TW202329961A - Novel nicotinamide compound and use therefor - Google Patents

Abstract

Provided is a novel dry eye treatment agent that has a strong tear secretion promotion effect. The present invention pertains to: 4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-carboxamide)phenyl]amino]nicotinamide, a salt thereof, or a solvate of either; and a pharmaceutical composition that contains said compound.

Description

新穎菸鹼醯胺化合物及其用途Novel nicotinamide compound and use thereof

本發明係關於有效作為乾眼症治療劑之新穎菸鹼醯胺化合物。The present invention relates to novel nicotinamide compounds which are effective as therapeutic agents for dry eye syndrome.

乾眼症係因於構成眼表面之淚液層與上皮層之間發生不良循環，而引起眼睛不適感或視機能異常的最常見之眼表面疾病，其在日本之推估患者數據說有2000萬人以上。又，近年來隨著在空調下之生活、影像顯示器終端(VDT)之長時間作業、隱形眼鏡配戴者之增加，乾眼症患者數逐年增加中。Dry eye is the most common ocular surface disease that causes eye discomfort or abnormal vision due to poor circulation between the tear layer and the epithelial layer that make up the eye surface. It is estimated that there are 20 million patients in Japan more than one person. In addition, in recent years, the number of patients with dry eye syndrome is increasing year by year due to living under air conditioning, long-time work of video display terminals (VDT), and the increase of contact lens wearers.

根據Tear Film & Ocular Surface Society於2017年之改訂版DEWSⅡ報告書，乾眼症係定義為「以淚液層之健全性出問題為特徵的多因子性之眼表面疾病，具有某些眼部自覺症狀，淚液層之不穩定性或高滲透壓、眼表面之發炎或障礙、知覺神經異常扮演病因之角色」，係被認為多因子所造成的疾病。又，於原因/病理論之分類中，其係被分類為淚液分泌減少型乾眼症(Aqueous deficient Dry Eye：ADDE)與淚液蒸發亢進型乾眼症(Evaporative Dry Eye：EDE)(非專利文獻1)。According to the revised DEWS II report of Tear Film & Ocular Surface Society in 2017, dry eye syndrome is defined as a multifactorial ocular surface disease characterized by problems with the integrity of the tear layer, with certain ocular symptoms , the instability or high osmotic pressure of the tear layer, inflammation or disorder of the ocular surface, and sensory nerve abnormalities play the role of the etiology", which is considered to be a disease caused by multiple factors. In addition, in the classification of cause/disease theory, it is classified into reduced tear secretion dry eye (Aqueous deficient Dry Eye: ADDE) and tear evaporative hyperactive dry eye (Evaporative Dry Eye: EDE) (non-patent literature 1).

習知之乾眼症藥物治療中，於日本僅有玻尿酸鈉點眼液(Hyalein(註冊商標)點眼液)，於美國僅有環孢素點眼液(Restasis(註冊商標))，現狀為在兩國僅各上市1種製品。因此，於乾眼症之治療時，除了此等藥物療法之外，有為了單純補充水分而單獨或併用人工淚液等之療法，並對嚴重病例使用將淚液之排出部位閉鎖的淚點栓塞***術、或淚點閉鎖術等外科性療法。又，亦使用接近淚液成分的自體血清點眼劑等院內製劑(非專利文獻2)。Among the known dry eye drug treatments, there is only sodium hyaluronate eye drops (Hyalein (registered trademark) eye drops) in Japan, and only cyclosporine eye drops (Restasis (registered trademark)) in the United States. Only one product is listed in each of the two countries. Therefore, in the treatment of dry eye, in addition to these drug therapies, there are treatments such as the use of artificial tears alone or in combination for simple hydration, and in severe cases, punctal embolization that blocks the drainage site of tears is used. , or punctal atresia and other surgical treatments. In addition, in-hospital preparations such as autologous serum eyedrops close to tear fluid components are also used (Non-Patent Document 2).

最近，基於改變淚液品質的概念，促進水分及黏蛋白之分泌的P2Y ₂受體促效藥滴舒適(Diquas)點眼液(地夸磷索四鈉，Diquafosol Sodium)、黏蛋白產生促進劑之膜固思達(Mucosta)點眼液(瑞巴匹特，Rebamipide)接續已被日本承認，治療藥之選項在增加中。其中，Diquas係作用於結膜上皮及杯狀細胞膜上之P2Y ₂受體，使細胞內之鈣濃度上升，藉此促進水分及黏蛋白之分泌，為具有強力之淚液分泌作用的乾眼症治療藥(非專利文獻3)。 Recently, based on the concept of changing tear quality, the P2Y ₂ receptor agonist drug Diquas eye drops (Diquafosol Sodium), which promotes the secretion of water and mucin, is one of the mucin production accelerators. The succession of Mucosta eye drops (Rebamipide, Rebamipide) has been recognized by Japan, and the options for treatment are increasing. Among them, Diquas acts on the P2Y ₂ receptors on the conjunctival epithelium and goblet cell membrane to increase the calcium concentration in the cells, thereby promoting the secretion of water and mucin, and is a dry eye treatment drug with a strong tear secretion effect (Non-Patent Document 3).

然而，乾眼症如被定義為多因子所造成的疾病般，其係難以利用一種藥劑完全克服多樣之原因所造成的疾病，且亦存在有藉由既有藥物無法充分治療的重症乾眼症患者。因此，現在仍期待開發出作用機轉不同、具有更強力之淚液分泌促進作用的乾眼症治療劑。 [先前技術文獻] [非專利文獻] However, as dry eye is defined as a disease caused by multiple factors, it is difficult to use one drug to completely overcome the disease caused by multiple factors, and there are also severe dry eyes that cannot be adequately treated by existing drugs patient. Therefore, the development of a therapeutic agent for dry eye syndrome that has a different mechanism of action and has a stronger lacrimal secretion-promoting effect is still desired. [Prior Art Literature] [Non-patent literature]

[非專利文獻1]Ocul. Surf., 15, 802-812(2017) [非專利文獻2]日藥理誌, 135, 138-141(2010) [非專利文獻3]IOVS, 42, 96-100(2001) [Non-Patent Document 1]Ocul. Surf., 15, 802-812(2017) [Non-Patent Document 2] Journal of Japanese Pharmacopoeia, 135, 138-141 (2010) [Non-Patent Document 3] IOVS, 42, 96-100 (2001)

(發明所欲解決之問題)(Problem to be solved by the invention)

本發明之課題在於提供具有更強力之淚液分泌促進作用的新穎乾眼症治療劑。 (解決問題之技術手段) The object of the present invention is to provide a novel therapeutic agent for dry eye syndrome having a stronger lacrimal secretion promoting action. (technical means to solve the problem)

有鑑於上述情況，本發明人等為了探索新穎乾眼症治療劑而進行潛心研究，結果發現，於正常兔及阿托平誘發乾眼症模式兔、眼窩外淚腺摘出模式鼠中，具有菸鹼醯胺骨架之新穎化合物係具有強力之淚液分泌促進作用，因而完成本發明。In view of the above situation, the inventors of the present invention conducted intensive research in order to explore a novel therapeutic agent for dry eye syndrome, and found that in normal rabbits, atropine-induced dry eye model rabbits, and extraorbital lacrimal gland extraction model mice, nicotine A novel compound with an amide skeleton has a strong lacrimal secretion-promoting effect, thus completing the present invention.

