a calcium (Ca ²⁺ ) dependent proteinase that contains zinc (Zn ²⁺ ) at its active sites and is a stromelysin and collagenase. About 18 are known, including families of agents and gelatinases. These MMP enzymes degrade the protein components of the connective tissue, namely collagen, laminin, proteoglycan, fibronectin, elastin, gelatin, etc., under biological conditions, leading to the growth and remodeling of joint tissue, bone tissue, connective tissue. These enzymes commonly contain zinc in their active sites and vary in activity depending on calcium, are secreted in the form of inactive preenzymes, activated outside of cells, and secreted with a natural inhibitor called TIMP (tissue inhibitor of metalloproteinase).

한편, MMP 억제제는 MMP의 과발현 및 과도한 활성화에 의해서 유발되는 각종질병의 예방 및 치료에 유용하다. 상기 질병의 예로는 류마토이드, 관절골염, 비정상 골흡수증, 골다공증, 치주염, 간질성 신염, 동맥경화증, 폐기종, 경변증, 각막손상, 종양세포의 전이, 침범, 또는 성장, 자가면역질병, 혈관유지, 또는 백혈구의 침범에 의해 유발되는 질병, 동맥혈화를 들 수 있다(참조: Beeley et al., Curr. Opin. Ther. Patents, 4(1):7-16, 1994). 예를 들면, 합성한 MMP 저해제가 난소암의 쥐 모델에서 기질의 리모델링의 저해작용과 함께 생체내(in vivo)에서 항암효과가 있음이 보고되었다(참조: Cancer Res., 53:2087, 1993). 특히, 암세포 성장에 필수적으로 요구되는 신혈관생성(angiogenesis) 단계에서 위의 MMP 효소 중 MMP-2와 MMP-9가 필수적으로 관여함이 알려져 있고(참조: Biochim. Biophys. Acta, 695, 1983), 또한, MMP 효소 중 MMP-1과 MMP-3는 류마티스성 관절염 환자의 활막(synovium)과 연골(cartilage)에서 정상치보다 아주 높은 농도로 발견되어, 상기한 MMP-1/MMP-3가 관절염의 진행에 중요한 역할을 한다고 알려져 있으므로(참조: Arthritis Rheum., 35:35-42, 1992), MMP-1/MMP-2에의 선택성이 관절통증 등의 부작용을 줄이는데 중요한 역할을 할 것으로 여겨지고 있다. 따라서, 최근의 연구는 선택적인 저해제의 개발에 집중되고 있으며, 이러한 MMP 저해제의 설계 및 합성에 대해서는 다각도로 연구되고 있다(참조: J. Enzyme Inhibitor,2:1-22, 1987; Current Medicinal Chemistry,2:743-762, 1995; Progress in Medicinal Chemistry,29:271-334, 1992; Exp. Opin. Ther. Patents,5:1287-1296, 1995; Drug Discovery Today,1:16-26, 1996; Chem. Rev.99:2735-2776, 1999).On the other hand, MMP inhibitors are useful for the prevention and treatment of various diseases caused by overexpression and excessive activation of MMP. Examples of the disease include rheumatoid, osteoarthritis, abnormal osteoporosis, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, emphysema, cirrhosis, corneal injury, tumor cell metastasis, invasion, or growth, autoimmune disease, vascular maintenance, Or diseases caused by invasion of leukocytes, arterialization (Beeley et al., Curr. Opin. Ther. Patents, 4 (1): 7-16, 1994). For example, it has been reported that the synthesized MMP inhibitor has an anti-cancer effect in vivo along with the inhibitory effect of substrate remodeling in a rat model of ovarian cancer (Cancer Res., 53: 2087, 1993). . In particular, it is known that MMP-2 and MMP-9 of the above MMP enzymes are essentially involved in the angiogenesis stage required for cancer cell growth (Biochim. Biophys. Acta, 695, 1983). In addition, MMP-1 and MMP-3 in the MMP enzymes were found to be higher than normal levels in synoviium and cartilage of rheumatoid arthritis patients. Since it is known to play an important role in progression (Arthritis Rheum., 35: 35-42, 1992), selectivity to MMP-1 / MMP-2 is believed to play an important role in reducing side effects such as joint pain. Therefore, recent research has focused on the development of selective inhibitors, and the design and synthesis of such MMP inhibitors has been studied at various angles (J. Enzyme Inhibitor, 2: 1-22, 1987; Current Medicinal Chemistry, 2: 743-762, 1995; Progress in Medicinal Chemistry, 29: 271-334, 1992; Exp. Opin.Ther. Patents, 5: 1287-1296, 1995; Drug Discovery Today, 1: 16-26, 1996; Chem Rev. 99: 2735-2776, 1999).

일반적으로, MMP 효소들의 활성부위에 아연 금속과 잘 배위하는 작용기를 가지는 화합물은 MMP의 촉매활성을 저해한다. 이와 같은 작용기로는 히드록사믹산(hydroxamic acid), 카르복실산, 포스포린산, 포스핀산, 티올 등이 알려져 있으며, 이러한 작용기를 이용하여 고안되고 합성된 MMP 저해제가 이미 공지되어 있다. 특히, 초기의 저해제로 기질유사체인 펩티드 골격을 가진 여러종의 숙신산 유도체가 합성되었는 바(참조: British Biotech, WO 9925693; Zeneca, WO 9843959, WO 9824759; Abbott, WO 9830551, WO9830541; PU, WO9732846; Roche, WO9901428, EP 897908; GW, WO 9838179; Sankyo, JP 95002797; DuPont, WO 9918074; Ono, WO 9919296; 및, Otsuka, EP 641323), 이러한 기질유사체 저해제들은 모두 Zn-배위기로 히드록사믹산을 가지는 것으로 알려져 있다.In general, compounds having functional groups that coordinate well with zinc metal in the active site of MMP enzymes inhibit the catalytic activity of MMP. Such functional groups are known as hydroxamic acid, carboxylic acid, phosphoric acid, phosphinic acid, thiol, and the like, and MMP inhibitors designed and synthesized using such functional groups are already known. In particular, several succinic acid derivatives having peptide backbones, substrate mimetics, have been synthesized as early inhibitors (British Biotech, WO 9925693; Zeneca, WO 9843959, WO 9824759; Abbott, WO 9830551, WO9830541; PU, WO9732846; Roche, WO9901428, EP 897908; GW, WO 9838179; Sankyo, JP 95002797; DuPont, WO 9918074; Ono, WO 9919296; and, Otsuka, EP 641323), all of these substrate-like inhibitors use hydroxamic acids as Zn-coordinates. It is known to have.

그러나, 전기 저해제들은 펩티드 유도체가 가지는 낮은 경구흡수도 및 MMP-1/MMP-2의 선택성이 낮다는 문제점을 가지고 있다. 전술한 문제점을 해결한 저해제로서 1996년에 비펩타이드성 저해제가 개발되었는데, 이들은 상기 기질 유사체 저해제들과는 구조적으로 완전히 다른데, 예를 들면, 하기와 같은 간단한 설포닐아미노산 유도체임이 보고된 바 있다(참조: USP 5,506,242; J. Med. Chem., 40:2525-2532, 1997).However, the electric inhibitors have problems of low oral absorption and low selectivity of MMP-1 / MMP-2 of the peptide derivative. In 1996, non-peptidyl inhibitors were developed as inhibitors to solve the above problems, which are structurally completely different from the substrate analog inhibitors. USP 5,506,242; J. Med. Chem., 40: 2525-2532, 1997).

설포닐아미노산 유도체의 MMP 저해제는 이후에도 다양하게 합성되어 보고되었는 바, 대표적인 예로서는 다음과 같은 화합물이 있다:MMP inhibitors of sulfonylamino acid derivatives have been synthesized and reported in various ways thereafter, and representative examples thereof include the following compounds:

상기 저해제들은 비교적 높은 MMP 활성억제 효과를 가지고 있으나, MMP-1/ MMP-2에의 선택성은 별로 높지 않으며(참조: Drugs of the Future, 24(1):16-21, 1999), 부작용으로서 관절통증이 보고되었다(참조: SCRIP, No. 2467, p19, August 27, 1999).These inhibitors have a relatively high inhibitory effect on MMP activity, but the selectivity to MMP-1 / MMP-2 is not very high (Drugs of the Future, 24 (1): 16-21, 1999) and as a side effect, joint pain Has been reported (SCRIP, No. 2467, p19, August 27, 1999).

따라서, MMP저해활성과 MMP-1/ MMP-2에의 선택성을 증가시켜, 부작용을 줄일 수 있는 신물질을 개발하여야 할 필요성이 끊임없이 대두되었다.Therefore, there is a constant need to develop new substances that can reduce side effects by increasing MMP inhibitory activity and selectivity to MMP-1 / MMP-2.

이에, 본 발명자들은 MMP저해활성과 MMP-1/ MMP-2에의 선택성을 증가시켜 부작용을 줄일 수 있는 신물질을 개발하고자 예의 연구노력한 결과, 새로이 합성된 설폰아미드 유도체가 시험관내(in vitro) 조건에서 MMP의 활성을 선택적으로 억제하는 것을 확인하고, 본 발명을 완성하게 되었다.Therefore, the present inventors have diligently researched to develop a new substance that can reduce side effects by increasing MMP inhibitory activity and selectivity to MMP-1 / MMP-2. As a result, newly synthesized sulfonamide derivatives were prepared under in vitro conditions. It was confirmed that the activity of MMP was selectively inhibited, and the present invention was completed.

결국, 본 발명의 주된 목적은 MMP의 활성을 저해하는 설폰아미드 유도체를 제공하는 것이다.After all, the main object of the present invention is to provide sulfonamide derivatives that inhibit the activity of MMP.

본 발명의 다른 목적은 전기 유도체의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for producing an electrical derivative.

본 발명은 MMP의 작용을 억제하는 다음 일반식 (I)의 설폰아미드 유도체 화합물, 그의 이성질체 및 이들의 약학적으로 허용되는 염과 전기 물질들의 제조방법을 제공한다.The present invention provides a method for preparing sulfonamide derivative compounds of the general formula (I), their isomers and their pharmaceutically acceptable salts and electrical substances which inhibit the action of MMP.

상기 식에서,Where

R₁은 X-R₄(이때, R₄는 C_1-12의 알킬, 카보씨클릭 아릴-저급알킬,R ₁ is XR _{4 wherein} R ₄ is C _1-12 alkyl, carbocyclic aryl-lower alkyl,

C_3-7의 씨클로알킬, C_3-7의 씨클로알킬-저급알킬, (옥소, 아C _3-7 cycloalkyl, C _3-7 cycloalkyl-lower alkyl, (oxo, sub

미노, 또는 티오)C_3-7의 씨클로알킬, (옥소, 아미노, 또는Mino, or thio) C _3-7 cycloalkyl, (oxo, amino, or

티오)C_3-7의 씨클로알킬-저급알킬, C_2-12의 저급알케닐, C_2-12 Thio) C _3-7 cycloalkyl-lower alkyl, C _2-12 lower alkenyl, C _2-12

의 저급알키닐, 카보씨클릭아릴, 헤테로씨클릭아릴, 헤테Lower alkynyl, carbocyclic aryl, heterocyclic aryl, hete

로씨클릭아릴-저급알킬, 비아릴, 할로저급알킬, 비아릴-Cyclic aryl-loweralkyl, biaryl, haloloweralkyl, biaryl-

저급알킬아릴알킬, 히드록시-저급알킬, 알콕시알킬, 아실Lower alkylarylalkyl, hydroxy-loweralkyl, alkoxyalkyl, acyl

옥시-저급알킬, 알킬 또는 아릴 (티오, 설피닐, 설포닐)Oxy-loweralkyl, alkyl or aryl (thio, sulfinyl, sulfonyl)

저급알킬, (아미노, 모노 또는 디 알킬아미노)저급알킬,Lower alkyl, (amino, mono or dialkylamino) lower alkyl,

아실아미노 저급알킬, (N-저급알킬-피페라지노 또는 N-Acylamino lower alkyl, (N-lower alkyl-piperazino or N-

카보씨클릭 또는 헤테로씨클릭 아릴-저급알킬피페라지Carbocyclic or heterocyclic aryl-lower alkylpiperazines

노)-저급알킬, (모포리노, 티오모포리노, 피페리디노, 피No) -lower alkyl, (morpholino, thiomorpholino, piperidino, blood

롤리디노, 피페리딜)-저급알킬이다), 또는 할라이드이며;Lololidino, piperidyl) -lower alkyl), or halide;

R₂는 수소, C_1-6의 저급알킬이고;R ₂ is hydrogen, C _1-6 lower alkyl;

R₃는 -OH, -NHOH 또는 OR₁₈(이때, OR₁₈는 C_1-6의 저급알킬, t-부R ₃ is —OH, —NHOH or OR ₁₈ wherein OR ₁₈ is C _1-6 lower alkyl, t-part

틸, 벤질 또는 씰릴기이다)이며;Butyl, benzyl or sealyl groups);

X는 S 또는 O이고; 및,X is S or O; And,

n은 0 내지 3의 정수이다.n is an integer of 0-3.

