KR20080036585A - Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity - Google Patents

Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity Download PDF

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KR20080036585A
KR20080036585A KR1020087001654A KR20087001654A KR20080036585A KR 20080036585 A KR20080036585 A KR 20080036585A KR 1020087001654 A KR1020087001654 A KR 1020087001654A KR 20087001654 A KR20087001654 A KR 20087001654A KR 20080036585 A KR20080036585 A KR 20080036585A
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demethoxy
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meoh
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aminothiocolhitchin
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가브리엘레 폰타나
이지오 봄바르델리
안토넬라 리바
파올로 모라쪼니
도나토 포카
마리아 루이사 겔미
쥐도 폰트레몰리
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Abstract

The present invention relates to 3-demethoxy-3-aminothiocolchicine glycosyl derivatives of general formula (I) in which R is hydrogen, methyl or hydroxymethyl. The compounds of formula (I) have myorelaxant and anti-inflammatory activity.

Description

근육 이완 및 항―염증 활성이 있는 티오콜히코시드 유사체{Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity}Thiocolchicoside analogues with myorelaxant and anti-inflammatory activity

본원 발명은 근육 이완(myorelaxant) 및 항-염증 활성이 있는 3-데메톡시-3-아미노티오콜히친(aminothiocolchicine) 유도체에 관한 것이다.The present invention relates to a 3-demethoxy-3-aminothiocolchicine derivative with muscle myorelaxant and anti-inflammatory activity.

근육 이완 약물은 근 긴장(muscle tone)을 감소시키는 특징을 공유하고 근육 수축(muscle contracture)과 같은, 조직 긴장(tissue tension)으로 인한 통증을 경감시키기 위해 통상적으로 사용되고 있다.Muscle relaxation drugs are commonly used to share features that reduce muscle tone and to relieve pain due to tissue tension, such as muscle contracture.

근육 수축은 운동 장치(locomotor apparatus)에서의 여러 질병에 대해 특징이 되고, 상기 질병과 관련된 통증의 지속성의 원인이 되는 주요 인자들 중 하나이다. 또한, 근육 수축은 염증성-류마티스 및 퇴행성 정형외과 질환에서 발생하고, 이들이 관절에 영향을 미칠 때에는, 통증뿐만 아니라, 관절 말단의 상호 운동성(mutual mobility)을 제한하고 결과적으로 영향을 받은 부위의 기능을 제한하는 경직(rigidity)을 일으키게 된다. 이러한 이유로 인하여, 근육을 이완시키고 수축시키지 않는(decontracting) 특징을 부여하는 분자에 대한 연구가 임상적 관점에서 주목할 만한 관심을 여전히 일으키고 있다. Muscle contraction is characterized for various diseases in locomotor apparatus and is one of the major factors that contribute to the persistence of pain associated with the disease. In addition, muscle contractions occur in inflammatory-rheumatic and degenerative orthopedic diseases, and when they affect the joints, they limit pain as well as the mutual mobility of the ends of the joints and consequently affect the function of the affected site. It causes limiting rigidity. For this reason, studies of molecules that confer characteristics that relax and decontract muscles still generate significant attention from the clinical point of view.

알려져 있는 바와 같이, 콜히친은 통풍에 대한 치료에서 오랜 기간 동안 폭넓게 사용된 슈도알칼로이드(pseudoalkaloid)이다. 티오콜히코시드(thiocolchicoside)(C10이 티오메틸기를 갖고 있고 3-위치에 있는 히드록시기가 글루코스 분자와 에테르화 반응하고 있는 콜히친 유도체)로 알려져 있는 3-데메틸-티오콜히친 글루코시드는 골격근의 염증성 상태의 수축의 치료를 위해 광범위하게 사용되고 있다(Ortopedia e Traumatologia Oggi XII, n. 4. 1992). 티오콜히코시드의 활성은 스트리크닌-민감성(strychnine-sensitive) 글리신 수용체와 상호작용하는 능력 때문이고 따라서 글리시노를-모방한(glycino-mimetic) 활성을 부여받은 화합물들이 근육 이완하는 특징으로 인하여 류마티스-정형외과 분야에서 사용될 수 있음이 최근에 입증되고 있다.As is known, colchicine is a pseudoalkaloid that has been widely used for a long time in the treatment for gout. 3-demethyl-thiocolhitchin glucoside, known as thiocolchicoside (a colchicine derivative in which C 10 has a thiomethyl group and the hydroxyl group in 3-position is etherified with glucose molecules), is an inflammatory state of skeletal muscle. It is widely used for the treatment of contraction of humans (Ortopedia e Traumatologia Oggi XII, n. 4. 1992). The activity of thiocolhicoside is due to its ability to interact with strychnine-sensitive glycine receptors and thus rheumatoid-like due to the muscle relaxation characteristics of compounds endowed with glycino-mimetic activity. It has recently been demonstrated that it can be used in the orthopedic field.