亦即，本發明提供以下[1]~[20]。 [1]一種4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺(化合物1)或其鹽或者該等之溶媒合物。 [2]一種淚液分泌促進劑，係以化合物1或其鹽或者該等之溶媒合物為有效成分。 [3]一種乾眼症之預防及/或治療劑，係以化合物1或其鹽或者該等之溶媒合物為有效成分。 [4]一種醫藥組成物，係含有化合物1或其鹽或者該等之溶媒合物而成。 [5]一種用於淚液分泌促進的醫藥組成物，係含有化合物1或其鹽或者該等之溶媒合物而成。 [6]一種用於乾眼症之預防及/或治療的醫藥組成物，係含有化合物1或其鹽或者該等之溶媒合物而成。 [7]一種淚液分泌促進方法，其特徵為，對需要治療之患者投予化合物1或其鹽或者該等之溶媒合物。 [8]一種乾眼症之預防及/或治療方法，其特徵為，對需要治療之患者投予化合物1或其鹽或者該等之溶媒合物。 [9]一種化合物1或其鹽或者該等之溶媒合物的使用，係用於製造淚液分泌促進劑。 [10]一種化合物1或其鹽或者該等之溶媒合物的使用，係用於製造乾眼症之預防及/或治療劑。 [11]一種(S)-4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺(化合物1b)或其鹽或者該等之溶媒合物。 [12]一種淚液分泌促進劑，係以化合物1b或其鹽或者該等之溶媒合物為有效成分。 [13]一種乾眼症之預防及/或治療劑，係以化合物1b或其鹽或者該等之溶媒合物為有效成分。 [14]一種醫藥組成物，係含有化合物1b或其鹽或者該等之溶媒合物而成。 [15]一種用於淚液分泌促進的醫藥組成物，係含有化合物1b或其鹽或者該等之溶媒合物而成。 [16]一種用於乾眼症之預防及/或治療的醫藥組成物，係含有化合物1b或其鹽或者該等之溶媒合物而成。 [17]一種淚液分泌促進方法，其特徵為，對需要治療之患者投予化合物1b或其鹽或者該等之溶媒合物。 [18]一種乾眼症之預防及/或治療方法，其特徵為，對需要治療之患者投予化合物1b或其鹽或者該等之溶媒合物。 [19]一種化合物1b或其鹽或者該等之溶媒合物的使用，係用於製造淚液分泌促進劑。 [20]一種化合物1b或其鹽或者該等之溶媒合物的使用，係用於製造乾眼症之預防及/或治療劑。 (對照先前技術之功效) That is, the present invention provides the following [1] to [20]. [1] A 4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formamido)phenyl]amino]nicotinamide (compound 1) or a salt thereof or a solvate thereof. [2] A lacrimal fluid secretion promoter, which contains Compound 1 or its salt or a solvent thereof as an active ingredient. [3] A preventive and/or therapeutic agent for dry eye syndrome, comprising Compound 1 or its salt or a solvent thereof as an active ingredient. [4] A pharmaceutical composition comprising Compound 1 or a salt thereof or a solvate thereof. [5] A pharmaceutical composition for promoting tear secretion, comprising Compound 1 or a salt thereof or a solvent thereof. [6] A pharmaceutical composition for the prevention and/or treatment of dry eye, comprising Compound 1 or its salt or a solvent thereof. [7] A method for promoting tear secretion, which comprises administering Compound 1 or a salt thereof or a vehicle thereof to a patient in need of treatment. [8] A method for preventing and/or treating dry eye, characterized by administering Compound 1 or a salt thereof or a vehicle thereof to a patient in need of treatment. [9] Use of Compound 1 or a salt thereof, or a solvent thereof, for the production of a lacrimal fluid secretion enhancer. [10] The use of compound 1 or its salt or the solvate thereof for the manufacture of a preventive and/or therapeutic agent for dry eye syndrome. [11] A (S)-4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-carboxamido)phenyl]amino]nicotine Amide (compound 1b) or a salt thereof or a solvate thereof. [12] A lacrimal secretion enhancer, which contains compound 1b or its salt or a solvate thereof as an active ingredient. [13] A preventive and/or therapeutic agent for dry eye syndrome, comprising compound 1b or a salt thereof or a solvent thereof as an active ingredient. [14] A pharmaceutical composition comprising compound 1b or a salt thereof or a solvate thereof. [15] A pharmaceutical composition for promoting tear secretion, comprising compound 1b or a salt thereof, or a solvent thereof. [16] A pharmaceutical composition for the prevention and/or treatment of dry eye, comprising compound 1b or a salt thereof or a solvent thereof. [17] A method for promoting tear secretion, which comprises administering Compound 1b or a salt thereof or a vehicle thereof to a patient in need of treatment. [18] A method for preventing and/or treating dry eye, characterized by administering compound 1b or a salt thereof or a vehicle thereof to a patient in need of treatment. [19] Use of compound 1b or a salt thereof, or a solvent thereof, for the production of a lacrimal fluid secretion enhancer. [20] Use of compound 1b or a salt thereof, or a solvent thereof, for the manufacture of a preventive and/or therapeutic agent for dry eye syndrome. (compared to the effect of previous technology)

本發明係提供對乾眼症治療有效的新穎藥劑。根據本發明，可提供具有強力之淚液分泌促進作用的新穎乾眼症治療劑。The present invention provides novel agents effective in the treatment of dry eye. According to the present invention, a novel therapeutic agent for dry eye syndrome having a potent lacrimal secretion promoting action can be provided.

本發明中，4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺係下式(1)之化學構造式所示的化合物。In the present invention, 4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formamido)phenyl]amino]nicotinamide A compound represented by the chemical structural formula of formula (1).

[化1] (1) 消旋物 (1a) R配置、旋光度(+) (1b) S配置、旋光度(-) [chemical 1] (1) Racemate (1a) R configuration, optical rotation (+) (1b) S configuration, optical rotation (-)

式(1)之化合物中，其存在因不對稱碳之存在而使偏光面右旋的異構物：(+)-(R)-4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺(化合物1a)、與使偏光面左旋之異構物：(-)-(S)-4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺(化合物1b)的光學異構物。又，於1a與1b共存的情況，若1a之含量較多則成為比旋光度(+)，若1b之含量較多則成為比旋光度(-)，本發明亦包含具有此等旋光度的光學異構物的混合物。Among the compounds of formula (1), there are isomers whose polarizing plane is right-handed due to the presence of an asymmetric carbon: (+)-(R)-4-[(3,5-difluorobenzyl)amino ]-6-[[3-(piperidine-3-formamido)phenyl]amino]nicotinamide (compound 1a), and the isomer that makes the polarization plane left-handed: (-)-(S )-4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formamido)phenyl]amino]nicotinamide (compound 1b) optical isomers. In addition, when 1a and 1b coexist, if the content of 1a is large, the specific optical rotation will be (+), and if the content of 1b is large, the specific optical rotation will be (-). The present invention also includes those having such optical rotations. Mixture of optical isomers.

本發明中，所謂消旋物係意指因手性化合物之2種鏡像異構物(enantiomer)等量存在而未顯示旋光性之狀態的化合物。In the present invention, the term "racemate" refers to a compound in a state where two kinds of enantiomers (enantiomers) of a chiral compound exist in equal amounts and do not show optical activity.

本發明中，可使用化合物1(消旋物)、化合物1a(R異構物)、化合物1b(S異構物)之任一者，由淚液分泌促進作用的觀點而言，更佳為化合物1b(S異構物)。In the present invention, any of compound 1 (racemate), compound 1a (R isomer), and compound 1b (S isomer) can be used, and the compound 1b (S isomer).