특별한 언급이 없는 한, 전기 설폰아미드 화합물의 모든 이성질체들은 본 발명의 범주에 속한다. 예를 들면, 알킬, 알콕시 알켄, 및 알킨의 경우, 이의 직쇄 및 분지쇄는 물론, 비대칭 탄소에 의해서 발생하는 이성체, 예컨대 분지된 알킬 또한 본 발명에 속한다.Unless otherwise noted, all isomers of the foregoing sulfonamide compounds are within the scope of the present invention. For example, in the case of alkyls, alkoxy alkenes, and alkynes, the straight and branched chains thereof, as well as isomers such as branched alkyls generated by asymmetric carbons, also belong to the invention.

본 발명의 약학적으로 허용되는 염에는 산 부가염, 수화물염이 포함된다. 본 발명의 일반식(I)의 화합물은 상응하는 염으로 전환시킬 수 있는데, 알칼리금속의 염(나트륨, 칼륨 등), 알칼리토금속의 염(칼슘, 마그네슘 등), 암모늄염, 약학적 유기아민의 비독성염 및 수용성염이 바람직하다. 본 발명의 일반식(I)의 화합물은 무기산의 염(염산염, 브롬화수소염, 요드화수소염, 황산염, 인산염, 질산염 등), 유기산의 염(아세트산, 락테이트, 타르타레이트, 옥살레이트, 푸마레이트, 글루쿠로네이트 등)의 상응하는 산 부가염으로 전환시킬 수 있는데, 비독성염 및 수용성염이 바람직하다. 본 발명의 일반식(I)의 화합물 및 이의 염은 당업계의 통상적인 방법에 의하여 상응하는 수화물로도 전환시킬 수 있다.Pharmaceutically acceptable salts of the present invention include acid addition salts, hydrate salts. Compounds of general formula (I) of the present invention can be converted to the corresponding salts, including salts of alkali metals (sodium, potassium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, non-toxic organic amines Preferred salts and water soluble salts are preferred. Compounds of the general formula (I) of the present invention are salts of inorganic acids (hydrochloride, hydrogen bromide, hydrogen iodide, sulfate, phosphate, nitrate, etc.), salts of organic acids (acetic acid, lactate, tartarate, oxalate, puma) Lysates, glucuronates, etc.), which can be converted to the corresponding acid addition salts, with non-toxic and water-soluble salts being preferred. The compounds of formula (I) and salts thereof of the present invention can also be converted to the corresponding hydrates by conventional methods in the art.

일반식(I)의 본 발명의 화합물 중에서, 씨클릭 아미노산의 구조에서 n의 숫자 및 치환체에 따라 하기 일반식의 각 설포닐아미드 유도체들이 바람직하다.Among the compounds of the present invention of general formula (I), each sulfonylamide derivative of the following general formula is preferred depending on the number and substituents of n in the structure of the cyclic amino acid.

상기 식에서,Where

R₁, R₂, R₃, 및 X는 일반식(Ⅰ)에서 이미 정의한 바와R ₁ , R ₂ , R ₃ , and X are as defined above in general formula (I).

동일하고;Same;

R₅는 히드록시, C_1-6의 알킬옥시, C_3-6카보씨클로알킬옥시,R ₅ is hydroxy, C _1-6 alkyloxy, C _3-6 carbocycloalkyloxy,

C_3-6카보씨클로알킬저급알킬옥시, C_3-6헤테로씨클로알C _3-6 carbocycloalkylloweralkyloxy, C _3-6 heterocycloal

킬저급알킬옥시, C_1-6의 알케닐옥시, C_1-6알키닐옥시,Alkyl lower alkyloxy, C _1-6 alkenyloxy, C _1-6 alkynyloxy,

카보씨클릭아릴저급알킬옥시, 헤테로씨클릭아릴저Carbocyclic aryl lower alkyloxy, heterocyclic aryl

급알킬옥시, 옥소, (알킬 또는 아릴)히드록시이미Tertiaryalkyloxy, oxo, (alkyl or aryl) hydroxyimi

도일, (N-치환된)히드라존, 씨클릭디티오란, 씨클Doyle, (N-substituted) hydrazone, cyclicdithiolane, cicle

릭디옥소란, 티올, C_1-6의 알킬티오, C_3-6카보씨클로Rixodioxane, thiol, C _1-6 alkylthio, C _3-6 carbocyclo

알킬티오, C_3-6카보씨클로알킬저급알킬티오, N, S 또Alkylthio, C _3-6 carbocycloalkylloweralkylthio, N, S or

는 O를 포함하는 C_3-6헤테로씨클로알킬저급알킬티Is C _3-6 heterocycloalkyllower alkylthi containing O

오, C_1-6의 알케닐티오, C_1-6알키닐티오, 카보씨클릭Oh, C _1-6 alkenylthio, C _1-6 alkynylthio, carbocyclic

아릴저급알킬티오, 헤테로씨클릭아릴저급알킬티오,Aryl lower alkylthio, heterocyclic aryl lower alkylthio,

아실티오이며;Acylthio;

R₆및 R₇기는 각각 같거나 다른 치환체로 수소, C_1-6의 저R ₆ and R ₇ groups are the same or different substituents each of hydrogen, C _1-6

급알킬 또는 (치환된)아릴이고;Tertiary alkyl or (substituted) aryl;

R₉, R₁₀, R₁₁및 R₁₂는 각각 같거나 다른 치환체로 수소,R ₉ , R ₁₀ , R ₁₁ and R ₁₂ are the same or different substituents each of hydrogen,

C_1-6의 저급알킬 또는 (치환된)아릴이며;C _1-6 lower alkyl or (substituted) aryl;

R₁₃, R₁₄, R₁₅및 R₁₆은 수소, 할라이드, 히드록시, C_1-6의 저R ₁₃ , R ₁₄ , R ₁₅ and R ₁₆ are hydrogen, halide, hydroxy, C _1-6 low

급알킬, C_1-6의 저급알킬옥시 또는 C_1-6의 저급알킬아Tert-alkyl, O-lower alkyl lower alkyloxy or a C _1-6 C _1-6

미노이고; 및,Mino; And,

Y는 C, N-R₁₇(이때, R₁₇은 수소, C_1-6의 저급알킬, 아릴, 카Y is C, NR ₁₇ (wherein R ₁₇ is hydrogen, C _1-6 lower alkyl, aryl, car

보씨클릭아릴저급알킬, 아실, 알킬설피닐, 알킬설Bocyclic cyclic lower alkyl, acyl, alkylsulfinyl, alkylsul

포닐, 알킬옥시카보닐, 벤질옥시카보닐, 아릴옥시Ponyl, Alkyloxycarbonyl, Benzyloxycarbonyl, Aryloxy

카보닐, 알킬아미노카보닐, 아릴아미노카보닐 또는Carbonyl, alkylaminocarbonyl, arylaminocarbonyl or

벤질아미노카보닐이다), O 또는 S이다.Benzylaminocarbonyl), O or S.

이하에서는, 일반식(Ⅰ)의 화합물의 제조방법을 공정별로 나누어 설명한다. 상기에서 정의한 R₁의 물리, 화학적 성질에 따라서 두가지 제조방법 모두 유용하거나, 둘 중 어느 한가지 제조방법으로만 제조가 가능하다.Below, the manufacturing method of the compound of general formula (I) is demonstrated according to process. Depending on the physical and chemical properties of R ₁ defined above, both manufacturing methods are useful, or only one of the two manufacturing methods can be prepared.

제조방법 1: R₃가 카르복실산(CO₂H) 또는 히드록사믹산(CONHOH)인 경우 Preparation Method 1 When R ₃ Is Carboxylic Acid (CO ₂ H) or Hydroxamic Acid (CONHOH)

제조방법 1에 의해서 R₁이 주로 방향족 고리가 없거나, 씨클릭알킬기가 아닌단순한 C_1-12의 알킬기인 화합물이 제조된다.Production method 1 produces a compound wherein R ₁ is predominantly free of aromatic rings or is a simple C _1-12 alkyl group that is not a cyclic alkyl group.

제 1공정: First step :

설포닐할라이드(Ⅱ)와 씨클릭 아미노산(Ⅲ)을 유기용매에서 염기의 존재하에 상온 이하의 온도에서 반응시켜 화합물(Ⅳ)을 수득한다: 이때, 출발물질인 설포닐할라이드(II)는 공지된 제조방법을 응용하여 제조한다(참조: USP 4820332, USP 5504098, USP 5985870, USP 5559081, EP 168264, USP 5973148, USP 5962490). 특히, R₁이 할라이드인 2-클로로벤즈티아졸설포닐할라이드(II)는 신규한 물질로서, R₁기가 2-아릴티오, 2-헤테로아릴티오, 씨클로알킬티오 등의 벤즈티아졸설폰아미드를 제조하기 위한 출발물질로서 사용된다.Sulfonyl halide (II) and cyclic amino acid (III) are reacted in an organic solvent at a temperature below room temperature in the presence of a base to give compound (IV): wherein the starting material sulfonyl halide (II) is known It is prepared by applying the preparation method (see USP 4820332, USP 5504098, USP 5985870, USP 5559081, EP 168264, USP 5973148, USP 5962490). In particular, 2-chlorobenzthiazolesulfonyl halide (II) wherein R ₁ is a halide is a novel substance, and R ₁ group is used to prepare benzthiazolesulfonamide such as 2-arylthio, 2-heteroarylthio, cycloalkylthio, and the like. Used as starting material for

다른 출발물질인 씨클릭 아미노산(III)은 하기 일반식으로 표시된다.Another starting material, cyclic amino acid (III), is represented by the following general formula.

상기 식에서,Where

R₂, R₃및 n은 일반식(Ⅰ)에서 이미 정의한 바와 동일하다.R ₂ , R ₃ and n are the same as defined in the general formula (I).

전기 씨클릭 아미노산(III) 중, 일반식(IIIa), (IIIb), (IIIc) 또는 (IIId)으로 표시되는 화합물이 바람직한데, 이들 역시 공지된 방법에 따라 제조된다(참조: US 5861,510, US 5753635, WO 97/20824, WO 98/08814, EP 803505, WO 98/08815, WO 98/08825, WO 98/08850, WO 98/50348, EP 878467).Of the aforementioned cyclic amino acids (III), compounds represented by general formulas (IIIa), (IIIb), (IIIc) or (IIId) are preferred, which are also prepared according to known methods (see US 5861,510). , US 5753635, WO 97/20824, WO 98/08814, EP 803505, WO 98/08815, WO 98/08825, WO 98/08850, WO 98/50348, EP 878467.

아울러, 유기용매로는 디클로로메탄 또는 디클로로에탄을 사용하고, 적당량의 염기, 바람직하게는 트리에틸아민 또는 N-메틸모포린을 사용한다.In addition, dichloromethane or dichloroethane is used as the organic solvent, and an appropriate amount of base, preferably triethylamine or N-methylmorpholine, is used.

제 2공정: Second process :

화합물(Ⅳ)을 알콜 수용액내에서 염기의 존재하에 가수분해하여 화합물(Ⅰ, R₃:OH)를 제조한다: 이때, 염기로는 주로 무기염을 사용하는데, 가장 바람직하게는 리튬히드록시드를 사용한다.Compound (IV) is hydrolyzed in the presence of a base in an aqueous alcohol solution to prepare compound (I, R ₃ : OH): wherein the base is mainly an inorganic salt, most preferably lithium hydroxide use.

제 3공정: Third process :

전기 제조한 화합물(Ⅰ, R₃:OH)로부터 축합반응에 의하여 화합물(Ⅰ, R₃:NHOH)를 추가로 제조할 수도 있다(참조: J. Med. Chem., 40:2525-2532, 1997; J. Med. Chem., 41:640-649, 1998).Compound (I, R ₃ : NHOH) may be further prepared from the previously prepared compound (I, R ₃ : OH) by condensation reaction (see J. Med. Chem., 40: 2525-2532, 1997). J. Med. Chem., 41: 640-649, 1998).

제조방법 2: R₁이 방향족 고리, 씨클릭알킬, 및 알콕시알킬의 치환체인 경우 Preparation Method 2 When R ₁ Is Substituent Of Aromatic Ring, Cyclyalkyl And Alkoxyalkyl

제조방법 2에 의해서 R₄가 C_3-7의 씨클로알킬, (옥소, 아미노, 또는 티오)C_3-7의 씨클로알킬, (옥소, 아미노, 또는 티오)C_3-7의 씨클로알킬-저급알킬, C_2-12의 저급알케닐, C_2-12의 저급알키닐, 카보씨클릭아릴, 헤테로씨클릭아릴, 헤테로씨클릭아릴-저급알킬, 비아릴, 할로저급알킬, 비아릴-저급알킬아릴알킬, 히드록시-저급알킬, 알콕시알킬, 아실옥시-저급알킬, 알킬 또는 아릴 (티오, 설피닐 또는 설포닐) 저급알킬, (아미노, 모노 또는 디 알킬아미노)저급알킬, 아실아미노 저급알킬, (N-저급알킬-피페라지노, N-카보씨클릭 또는 헤테로씨클릭 아릴-저급알킬피페라지노)-저급알킬 또는 (모포리노, 티오모포리노, 피페리디노, 피롤리디노 또는 피페리딜)-저급알킬인 화합물이 제조된다.According to Preparation 2 R ₄ is C _3-7 cycloalkyl, (oxo, amino, or thio) C _3-7 cycloalkyl, (oxo, amino, or thio) C _3-7 cycloalkyl-lower alkyl , C _2-12 lower alkenyl, C _2-12 lower alkynyl, carbocyclic aryl, heterocyclic aryl, heterocyclic aryl-lower alkyl, biaryl, halolower alkyl, biaryl-lower alkylaryl Alkyl, hydroxy-lower alkyl, alkoxyalkyl, acyloxy-lower alkyl, alkyl or aryl (thio, sulfinyl or sulfonyl) lower alkyl, (amino, mono or di alkylamino) lower alkyl, acylamino lower alkyl, ( N-lower alkyl-piperazino, N-carbocyclic or heterocyclic aryl-lower alkylpiperazino) -lower alkyl or (morpholino, thiomorpholino, piperidino, pyrrolidino or piperidyl) A compound that is lower alkyl is prepared.