본원 발명은 하기 일반식 (I)의 3-데메톡시-3-아미노티오콜히친 글리코실 유도체에 관한 것이다.The present invention relates to a 3-demethoxy-3-aminothiocolchicine glycosyl derivative of the following general formula (I).

Figure 112008004909587-PCT00001
Figure 112008004909587-PCT00001

상기에서 R은 수소, 메틸 또는 히드록시메틸이다. Wherein R is hydrogen, methyl or hydroxymethyl.

따라서, 3-데메톡시-3-아미노티오콜히친의 펜토오스(pentose) 및 헥소오스(hexose) D- 및 L-글리코피라노시드의 알파 아노머(alpha anomer)와 베타 아노머(beta anomer)가 식 (I)의 화합물에 포함된다.Thus, the alpha anomers and beta anomers of pentose and hexose D- and L-glycopyrronosides of 3-demethoxy-3-aminothiocolchin Included in the compound of formula (I).

본원 발명의 화합물은 일반적으로 하기 3-데메톡시-3-아미노티오콜히친(II)과Compounds of the present invention generally comprise the following 3-demethoxy-3-aminothiocolchicine (II)

Figure 112008004909587-PCT00002
Figure 112008004909587-PCT00002

하기 식 (III)의 보호된 글리코피라노시드의 반응에 의해 제조된다.It is prepared by the reaction of a protected glycopyranoside of formula (III).

Figure 112008004909587-PCT00003
Figure 112008004909587-PCT00003

상기에서 X는 OH, F, Cl, Br, I이고,Wherein X is OH, F, Cl, Br, I,

R2는 수소, 메틸, -CH2-O-R3이고;R 2 is hydrogen, methyl, —CH 2 —OR 3 ;

R3은 수소 또는 히드록시-보호기이다.R 3 is hydrogen or a hydroxy-protecting group.

X기 중, 불소와 브롬이 바람직하다. 보호기 중, 아세틸기가 바람직하다.Of the X groups, fluorine and bromine are preferable. Among the protecting groups, an acetyl group is preferable.

3-데메톡시-3-아미노티오콜히친(II)은 WO 00/35865의 Clark D. 등에 의해 개시된 바와 같은 Buchwald 반응에 의해 3-O-데메틸티오콜히친 트리플레이트, 토실레이트 또는 메실레이트로부터 제조된다.3-demethoxy-3-aminothiocolchicine (II) is prepared from 3-O-demethylthiocolchicine triflate, tosylate or mesylate by the Buchwald reaction as disclosed by Clark D. et al. Of WO 00/35865. .

보다 상세하게는, 3-데메톡시-3-아미노티오콜히친은 선택적으로는 히드록시 잔기에서 보호된 적당한 글리코시드와 반응하게 된다. 상기 반응은 바람직하게는 알코올(MeOH)로부터 선택되는 극성 양성자성(protic) 용매에서, 25℃ 내지 상기 용매가 끓는 온도의 온도 범위에서 수행된다. 반응은 일반적으로 8 시간 내지 6일의 시간 후에 걸쳐 완료된다. 필요하다면, 또한 중간체의 회수 없이 반응 조 생성물(reaction crude)에서 보호기의 가수 분해가 바로 수행될 수 있다.More specifically, 3-demethoxy-3-aminothiocolchinchin is optionally reacted with a suitable glycoside protected at the hydroxy moiety. The reaction is preferably carried out in a polar protic solvent selected from alcohol (MeOH), in the temperature range of 25 ° C. to the temperature at which the solvent is boiling. The reaction is generally completed after a time of 8 hours to 6 days. If necessary, hydrolysis of the protecting group can also be carried out directly in the reaction crude without recovery of the intermediate.