作為化合物1之鹽，只要是作為醫藥所容許之鹽則無特別限制。作為化合物1之鹽可列舉酸加成鹽，可舉例如：鹽酸、氫溴酸、氫碘酸、硫酸、硝酸、磷酸等無機酸鹽；或甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、反丁烯二酸、順丁烯二酸、乳酸、蘋果酸、酒石酸、檸檬酸、甲磺酸、乙磺酸、苯磺酸、對甲苯磺酸、天冬胺酸、麩胺酸等有機酸鹽。The salt of Compound 1 is not particularly limited as long as it is a pharmaceutically acceptable salt. As the salt of compound 1, an acid addition salt can be mentioned, for example: inorganic acid salts such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; or formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, Malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid , glutamic acid and other organic acid salts.

作為化合物1之溶媒合物，可列舉：經加成水之水合物、經加成乙醇之醇合物等。Examples of the solvate of Compound 1 include hydrates to which water has been added, alcoholates to which ethanol has been added, and the like.

本發明之化合物1可藉由各種公知之方法進行製造，並無特別限制，例如，如後述實施例所記載般，可依下述反應式進行製造。Compound 1 of the present invention can be produced by various known methods and is not particularly limited. For example, as described in the examples below, it can be produced according to the following reaction formula.

[化2] [Chem 2]

[上述反應式中，X ¹及X ²表示鹵素原子，P表示胺基之保護基。] [In the above reaction formula, ^X1 and ^X2 represent a halogen atom, and P represents a protecting group for an amino group. ]

步驟1係使吡啶衍生物(2)與胺衍生物(3)反應而製造化合物(4)的步驟。吡啶衍生物(2)中之X ¹及X ²表示氟、氯、溴、碘等鹵素原子，特佳為氯。此反應可於無溶媒下進行，或者於甲醇、乙醇、或2-丙醇等醇類；二***、四氫呋喃、或1,4-二㗁烷等醚類；苯、甲苯或二甲苯等芳香族烴類；二氯甲烷、氯仿、或1,2-二氯乙烷等鹵化烴類；N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、N-甲基吡咯啶酮、乙腈、或醋酸乙酯等有機溶媒中進行，較佳係無溶媒或使用醇類作為溶媒。又，視需要可於三乙胺、三丁胺、N,N-二甲基苯胺、N,N-二異丙基乙胺、吡啶、N,N-二甲胺基吡啶等有機鹼；或碳酸鉀、碳酸鈉、碳酸氫鈉、氫氧化鈉等無機鹼的存在下進行反應。原料比率係相對於吡啶衍生物(2)1莫耳，胺衍生物(3)較佳為0.5~10莫耳、更佳為0.5~2莫耳。反應溫度較佳為0~300℃、更佳為0~150℃，反應時間較佳為1~24小時、更佳為2~6小時。 Step 1 is a step of producing compound (4) by reacting pyridine derivative (2) with amine derivative (3). ^X1 and ^X2 in the pyridine derivative (2) represent halogen atoms such as fluorine, chlorine, bromine, iodine, etc., particularly preferably chlorine. This reaction can be carried out without a solvent, or in alcohols such as methanol, ethanol, or 2-propanol; ethers such as diethyl ether, tetrahydrofuran, or 1,4-dioxane; aromatics such as benzene, toluene, or xylene. Hydrocarbons; halogenated hydrocarbons such as dichloromethane, chloroform, or 1,2-dichloroethane; N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrole Pyridone, acetonitrile, or ethyl acetate and other organic solvents, preferably no solvent or use alcohols as solvents. Also, if necessary, it can be mixed with organic bases such as triethylamine, tributylamine, N,N-dimethylaniline, N,N-diisopropylethylamine, pyridine, N,N-dimethylaminopyridine; or The reaction is carried out in the presence of inorganic bases such as potassium carbonate, sodium carbonate, sodium bicarbonate, and sodium hydroxide. The raw material ratio is preferably 0.5-10 moles, more preferably 0.5-2 moles, of the amine derivative (3) relative to 1 mole of the pyridine derivative (2). The reaction temperature is preferably 0-300°C, more preferably 0-150°C, and the reaction time is preferably 1-24 hours, more preferably 2-6 hours.

步驟2係於酸性條件下，使化合物(4)與苯胺衍生物(5)反應而製造化合物(6)的步驟。此反應可於無溶媒下進行，或者於甲醇、乙醇、或2-丙醇等醇類；二***、二苯基醚、四氫呋喃、或1,4-二㗁烷等醚類；苯、甲苯或二甲苯等芳香族烴類；二氯甲烷、氯仿、或1,2-二氯乙烷等鹵化烴類；N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、N-甲基吡咯啶酮、乙腈、或醋酸乙酯等有機溶媒中進行，較佳係使用二苯基醚等醚類作為溶媒。作為酸觸媒，可使用鹽酸、硫酸等無機酸；或甲磺酸、苯磺酸等有機酸。原料比率係相對於化合物(4)1莫耳，苯胺衍生物(5)較佳為0.5~10莫耳、更佳為0.5~3莫耳。酸係相對於化合物(4)1莫耳，較佳為0.1~10莫耳、更佳為0.5~3莫耳。反應溫度較佳為100~200℃、更佳為150~200℃，反應時間較佳為5分鐘~8小時、更佳為10分鐘~2小時。Step 2 is a step of producing compound (6) by reacting compound (4) with aniline derivative (5) under acidic conditions. This reaction can be carried out without solvent, or in alcohols such as methanol, ethanol, or 2-propanol; ethers such as diethyl ether, diphenyl ether, tetrahydrofuran, or 1,4-dioxane; benzene, toluene or Aromatic hydrocarbons such as xylene; Halogenated hydrocarbons such as dichloromethane, chloroform, or 1,2-dichloroethane; N,N-dimethylformamide, N,N-dimethylacetamide, Carry out in an organic solvent such as N-methylpyrrolidone, acetonitrile, or ethyl acetate, preferably ethers such as diphenyl ether are used as the solvent. As the acid catalyst, inorganic acids such as hydrochloric acid and sulfuric acid, or organic acids such as methanesulfonic acid and benzenesulfonic acid can be used. The raw material ratio is preferably 0.5 to 10 moles, more preferably 0.5 to 3 moles, of the aniline derivative (5) relative to 1 mole of the compound (4). The acid system is preferably 0.1 to 10 mol, more preferably 0.5 to 3 mol, relative to 1 mol of the compound (4). The reaction temperature is preferably 100-200°C, more preferably 150-200°C, and the reaction time is preferably 5 minutes-8 hours, more preferably 10 minutes-2 hours.