제 1공정: First step :

설포닐할라이드(Ⅱ, R₁:C_l)와 씨클릭 아미노산(Ⅲ)을 유기용매에서 염기의 존재하에 상온 이하의 온도에서 반응시켜 화합물(Ⅴ)을 수득한다: 이때, 설포닐할라이드(Ⅱ, R₁:C_l)는 2-클로로벤즈티아졸을 클로로설포닐화하여 수득하며, 전기 제조방법 1의 제 1공정과 동일한 방법으로 화합물(Ⅴ)를 수득한다.Sulfonyl halide (II, R ₁ : _Cl ) and cyclic amino acid (III) are reacted in an organic solvent at a temperature below room temperature in the presence of a base to give compound (V): wherein sulfonyl halide (II, R ₁ : C ₁ ) is obtained by chlorosulfonylation of 2-chlorobenzthiazole, to obtain compound (V) in the same manner as in the first step of Preparation Method 1 above.

제 2공정: Second process :

화합물(Ⅴ)를 유기용매에서 염기의 존재하에 70-80℃로 가열하여 화합물(Ⅵ)를 수득한다: 이때, 유기용매는 바람직하게는 MeCN, THF 또는 DMF을 사용하고, 염기는 바람직하게는 K₂CO₃또는 NaHCO₃을 사용한다.Compound (V) is heated to 70-80 ° C. in the presence of a base in an organic solvent to afford compound (VI), wherein the organic solvent is preferably MeCN, THF or DMF, and the base is preferably K ₂ CO ₃ or NaHCO ₃ is used.

제 3공정: Third process :

전기 제조방법 1의 제 2공정과 동일한 방법으로 화합물(Ⅳ)를 알콜 수용액 내에서 염기의 존재하에 가수분해하여 화합물(Ⅰ, R₃:OH)를 제조한다.Compound (IV) is hydrolyzed in the presence of a base in an aqueous alcohol solution to prepare compound (I, R ₃ : OH) in the same manner as in the second step of Preparation Method 1 above.

제 4공정: 4th process :

전기 제조방법 1의 제 3공정과 동일한 방법으로, 화합물(Ⅰ, R₃:OH)로부터 축합반응에 의하여 화합물(Ⅰ, R₃:NHOH)를 추가로 제조할 수도 있다.Compound (I, R ₃ : NHOH) may be further produced by a condensation reaction from compound (I, R ₃ : OH) in the same manner as in the third step of Electric Production Method 1.

한편, 제조방법 1 및 제조방법 2에서 사용된 설포닐할라이드(II)는 다음과 같이 제조된다.On the other hand, sulfonyl halide (II) used in Preparation Method 1 and Preparation Method 2 is prepared as follows.

제 1공정: First step :

화합물(Ⅵ)를 유기용매에서 상온 내지 100℃의 온도에서 무기염 또는 유기염을 사용하여 알킬할라이드와 치환반응시켜 화합물(Ⅶ)을 수득한다: 이때, 화합물(Ⅵ)는 바람직하게는 메캅토벤즈티아졸, 메캅토벤즈옥사졸, 히드록시벤즈티아졸, 히드록시벤즈옥사졸, 할로벤즈티아졸 또는 할로벤즈옥사졸을 사용하고, 유기용매는 물 및 물과 혼합가능한 유기용매와의 혼합용매를 사용함이 바람직하다.Compound (VI) is substituted with an alkyl halide using an inorganic salt or an organic salt at a temperature ranging from room temperature to 100 ° C. in an organic solvent to obtain compound (VII), wherein compound (VI) is preferably mecaptobenz Thiazole, mecaptobenzoxazole, hydroxybenzthiazole, hydroxybenzoxazole, halobenzthiazole or halobenzoxazole are used, and the organic solvent is a mixed solvent of water and an organic solvent that can be mixed with water. It is preferable to use.

제 2공정: Second process :

화합물(Ⅶ)을 할로겐화된 유기용매 내에서 가열환류 조건에서 5 내지 10일간 클로로설포닐화하거나, 또는 용매없이 70 내지 150℃에서 12 내지 24시간동안 클로로설포닐화하여, 설포닐할라이드(Ⅱ) 및 설폰산화합물(Ⅷ)을 수득하고, 에틸초산으로 전기 두 수득물을 분리하여 설포닐할라이드(Ⅱ)를 제조한다: 이때, 할로겐화된유기용매는 디클로로메탄, 클로로포름 또는 디클로로에탄을 사용함이 바람직하고, 용매없이 반응할 경우, 반응조건은 온도가 70-150℃까지 가능하나, 주로 100-110℃가 바람직하다. 선택적으로, 분리된 설폰산화합물(Ⅷ)을 용매에서 가열환류 또는 용매없이 가열환류하는 조건에서 할로겐화 시약을 이용하여 설포닐할라이드(Ⅱ)로 제조하는 공정을 포함할 수도 있다. 이때의 유기용매는 바람직하게는 MeCN 또는 디클로로에탄을 사용하며, 할로겐화 시약은 SOCl₂, POCl₃또는 PCl₅을 사용함이 바람직하다.Compound (iii) is chlorosulfonylated for 5 to 10 days in a reflux condition in a halogenated organic solvent or chlorosulfonylated at 70 to 150 ° C. for 12 to 24 hours without solvent to form sulfonyl halide (II) and sulfide. Sulfonyl halide (II) is obtained by distilling the two compounds obtained with ethyl acetate, in which the halogenated organic solvent is preferably dichloromethane, chloroform or dichloroethane, When reacting without, the reaction conditions may be up to 70-150 ° C, but mainly 100-110 ° C is preferred. Optionally, the method may comprise the step of preparing the sulfonyl halide (II) using a halogenated reagent under the conditions of heating the refluxed separated sulfonic acid compound in the solvent or refluxing the solvent without heating. In this case, the organic solvent is preferably MeCN or dichloroethane, and the halogenation reagent is preferably SOCl ₂ , POCl ₃ or PCl ₅ .

이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. .

실시예 1: 2-치환된 6-벤즈티아졸설포닐 클로라이드(II)의 제조 Example 1 Preparation of 2-Substituted 6-Benzthiazolesulfonyl Chloride (II)

6-벤즈티아졸설포닐 클로라이드(Ⅱ)는 다음의 2-n-부틸티오-6-벤즈티아졸설포닐 클로라이드의 제조방법을 응용하여 제조할 수 있다.6-benzthiazolesulfonyl chloride (II) can be manufactured by applying the following manufacturing method of 2-n-butylthio-6-benzthiazolesulfonyl chloride.

2-머캅토벤즈티아졸(83.4g, 0.5mol)을 100mL의 메탄올에 분산시킨 후, NaOH(24g)을 물 50mL에 용해시킨 용액을 적가하였다. 이어, 2-머캅토벤즈티아졸이완전히 용해된 다음, n-부틸브로마이드(54mL, 0.5mol)를 가하였다. 반응용액을 12시간동안 가열환류시킨 후, 메탄올을 감압제거하고 에틸초산(300mL)을 가하여, 물, 1M K₂CO₃로 차례로 세척하고 분리된 유기용액에 MgSO₄를 가하여 건조시킨 다음, 감압증류하여 순수한 2-n-부틸티오-6-벤즈티아졸을 약 100g(89%) 수득하였다. 더 이상의 정제없이 500mL의 플라스크에 옮긴 후, 0℃로 냉각하고, 클로로설폰산(130g, 2.5당량)을 천천히 적가하였다. 완전히 적가한 후, 반응용액을 약 110℃로 가열하여 24시간 반응시켰다. 출발물질이 완전히 사라지면 반응액을 상온으로 냉각시키고, 얼음물을 가하여 강하게 교반하였다. 고체생성물을 여과하여 수득하고 여과된 고체에 에틸초산(300mL)을 가하여 1시간 정도 교반하였다. 교반후 용해되지 않은 고체를 여과하고, 에틸초산으로 세척하여 2-n-부틸티오-6-벤즈티아졸설폰산(30g)을 수득하였다. 그런 다음, 에틸초산 잔여용액을 활성탄 5g과 MgSO₄로 처리하여 약 1시간 동안 교반하고, 활성탄과 MgSO₄를 여과하여 제거하고 용매를 감압 건조하여 2-n-부틸티오-6-벤즈티아졸설포닐 클로라이드(약 60g)를 고체상태로 수득하였다. 수득한 고체에 n-헥산(150mL)를 가하여 1시간 교반후 여과하여 순수한 2-n-부틸티오-6-벤즈티아졸설포닐 클로라이드(55g)를 수득하였다. 수득한 2-n-부틸티오-6-벤즈티아졸설폰산(30g)에 SOCl₂를 용매 및 시약으로 30mL 가하고, 5시간 가열환류하고 감압건조하여 물로 처리하고 생기는 고체를 여과하여 얻고, 이 고체에 에틸초산(100mL)을 가하여 1시간 정도 교반하였다. 에틸초산 용액을 활성탄 5g과MgSO₄로 처리하여, 약 1시간 동안 교반하고 활성탄과 MgSO₄를 여과하여 제거한 다음, 용매를 감압 건조하여 2-n-부틸티오-6-벤즈티아졸설포닐 클로라이드(약 30g)를 고체상태로 수득하였다. 수득한 고체를 전기 방법과 동일하게 n-헥산(50mL)으로 정제하여, 순수한 2-n-부틸티오-6-벤즈티아졸설포닐 클로라이드(25g)를 수득하였다. 결과적으로, 두 과정을 통해 약 80g(약 56%) 표제화합물을 제조하였다.2-mercaptobenzthiazole (83.4 g, 0.5 mol) was dispersed in 100 mL of methanol, and then a solution of NaOH (24 g) dissolved in 50 mL of water was added dropwise. Then 2-mercaptobenzthiazole was completely dissolved, and then n-butyl bromide (54 mL, 0.5 mol) was added. After the reaction solution was heated to reflux for 12 hours, methanol was removed under reduced pressure, ethyl acetate (300 mL) was added thereto, washed with water and 1 M K ₂ CO _{3 in} that order, MgSO ₄ was added to the separated organic solution, and dried under reduced pressure. To yield about 100 g (89%) of pure 2-n-butylthio-6-benzthiazole. Transfer to a 500 mL flask without further purification, cool to 0 ° C., and slowly add dropwise chlorosulfonic acid (130 g, 2.5 equiv). After completely added dropwise, the reaction solution was heated to about 110 ° C and reacted for 24 hours. When the starting material disappeared completely, the reaction solution was cooled to room temperature, ice water was added thereto, and the mixture was stirred vigorously. The solid product was obtained by filtration, ethyl acetate (300 mL) was added to the filtered solid, and the mixture was stirred for about 1 hour. After stirring, the undissolved solid was filtered and washed with ethyl acetate to give 2-n-butylthio-6-benzthiazolesulfonic acid (30 g). Then, the remaining solution of ethyl acetate was treated with 5 g of activated carbon and MgSO ₄ , stirred for about 1 hour, the activated carbon and MgSO ₄ were filtered off, and the solvent was dried under reduced pressure to obtain 2-n-butylthio-6-benzthiazolsulfonyl. Chloride (about 60 g) was obtained in the solid state. N-hexane (150 mL) was added to the obtained solid, followed by stirring for 1 hour to obtain pure 2-n-butylthio-6-benzthiazolesulfonyl chloride (55 g). 30 mL of SOCl ₂ was added to the obtained 2-n-butylthio-6-benzthiazolesulfonic acid (30 g) with a solvent and a reagent. The mixture was heated under reflux for 5 hours, dried under reduced pressure, treated with water, and the resulting solid was filtered off to obtain a solid. Ethyl acetic acid (100 mL) was added and the mixture was stirred for about 1 hour. The ethyl acetate solution was treated with 5 g of activated carbon and MgSO ₄ , stirred for about 1 hour, the activated carbon and MgSO ₄ were removed by filtration, and the solvent was dried under reduced pressure to obtain 2-n-butylthio-6-benzthiazolesulfonyl chloride (about 30 g) was obtained in the solid state. The obtained solid was purified with n-hexane (50 mL) in the same manner as the above method to obtain pure 2-n-butylthio-6-benzthiazolesulfonyl chloride (25 g). As a result, about 80 g (about 56%) of the title compound were prepared through two procedures.