반응이 마이크로파와 함께 수행되었을 때에는 반응 시간의 현저한 감소와 수득률의 현저한 증가가 관찰되었다. 보다 상세하게는, 3-데메톡시-3-아미노티오콜히친은 바람직하게는 MeOH와 같은 알코올로부터 선택되는 극성 양성자성 용매에서, 110℃에서, 150 와트(watt) 전력(power)과 함께 적절한 글리코시드와 반응하게 된다. 반응은 일반적으로 3 시간 후에 완료된다.When the reaction was carried out with microwaves, a significant decrease in reaction time and a significant increase in yield were observed. More specifically, 3-demethoxy-3-aminothiocolchicine is a suitable glycoside with 150 watt power, at 110 ° C., in a polar protic solvent, preferably selected from alcohols such as MeOH. Will react with. The reaction is generally completed after 3 hours.

그 결과 생성되는 생성물이 리간드로서 [3H]스트리키닌을 사용하여 랫트 척수의 스트리키닌-민감성 결합 부위에 대한 친화도를 입증하기 위한 변이 검사(displacement test)에 의해 인 비트로(in vitro)에서 테스트되었다. 그 결과는 유도체는 척수의 스트리키닌-민감성 글리신 수용체에서 알로스테릭(allosteric) 화합물로 작용하였음을 제안한다. 이러한 상호 작용은 본원 발명 화합물의 근육 이완 활성을 표시한다(Cimino M. et al ., Eur . J. Pharmacol . 1996, 318. 201-204; Balduini W. et al ., Neuropharmacol. 2001, 40. 1044-1049).The resulting product was in vitro by a displacement test to demonstrate affinity for the strikinin-sensitive binding site of the rat spinal cord using [3H] strikinin as ligand. Was tested. The results suggest that the derivative acted as an allosteric compound at the spinkinin-sensitive glycine receptor in the spinal cord. This interaction indicates the muscle relaxation activity of the compounds of the invention (Cimino M. et al . , Eur . J. Pharmacol . 1996, 318. 201-204; Balduini W. et al . , Neuropharmacol . 2001, 40. 1044-1049).

식 II의 화합물은 활성이 있는 것으로 입증되었고 따라서 본원 발명의 화합물은 또한 근육 이완 활성이 있는 의약의 제조를 위한 본원 발명의 화합물의 용도에 관한 것이다.The compounds of formula II have been shown to be active and therefore the compounds of the present invention also relate to the use of the compounds of the invention for the preparation of a medicament with muscle relaxation activity.

Figure 112008004909587-PCT00004
Figure 112008004909587-PCT00004

본원 발명의 화합물은 Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N. Y., U.S.A.에서 보고된 것과 같이, 부형제 및 통상적인 방법으로, 경구, 정맥 내, 근육 내, 경피, 및 국부 투여를 위한 약제학적 제제로서 제제화될 수 있다. 비경구 또는 국부 투여를 위한 리포좀형 제제(liposomial form)의 제조를 위해 유용한 부형제 중, 천연 및 합성 포스포리피드가 특히 바람직하다. 투여량은 질병 및 투여 경로에 따라 하루 당 5 mg 내지 50 mg이 될 수 있다.The compounds of the present invention are excipients and agents for conventional oral, intravenous, intramuscular, transdermal, and topical administration, as reported in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA. It can be formulated as a pharmaceutical preparation. Of the excipients useful for the preparation of liposomial forms for parenteral or topical administration, natural and synthetic phospholipids are particularly preferred. The dosage can be 5 mg to 50 mg per day, depending on the disease and the route of administration.

이제, 본원 발명이 소정의 실시예에 의해 보다 상세하게 설명될 것이다.The invention will now be described in more detail by certain examples.