步驟3係使化合物(6)與哌啶衍生物(7)反應而製造化合物(8)的步驟。作為所使用之縮合試劑並無特別限制，可舉例如：N,N’-二環己基碳二亞胺(DCC)、1-乙基-3-(3’-二甲胺基丙基)碳二亞胺鹽酸鹽(WSC‧HCl)、六氟磷酸2-(7-氮雜-1H-苯并***-1-基)-1,1,3,3-四甲基脲(HATU)、1,1’-羰基二咪唑(CDI)、疊氮磷酸二苯酯(DPPA)、三氯氧磷/吡啶、三苯基膦/N-溴琥珀醯亞胺等，視情況，進一步作為添加劑，可舉例如：N-羥基琥珀醯亞胺(HONSu)、1-羥基苯并***水合物(HOBt‧H ₂O)等。本步驟所使用之縮合劑與添加劑的較佳組合，可列舉1-乙基-3-(3’-二甲胺基丙基)碳二亞胺鹽酸鹽(WSC‧HCl)與1-羥基苯并***水合物(HOBt‧H ₂O)的組合。又，為了加速反應，亦可進一步添加三乙胺、N,N-二異丙基乙胺、二氮雜雙環十一烯等之非親核鹼。所使用之溶媒並無特別限制，可舉例如：N,N-二甲基甲醯胺、四氫呋喃、二㗁烷、環戊基甲基醚、二氯甲烷、二氯乙烷等有機溶媒，較佳為N,N-二甲基甲醯胺。原料比率係相對於化合物(6)1莫耳，哌啶衍生物(7)較佳為0.5~10莫耳、更佳為0.5~3莫耳。縮合試劑之使用量係相對於化合物(6)1莫耳，較佳為0.1~10莫耳、更佳為0.5~5莫耳。反應溫度較佳為-30~150℃、更佳為0~100℃，反應時間較佳為1分鐘~48小時、更佳為30分鐘~24小時。 Step 3 is a step of producing compound (8) by reacting compound (6) with a piperidine derivative (7). The condensation reagent used is not particularly limited, and examples include: N,N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3'-dimethylaminopropyl)carbon Diimine hydrochloride (WSC‧HCl), 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate (HATU) , 1,1'-carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), phosphorus oxychloride/pyridine, triphenylphosphine/N-bromosuccinimide, etc., as the case may be, further used as additives , for example: N-hydroxysuccinimide (HONSu), 1-hydroxybenzotriazole hydrate (HOBt‧H ₂ O) and the like. The preferred combination of condensing agent and additives used in this step can include 1-ethyl-3-(3'-dimethylaminopropyl) carbodiimide hydrochloride (WSC‧HCl) and 1-hydroxy A combination of benzotriazole hydrate (HOBt‧H ₂ O). Also, in order to accelerate the reaction, a non-nucleophilic base such as triethylamine, N,N-diisopropylethylamine, diazabicycloundecene, etc. may be further added. The solvent used is not particularly limited, and examples include organic solvents such as N,N-dimethylformamide, tetrahydrofuran, dioxane, cyclopentyl methyl ether, methylene chloride, and ethylene dichloride. Preferred is N,N-dimethylformamide. The raw material ratio is preferably 0.5-10 moles, more preferably 0.5-3 moles, of the piperidine derivative (7) relative to 1 mole of the compound (6). The amount of the condensation reagent used is preferably 0.1-10 moles, more preferably 0.5-5 moles relative to 1 mole of compound (6). The reaction temperature is preferably -30~150°C, more preferably 0~100°C, and the reaction time is preferably 1 minute~48 hours, more preferably 30 minutes~24 hours.

步驟4係進行化合物(8)之胺基之脫保護反應，而製造化合物(1)的步驟。脫保護之方法及條件係視保護基P的種類而異。例如，苄基、苄氧基羰基可藉由接觸氫加成進行脫保護，第三丁氧基羰基可藉由酸進行脫保護，其方法可參考有機化學中一般所使用的方法(例如Protective Group in Organic Synthesis Third Edition, John Wiley & Sons, Inc., 1999記載之方法)而進行。Step 4 is a step of producing compound (1) by deprotecting the amino group of compound (8). The method and conditions of deprotection vary depending on the type of protecting group P. For example, benzyl and benzyloxycarbonyl can be deprotected by contacting hydrogen addition, and tertiary butoxycarbonyl can be deprotected by acid. The method can refer to the methods generally used in organic chemistry (such as Protective Group in Organic Synthesis Third Edition, John Wiley & Sons, Inc., the method recorded in 1999).

化合物1或其鹽或者該等之溶媒合物係如後述實施例所示，對正常兔及阿托平誘發乾眼症模式兔顯示優越的淚液分泌促進作用。又，對眼窩外淚腺摘出模式鼠亦顯示優越的角膜障礙抑制作用。進而，該等作用係較Diquafosol Sodium明顯優越。因此，化合物1或其鹽或者該等之溶媒合物係有效作為淚液分泌促進劑及乾眼症之預防及/或治療劑。Compound 1 or its salts or their solvates, as shown in the examples below, exhibited superior lacrimal secretion-promoting effects on normal rabbits and atropine-induced dry eye model rabbits. In addition, it also exhibits superior corneal dysfunction inhibitory effect on extraorbital lacrimal gland extraction model mice. Furthermore, these effects are significantly superior to Diquafosol Sodium. Therefore, Compound 1 or its salts or their solvates are effective as a lacrimal secretion enhancer and a preventive and/or therapeutic agent for dry eye.

本發明中，所謂「乾眼症」係包括乾性角結膜炎，且亦包括淚液分泌減少型及淚液蒸發亢進型之任一類型的乾眼症。淚液分泌減少型乾眼症係分類為薛格連氏症候群所伴隨之乾眼症與非薛格連氏症候群型之乾眼症。非薛格連氏症候群型之乾眼症可列舉：先天性無淚腺症、類肉瘤病、因骨髓移植等所造成之移植物抗宿主疾病等淚腺疾病所伴隨者；以眼的類天皰瘡、史蒂芬-強森症候群、沙眼等為原因之淚器閉塞所伴隨者；以糖尿病、角膜屈光矯正手術等為原因之反射性分泌低下所伴隨者等。又，淚液蒸發亢進型乾眼症可列舉：以瞼板腺機能不全、眼瞼炎等為原因之油層減少所伴隨者；以眼球突出、兔眼等為原因之瞬目不全或閉瞼不全所伴隨者；因隱形眼鏡配戴所造成之淚液穩定性降低所伴隨者；來自胚細胞之黏蛋白分泌降低所伴隨者；因VDT作業所伴隨者等。In the present invention, the so-called "dry eye" includes keratoconjunctivitis sicca, and also includes any type of dry eye of the decreased tear secretion type and the increased tear evaporation type. Dry eye with reduced tear secretion is classified into dry eye associated with Sjögren's syndrome and dry eye without Sjögren's syndrome. Examples of non-Sjögren syndrome dry eye include: congenital anolacrimal gland disease, sarcoid disease, graft-versus-host disease caused by bone marrow transplantation, etc. accompanied by lacrimal gland diseases; pemphigoid of the eye, Stephen - Those who are accompanied by lacrimal organ occlusion caused by Johnson's syndrome, trachoma, etc.; those who are accompanied by low reflex secretion caused by diabetes, corneal refractive surgery, etc. In addition, hypertear evaporative dry eye syndrome includes: those accompanied by reduction of oil layer caused by meibomian gland insufficiency, blepharitis, etc.; those accompanied by decreased tear stability caused by wearing contact lenses; those accompanied by decreased mucin secretion from germ cells; those accompanied by VDT operations, etc.

本發明之醫藥組成物係含有化合物1、其鹽或者該等之溶媒合物者，其可單獨使用，但通常係調配醫藥所容許之載體、添加物等而使用。醫藥組成物之投予形態並無特別限定，可配合治療目的而適當選擇。例如，可為經口劑、注射劑、栓劑、軟膏劑、吸入劑、點眼劑、點鼻劑、貼附劑等任一種。適合此等投予形態之醫藥組成物可藉由公知之製劑方法進行製造。The pharmaceutical composition of the present invention contains Compound 1, its salt, or its solvate, and it can be used alone, but it is usually used by mixing pharmaceutically acceptable carriers, additives, and the like. The administration form of the pharmaceutical composition is not particularly limited, and can be appropriately selected according to the purpose of treatment. For example, any of oral preparations, injections, suppositories, ointments, inhalants, eye drops, nasal drops, and patches can be used. Pharmaceutical compositions suitable for such administration forms can be produced by known formulation methods.