¹H NMR(300MHz, CDCl₃): δ1.1(t, 3H), 1.5(m, 2H), 1.8(m, 2H), 3.4(t, ¹ H NMR (300 MHz, CDCl ₃ ): δ 1.1 (t, 3H), 1.5 (m, 2H), 1.8 (m, 2H), 3.4 (t,

2H), 8.0(dd, 2H), 8.45(s, 1H)2H), 8.0 (dd, 2H), 8.45 (s, 1H)

실시예 2: 2-n-펜틸티오-6-벤즈티아졸설포닐 클로라이드 Example 2 2-n-pentylthio-6-benzthiazolesulfonyl chloride

1-브로모펜탄을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법으로 표제화합물 2-n-펜틸티오-6-벤즈티아졸설포닐 클로라이드를 제조하였다.Except for using 1-bromopentane, the title compound 2-n-pentylthio-6-benzthiazolesulfonyl chloride was prepared in the same manner as in Example 1.

¹H NMR(300MHz, CDCl₃): δ0.95(t, 3H), 1.4(m, 4H), 1.9(p, 2H), 3.4(t, 2H), 7.9(dd, 2H), 8.3(s, 1H) ¹ H NMR (300 MHz, CDCl ₃ ): δ 0.95 (t, 3H), 1.4 (m, 4H), 1.9 (p, 2H), 3.4 (t, 2H), 7.9 (dd, 2H), 8.3 (s , 1H)

실시예 3: 2-n-헥실티오-6-벤즈티아졸설포닐 클로라이드 Example 3 2-n-hexylthio-6-benzthiazolesulfonyl chloride

1-브로모헥산을 사용하는 것을 제외하고는, 실시예 1과 동일한 방법으로 표제화합물 2-n-헥실티오-6-벤즈티아졸설포닐 클로라이드를 제조하였다.Except for using 1-bromohexane, the title compound 2-n-hexylthio-6-benzthiazolesulfonyl chloride was prepared in the same manner as in Example 1.

¹H NMR(300MHz, CDCl₃): δ0.9(t, 3H), 1.35(m, 4H), 1.5(m, 2H), 1.85(p, 2H), 3.4(t, 2H), 8.0(dd, 2H), 8.45(s, 1H) ¹ H NMR (300 MHz, CDCl ₃ ): δ 0.9 (t, 3H), 1.35 (m, 4H), 1.5 (m, 2H), 1.85 (p, 2H), 3.4 (t, 2H), 8.0 (dd , 2H), 8.45 (s, 1H)

실시예 4: 2-씨클로헥실메틸티오-6-벤즈티아졸설포닐 클로라이드 Example 4 : 2-cyclohexylmethylthio-6-benzthiazolesulfonyl chloride

씨클로헥실메틸브로마이드를 사용하는 것을 제외하고는, 실시예 1과 동일한 방법으로 표제화합물 2-씨클로헥실메틸티오-6-벤즈티아졸설포닐 클로라이드를 제조하였다.Except for using cyclohexylmethylbromide, the title compound 2-cyclohexylmethylthio-6-benzthiazolesulfonyl chloride was prepared in the same manner as in Example 1.

¹H NMR(300MHz, CDCl₃): δ1.0(m, 6H), 1.7(m, 3H), 1.9(bd, 2H), ¹ H NMR (300 MHz, CDCl ₃ ): δ 1.0 (m, 6H), 1.7 (m, 3H), 1.9 (bd, 2H),

2.1(m, 1H), 3.3(d, 2H), 7.8(dd, 2H), 8.25(s,1H)2.1 (m, 1H), 3.3 (d, 2H), 7.8 (dd, 2H), 8.25 (s, 1H)

실시예 5: 2-클로로-6-벤즈티아졸설포닐 클로라이드 Example 5 2-Chloro-6-benzthiazolesulfonyl chloride

2-클로로-6-벤즈티아졸(1.7g, 10mmol)을 0℃로 냉각한 다음, 클로로설폰산(3.3mL)을 천천히 적가하고, 반응용액을 약 120℃로 가열하여 24시간 동안 반응시켰다. 출발물질이 완전히 소멸된 후, 반응액을 상온으로 냉각하고, 얼음물을 가하여 강하게 교반하였다. 이에, 에틸초산(30mL)를 가하여 추출물을 수득하고, 이를 물로 세척하고 활성탄 5g과 MgSO₄로 처리한 다음, 약 1시간 동안 교반하였다. 활성탄과 MgSO₄를 여과하여 제거한 다음, 용매를 감압건조하여 2-클로로-6-벤즈티아졸설포닐 클로라이드를 수득하였다. 수득한 화합물을 n-헥산으로 용출시키는 실리카겔상에서 크로마토그라피로 정제하여, 표제화합물 2-클로로-6-벤즈티아졸설포닐 클로라이드(1.88g, 70%)를 액체상태로 제조하였다.After 2-chloro-6-benzthiazole (1.7 g, 10 mmol) was cooled to 0 ° C., chlorosulfonic acid (3.3 mL) was slowly added dropwise, and the reaction solution was heated to about 120 ° C. for 24 hours. After the starting material disappeared completely, the reaction solution was cooled to room temperature, ice water was added thereto, and the mixture was stirred vigorously. To this, ethyl acetate (30 mL) was added to obtain an extract, which was washed with water, treated with 5 g of activated carbon and MgSO ₄ , and then stirred for about 1 hour. Activated carbon and MgSO ₄ were removed by filtration, and then the solvent was dried under reduced pressure to give 2-chloro-6-benzthiazolesulfonyl chloride. The obtained compound was purified by chromatography on silica gel eluting with n-hexane to give the title compound 2-chloro-6-benzthiazolesulfonyl chloride (1.88 g, 70%) in the liquid state.

¹H NMR(300MHz, CDCl₃): δ7.9(d, 1H), 8.0(d, 1H), 8.3(s, 1H) ¹ H NMR (300 MHz, CDCl ₃ ): δ7.9 (d, 1H), 8.0 (d, 1H), 8.3 (s, 1H)

실시예 6: (2R)-N-[2-(n-펜틸티오벤즈티아졸-6-설포닐)]-2-메틸카르복실피롤리딘 Example 6 : (2R) -N- [2- (n-pentylthiobenzthiazole-6-sulfonyl)]-2-methylcarboxypyrrolidine

(D)-프롤린메틸 에스테르 염산 염(0.29g, 1.75mmol)을 디클로로메탄 (3mL)에 분산시킨 후, 0℃로 냉각하였다. 트리에틸아민(0.73mL, 3당량)을 가하여 온도를 0℃로 유지하면서, 상기 실시예 2에서 제조한 2-n-펜틸티오-6-벤즈티아졸설포닐 클로라이드(0.35g, 1.0당량)를 디클로로메탄(2mL)에 용해시킨 용액을 적가하였다.출발물질이 소멸된 후(약 5시간), 1N HCl용액으로 유기층을 세척한 다음, MgSO₄로 건조하고 감압증류 후, 진공건조하여 (2R)-N-[2-(n-펜틸티오벤즈티아졸-6-설포닐) ]-2-메틸카르복실피롤리딘(0.17g, 23%)을 제조하였다.(D) -Prolinemethyl ester hydrochloride salt (0.29 g, 1.75 mmol) was dispersed in dichloromethane (3 mL) and then cooled to 0 ° C. Triethylamine (0.73 mL, 3 equiv) was added thereto and the temperature was maintained at 0 ° C., while 2-n-pentylthio-6-benzthiazolesulfonyl chloride (0.35 g, 1.0 equiv) prepared in Example 2 was diluted. The solution dissolved in methane (2 mL) was added dropwise. After the starting material disappeared (about 5 hours), the organic layer was washed with 1N HCl solution, dried over MgSO ₄ , distilled under reduced pressure, and dried under vacuum (2R)-. N- [2- (n-pentylthiobenzthiazole-6-sulfonyl)]-2-methylcarboxypyrrolidine (0.17 g, 23%) was prepared.

¹H NMR(300MHz, CDCl₃): δ0.93(t, 3H), 1.45(m, 4H), 1.84(m, 3H), 2.0(m, 3H), 3.37(t, 3H), 3.5(m, 1H), 3.7(s, 3H), 4.4(t, 1H), 7.9(m, 2H), 8.3(s, 1H) ¹ H NMR (300 MHz, CDCl ₃ ): δ 0.93 (t, 3H), 1.45 (m, 4H), 1.84 (m, 3H), 2.0 (m, 3H), 3.37 (t, 3H), 3.5 (m , 1H), 3.7 (s, 3H), 4.4 (t, 1H), 7.9 (m, 2H), 8.3 (s, 1H)

실시예 7: (2R)-N-[2-(n-펜틸티오벤즈티아졸-6-설포닐)]-2-피롤리딜카르복실산 Example 7 : (2R) -N- [2- (n-pentylthiobenzthiazole-6-sulfonyl)]-2-pyrrolidylcarboxylic acid

상기 실시예 6에서 제조된 (2R)-N-[2-(n-펜틸티오벤즈티아졸-6-설포닐)]-2-메틸카르복실피롤리딘(0.17g, 0.4mmol)을 THF/H₂O(2mL/2mL)용매에 용해시킨 후, LiOH(0.083g, 5당량)을 가하여 6시간 동안 가열환류하였다. 반응 후, 용매를 감압증류하고 1N HCl용액으로 산처리한 다음, 에틸초산(10mL)을 가하여 추출물을 수득하였다. 수득한 추출물을 NaCl용액으로 세척한 후, MgSO₄로 건조하고 감압증류한 다음, 진공건조하여 표제화합물 (2R)-N-[2-(n-펜틸티오벤즈티아졸-6-설포닐)]-2-피롤리딜카르복실산(160mg, 97%)을 제조하였다.(2R) -N- [2- (n-pentylthiobenzthiazole-6-sulfonyl)]-2-methylcarboxypyrrolidine (0.17 g, 0.4 mmol) prepared in Example 6 was prepared by THF / After dissolving in H ₂ O (2 mL / 2 mL) solvent, LiOH (0.083 g, 5 equivalents) was added thereto, followed by heating to reflux for 6 hours. After the reaction, the solvent was distilled under reduced pressure, acid treated with 1N HCl solution, and ethyl acetate (10 mL) was added to obtain an extract. The obtained extract was washed with NaCl solution, dried over MgSO ₄ , distilled under reduced pressure, and then vacuum dried to give the title compound (2R) -N- [2- (n-pentylthiobenzthiazole-6-sulfonyl)]. 2-Pyrrolidylcarboxylic acid (160 mg, 97%) was prepared.

¹H NMR(300MHz, CDCl₃): δ0.93(t, 3H), 1.45(m, 4H), 1.82(m, 3H), ¹ H NMR (300 MHz, CDCl ₃ ): δ 0.93 (t, 3H), 1.45 (m, 4H), 1.82 (m, 3H),

1.83(m, 2H), 2.15(m, 1H), 3.3(m, 1H),1.83 (m, 2H), 2.15 (m, 1H), 3.3 (m, 1H),

3.38(t, 2H), 3.6(m, 1H), 4.35(m, 1H),3.38 (t, 2H), 3.6 (m, 1H), 4.35 (m, 1H),

7.95(dd, 2H), 8.3(s, 1H)7.95 (dd, 2H), 8.3 (s, 1H)

실시예 8: (2R)-N-[2-(n-헥실티오벤즈티아졸-6-설포닐)]-2-피롤리딜카르복실산 Example 8 (2R) -N- [2- (n-hexylthiobenzthiazole-6-sulfonyl)]-2-pyrrolidylcarboxylic acid

¹H NMR(300MHz, CDCl₃): δ0.90(t, 3H), 1.33(m, 4H), 1.49(m, 2H), 1.8(m, 3H), 1.87(m, 2H), 2.2(m, 1H), 3.3(q, 1H), 3.38(t, 2H), 3.6(m, 1H), 4.3(m, 1H), 7.95(dd, 2H), 8.3(s, 1H) ¹ H NMR (300 MHz, CDCl ₃ ): δ 0.90 (t, 3H), 1.33 (m, 4H), 1.49 (m, 2H), 1.8 (m, 3H), 1.87 (m, 2H), 2.2 (m , 1H), 3.3 (q, 1H), 3.38 (t, 2H), 3.6 (m, 1H), 4.3 (m, 1H), 7.95 (dd, 2H), 8.3 (s, 1H)

실시예 9: (3R)-1,2,3,4-테트라히드로-N-[2-(n-펜틸티오벤즈티아졸-6-설포닐)]-3-이소퀴놀린카르복실산의 제조 Example 9 Preparation of (3R) -1,2,3,4-tetrahydro-N- [2- (n-pentylthiobenzthiazole-6-sulfonyl)]-3-isoquinolinecarboxylic acid

공지된 방법(참조: Beil,22(1):506)에 의하여 제조한 (3R)-1,2,3,4-테트라히드로-3-이소퀴놀린카르복실산(0.2g, 1mmol)을 디클로로메탄(3mL)에 분산시킨 후, 0℃로 냉각하였다. 이에, 트리에틸아민(0.4mL, 3당량)을 가하여 온도를 0℃로 유지하면서, 상기 실시예 2에서 제조한 2-n-펜틸티오-6-벤즈티아졸설포닐 클로라이드(0.26g, 1.0당량)를 디클로로메탄(2mL)에 용해시킨 용액을 적가하였다. 출발물질이 소멸된 후(약 5시간), 1N HCl용액으로 처리한 다음, 분리된 유기층을 소금물로 세척하고, MgSO₄로 건조하며 감압증류하고 진공건조하여 표제화합물 (3R)-1,2,3,4-테트라히드로-N-[2-(n-펜틸티오벤즈티아졸-6-설포닐)]-3-이소퀴놀린카르복실산(0.3g, 63%)을 제조하였다.(3R) -1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (0.2 g, 1 mmol) prepared by a known method (see Beil, 22 (1): 506) was converted to dichloromethane. After dispersion in (3 mL), the mixture was cooled to 0 ° C. To this, 2-ethyl-pentylthio-6-benzthiazolesulfonyl chloride (0.26 g, 1.0 equivalent) prepared in Example 2 was added while adding triethylamine (0.4 mL, 3 equivalents) and maintaining the temperature at 0 ° C. Was added dropwise to a solution dissolved in dichloromethane (2 mL). After the disappearance of the starting material (about 5 hours), the solution was treated with 1N HCl solution, and the separated organic layer was washed with brine, dried over MgSO ₄ , distilled under reduced pressure, and dried in vacuo to give the title compound (3R) -1,2, 3,4-Tetrahydro-N- [2- (n-pentylthiobenzthiazole-6-sulfonyl)]-3-isoquinolinecarboxylic acid (0.3 g, 63%) was prepared.