실험 부분Experimental part

녹는점은 Buchi 510 장치를 사용하여 측정되었다. NMR 스펙트럼은 Bruker AC 500 기구를 사용하여 얻어졌다. IR 스펙트럼은 Jasco IR Report 100 분광계로 얻어졌다. 반응은 Milstone Micro SYNTH 마이크로파 오븐(microwave oven)에서 수행되었다. [α]25D 값은 343- PLUS Perkin-Helmer 폴라리미터(polarimeter)로 측정되었다.Melting points were measured using a Buchi 510 device. NMR spectra were obtained using a Bruker AC 500 instrument. IR spectra were obtained with a Jasco IR Report 100 spectrometer. The reaction was performed in a Milstone Micro SYNTH microwave oven. [α] 25 D values were measured with a 343-PLUS Perkin-Helmer polarimeter.

실시예Example 1. 3- 1-3 OO -- 트리플루오로메탄술포닐Trifluoromethanesulfonyl -3--3- OO -- 데메틸티오콜히친Demethylthiocolchin

무수 CH2Cl2(50 mL)에 넣은 3-O-데메틸티오콜히친(2 g, 4.98 mmoles)과 p-DMAP(1.77 g, 15.78 mmoles)의 용액에, 트리플릭 무수물(triflic anhydride)(1.24 ml, 7.40 mmoles)이 질소 분위기 하에서 0℃에서 첨가되었다.Triflic anhydride (1.24) in a solution of 3-O-demethylthiocolchicine (2 g, 4.98 mmoles) and p-DMAP (1.77 g, 15.78 mmoles) in anhydrous CH 2 Cl 2 (50 mL). ml, 7.40 mmoles) was added at 0 ° C. under a nitrogen atmosphere.

0℃에서 20시간 동안, 및 실온에서 3시간 동안 교반을 계속하였다. 반응을 TLC 분석으로 모니터하였다(10:1 CH2Cl2/MeOH, Rf: 출발 물질 = 0.27, 생성물 = 0.38). 용매를 증발시킨 후에, 얻은 잔여물을 CH2Cl2/MeOH 혼합물을 사용하여(극성 구배(polarity gradient)를 증가시킴) 알루미나에서 컬럼 크로마토그래피에 의해 정제하였다. 에탄올에서 결정화한 후에, 생성물(1.84 g, 70%)을 노란색 고체로 얻었다.Stirring was continued at 0 ° C. for 20 hours and at room temperature for 3 hours. The reaction was monitored by TLC analysis (10: 1 CH 2 Cl 2 / MeOH, Rf: starting material = 0.27, product = 0.38). After evaporation of the solvent, the obtained residue was purified by column chromatography on alumina using a CH 2 Cl 2 / MeOH mixture (increasing polarity gradient). After crystallization in ethanol, the product (1.84 g, 70%) was obtained as a yellow solid.