於調製經口用固形製劑時，可對化合物1添加賦形劑、進而視需要之結合劑、崩解劑、潤滑劑、著色劑、矯味劑、矯臭劑等後，藉由常法製造錠劑、被覆錠劑、顆粒劑、散劑、膠囊劑等。添加劑可為該領域中一般所使用者。例如，作為賦予劑，可列舉：乳糖、白糖、氯化鈉、葡萄糖、澱粉、碳酸鈣、高嶺土、微晶纖維素、矽酸等。作為結合劑，可列舉：水、乙醇、丙醇、單糖漿、葡萄糖液、澱粉液、明膠液、羧甲基纖維素、羥丙基纖維素、羥丙基澱粉、甲基纖維素、乙基纖維素、蟲膠、磷酸鈣、聚乙烯吡咯啶酮等。作為崩解劑，可列舉：乾燥澱粉、海藻酸鈉、寒天粉末、碳酸氫鈉、碳酸鈣、月桂基硫酸鈉、硬脂酸單甘油酯、乳酸等。作為潤滑劑，可列舉：精製滑石、硬脂酸鹽、硼砂、聚乙二醇等。作為矯味劑，可列舉：白糖、橙皮、檸檬酸、酒石酸等。When preparing oral solid preparations, excipients, and optionally binders, disintegrants, lubricants, coloring agents, flavoring agents, and odorants can be added to compound 1, and tablets can be produced by conventional methods , coated tablets, granules, powders, capsules, etc. The additives may be those generally used in this field. For example, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid etc. are mentioned as an imparting agent. Examples of binders include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl Cellulose, shellac, calcium phosphate, polyvinylpyrrolidone, etc. Examples of the disintegrant include dry starch, sodium alginate, agarose powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceryl stearate, and lactic acid. As a lubricant, purified talc, stearate, borax, polyethylene glycol, etc. are mentioned. As a flavoring agent, sugar, orange peel, citric acid, tartaric acid, etc. are mentioned.

於調製經口用液體製劑時，可對化合物1添加矯味劑、緩衝劑、穩定化劑、矯臭劑等，並藉由常法製造內服液劑、糖漿劑、酏劑等。作為矯味劑可為上述所列舉者，作為緩衝劑可列舉檸檬酸鈉等，作為穩定化劑可列舉：龍膠、***膠、明膠等。When preparing oral liquid preparations, flavoring agents, buffers, stabilizers, odorants, etc. may be added to Compound 1, and oral liquids, syrups, elixirs, etc. may be produced by conventional methods. As the flavoring agent, those listed above can be used. As the buffering agent, sodium citrate and the like can be mentioned. As the stabilizing agent, dragon gum, gum arabic, gelatin and the like can be mentioned.

於調製注射劑時，可對化合物1添加pH調節劑、緩衝劑、穩定化劑、等張化劑、局部麻醉劑等，並藉由常法製造皮下、肌肉及靜脈內注射劑。作為pH調節劑及緩衝劑可列舉：檸檬酸鈉、乙酸鈉、磷酸鈉等。作為穩定化劑可列舉：焦亞硫酸鈉、乙二胺四乙酸鈉、巰乙酸、硫代乳酸等。作為局部麻醉劑可列舉：普羅卡因鹽酸鹽、利多卡因鹽酸鹽等。作為等張化劑可列舉：氯化鈉、葡萄糖等。When preparing injections, compound 1 can be added with pH regulators, buffers, stabilizers, isotonic agents, local anesthetics, etc., and subcutaneous, intramuscular and intravenous injections can be produced by conventional methods. As a pH adjuster and a buffering agent, sodium citrate, sodium acetate, sodium phosphate, etc. are mentioned. Examples of the stabilizer include sodium metabisulfite, sodium edetate, thioglycolic acid, and thiolactic acid. Examples of the local anesthetic include procaine hydrochloride, lidocaine hydrochloride, and the like. As an isotonic agent, sodium chloride, glucose, etc. are mentioned.

於調製栓劑時，可對化合物1添加公知之栓劑用載體，例如：聚乙二醇、羊毛脂、可可脂、脂肪酸三甘油酯等、進而視需要之Tween(註冊商標)等界面活性劑等後，藉由常法進行製造。When preparing suppositories, known suppository carriers can be added to compound 1, such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglycerides, etc., and if necessary, surfactants such as Tween (registered trademark), etc. , manufactured by conventional methods.

點眼劑可為水性點眼劑、非水性點眼劑、懸浮性點眼劑、乳濁性點眼劑、眼軟膏等任一種。此種製劑係作為適合投予形態的組成物，可視需要調配藥學上所容許之載體，例如：等張化劑、鉗合劑、穩定化劑、pH調節劑、防腐劑、抗氧化劑、助溶劑、黏稠化劑等，並藉由從業者公知之(製劑)方法進行製造。於調製點眼劑時，例如，可將所需之上述成分溶解或懸浮於滅菌精製水、生理食鹽水等水性溶劑；或棉籽油、大豆油、芝麻油、花生油等植物油等非水性溶劑中，調整為既定滲透壓，藉由施行過濾滅菌等滅菌處理而進行。又，於調製眼軟膏劑時，除了上述各種成分之外，可含有軟膏基劑。作為上述軟膏基劑並無特別限定，較佳可列舉：凡士林、流動石蠟、聚乙烯等油性基劑；使油相與水相藉由界面活性劑等經乳化的乳劑性基劑；包含羥丙基甲基纖維素、羧甲基纖維素、聚乙二醇等的水溶性基劑等。The eye drops may be any of aqueous eye drops, non-aqueous eye drops, suspension eye drops, emulsified eye drops, ophthalmic ointments, and the like. This preparation is a composition suitable for administration, and pharmaceutically acceptable carriers can be formulated as needed, such as isotonic agents, chelating agents, stabilizers, pH regulators, preservatives, antioxidants, solubilizers, Viscosifiers and the like are produced by a (preparation) method known to practitioners. When preparing eye drops, for example, the required above-mentioned ingredients can be dissolved or suspended in aqueous solvents such as sterilized purified water and physiological saline; or in non-aqueous solvents such as cottonseed oil, soybean oil, sesame oil, peanut oil and other vegetable oils, and adjust The predetermined osmotic pressure is carried out by performing sterilization treatment such as filtration sterilization. Moreover, when preparing an ophthalmic ointment, an ointment base may be contained in addition to the above-mentioned various components. The above-mentioned ointment base is not particularly limited, and preferred examples include: oily bases such as petrolatum, liquid paraffin, polyethylene, etc.; emulsion bases in which the oil phase and the water phase are emulsified by surfactants, etc.; Water-soluble bases such as methyl cellulose, carboxymethyl cellulose, polyethylene glycol, etc.

又，亦可使用作為眼內植入用製劑。眼內植入用製劑可使用生物降解性聚合物，例如：聚乳酸、聚乙醇酸、乳酸/乙醇酸共聚合體、羥丙基纖維素等生物降解性聚合物而調製。In addition, it can also be used as a preparation for intraocular implantation. Preparations for intraocular implantation can be prepared using biodegradable polymers such as polylactic acid, polyglycolic acid, lactic acid/glycolic acid copolymer, hydroxypropyl cellulose and other biodegradable polymers.