¹H NMR(300MHz, CDCl₃): δ0.92(t, 3H), 1.4(m, 4H), 1.83(m, 2H), 3.18(d, 2H), 3.35(t, 2H), 4.6(dd, 2H), 5.0(t, 1H), 7.15(m, 4H), 7.83(m, 2H), 8.25(s, 1H) ¹ H NMR (300 MHz, CDCl ₃ ): δ 0.92 (t, 3H), 1.4 (m, 4H), 1.83 (m, 2H), 3.18 (d, 2H), 3.35 (t, 2H), 4.6 (dd , 2H), 5.0 (t, 1H), 7.15 (m, 4H), 7.83 (m, 2H), 8.25 (s, 1H)

실시예 10: (±)-1,2,3,4-테트라히드로-N-[2-(n-펜틸티오벤즈티아졸-6-설포닐)]-3-메틸-3-이소퀴놀린카르복실산메틸에스테르의 제조 Example 10 (±) -1,2,3,4-tetrahydro-N- [2- (n-pentylthiobenzthiazole-6-sulfonyl)]-3-methyl-3-isoquinolinecarboxyl Preparation of Acid Methyl Ester

공지된 방법에 의하여 제조된 (±)-1,2,3,4-테트라히드로-3-메틸-3-이소퀴놀린카르복실산메틸에스테르(0.16g, 0.78mmol)를 디클로로메탄(3mL)에 분산시킨 후, 0℃로 냉각하였다. 이어, 트리에틸아민(0.73mL, 3당량)을 가하여 온도를 0℃로 유지하면서, 전기 실시예 2에서 제조한 2-n-펜틸티오-6-벤즈티아졸설포닐 클로라이드(0.35g, 1.0당량)를 디클로로메탄 (2mL)에 용해시킨 용액을 적가하였다. 출발물질이 소멸된 후(약 5시간), 1N HCl용액으로 유기층을 세척하고, MgSO₄로 건조하며 감압증류하고 진공건조하여 표제화합물 (±)-1,2,3,4-테트라히드로-N-[2-(n-펜틸티오벤즈티아졸-6-설포닐)]-3-메틸-3-이소퀴놀린카르복실산메틸에스테르(0.17g, 23%)를 제조하였다.(±) -1,2,3,4-tetrahydro-3-methyl-3-isoquinolinecarboxylic acid methyl ester (0.16 g, 0.78 mmol) prepared by a known method was dispersed in dichloromethane (3 mL). After cooling, the mixture was cooled to 0 ° C. Then, 2-ethyl-pentylthio-6-benzthiazolesulfonyl chloride (0.35 g, 1.0 equivalent) prepared in Example 2 was added while adding triethylamine (0.73 mL, 3 equivalents) and maintaining the temperature at 0 ° C. Was dissolved in dichloromethane (2 mL) dropwise. After disappearance of the starting material (about 5 hours), the organic layer was washed with 1N HCl solution, dried over MgSO ₄ , distilled under reduced pressure and vacuum dried to give the title compound (±) -1,2,3,4-tetrahydro-N -[2- (n-pentylthiobenzthiazole-6-sulfonyl)]-3-methyl-3-isoquinolinecarboxylic acid methyl ester (0.17 g, 23%) was prepared.

¹H NMR(300MHz, CDCl₃): δ0.93(t, 3H), 1.45(m, 4H), 1.58(s, 3H), 1.84(m, 2H), 2.88(d, 1H), 3.25(d, 1H), 3.36(t, ¹ H NMR (300 MHz, CDCl ₃ ): δ 0.93 (t, 3H), 1.45 (m, 4H), 1.58 (s, 3H), 1.84 (m, 2H), 2.88 (d, 1H), 3.25 (d , 1H), 3.36 (t,

2H), 3.80(s, 3H), 4.4(dd, 2H), 7.2(m,2H), 3.80 (s, 3H), 4.4 (dd, 2H), 7.2 (m,

4H), 7.89(m, 2H), 8.3(s, 1H)4H), 7.89 (m, 2H), 8.3 (s, 1H)

실시예 11: (±)-1,2,3,4-테트라히드로-N-[2-(n-펜틸티오벤즈티아졸-6-설포닐)]-3-메틸-3-이소퀴놀린카르복실산의 제조 Example 11 (±) -1,2,3,4-tetrahydro-N- [2- (n-pentylthiobenzthiazole-6-sulfonyl)]-3-methyl-3-isoquinolinecarboxyl Manufacture of acid

(±)-1,2,3,4-테트라히드로-N-[2-(n-펜틸티오벤즈티아졸-6-설포닐)]-3-메틸-3-이소퀴놀린카르복실산메틸에스테르(0.17g, 0.337mmol)를 THF/H₂O (2mL/2mL)용매에 용해시킨 후, LiOH(0.071g, 5당량)을 가하여 6시간 동안 가열환류하였다. 이어, 용매를 감압증류하고, 1N HCl용액으로 산처리한 다음, 이에 에틸초산(10mL)을가하여 추출물을 수득하였다. 수득한 추출물을 소금물로 세척한 후, MgSO₄로 건조하고 감압증류한 다음, 진공건조하여 표제화합물 (±)-1,2,3,4-테트라히드로-N-[2-(n-펜틸티오벤즈티아졸-6-설포닐)]-3-메틸-3-이소퀴놀린카르복실산(100mg, 60%)을 제조하였다.(±) -1,2,3,4-tetrahydro-N- [2- (n-pentylthiobenzthiazole-6-sulfonyl)]-3-methyl-3-isoquinolinecarboxylic acid methyl ester ( 0.17 g, 0.337 mmol) was dissolved in THF / H ₂ O (2 mL / 2 mL) solvent, and LiOH (0.071 g, 5 equivalents) was added thereto, followed by heating to reflux for 6 hours. Subsequently, the solvent was distilled under reduced pressure, acid treated with 1N HCl solution, and ethyl acetate (10 mL) was added thereto to obtain an extract. The obtained extract was washed with brine, dried over MgSO ₄ , distilled under reduced pressure, and then vacuum dried to give the title compound (±) -1,2,3,4-tetrahydro-N- [2- (n-pentylthio Benzthiazole-6-sulfonyl)]-3-methyl-3-isoquinolinecarboxylic acid (100 mg, 60%).

¹H NMR(300MHz, CDCl₃): δ0.93(t, 3H), 1.45(m, 4H), 1.64(s, 3H), 1.84(m, 2H), 2.96(d, 1H), 3.31(d, 1H), 3.37(t, ¹ H NMR (300 MHz, CDCl ₃ ): δ 0.93 (t, 3H), 1.45 (m, 4H), 1.64 (s, 3H), 1.84 (m, 2H), 2.96 (d, 1H), 3.31 (d , 1H), 3.37 (t,

2H), 4.4(dd, 2H), 7.0(d, 4H), 7.20(m, 3H)2H), 4.4 (dd, 2H), 7.0 (d, 4H), 7.20 (m, 3H)

7.91(m, 2H), 8.33(s, 1H)7.91 (m, 2 H), 8.33 (s, 1 H)

실시예 12: (3S)-4-(2-씨클로헥실메틸티오벤즈티아졸-6-설포닐)-2,2-디메틸 -테트라히디로-2H-1,4-티아진-3-카르복실산의 제조 Example 12 (3S) -4- (2-cyclohexylmethylthiobenzthiazole-6-sulfonyl) -2,2-dimethyl-tetrahydrodi-2H-1,4-thiazine-3-carboxyl Manufacture of acid

공지된 방법(참조: WO 9720824)에 의하여 제조된 (3S)-2,2-디메틸-테트라히디로-2H-1,4-티아진-3-카르복실산(0.93g, 5.31mmol)을 DMF(7mL)에 용해시킨 후, 상온에서 DBU(0.95mL, 1.2당량)을 가하고 1시간 동안 교반한 다음, 디메틸덱실실릴클로라이드(1.15mL, 1.1당량)를 상온에서 가하고, 5시간 동안 교반하였다. 얼음물/헥산:티부틸메틸에테르(7mL:7mL) 용액에 반응물을 가하고 약하게 흔들어 주었다. 유기층을 MgSO₄로 건조하고 감압증류한 후, 진공건조하여 (3S)-디메틸덱실실릴-2,2-디메틸-테트라히드로-2H-1,4-티아진-3-카르복실레이트(1.5g)를 액체 상태로 수득하였다. 이를 EDC(15mL)에 용해시킨 후, 0℃로 냉각하고, 이에 N-메틸몰폴린(0.62mL, 1.2당량)을 가한 다음, 30분간 교반하였다. 2-씨클로헥실메틸티오-6-벤즈티아졸설포닐 클로라이드(1.7g, 1당량)를 EDC(5mL)에 용해시킨 후, 상기 반응 혼합물에 적가하였다. 출발물질이 소멸된 후, 에틸초산(10mL)을 가하여 추출물을 수득하고, 추출물을 소금물로 세척한 다음, MgSO₄로 건조하고 감압증류하며 진공건조하여, (3S)-4-(2-씨클로헥실메틸티오벤즈티아졸-6-설포닐)-2,2-디메틸-테트라히디로-2H-1,4-티아진-3-카르복실산 디메틸덱실실릴 에스테르를 수득하였다. 전기 수득물을 메탄올(20mL)에 용해시킨 후, 4시간 동안 가열환류하고 용매를 감압증류한 다음, 2N HCl을 사용하여 pH 2로 조절하고 에틸초산으로 추출하였다. 전기 추출물을 MgSO₄로 건조하고 감압증류 후, 진공건조하여 수득한 잔류 혼합물을 에틸초산/헥산(1/5)용액으로 용출시키는 실리카겔상에서 크로마토그라피로 정제하여, 표제화합물 (3S)-4-(2-씨클로헥실메틸티오벤즈티아졸-6-설포닐)-2,2-디메틸-테트라히디로-2H-1,4-티아진-3-카르복실산(1.08g, 40%)을 제조하였다.(3S) -2,2-dimethyl-tetrahydrodi-2H-1,4-thiazine-3-carboxylic acid (0.93 g, 5.31 mmol) prepared by a known method (see WO 9720824) was prepared by DMF. After dissolving in (7 mL), DBU (0.95 mL, 1.2 equiv) was added at room temperature, stirred for 1 hour, and then dimethyldecylsilyl chloride (1.15 mL, 1.1 equiv) was added at room temperature, and stirred for 5 hours. The reaction was added to an ice water / hexane: thibutyl methyl ether (7 mL: 7 mL) solution, and the solution was gently shaken. The organic layer was dried over MgSO ₄ , distilled under reduced pressure, and then dried in vacuo to afford (3S) -dimethyldecylsilyl-2,2-dimethyl-tetrahydro-2H-1,4-thiazine-3-carboxylate (1.5 g). Was obtained in the liquid state. It was dissolved in EDC (15 mL), cooled to 0 ° C., and N-methylmorpholine (0.62 mL, 1.2 equiv) was added thereto, followed by stirring for 30 minutes. 2-cyclohexylmethylthio-6-benzthiazolesulfonyl chloride (1.7 g, 1 equiv) was dissolved in EDC (5 mL) and then added dropwise to the reaction mixture. After the disappearance of the starting material, ethyl acetate (10 mL) was added to obtain an extract, the extract was washed with brine, dried over MgSO ₄ , distilled under reduced pressure and vacuum dried, (3S) -4- (2-cyclohexyl). Methylthiobenzthiazole-6-sulfonyl) -2,2-dimethyl-tetrahydrodi-2H-1,4-thiazine-3-carboxylic acid dimethyldexylsilyl ester was obtained. The obtained product was dissolved in methanol (20 mL), heated to reflux for 4 hours, the solvent was distilled under reduced pressure, adjusted to pH 2 with 2N HCl, and extracted with ethyl acetate. The extract was dried over MgSO ₄ , distilled under reduced pressure, and then dried in vacuo to be purified by chromatography on silica gel, eluting with ethyl acetate / hexane (1/5) solution, to give the title compound (3S) -4- ( 2-Cyclohexylmethylthiobenzthiazole-6-sulfonyl) -2,2-dimethyl-tetrahydrodi-2H-1,4-thiazine-3-carboxylic acid (1.08 g, 40%) was prepared. .