Figure 112008004909587-PCT00005
Figure 112008004909587-PCT00005

실시예Example 2. 3- 2. 3- 데메톡시Demethoxy -3--3- 아미노티오콜히친Aminothiocolhitchin

Cs2CO3(685 mg, 2.09 mmoles), Pd(OAc)2(68 mg, 0.29 mmoles) 및 (±)BINAP290 mg, 0.44 mmoles) 및 실시예 1에서 얻은 화합물(800 mg, 1.48 mmoles)을 질소 분위기 하에서 Schlenk 둥근-바닥 플라스크에 넣었다. 얻은 혼합물을 2 시간 동안 진공 상태에서 40℃에서 가열하였다. 냉각시킨 후에, 적절하게 가스를 제거한 무수 톨루엔(3 ml)과 벤조페논 이민(0.25 ml, 1.49 mmoles)을 첨가하였다. 상기 둥근-바닥 플라스크를 고무 마개로 밀봉하였고, 질소로 포화시켰다. 얻은 반응 혼합물을 실온에서 45분 동안 교반하였고, 그런 다음 120℃에서 16 시간 동안 가열하였고, TLC 분석(20: 1 CH2Cl2/MeOH)으로 모니터하였다. 얻은 혼합물을 실온까지 냉각시켰고, AcOEt로 희석시켰고, 여과하였고, 감압하에서 농축하였다. 목표로 하는 이미노 첨가물을 포함하는 정제되지 않은 상태의 생성물을 실온에서 MeOH(15 ml)에 용해시켰다. 얻은 용액에 AcONa(509 mg, 6.21 mmoles)와 NH2OH HCl(323 mg, 4.65 mmoles)를 첨가하였다. 30분 후에, 얻은 혼합물을 CH2Cl2(5 ml)로 희석하였고, 2N HCl로 pH 2까지 산성으로 만들었다. 유기층을 분리하였고, 수용액 층을 25% NaOH 용액으로 알칼리성으로 만들었고, CH2Cl2 (3x20 ml)으로 추출하였다. 유기층에서 Na2SO4로 물을 제거하였고, 감압 하에서 농축시켜, 목표로 하는 생성물(TLC 10: 1.5 CH2Cl2/MeOH Rf 0.43)을 얻었고, 그런 다음 EtOH로 결정화시켰다(373 mg, 60%).Cs 2 CO 3 (685 mg, 2.09 mmoles), Pd (OAc) 2 (68 mg, 0.29 mmoles) and (±) BINAP290 mg, 0.44 mmoles) and the compound obtained in Example 1 (800 mg, 1.48 mmoles) Placed in a Schlenk round-bottom flask under atmosphere. The resulting mixture was heated at 40 ° C. under vacuum for 2 hours. After cooling, appropriately degassed anhydrous toluene (3 ml) and benzophenone imine (0.25 ml, 1.49 mmoles) were added. The round-bottom flask was sealed with a rubber stopper and saturated with nitrogen. The resulting reaction mixture was stirred at room temperature for 45 minutes, then heated at 120 ° C. for 16 hours and monitored by TLC analysis (20: 1 CH 2 Cl 2 / MeOH). The resulting mixture was cooled to room temperature, diluted with AcOEt, filtered and concentrated under reduced pressure. The crude product containing the desired imino additive was dissolved in MeOH (15 ml) at room temperature. AcONa (509 mg, 6.21 mmoles) and NH 2 OH HCl (323 mg, 4.65 mmoles) were added to the resulting solution. After 30 minutes, the resulting mixture was diluted with CH 2 Cl 2 (5 ml) and made acidic to pH 2 with 2N HCl. The organic layer was separated and the aqueous layer was made alkaline with 25% NaOH solution and extracted with CH 2 Cl 2 (3 × 20 ml). Water was removed with Na 2 SO 4 in the organic layer and concentrated under reduced pressure to afford the desired product (TLC 10: 1.5 CH 2 Cl 2 / MeOH Rf 0.43), which was then crystallized with EtOH (373 mg, 60%).

Figure 112008004909587-PCT00006
Figure 112008004909587-PCT00006

Figure 112008004909587-PCT00007
Figure 112008004909587-PCT00007

실시예Example 3. 3-- 3. 3-- 데메톡시Demethoxy -3--3- 아미노티오콜히친Aminothiocolhitchin 글리코시드의 합성을 위한 일반적인 방법 General method for the synthesis of glycosides

방법 A. MeOH(8.5 ml)에 넣은 3-데메톡시-3-아미노티오콜히친(404 mg, 1 mmole)의 용액에 상업용 글리코피라노시드(1 mmole)를 첨가하였고, 얻은 혼합물을 밀봉된 시험관에서 80℃에서 6일 동안 가열시켰다. 반응을 TLC 분석(10:1.5 CH2Cl2/MeOH)으로 모니터하였다. 용매를 감압 하에서 증발시켰고, 정제되지 않은 반응 혼합물의 TLC 분석은 출발 물질(8-10%)과 아미노글리코시드의 아이소머 혼합물의 존재를 나타내었으며, 이들은 실리카 겔에서 컬럼 크로마토그래피에 의해 분리되었고(100: 1 내지 100:5 CH2Cl2/MeOH), MeOH/iPr2O로부터 결정화되어, 목표로 하는 화합물을 얻었다.Method A. To a solution of 3-demethoxy-3-aminothiocolchinine (404 mg, 1 mmole) in MeOH (8.5 ml) was added commercial glycopyranoside (1 mmole) and the resulting mixture was added in a sealed test tube. Heated at 80 ° C. for 6 days. The reaction was monitored by TLC analysis (10: 1.5 CH 2 Cl 2 / MeOH). The solvent was evaporated under reduced pressure and TLC analysis of the crude reaction mixture showed the presence of an isomer mixture of starting material (8-10%) and aminoglycoside, which were separated by column chromatography on silica gel ( 100: 1 to 100: 5 CH 2 Cl 2 / MeOH) and MeOH / iPr 2 O to crystallize to obtain the target compound.