在將化合物1或其鹽或者該等之溶媒合物用於乾眼症之預防或治療時，於選擇點眼劑或眼軟膏作為劑形的情況，可依1日1~10次、較佳為1日1~8次、更佳為1日2~6次投予至眼局部。其投予量係視患者之體重、年齡、性別、症狀、投予形態及投予次數等而異，通常對於成人，以化合物1計，可列舉：1日0.025~10000μg、較佳為0.025~2000μg、更佳為0.1~2000μg的範圍。 [實施例] When using Compound 1 or its salt or the solvate thereof for the prevention or treatment of dry eye, in the case of eye drops or eye ointment as the dosage form, it can be administered 1 to 10 times a day, preferably 1 to 10 times a day. 1-8 times a day, more preferably 2-6 times a day to the local eye. The dose varies depending on the patient's weight, age, gender, symptoms, form of administration, and frequency of administration. Usually, for adults, the compound 1 includes: 0.025 to 10,000 μg per day, preferably 0.025 to 10,000 μg per day. 2000 μg, more preferably in the range of 0.1 to 2000 μg. [Example]

以下，藉由實施例更詳細說明本發明，但此等實施例並非限制本發明。又，化合物之光學純度係由HPLC決定。又，化合物之比旋光度係依下述條件進行測定。 ＜HPLC條件＞ 檢測器：紫外吸光光度計(測定波長：254nm) 管柱：CHIRALPAK IE(Daicel) 內徑4.6mm、長150mm、粒徑5μm 管柱溫度：40℃ 移動相：於甲醇中0.1%異丙胺 流量：1.0mL/min 注入量：5μL 試料：0.5mg/mL(藉由甲醇稀釋) ＜比旋光度＞ 旋光計：日本分光股份有限公司 P-2200。 比旋光度[α]20D(20℃，鈉之D射線589nm)。 Hereinafter, the present invention will be described in detail by means of examples, but these examples do not limit the present invention. Also, the optical purity of the compounds was determined by HPLC. In addition, the specific rotation of the compound was measured under the following conditions. <HPLC conditions> Detector: UV absorbance photometer (measurement wavelength: 254nm) Column: CHIRALPAK IE (Daicel) Inner diameter 4.6mm, length 150mm, particle size 5μm Column temperature: 40°C Mobile phase: 0.1% isopropylamine in methanol Flow: 1.0mL/min Injection volume: 5μL Sample: 0.5mg/mL (diluted by methanol) ＜Specific rotation＞ Polarimeter: JASCO Co., Ltd. P-2200. Specific rotation [α] 20D (20°C, sodium D-ray 589nm).

[實施例1] 4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺(化合物1)之製造 (步驟1)6-氯-4-[(3,5-二氟苄基)胺基]菸鹼醯胺之製造 [Example 1] 4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formamido)phenyl]amino]nicotinamide ( Compound 1) Manufacture (Step 1) Production of 6-chloro-4-[(3,5-difluorobenzyl)amino]nicotinamide

[化3] [Chem 3]

將根據US2006/0217417公報記載之方法所合成的4,6-二氯吡啶-3-甲醯胺28.7g溶解於乙醇130mL，加入3,5-二氟苄基胺22.8g與N,N-二異丙基乙胺52.4mL，於80℃加熱回流24小時。冷卻至室溫後，加入水，濾取析出結晶，以水及己烷洗淨，並風乾，藉此得到白色結晶之6-氯- 4-[(3,5-二氟苄基)胺基]菸鹼醯胺38.9g(87%)。Dissolve 28.7 g of 4,6-dichloropyridine-3-carboxamide synthesized by the method described in US2006/0217417 in 130 mL of ethanol, add 22.8 g of 3,5-difluorobenzylamine and N,N-difluorobenzylamine 52.4 mL of isopropylethylamine was heated to reflux at 80°C for 24 hours. After cooling to room temperature, water was added, the precipitated crystals were collected by filtration, washed with water and hexane, and air-dried to obtain 6-chloro-4-[(3,5-difluorobenzyl)amino as white crystals ] Nicotinamide 38.9g (87%).

1H-NMR(400MHz, CDCl3)δ: 4.43 (2H, d, J = 5.8 Hz), 5.86 (2H, br), 6.42 (1H, s), 6.75 (1H, dddd, J = 7.7,.7.7, 2.3, 2.3 Hz), 6.80-6.87 (1H, m), 8.32 (1H, s), 9.02 (1H, br).1H-NMR(400MHz, CDCl3)δ: 4.43 (2H, d, J = 5.8 Hz), 5.86 (2H, br), 6.42 (1H, s), 6.75 (1H, dddd, J = 7.7, .7.7, 2.3 , 2.3 Hz), 6.80-6.87 (1H, m), 8.32 (1H, s), 9.02 (1H, br).

(步驟2)6-[(3-胺基苯基)胺基]-4-[(3,5-二氟苄基)胺基]菸鹼醯胺之製造(Step 2) Production of 6-[(3-aminophenyl)amino]-4-[(3,5-difluorobenzyl)amino]nicotinamide

[化4] [chemical 4]

將步驟1所得6-氯-4-[(3,5-二氟苄基)胺基]菸鹼醯胺(12.0g)、1,3-苯二胺(10.9g)及氯化1-丁基-3-甲基-1H-3-咪唑鎓(14.1g)加入至二苯基醚(6.9g)。於此混合物中添加甲磺酸(7.85mL)後，於170℃之浴內攪拌30分鐘。放冷後，將反應混合物以庚烷洗淨3次，於殘渣中加入7N氨-甲醇(35mL)。將析出物碎解後，於混合物中添加氯仿(20mL)、水(20mL)及飽和碳酸氫鈉水溶液(10mL)，並攪拌混合物。藉由將所析出之結晶進行濾取及乾燥，得到6-[(3-胺基苯基)胺基]-4-[(3,5-二氟苄基)胺基]菸鹼醯胺14.6g(98%)。6-chloro-4-[(3,5-difluorobenzyl)amino]nicotinamide (12.0g), 1,3-phenylenediamine (10.9g) and 1-butyl chloride obtained in step 1 Diphenyl-3-methyl-1H-3-imidazolium (14.1 g) was added to diphenyl ether (6.9 g). After adding methanesulfonic acid (7.85 mL) to this mixture, it stirred in the bath of 170 degreeC for 30 minutes. After standing to cool, the reaction mixture was washed three times with heptane, and 7N ammonia-methanol (35 mL) was added to the residue. After the precipitate was decomposed, chloroform (20 mL), water (20 mL) and saturated aqueous sodium bicarbonate solution (10 mL) were added to the mixture, and the mixture was stirred. By filtering and drying the precipitated crystals, 6-[(3-aminophenyl)amino]-4-[(3,5-difluorobenzyl)amino]nicotinamide 14.6 g (98%).

1H-NMR (DMSO-d6) δ：9.03 (t, 1 H), 8.57 (s, 1 H), 8.36 (s, 1 H), 7.77 (br., 2 H), 7.12 (tt, 1 H), 7.00 (br d, 2 H), 6.80 (t, 1 H), 6.73 (s, 1 H), 6.50 (d, 1 H), 6.12 (d, 1 H), 5 80 (s, 1 H), 4.91 (s, 2 H), 4.41 (d, 2 H).1H-NMR (DMSO-d6) δ: 9.03 (t, 1 H), 8.57 (s, 1 H), 8.36 (s, 1 H), 7.77 (br., 2 H), 7.12 (tt, 1 H) , 7.00 (br d, 2 H), 6.80 (t, 1 H), 6.73 (s, 1 H), 6.50 (d, 1 H), 6.12 (d, 1 H), 5 80 (s, 1 H) , 4.91 (s, 2 H), 4.41 (d, 2 H).