¹H NMR(300MHz, CDCl₃): δ1.1(m, 2H), 1.25(m, 4H), 1.37(s, 3H), 1.64(s, 3H), 1.74(m, 3H), 1.9(m, 2H), 2.5(d, 1H), 3.15(m, 1H), 3.21(d, H), 3.7(m, 1H), 4.12(m, 1H), 4.47(s, 1H), 7.74(d, 1H), 7.84(d, 1H),8.2(s, 1H) ¹ H NMR (300 MHz, CDCl ₃ ): δ 1.1 (m, 2H), 1.25 (m, 4H), 1.37 (s, 3H), 1.64 (s, 3H), 1.74 (m, 3H), 1.9 (m , 2H), 2.5 (d, 1H), 3.15 (m, 1H), 3.21 (d, H), 3.7 (m, 1H), 4.12 (m, 1H), 4.47 (s, 1H), 7.74 (d, 1H), 7.84 (d, 1H), 8.2 (s, 1H)

실시예 13: (3S)-4-[2-(n-부틸티오벤즈티아졸-6-설포닐)]-2,2-디메틸-테트라히디로-2H-1,4-티아진-3-카르복실산의 제조 Example 13 : (3S) -4- [2- (n-butylthiobenzthiazole-6-sulfonyl)]-2,2-dimethyl-tetrahydrodi-2H-1,4-thiazine-3- Preparation of Carboxylic Acids

¹H NMR(300MHz, CDCl₃): δ0.98(t, 3H), 1.38(s, 3H), 1.53(m, 2H), 1.65(s, 3H), 1.82(m, 2H), 2.5(d, 1H), 3.15(m, ¹ H NMR (300 MHz, CDCl ₃ ): δ 0.98 (t, 3H), 1.38 (s, 3H), 1.53 (m, 2H), 1.65 (s, 3H), 1.82 (m, 2H), 2.5 (d , 1H), 3.15 (m,

1H), 3.33(t, 2H), 3.7(m, 1H), 4.1(d, 1H),1H), 3.33 (t, 2H), 3.7 (m, 1H), 4.1 (d, 1H),

4.5(s, 1H), 7.75(d, 1H), 7.87(d, 1H),4.5 (s, 1H), 7.75 (d, 1H), 7.87 (d, 1H),

8.2(s, 1H)8.2 (s, 1H)

실시예 14: (3S)-4-[2-(n-헥실티오벤즈티아졸-6-설포닐)]-2,2-디메틸-테트라히디로-2H-1,4-티아진-3-카르복실산의 제조 Example 14 (3S) -4- [2- (n-hexylthiobenzthiazole-6-sulfonyl)]-2,2-dimethyl-tetrahydrodi-2H-1,4-thiazine-3- Preparation of Carboxylic Acids

¹H NMR(300MHz, CDCl₃): δ0.92(t, 3H), 1.38(m, 4H), 1.39(s, 3H), 1.50(m, 2H), 1.67(s, 3H), 1.82(m, 2H), 2.5(d, ¹ H NMR (300 MHz, CDCl ₃ ): δ 0.92 (t, 3H), 1.38 (m, 4H), 1.39 (s, 3H), 1.50 (m, 2H), 1.67 (s, 3H), 1.82 (m , 2H), 2.5 (d,

1H), 3.2(m, 1H), 3.31(t, 2H), 3.75(m,1H), 3.2 (m, 1H), 3.31 (t, 2H), 3.75 (m,

1H), 4.16(d, 1H), 4.5(s, 1H), 7.77(d,1H), 4.16 (d, 1H), 4.5 (s, 1H), 7.77 (d,

1H), 7.89(d, 1H), 8.22(s, 1H)1H), 7.89 (d, 1H), 8.22 (s, 1H)

실시예 15: (2R)-N-히드록시-1-[2-(n-펜틸티오벤즈티아졸-6-설포닐)]-2-피롤리딜카르복실아미드의 제조 Example 15 Preparation of (2R) -N-hydroxy-1- [2- (n-pentylthiobenzthiazole-6-sulfonyl)]-2-pyrrolidylcarboxyamide

실시예 7에서 제조한 (2R)-N-[2-(n-펜틸티오벤즈티아졸-6-설포닐)]-2-피롤리딜카르복실산(0.16g, 0.39mmol)을 디클로로메탄(2mL)에 용해시키고 0℃로 냉각한 후, 옥살릴클로라이드(0.1mL, 3당량)를 가한 다음, 촉매량의 DMF를 가하여 상온에서 3시간 반응시켰다. 전기 반응물을 감압증류하여 용매를 제거한 다음, 감압건조하여 얻어지는 잔류물을 THF(1mL)에 용해시켰다. 히드록실아민 염산염(0.27g, 10당량) 및 NaHCO₃(0.39g, 12당량)을 THF/H₂O(2mL/2mL)에 용해시키고 0℃로 냉각하였다. 전기에서 수득한 산 클로라이드/THF용액을 0℃에서 히드록실아민 용액에 천천히 적가하였다. 1시간 후에 용매를 제거한 후, 에틸초산(5mL)으로 추출하고 물 및 0.1N HCl로 세척한 다음, MgSO₄로 건조하고 감압증류하며 진공건조하여, 표제화합물 (2R)-N-히드록시-1-[2-(n-펜틸티오벤즈티아졸-6-설포닐)]-2-피롤리딜카르복실아미드(0.14g, 84%)를 제조하였다.(2R) -N- [2- (n-pentylthiobenzthiazole-6-sulfonyl)]-2-pyrrolidylcarboxylic acid (0.16 g, 0.39 mmol) prepared in Example 7 was diluted with dichloromethane ( 2 mL), cooled to 0 ° C., oxalyl chloride (0.1 mL, 3 equiv) was added thereto, and then a catalytic amount of DMF was added thereto to react at room temperature for 3 hours. The reaction was distilled under reduced pressure to remove the solvent, and then the residue obtained by drying under reduced pressure was dissolved in THF (1 mL). Hydroxylamine hydrochloride (0.27 g, 10 equiv) and NaHCO ₃ (0.39 g, 12 equiv) were dissolved in THF / H ₂ O (2 mL / 2 mL) and cooled to 0 ° C. The acid chloride / THF solution obtained above was slowly added dropwise to the hydroxylamine solution at 0 ° C. After 1 hour, the solvent was removed, extracted with ethyl acetate (5 mL), washed with water and 0.1N HCl, dried over MgSO ₄ , distilled under reduced pressure and vacuum dried to obtain the title compound (2R) -N-hydroxy-1 -[2- (n-pentylthiobenzthiazole-6-sulfonyl)]-2-pyrrolidylcarboxyamide (0.14 g, 84%) was prepared.

¹H NMR(300MHz, CDCl₃): δ0.93(t, 3H), 1.43(m, 4H), 1.6(m, 2H), 1.8(m, 4H), 2.2(m, 1H), 3.2(m, 1H), 3.37(t, 2H),3.6(m, 1H), 4.2(d, 1H), 7.94(dd, 2H), 8.3(s, 1H), 9.5(s, 1H) ¹ H NMR (300 MHz, CDCl ₃ ): δ 0.93 (t, 3H), 1.43 (m, 4H), 1.6 (m, 2H), 1.8 (m, 4H), 2.2 (m, 1H), 3.2 (m , 1H), 3.37 (t, 2H), 3.6 (m, 1H), 4.2 (d, 1H), 7.94 (dd, 2H), 8.3 (s, 1H), 9.5 (s, 1H)

실시예 16: (2R)-N-히드록시-1-[2-(n-헥실티오벤즈티아졸-6-설포닐)]-2-피롤리딜카르복실아미드의 제조 Example 16 Preparation of (2R) -N-hydroxy-1- [2- (n-hexylthiobenzthiazole-6-sulfonyl)]-2-pyrrolidylcarboxyamide

¹H NMR(300MHz, CDCl₃): δ0.9(t, 3H), 1.33(m, 4H), 1.45(m, 2H), 1.6(m, 2H), 1.8(m, 3H), 2.2(m, 1H), 3.2(m, 1H), 3.38(t, 2H), 3.6(m, 1H), 4.2(d, 1H), 7.94(dd, 2H), 8.3(s, 1H), 9.5(s, 1H) ¹ H NMR (300 MHz, CDCl ₃ ): δ 0.9 (t, 3H), 1.33 (m, 4H), 1.45 (m, 2H), 1.6 (m, 2H), 1.8 (m, 3H), 2.2 (m , 1H), 3.2 (m, 1H), 3.38 (t, 2H), 3.6 (m, 1H), 4.2 (d, 1H), 7.94 (dd, 2H), 8.3 (s, 1H), 9.5 (s, 1H)

실시예 17: (3R)-N-히드록시-1,2,3,4-테트라히드로-2-[2-(n-펜틸티오벤즈티아졸-6-설포닐)]-3-이소퀴놀린카르복실아미드의 제조 Example 17 (3R) -N-hydroxy-1,2,3,4-tetrahydro-2- [2- (n-pentylthiobenzthiazole-6-sulfonyl)]-3-isoquinolinecar Preparation of Compound Amide

실시예 9에서 제조한 (3R)-1,2,3,4-테트라히드로-2-[2-(n-펜틸티오벤즈티아졸-6-설포닐)]-3-이소퀴놀린카르복실산(0.2g, 0.42mmol)을 디클로로메탄(2mL)에 용해시키고 0℃로 냉각하였다. 이에, 옥살릴클로라이드(0.11mL, 3당량)를 가하고, 촉매량의 DMF를 가하여 상온에서 3시간 동안 반응시켰다. 이를 감압증류하여 용매를 제거시킨 다음 감압건조하여 얻어지는 잔류물을 THF(1mL)에 용해시켰다. 히드록실아민 염산염(0.29g, 10당량), NaHCO₃(0.42g, 12당량)을 THF/H₂O(2mL/2mL)에 용해시키고 0℃로 냉각하였다. 전기 수득한 산 클로라이드/THF용액을 0℃에서 히드록실아민 용액에 천천히 적가하였다. 1시간 후에 용매를 제거한 후, 에틸초산(5mL)으로 추출하고 물 및 0.1N HCl로 세척한 다음, MgSO₄로 건조하고 감압증류하며 진공건조하여, (3R)-N-히드록시-1,2,3,4-테트라히드로-2-[2-(n-펜틸티오벤즈티아졸-6-설포닐)]-3-이소퀴놀린카르복실아미드(0.2g, 99%)를 제조하였다.(3R) -1,2,3,4-tetrahydro-2- [2- (n-pentylthiobenzthiazole-6-sulfonyl)]-3-isoquinolinecarboxylic acid prepared in Example 9 ( 0.2 g, 0.42 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Oxalyl chloride (0.11 mL, 3 equiv) was added thereto, and a catalytic amount of DMF was added thereto, followed by reaction at room temperature for 3 hours. After distillation under reduced pressure to remove the solvent, the residue obtained by drying under reduced pressure was dissolved in THF (1 mL). Hydroxylamine hydrochloride (0.29 g, 10 equiv), NaHCO ₃ (0.42 g, 12 equiv) was dissolved in THF / H ₂ O (2 mL / 2 mL) and cooled to 0 ° C. The obtained acid chloride / THF solution was slowly added dropwise to the hydroxylamine solution at 0 ° C. After 1 hour, the solvent was removed, extracted with ethyl acetate (5 mL), washed with water and 0.1N HCl, dried over MgSO ₄ , distilled under reduced pressure and vacuum dried, to obtain (3R) -N-hydroxy-1,2 , 3,4-tetrahydro-2- [2- (n-pentylthiobenzthiazole-6-sulfonyl)]-3-isoquinolinecarboxyamide (0.2 g, 99%) was prepared.