방법 B. MeOH(8.5 ml)에 넣은 3-O-데메톡시-3-아미노티오콜히친(404 mg, 1 mmole)의 용액에 상업용 글리코피라노시드(1 mmole)를 첨가하였고, 얻은 혼합물을 마이크로파 오븐에서 4 시간 동안 110℃에서 150 와트에서 가열시켰다. 반응을 TLC 분석(10: 1.5 CH2Cl2/MeOH)으로 모니터하였다. 용매를 감압 하에서 제거하였고, 정제되지 않은 반응 혼합물의 TLC 분석은 출발 물질 미량과 아미노글리코시드의 아이소머 혼합물의 존재를 나타내었으며, 이들은 실리카 겔에서 컬럼 크로마토그래피에 의해 분리되었고(100: 1 내지 100:5 CH2Cl2/MeOH), MeOH/iPr2O로 재결정화되어, 목표로 하는 화합물을 얻었다.Method B. To a solution of 3-O-demethoxy-3-aminothiocolchicine (404 mg, 1 mmole) in MeOH (8.5 ml) was added commercial glycopyranoside (1 mmole) and the resulting mixture was microwave oven. Heated at 150 ° C. at 110 ° C. for 4 h. The reaction was monitored by TLC analysis (10: 1.5 CH 2 Cl 2 / MeOH). The solvent was removed under reduced pressure, TLC analysis of the crude reaction mixture showed the presence of starting material traces and isomer mixture of aminoglycosides, which were separated by column chromatography on silica gel (100: 1 to 100). : 5 CH 2 Cl 2 / MeOH) and MeOH / iPr 2 O to recrystallize to obtain the target compound.

하기의 표는 제조 과정의 수득률과 부분입체이성질체 선택(diastereoselection)을 나타낸다.The table below shows the yield and diastereoselection of the preparation process.

Figure 112008004909587-PCT00008
Figure 112008004909587-PCT00008

실시예Example 4. 3-N-α-D- 4. 3-N-α-D- 글루코피라노실Glucopyranosyl -3-O--3-O- 데메톡시Demethoxy -3--3- 아미노티오콜히친Aminothiocolhitchin

Figure 112008004909587-PCT00009
Figure 112008004909587-PCT00009

실시예Example 5. 3-N-β-D- 5. 3-N-β-D- 글루코피라노실Glucopyranosyl -3-O--3-O- 데메톡시Demethoxy -3--3- 아미노티오콜히친Aminothiocolhitchin

Figure 112008004909587-PCT00010
Figure 112008004909587-PCT00010

실시예Example 6. 6. 3-N-α-D-3-N-α-D- 아라비노피라노실Arabinopyranosil -3-O--3-O- 데메톡시Demethoxy -3--3- 아미노티오콜히친Aminothiocolhitchin

Figure 112008004909587-PCT00011
Figure 112008004909587-PCT00011

Figure 112008004909587-PCT00012
Figure 112008004909587-PCT00012

실시예Example 7. 3-N-β-D- 7. 3-N-β-D- 아라비노피라노실Arabinopyranosil -3-O--3-O- 데메톡시Demethoxy -3--3- 아미노티오콜히친Aminothiocolhitchin

Figure 112008004909587-PCT00013
Figure 112008004909587-PCT00013

실시예Example 8. 3-N-α-D- 8. 3-N-α-D- 릭소피라노실Lixospiranosil (( lyxopyranosyllyxopyranosyl )-3-O-) -3-O- 데메톡시Demethoxy -3--3- 아미노티오콜히친Aminothiocolhitchin

Figure 112008004909587-PCT00014
Figure 112008004909587-PCT00014

Figure 112008004909587-PCT00015
Figure 112008004909587-PCT00015

실시예Example 9. 9. 3-N-β-D-3-N-β-D- 릭소피라노실Lixospiranosil -3-O--3-O- 데메톡시Demethoxy -3--3- 아미노티오콜히친Aminothiocolhitchin

Figure 112008004909587-PCT00016
Figure 112008004909587-PCT00016

실시예Example 10. 3-N-α-D- 10. 3-N-α-D- 자일로피라노실Xylopyranosyl (( xylopyranosylxylopyranosyl )-3-O-) -3-O- 데메톡시Demethoxy -3--3- 아미노티오콜히친Aminothiocolhitchin