(步驟3) 第三丁基3-[[3-[[5-胺甲醯基-4-[(3,5-二氟苄基)胺基]吡啶-2-基]胺基]苯基]胺甲醯基]哌啶-1-羧酸酯之製造(Step 3) tert-butyl 3-[[3-[[5-aminoformyl-4-[(3,5-difluorobenzyl)amino]pyridin-2-yl]amino]phenyl Production of ]carbamoyl]piperidine-1-carboxylate

[化5] [chemical 5]

將步驟2所得6-[(3-胺基苯基)胺基]-4-[(3,5-二氟苄基)胺基]菸鹼醯胺(1.00g)及N-(第三丁氧基羰基)哌啶-3-羧酸(0.93g)溶解於N,N-二甲基甲醯胺(4.5mL)。於冰浴內經攪拌之此溶液中添加N,N-二異丙基乙胺(1.18mL)、1-羥基苯并***水合物(0.83g)及1-乙基-3-(3’-二甲胺基丙基)碳二亞胺鹽酸鹽(0.83g)。移除冰浴後，將混合物於室溫攪拌12小時。加入醋酸乙酯(20mL)及水(10mL)，攪拌混合物後，分離為有機層與水層。將水層以醋酸乙酯(15mL)萃取2次。合併有機層，以水、飽和碳酸氫鈉水溶液及飽和食鹽水洗淨，以無水硫酸鈉乾燥後，進行減壓濃縮。將殘渣以矽膠管柱層析法(甲醇-二氯甲烷)進行精製，並將所得餾分(fraction)由醋酸乙酯及庚烷進行結晶化，藉此得到第三丁基3-[[3-[[5-胺甲醯基-4-[(3,5-二氟苄基)胺基]吡啶-2-基]胺基]苯基]胺甲醯基]哌啶-1-羧酸酯1.22g(78%)。6-[(3-aminophenyl)amino]-4-[(3,5-difluorobenzyl)amino]nicotinamide (1.00g) and N-(tert-butyl Oxycarbonyl)piperidine-3-carboxylic acid (0.93 g) was dissolved in N,N-dimethylformamide (4.5 mL). To this stirred solution in an ice bath were added N,N-diisopropylethylamine (1.18 mL), 1-hydroxybenzotriazole hydrate (0.83 g) and 1-ethyl-3-(3'- Dimethylaminopropyl)carbodiimide hydrochloride (0.83g). After removing the ice bath, the mixture was stirred at room temperature for 12 hours. Ethyl acetate (20 mL) and water (10 mL) were added, and the mixture was stirred and separated into an organic layer and an aqueous layer. The aqueous layer was extracted twice with ethyl acetate (15 mL). The organic layers were combined, washed with water, saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol-dichloromethane), and the resulting fraction was crystallized from ethyl acetate and heptane to obtain tert-butyl 3-[[3- [[5-Aminoformyl-4-[(3,5-difluorobenzyl)amino]pyridin-2-yl]amino]phenyl]carbamoyl]piperidine-1-carboxylate 1.22g (78%).

(步驟4) 4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺之製造(Step 4) Production of 4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-carboxamido)phenyl]amino]nicotinamide

[化6] [chemical 6]

將步驟3所得第三丁基3-[[3-[[5-胺甲醯基-4-[(3,5-二氟苄基)胺基]吡啶-2-基]胺基]苯基]胺甲醯基]哌啶-1-羧酸酯(1.22g)溶解於二氯甲烷(6.7mL)。於此溶液中添加三氟乙酸(1.62mL)，於室溫攪拌12小時。將反應混合物減壓濃縮，於殘渣中添加甲醇後，再次減壓濃縮。將殘渣以矽膠管柱層析法(甲醇-二氯甲烷、氨-甲醇-二氯甲烷)進行精製，將所得固體(607mg)由乙醇及水進行結晶化，藉此得到4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺362mg(36%)。The third butyl 3-[[3-[[5-aminoformyl-4-[(3,5-difluorobenzyl)amino]pyridin-2-yl]amino]phenyl obtained in step 3 ]carbamoyl]piperidine-1-carboxylate (1.22 g) was dissolved in dichloromethane (6.7 mL). Trifluoroacetic acid (1.62 mL) was added to this solution, followed by stirring at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, methanol was added to the residue, and then concentrated under reduced pressure again. The residue was purified by silica gel column chromatography (methanol-dichloromethane, ammonia-methanol-dichloromethane), and the resulting solid (607 mg) was crystallized from ethanol and water to obtain 4-[(3, 5-difluorobenzyl)amino]-6-[[3-(piperidin-3-carboxamido)phenyl]amino]nicotinamide 362 mg (36%).

1H-NMR (DMSO-d6) δ：9.88 (s, 1 H), 9.05 (t, 1 H), 8.86 (s, 1 H), 8.39 (s, 1 H), 7.83 (br s, 2 H), 6.95-7.20 (m, 7 H), 5.86 (s, 1 H), 4.44 (d, 2 H), 3.00 (m, 1 H), 2.83 (m, 1 H), 2.40-2.65 (m, 3 H), 2.15 (br s, 1 H), 1.84 (m, 1 H), 1.59 (m, 2 H), 1.35 (m, 1 H).1H-NMR (DMSO-d6) δ: 9.88 (s, 1 H), 9.05 (t, 1 H), 8.86 (s, 1 H), 8.39 (s, 1 H), 7.83 (br s, 2 H) , 6.95-7.20 (m, 7 H), 5.86 (s, 1 H), 4.44 (d, 2 H), 3.00 (m, 1 H), 2.83 (m, 1 H), 2.40-2.65 (m, 3 H), 2.15 (br s, 1 H), 1.84 (m, 1 H), 1.59 (m, 2 H), 1.35 (m, 1 H).

[實施例2] (R)-4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺(1a)之製造 於實施例1之步驟3中，將N-(第三丁氧基羰基)哌啶-3-羧酸改變為(R)-N-(第三丁氧基羰基)哌啶-3-羧酸，並應用相同之操作，藉此得到(R)-4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺。 [Example 2] (R)-4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formamido)phenyl]amino]nicotine Production of basic amides (1a) In step 3 of Example 1, change N-(tertiary butoxycarbonyl)piperidine-3-carboxylic acid to (R)-N-(tertiary butoxycarbonyl)piperidine-3-carboxylic acid , and apply the same operation, thereby obtaining (R)-4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formamido)phenyl ]amino]nicotinamide.

[化7] [chemical 7]

光學純度：98.5%ee 比旋光度[α] ²⁰ _D：+14.4 Optical purity: 98.5%ee Specific rotation [α] ²⁰ _D : +14.4

[實施例3] (S)-4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺(1b)之製造 於實施例1之步驟3中，將N-(第三丁氧基羰基)哌啶-3-羧酸改變為(S)-N-(第三丁氧基羰基)哌啶-3-羧酸，並應用相同之操作，藉此得到(S)-4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺。 [Example 3] (S)-4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formamido)phenyl]amino]nicotine Production of basic amides (1b) In step 3 of Example 1, change N-(tertiary butoxycarbonyl)piperidine-3-carboxylic acid to (S)-N-(tertiary butoxycarbonyl)piperidine-3-carboxylic acid , and apply the same operation, thereby obtaining (S)-4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formamido)phenyl ]amino]nicotinamide.

[化8] [chemical 8]

光學純度：98.8%ee 比旋光度[α] ²⁰ _D：-14.3 Optical purity: 98.8%ee Specific rotation [α] ²⁰ _D : -14.3

[試驗例1]  對於使用正兔常之淚液分泌的效果 1. 被試驗化合物溶液之調製 A. 化合物1溶液之調製 將既定量之化合物1溶解於生理食鹽水，依pH成為5.5之方式藉由HCl或NaOH進行調整，調製所需濃度之化合物1溶液。 B. Diquafosol Sodium溶液之調製 Diquafosol Sodium溶液係使用Diquas(註冊商標)點眼液3%(參天製藥股份有限公司)。 [Experiment 1] For the effect of normal rabbit tear secretion 1. Preparation of test compound solution A. Preparation of compound 1 solution A predetermined amount of Compound 1 was dissolved in physiological saline, and adjusted with HCl or NaOH in such a way that the pH became 5.5, to prepare a Compound 1 solution with a desired concentration. B. Preparation of Diquafosol Sodium Solution Diquafosol Sodium solution system uses Diquas (registered trademark) eye drops 3% (Shentian Pharmaceutical Co., Ltd.).