¹H NMR(300MHz, CDCl₃): δ0.92(t, 3H), 1.41(m, 4H), 1.8(m, 2H), 2.65(m, 1H), 3.15(m, 1H), 3.35(t, 2H), 4.5(m, 3H), 7.09(m, 4H), 7.8(dd, 2H), 8.16(s, 1H), 9.4(s, 1H) ¹ H NMR (300 MHz, CDCl ₃ ): δ 0.92 (t, 3H), 1.41 (m, 4H), 1.8 (m, 2H), 2.65 (m, 1H), 3.15 (m, 1H), 3.35 (t , 2H), 4.5 (m, 3H), 7.09 (m, 4H), 7.8 (dd, 2H), 8.16 (s, 1H), 9.4 (s, 1H)

실시예 18: (±)-N-히드록시-1,2,3,4-테트라히드로-2-[2-(n-펜틸티오벤즈티아졸-6-설포닐)]-3-메틸-3-이소퀴놀린카르복실아미드의 제조 Example 18 (±) -N-hydroxy-1,2,3,4-tetrahydro-2- [2- (n-pentylthiobenzthiazole-6-sulfonyl)]-3-methyl-3 Preparation of Isoquinolinecarboxyamide

¹H NMR(300MHz, CDCl₃): δ0.93(t, 3H), 1.40(m, 4H), 1.65(s, 3H), 1.83(m, 2H), 2.85(d, 1H), 3.24(d, 1H), 3.38(t, ¹ H NMR (300 MHz, CDCl ₃ ): δ 0.93 (t, 3H), 1.40 (m, 4H), 1.65 (s, 3H), 1.83 (m, 2H), 2.85 (d, 1H), 3.24 (d , 1H), 3.38 (t,

2H), 4.42(d, 1H), 4.55(d, 1H), 7.24(m,2H), 4.42 (d, 1H), 4.55 (d, 1H), 7.24 (m,

4H), 7.87(m, 2H), 8.28(s, 1H), 8.8(s, 1H)4H), 7.87 (m, 2H), 8.28 (s, 1H), 8.8 (s, 1H)

실시예 19: (3S)-N-히드록시-4-(2-씨클로헥실메틸티오벤즈티아졸-6-설포닐) -2,2-디메틸-테트라히디로-2H-1,4-티아진-3-카르복실아미드의 제조 Example 19 (3S) -N-hydroxy-4- (2-cyclohexylmethylthiobenzthiazole-6-sulfonyl) -2,2-dimethyl-tetrahydrodi-2H-1,4-thiazine Preparation of 3-carboxyamide

실시예 12에서 제조한 (3S)-4-(2-씨클로헥실메틸티오벤즈티아졸-6-설포닐)-2,2-디메틸-테트라히디로-2H-1,4-티아진-3-카르복실산(0.84g, 1.68mmol)을 디클로로메탄(2mL)에 용해시키고 0℃로 냉각하였다. 이에, 옥살릴클로라이드(0.44mL, 3당량)를 가하고, 촉매량의 DMF를 가하여 상온에서 3시간 반응시켰다. 이를 감압증류하여 용매를 제거시킨 다음, 감압건조하여 얻어지는 잔류물을 THF(1mL)에 용해시켰다. 히드록실아민 염산염(1.17g, 10당량) 및 NaHCO₃(1.69g, 12당량)을 THF/H₂O(2mL/2mL)에 용해시키고, 0℃로 냉각하였다. 전기에서 수득한 산 클로라이드/THF용액을 0℃에서 히드록실아민 용액에 천천히 적가하였다. 1시간 경과후에 용매를 제거하고, 에틸초산(5mL)으로 추출하고 물 및 0.1N HCl로 세척한 다음, MgSO₄로 건조하고 감압증류하며 진공건조함으로써, 표제화합물 (3R)-N-히드록시-1,2,3,4-테트라히드로-2-[2-(n-펜틸티오벤즈티아졸-6-설포닐)]-3-이소퀴놀린카르복실아미드(0.87g, 100%)를 제조하였다.(3S) -4- (2-cyclohexylmethylthiobenzthiazole-6-sulfonyl) -2,2-dimethyl-tetrahydrodi-2H-1,4-thiazine-3- prepared in Example 12 Carboxylic acid (0.84 g, 1.68 mmol) was dissolved in dichloromethane (2 mL) and cooled to 0 ° C. Oxalyl chloride (0.44 mL, 3 equiv) was added thereto, and a catalytic amount of DMF was added thereto, followed by reaction at room temperature for 3 hours. After distilling under reduced pressure to remove the solvent, the residue obtained by drying under reduced pressure was dissolved in THF (1 mL). Hydroxylamine hydrochloride (1.17 g, 10 equiv) and NaHCO ₃ (1.69 g, 12 equiv) were dissolved in THF / H ₂ O (2 mL / 2 mL) and cooled to 0 ° C. The acid chloride / THF solution obtained above was slowly added dropwise to the hydroxylamine solution at 0 ° C. After 1 hour, the solvent was removed, extracted with ethyl acetate (5 mL), washed with water and 0.1N HCl, dried over MgSO ₄ , distilled under reduced pressure and vacuum dried to give the title compound (3R) -N-hydroxy- 1,2,3,4-tetrahydro-2- [2- (n-pentylthiobenzthiazole-6-sulfonyl)]-3-isoquinolinecarboxyamide (0.87 g, 100%) was prepared.

¹H NMR(300MHz, CDCl₃): δ1.22(m, 5H), 1.28(s, 3H), 1.58(s, 3H), 1.74(m, 4H), 1.9(d, 2H), 2.45(d, 1H), 3.1(m, 1H), 3.28(d, 2H), 3.8(m, 2H), 4.3(s, 1H), ¹ H NMR (300 MHz, CDCl ₃ ): δ1.22 (m, 5H), 1.28 (s, 3H), 1.58 (s, 3H), 1.74 (m, 4H), 1.9 (d, 2H), 2.45 (d , 1H), 3.1 (m, 1H), 3.28 (d, 2H), 3.8 (m, 2H), 4.3 (s, 1H),

7.77(d, 1H), 7.87(d, 1H), 8.21(s, 1H),7.77 (d, 1 H), 7.87 (d, 1 H), 8.21 (s, 1 H),

10.8(s, 1H)10.8 (s, 1H)

실시예 20: (3S)-N-히드록시-4-[2-(n-부틸티오벤즈티아졸-6-설포닐)]-2,2-디메틸-테트라히디로-2H-1,4-티아진-3-카르복실아미드의 제조 Example 20 (3S) -N-hydroxy-4- [2- (n-butylthiobenzthiazole-6-sulfonyl)]-2,2-dimethyl-tetrahydrodi-2H-1,4- Preparation of Thiazine-3-carboxyamide

¹H NMR(300MHz, CDCl₃): δ0.98(t, 3H), 1.29(s, 3H), 1.53(m, 4H), 1.60(s, 3H), 1.83(m, 2H), 2.5(d, 1H), 3.2(m, 2H), 3.38(t, 2H), 4.1(d, 1H), 4.6(s, 1H), ¹ H NMR (300 MHz, CDCl ₃ ): δ 0.98 (t, 3H), 1.29 (s, 3H), 1.53 (m, 4H), 1.60 (s, 3H), 1.83 (m, 2H), 2.5 (d , 1H), 3.2 (m, 2H), 3.38 (t, 2H), 4.1 (d, 1H), 4.6 (s, 1H),

7.1(s, 1H), 7.8(d, 1H), 7.9(d, 1H),7.1 (s, 1H), 7.8 (d, 1H), 7.9 (d, 1H),

8.23(s, 1H), 9.7(s, 1H)8.23 (s, 1H), 9.7 (s, 1H)

실시예 21: (3S)-N-히드록시-4-[2-(n-헥실티오벤즈티아졸-6-설포닐)]-2,2-디메틸-테트라히디로-2H-1,4-티아진-3-카르복실아미드의 제조 Example 21 (3S) -N-hydroxy-4- [2- (n-hexylthiobenzthiazole-6-sulfonyl)]-2,2-dimethyl-tetrahydrodi-2H-1,4- Preparation of Thiazine-3-carboxyamide

¹H NMR(300MHz, CDCl₃): δ0.93(t, 3H), 1.26(s, 3H), 1.35(m, 4H), 1.5(m, 2H), 1.58(s, 3H), 1.9(m, 2H), 2.5(d, 1H), 3.1(m, 1H), 3.37(m, 3H), 3.78(t, 2H), 4.0(d, 1H), 4.53(s, 1H), 7.8(dd, 2H), 8.2(s, 1H), 9.9(s, 1H) ¹ H NMR (300 MHz, CDCl ₃ ): δ 0.93 (t, 3H), 1.26 (s, 3H), 1.35 (m, 4H), 1.5 (m, 2H), 1.58 (s, 3H), 1.9 (m , 2H), 2.5 (d, 1H), 3.1 (m, 1H), 3.37 (m, 3H), 3.78 (t, 2H), 4.0 (d, 1H), 4.53 (s, 1H), 7.8 (dd, 2H), 8.2 (s, 1H), 9.9 (s, 1H)

실시예 22: 시험관내에서의 젤라티나제 A(MMP-2)억제 Example 22 Inhibition of Gelatinase A (MMP-2) in Vitro

본 검정은 형광합성펩타이드 기질((7-methoxycoumarin-4-acetyl- Pro-Leu-Gly-Leu-β-(2,4-dinitrophenylamino)Ala-Ala-Arg-NH₂(Sigma Chem. Co., U.S.A.))을 젤라티나제 A 효소(Boehringer Manneheim cat# 1782916, from human fibrosarcoma cells)가 절단하여 생성되는 형광물질(7-methoxycoumarin-4-acetyl-Pro-Leu-Gly)의 형광량을 측정하여 수행하였다.This assay was performed using a fluoropeptide substrate ((7-methoxycoumarin-4-acetyl-Pro-Leu-Gly-Leu-β- (2,4-dinitrophenylamino) Ala-Ala-Arg-NH ₂ (Sigma Chem. Co., USA). )) Was performed by measuring the amount of fluorescence of the fluorescent substance (7-methoxycoumarin-4-acetyl-Pro-Leu-Gly) produced by cleaving gelatinase A enzyme (Boehringer Manneheim cat # 1782916, from human fibrosarcoma cells). .

형광합성기질을 이용한 효소반응은 96웰 플레이트에 탐색시료와 TNBC 완충용액(25mM Tris-HCl, pH 7.5, 0.1M NaCl, 0.01% Brij-35, 5mM CaCl₂), 효소반응 직전 1 mM의 APMA(aminophenylmercuric acetate)로 37℃에서 30분간 활성화시킨 젤라티나제 A 효소(웰내 최종농도: 4.17nM), 및 기질인 형광합성펩타이드(웰내 최종농도: 9.15uM)를 넣어 37℃에서 30분간 반응시킨 후, 웰플레이트 리더가 장착된 형광분석기(spectrofluorimeter, Fmax(molecular device))로 여기(excitation) 328nm,발광(emission) 393nm에서 형광량을 측정하였다. 저해율(%)은 저해제를 넣은 것의 반응전 형광량(A)과 반응후의 형광량(B), 저해제를 넣지 않은 것의 반응전 형광량(C)과 반응후 형광량(D)으로부터 다음과 같이 계산하였다:Enzymatic reaction using fluorescence synthesis substrate was performed in 96-well plate with test sample and TNBC buffer (25 mM Tris-HCl, pH 7.5, 0.1 M NaCl, 0.01% Brij-35, 5 mM CaCl ₂ ), 1 mM APMA ( After gelatinase A enzyme (final concentration: 4.17 nM) activated with aminophenylmercuric acetate for 30 minutes at 37 ° C., and a fluorescent synthetic peptide (final concentration: 9.15 uM in the well), which was reacted for 30 minutes at 37 ° C., Fluorescence was measured at an excitation of 328 nm and emission of 393 nm with a fluorescence analyzer equipped with a well plate reader (spectrofluorimeter, Fmax (molecular device)). The inhibition rate (%) is calculated as follows from the amount of fluorescence before reaction (A) with the inhibitor, the amount of fluorescence after the reaction (B), the amount of fluorescence before the reaction without the inhibitor (C) and the amount of fluorescence after the reaction (D) as follows: Was:

실시예 23: 시험관내에서의 젤라티나제 B(MMP-9)억제 Example 23 Inhibition of Gelatinase B (MMP-9) in Vitro

젤라티나제 B 효소(Boehringer Manneheim cat# 1758896, From Human blood)를 사용하고, 젤라티나제 B 효소의 농도(웰내 최종농도: 2.715nM) 및 기질인 형광합성펩타이드의 농도(웰내 최종농도: 4.575uM)를 달리하는 것을 제외하고는, 실시예 22와 동일한 방법으로 시험관내에서의 젤라티나제 B(MMP-9)의 저해율을 측정하였다.Using gelatinase B enzyme (Boehringer Manneheim cat # 1758896, From Human blood), the concentration of gelatinase B enzyme (final concentration in wells: 2.715 nM) and the concentration of fluorescent synthetic peptide as a substrate (final concentration in a well: 4.575 uM) Except for), the inhibition rate of gelatinase B (MMP-9) in vitro was measured in the same manner as in Example 22.

실시예 24: 시험관내에서의 콜라게나제(MMP-1)억제 Example 24 Inhibition of Collagenase (MMP-1) in Vitro

콜라게나제 효소(AngioLab. Co.Ltd)를 사용하고, 콜라게나제 효소의 농도(웰내 최종농도: 2.715nM) 및 기질인 형광합성펩타이드의 농도(웰내 최종농도: 7.25nM)를 달리하는 것을 제외하고는, 실시예 22와 동일한 방법으로 시험관내에서의 콜라게나제(MMP-1)의 저해율을 측정하였다.Using a collagenase enzyme (AngioLab. Co. Ltd.), except that the collagenase enzyme concentration (final concentration in the well: 2.715nM) and the concentration of the fluorescent synthesis peptide as a substrate (final concentration in the well: 7.25nM) In the same manner as in Example 22, the inhibition rate of collagenase (MMP-1) in vitro was measured.