Figure 112008004909587-PCT00017
Figure 112008004909587-PCT00017

Figure 112008004909587-PCT00018
Figure 112008004909587-PCT00018

실시예Example 11. 3-N-β-D- 11.3-N-β-D- 자일로피라노실Xylopyranosyl -3-O--3-O- 데메톡시Demethoxy -3--3- 아미노티오콜히친Aminothiocolhitchin

Figure 112008004909587-PCT00019
Figure 112008004909587-PCT00019

실시예Example 12. 12. 3-N-α-L-3-N-α-L- 람노피라노실Rhamnopyranosil (( rhamnopyranosylrhamnopyranosyl )-3-O-) -3-O- 데메톡시Demethoxy -3--3- 아미노Amino 티오콜히친Thiocolchin

Figure 112008004909587-PCT00020
Figure 112008004909587-PCT00020

실시예Example 13. 3-N-β-D- 13. 3-N-β-D- 만노피라노실Mannopyranosil (( mannopyranosylmannopyranosyl )-3-O-) -3-O- 데메톡시Demethoxy -3--3- 아미노Amino 티오콜히친Thiocolchin

Figure 112008004909587-PCT00021
Figure 112008004909587-PCT00021

실시예Example 14. 14. 3-N-β-L-3-N-β-L- 푸코피라노실Fucopyranosil (( fucopyranosylfucopyranosyl )-3-O-) -3-O- 데메톡시Demethoxy -3--3- 아미노티오콜히친Aminothiocolhitchin

Figure 112008004909587-PCT00022
Figure 112008004909587-PCT00022

Claims (5)

R이 수소, 메틸 또는 히드록시메틸인 하기 일반식 (I)의 화합물.A compound of formula (I) below, wherein R is hydrogen, methyl or hydroxymethyl.
Figure 112008004909587-PCT00023
Figure 112008004909587-PCT00023
 3-N-D-자일로피라노실(xylopyransoyl)-3-O-데메톡시-3-아미노티오콜히친;3-N-D-xylopyranosyl-3-O-demethoxy-3-aminothiocolchicin; 3-N-D-글루코피라노실-3-O-데메톡시-3-아미노티오콜히친;3-N-D-glucopyranosyl-3-O-demethoxy-3-aminothiocolchicine; 3-N-D-만노피라노실-3-O-데메톡시-3-아미노티오콜히친;3-N-D-mannopyranosyl-3-O-demethoxy-3-aminothiocolchicin; 3-N-D-아라비노피라노실-3-O-데메톡시-3-아미노티오콜히친;3-N-D-arabinopyranosyl-3-O-demethoxy-3-aminothiocolhitchin; 3-N-D-릭소피라노실(lyxopyranosyl)-3-O-데메톡시-3-아미노티오콜히친;3-N-D-lyxopyranosyl-3-O-demethoxy-3-aminothiocolchicin; 3-N-L-람노피라노실(rhamnopyranosyl)-3-O-데메톡시-3-아미노티오콜히친;3-N-L-rhamnopyranosyl-3-O-demethoxy-3-aminothiocolchicin; 3-N-L-푸코피라노실(fucopyranosyl)-3-O-데메톡시-3-아미노티오콜히친로부터 선택되는 화합물. 3-N-L-fucopyranosyl-3-O-demethoxy-3-aminothiocolchchin. 허용가능한 캐리어(carrier) 및/또는 부형제와 혼합된 제1항 또는 제2항의 화합물을 포함하는 약제학적 조성물. A pharmaceutical composition comprising the compound of claim 1 in admixture with an acceptable carrier and / or excipient. 근육 이완(myorelaxant) 및 항-염증 활성을 갖는 의약의 제조를 위한, 제1항 및 제2항의 화합물의 용도.Use of the compounds of claims 1 and 2 for the manufacture of a medicament having myorelaxant and anti-inflammatory activity. 근육 이완 활성을 갖는 의약의 제조를 위한, 하기 식 (II)의 화합물의 용도.Use of a compound of formula (II) below for the manufacture of a medicament having muscle relaxation activity.
Figure 112008004909587-PCT00024
Figure 112008004909587-PCT00024
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