번호number R₁ R ₁ R₃ R ₃ XX IC₅₀(nM)MMP-2IC ₅₀ (nM) MMP-2 IC₅₀(nM)MMP-9IC ₅₀ (nM) MMP-9 IC₅₀(nM)MMP-1IC ₅₀ (nM) MMP-1 1One n-펜틸티오n-pentylthio OHOH SS 12101210 80508050 22 n-펜틸티오n-pentylthio NHOHNHOH SS 5.85.8 4.24.2 33 n-헥실티오n-hexylthio OHOH SS 944944 1410014100 44 n-헥실티오n-hexylthio NHOHNHOH SS 5.65.6 1One

번호number R₁ R ₁ R₂ R ₂ R₃ R ₃ XX IC₅₀(nM)MMP-2IC ₅₀ (nM) MMP-2 IC₅₀(nM)MMP-9IC ₅₀ (nM) MMP-9 IC₅₀(nM)MMP-1IC ₅₀ (nM) MMP-1 1One n-펜틸티오n-pentylthio HH OHOH SS 380380 12901290 22 n-펜틸티오n-pentylthio HH NHOHNHOH SS 0.40.4 0.60.6 33 n-펜틸티오n-pentylthio CH₃ CH ₃ OHOH SS 3746037460 207257207257 44 n-펜틸티오n-pentylthio CH₃ CH ₃ NHOHNHOH SS 10001000 20522052

번호number R₁ R ₁ R₉:_:R₁₀ R _9:: R ₁₀ R₃ R ₃ YY IC₅₀(nM)MMP-2IC ₅₀ (nM) MMP-2 IC₅₀(nM)MMP-9IC ₅₀ (nM) MMP-9 IC₅₀(nM)MMP-1IC ₅₀ (nM) MMP-1 1One n-부틸티오n-butylthio CH₃: CH₃ CH ₃ : CH ₃ OHOH SS 483483 14741474 22 n-부틸티오n-butylthio CH₃: CH₃ CH ₃ : CH ₃ NHOHNHOH SS 0.40.4 0.40.4 33 n-헥실티오n-hexylthio CH₃: CH₃ CH ₃ : CH ₃ OHOH SS 172172 795795 44 n-헥실티오n-hexylthio CH₃: CH₃ CH ₃ : CH ₃ NHOHNHOH SS 0.30.3 0.40.4 150150 55 시클로헥실메틸Cyclohexylmethyl CH₃: CH₃ CH ₃ : CH ₃ OHOH SS 4646 232232 66 시클로헥실메틸Cyclohexylmethyl CH₃: CH₃ CH ₃ : CH ₃ NHOHNHOH SS 0.70.7 1One 77 MeOMeO H : HH: H OHOH CH₂ CH ₂ 1610016100 1340013400 88 에틸티오Ethylthio H : HH: H OHOH CH₂ CH ₂ 15601560 30303030 99 에틸티오Ethylthio H : HH: H NHOHNHOH CH₂ CH ₂ 2.02.0 9.09.0 1010 n-부틸티오n-butylthio H : HH: H OHOH CH₂ CH ₂ 120120 18201820 1111 n-부틸티오n-butylthio H : HH: H NHOHNHOH CH₂ CH ₂ 1.31.3 0.70.7 1212 n-헥실티오n-hexylthio H : HH: H OHOH CH₂ CH ₂ 8686 22702270 1313 n-헥실티오n-hexylthio H : HH: H NHOHNHOH CH₂ CH ₂ 1.81.8 2.82.8 1414 n-헵틸티오n-heptylthio H : HH: H OHOH CH₂ CH ₂ 4949 22502250 1515 n-헵틸티오n-heptylthio H : HH: H NHOHNHOH CH₂ CH ₂ 1.71.7 8.98.9 1616 n-옥틸티오n-octylthio H : HH: H OHOH CH₂ CH ₂ 5353 19501950 1717 n-옥틸티오n-octylthio H : HH: H NHOHNHOH CH₂ CH ₂ 3.63.6 21.821.8 1818 시클로헥실메틸Cyclohexylmethyl H : HH: H OHOH CH₂ CH ₂ 3131 680680 1919 시클로헥실메틸Cyclohexylmethyl H : HH: H NHOHNHOH CH₂ CH ₂ 0.50.5 1.91.9

이상에서 상세히 설명하고 입증하였듯이, 본 발명은 MMP의 작용을 억제하는 설폰아미드 유도체 화합물, 그의 이성질체 및 이들의 약학적으로 허용되는 염과 전기 물질들의 제조방법을 제공한다. 본 발명의 설폰아미드 유도체 화합물은 시험관내(in vitro) 조건에서 MMP의 활성을 선택적으로 억제하는 바, 전기 설폰아미드 유도체를 유효성분으로 하는 MMP 억제제는 MMP의 과발현 및 과도한 활성화에 의해서 유발되는 각종질병의 예방 및 치료에 유용하게 사용될 수 있을 것이다.As described and demonstrated in detail above, the present invention provides a sulfonamide derivative compound, an isomer thereof, and a pharmaceutically acceptable salt thereof and a method for preparing the same, which inhibit the action of MMP. The sulfonamide derivative compounds of the present invention selectively inhibit the activity of MMP under in vitro conditions, and MMP inhibitors comprising the sulfonamide derivative as an active ingredient are various diseases caused by overexpression and excessive activation of MMP. It may be useful for the prevention and treatment of

Claims (7)

하기 일반식(Ⅰ)로 표시되는 화합물, 그의 이성질체 및 이들의 약학적으로 허용되는 염:Compounds represented by the following general formula (I), isomers thereof and pharmaceutically acceptable salts thereof: 상기 식에서,Where R₁은 X-R₄(이때, R₄는 C_1-12의 알킬, C_3-7의 카보씨클릭 아릴-C_1-6의 저급알킬, C_3-7의 씨클로알킬, C_3-7의 씨클로알킬-C_1-6의 저급알킬, (옥소, 아미노 또는 티오)C_3-7의 씨클로알킬, (옥소, 아미노 또는 티오)C_3-7의 씨클로알킬-C_1-6의 저급알킬, C_2-12의 저급알케닐, C_2-12의 저급알키닐, C_3-7의 카보씨클릭아릴, C_3-7의 헤테로씨클릭아릴, C_3-7의 헤테로씨클릭아릴-C_1-6의 저급알킬, C_4-7의 비아릴, C_1-6의 할로저급알킬, C_4-7의 비아릴-C_4-10의 저급알킬아릴알킬, 히드록시-C_1-6의 저급알킬, C_2-8의 알콕시알킬, C_1-5의 아실옥시-C_1-6의 저급알킬, C_1-6의 알킬 또는 아릴 (티오, 설피닐 또는 설포닐)C_1-6의 저급알킬, (아미노, 모노 또는 디 C_1-6의 알킬아미노)C_1-6의 저급알킬, C_1-5의 아실아미노 C_1-6의 저급알킬, (N-C_1-6의 저급알킬-피페라지노, C_3-7의 N-카보씨클릭 또는 헤테로씨클릭아릴-C_1-6의 저급알킬피페라지노)-C_1-6의 저급알킬 또는 (모포리노, 티오모포리노, 피페리디노, 피롤리디노 또는 피페리딜)C_1-6의 저급알킬이다), 또는 할라이드이며;R ₁ is XR _{4 wherein} R ₄ is C _1-12 alkyl, C _3-7 carbocyclic aryl-C _1-6 lower alkyl, C _3-7 cycloalkyl, C _3-7 cyclo -C _1-6 alkyl, lower alkyl, (oxo, amino or thio) C _3-7 cyclo alkyl, (oxo, amino or thio) alkyl lower alkyl, the cyclo -C _1-6 of C _3-7, C _{2 -12} lower alkenyl, C _2-12 lower alkynyl, C _3-7 carbocyclic aryl, C _3-7 heterocyclic aryl, C _3-7 heterocyclic aryl-C _1-6 Lower alkyl, C _4-7 biaryl, C _1-6 halolower alkyl, C _4-7 biaryl-C _4-10 lower alkylarylalkyl, hydroxy-C _1-6 lower alkyl, C _2-8 alkoxyalkyl, C _1-5 acyloxy-C _1-6 lower alkyl, C _1-6 alkyl or aryl (thio, sulfinyl or sulfonyl) C _1-6 lower alkyl, ( Amino, mono or diC _1-6 alkylamino) C _1-6 lower alkyl, C _1-5 acylamino C _1-6 lower alkyl, (lower alkyl-piperazino of NC _1-6 , C _3-7 Carbonyl or heteroaryl-lower alkyl N- said click of said aryl -C _1-6 piperazino) lower alkyl or -C _1-6 (blanket Reno, thio blanket Reno, piperidino, pyrrolidino or piperidyl C _1-6 lower alkyl), or halide; R₂는 수소 또는 C_1-6의 저급알킬이고;R ₂ is hydrogen or lower alkyl of C _1-6 ; R₃는 -OH, -NHOH 또는 OR₁₈(이때, OR₁₈는 C_1-6의 저급알킬, t-부틸, 벤질 또는 C_3-9의 씰릴기이다)이며;R ₃ is —OH, —NHOH or OR ₁₈ , wherein OR ₁₈ is C _1-6 lower alkyl, t-butyl, benzyl or C _3-9 sealyl group; X는 S 또는 O이고; 및,X is S or O; And, n은 0 내지 3의 정수이다.n is an integer of 0-3. 삭제delete 제 1항에 있어서,The method of claim 1, 메트릭스메탈로프로테이나제 저해활성을 나타내는 것을 특징으로 하는It exhibits a matrix metalloproteinase inhibitory activity 화합물, 그의 이성질체 및 이들의 약학적으로 허용되는 염.Compounds, isomers thereof and pharmaceutically acceptable salts thereof. (ⅰ) 설포닐할라이드(Ⅱ)와 씨클릭 아미노산(Ⅲ)을 극성유기용매에서 유기염기의 존재하에 반응시켜 화합물(Ⅳ)을 수득하는 공정;(Iii) reacting sulfonyl halide (II) with cyclic amino acid (III) in the presence of an organic base in a polar organic solvent to obtain compound (IV); (ⅱ) 화합물(Ⅳ)을 C_1-4의 알콜 수용액내에서 무기염기의 존재하에 가수분해하여 화합물(Ⅰ, R₃:OH)를 제조하거나, 또는 전기 화합물(Ⅰ, R₃:OH)로부터 축합반응에 의하여 화합물(Ⅰ, R₃:NHOH)를 제조하는 공정을 추가로 포함하는And (ⅱ) is hydrolyzed in the presence of an inorganic base of the compound (Ⅳ) in the aqueous alcohol solution of C _1-4 compound _{(Ⅰ, R 3: OH)} : prepared from, or electricity compound (Ⅰ OH, R ₃₎ the Further comprising the step of preparing a compound (I, R ₃ : NHOH) by a condensation reaction 일반식(Ⅰ)의 화합물을 제조하는 방법:Method for preparing a compound of formula (I): 상기 식에서,Where R₁, R₂, R₃, X 및 n은 일반식(Ⅰ)에서 정의한 바와 동일하다.R ₁ , R ₂ , R ₃ , X and n are the same as defined in general formula (I). 제 4항에 있어서,The method of claim 4, wherein (ⅱ)공정의 염기는 리튬히드록시드인 것을 특징으로 하는(Ii) The base of the process is characterized in that the lithium hydroxide 일반식(Ⅰ)의 화합물을 제조하는 방법.A process for preparing the compound of formula (I). (ⅰ) 설포닐할라이드(Ⅱ, R₁:C_l)와 씨클릭 아미노산(Ⅲ)을 극성유기용매에서 유기염기의 존재하에 반응시켜 화합물(Ⅴ)를 수득하는 공정:(Iii) a process of reacting sulfonyl halide (II, R ₁ : _Cl ) with cyclic amino acid (III) in the presence of an organic base in a polar organic solvent to obtain compound (V): (ⅱ) 화합물(Ⅴ)를 극성유기용매에서 무기염기의 존재하에 70 내지 80℃로 가열하여 화합물(Ⅳ)를 수득하는 공정;(Ii) heating compound (V) to 70 to 80 ° C. in a polar organic solvent in the presence of an inorganic base to obtain compound (IV); (ⅲ) 화합물(Ⅳ)를 C_1-4의 알콜 수용액 내에서 무기염기의 존재하에 가수분해하여 화합물(Ⅰ, R₃:OH)를 제조하거나, 또는 전기 화합물(Ⅰ, R₃:OH)로부터 축합반응에 의하여 화합물(Ⅰ, R₃:NHOH)를 제조하는 공정을 추가로 포함하는From (ⅲ) compound (Ⅳ) hydrolysis in the presence of an inorganic base in aqueous alcohol solution of the compound _1-4 C _{(Ⅰ, R 3:: OH} ) , or a manufacturing or electrical compound (Ⅰ OH, R ₃₎ Further comprising the step of preparing a compound (I, R ₃ : NHOH) by a condensation reaction 일반식(Ⅰ)의 화합물을 제조하는 방법:Method for preparing a compound of formula (I): 상기 식에서,Where 화합물(Ⅲ)는Compound (III) is 이고(이때, R₃는 OH 또는 OR₁₈(이때, OR₁₈는 Where R ₃ is OH or OR _{18 where} OR ₁₈ is C_1-6의 저급알킬, t-부틸, 벤질 또는 씰릴기이다)); 및,C _1-6 lower alkyl, t-butyl, benzyl or sealyl group)); And, R₁, R₂, R₃, X 및 n은 일반식(Ⅰ)에서 정의한 바와 동일하다.R ₁ , R ₂ , R ₃ , X and n are the same as defined in general formula (I). 제 6항에 있어서,The method of claim 6, (ⅲ) 공정의 염기는 리튬히드록시드인 것을 특징으로 하는(Iii) the base of the step is lithium hydroxide, characterized in that 일반식(Ⅰ)의 화합물을 제조하는 방법.A process for preparing the compound of formula (I).