2. 試驗方法 A. 試驗所使用之藥劑及動物 化合物1溶液：0.001%溶液、0.01%溶液(點眼量：50μL) Diquafosol Sodium溶液：3%溶液(點眼量：50μL) 實驗動物：JW系白色兔(性別：體重約2kg，雄性，一群3~4隻) B：淚液之測定、點眼及評價方法 在正常JW系雄性白色兔之下眼瞼***淚液測試(Schirmer tear)紙並計測5分鐘內濕潤的長度。將0.001%、0.01%之化合物1溶液、或3% Diquafosol Sodium溶液50μL進行點眼，於點眼1小時後再次在下眼瞼***淚液測試紙並計測5分鐘內濕潤的長度。點眼及評價係於兩眼實施，將各眼數據視為1例處理。所得數值係以點眼前為100%進行換算，依相對於點眼前之淚液增加率之形式表示。統計分析係依司徒頓t檢定(Student's t-test)進行。 2. Test method A. Drugs and animals used in the test Compound 1 solution: 0.001% solution, 0.01% solution (eye volume: 50 μL) Diquafosol Sodium solution: 3% solution (eye volume: 50μL) Experimental animal: JW white rabbit (gender: weight about 2kg, male, a group of 3~4 rabbits) B: Determination of tears, instillation and evaluation methods A Schirmer tear paper was inserted into the lower eyelid of normal JW male white rabbits and the length of wetting within 5 minutes was measured. 0.001%, 0.01% Compound 1 solution, or 50 μL of 3% Diquafosol Sodium solution was instilled into the eye, and 1 hour after the eye was instilled, the tear test paper was inserted into the lower eyelid again and the wet length was measured within 5 minutes. Eye dotting and evaluation were carried out on both eyes, and the data of each eye was treated as one case. The obtained value is converted based on 100% in front of the point, and expressed in the form of the increase rate of tears relative to the point in front of the point. Statistical analysis was performed by Student's t-test.

3. 結果及考察 圖3表示經被試驗化合物溶液點眼1小時後相對於點眼前之淚液增加率。化合物1溶液之0.001%及0.01%、以及3% Diquafosol Sodium溶液分別顯示131%、168%及169%之淚液增加率，相較於點眼前， 0.01%以上之濃度之化合物1溶液及3% Diquafosol Sodium溶液確認到有顯著性差異。 3. Results and investigation Fig. 3 shows the rate of increase of tear fluid relative to the eye of the eye after 1 hour of instillation of the test compound solution. 0.001% and 0.01% of compound 1 solution, and 3% Diquafosol Sodium solution showed 131%, 168% and 169% tear increase rate, respectively, compared with 0.01% concentration of compound 1 solution and 3% Diquafosol A significant difference was confirmed for the Sodium solution.

[試驗例2]  消旋物及光學異構物對於使用正兔常之淚液分泌的效果比較消旋物與光學異構物1a及1b對淚液分必的效果。[Test Example 2] The effect of racemate and optical isomer on tear secretion in normal rabbits was compared to the effect of racemate and optical isomer 1a and 1b on tear secretion.

1. 被試驗化合物溶液之調製 A. 化合物1a溶液之調製 將既定量之化合物1a溶解於生理食鹽水，依pH成為5.5之方式藉由HCl或NaOH進行調整，調製所需濃度之化合物1a溶液。 B. 化合物1b溶液之調製 將既定量之化合物1b溶解於生理食鹽水，依pH成為5.5之方式藉由HCl或NaOH進行調整，調製所需濃度之化合物1b溶液。 1. Preparation of test compound solution A. Preparation of compound 1a solution A predetermined amount of compound 1a was dissolved in physiological saline, adjusted with HCl or NaOH so that the pH became 5.5, and a compound 1a solution with a desired concentration was prepared. B. Preparation of compound 1b solution A predetermined amount of compound 1b was dissolved in physiological saline, and adjusted with HCl or NaOH in such a way that the pH became 5.5 to prepare a compound 1b solution with a desired concentration.

2. 試驗方法 A. 試驗所使用之藥劑及動物 消旋物溶液：0.003%溶液(點眼量：50μL) 化合物1a溶液：0.003%溶液(點眼量：50μL) 化合物1b溶液：0.003%溶液(點眼量：50μL) 實驗動物：JW系白色兔(性別：體重約2kg，雄性，一群8隻) 2. Test method A. Drugs and animals used in the test Racemate solution: 0.003% solution (injection volume: 50μL) Compound 1a solution: 0.003% solution (eye volume: 50 μL) Compound 1b solution: 0.003% solution (eye volume: 50 μL) Experimental animals: JW white rabbits (gender: weighing about 2kg, male, a group of 8)

B：淚液之測定、點眼及評價方法 在正常JW系雄性白色兔之下眼瞼***淚液測試紙並計測5分鐘內濕潤的長度。將0.003%消旋物溶液、化合物1a溶液或化合物1b溶液50μL進行點眼，於點眼1小時後再次在下眼瞼***淚液測試紙並計測5分鐘內濕潤的長度。點眼及評價係於兩眼實施，將各眼數據視為1例處理。所得數值係以點眼前為100%進行換算，依相對於點眼前之淚液增加率之方式表示。統計分析係依司徒頓t檢定進行。 B: Determination of tears, instillation and evaluation methods Insert tear test paper into the lower eyelid of normal JW male white rabbits and measure the length of wetting within 5 minutes. 50 μL of 0.003% racemate solution, compound 1a solution or compound 1b solution was instilled into the eye, and 1 hour after the eye was instilled, the tear test paper was inserted into the lower eyelid again and the length of wetting within 5 minutes was measured. Eye dotting and evaluation were carried out on both eyes, and the data of each eye was treated as one case. The obtained value is converted based on 100% in front of the point, and expressed in terms of the increase rate of tears relative to the point in front of the point. Statistical analysis was performed by Stuton's t test.

3. 結果及考察 圖4表示經被試驗化合物溶液點眼1小時後相對於點眼前之淚液增加率。消旋物溶液0.003%、化合物1a溶液及化合物1b溶液分別顯示129%、124%及143%之淚液增加率，相較於點眼前確認到有顯著性差異。另一方面，相對於點眼前，化合物1b溶液之淚液增加率較化合物1a溶液高。 3. Results and investigation Fig. 4 shows the rate of increase of tear fluid relative to the eyes of the eyes 1 hour after the test compound solution was instilled. The racemate solution 0.003%, the compound 1a solution and the compound 1b solution showed 129%, 124% and 143% tear fluid increase rate, respectively, and a significant difference was confirmed compared to the point before the spot. On the other hand, relative to the eye point, the increase rate of tear fluid of the compound 1b solution is higher than that of the compound 1a solution.

[試驗例3]  對於使用阿托平誘發乾眼症模式兔之淚液分泌的效果 使用已報告為乾眼症模式之阿托平誘發乾眼症模式(Acta Pharm. 58;163-173(2008))，檢討經被試驗化合物溶液點眼時之淚液分泌增加作用。 [Test Example 3] The effect of using atropine to induce tear secretion in rabbits with dry eye syndrome Using the atropine-induced dry eye model (Acta Pharm. 58; 163-173 (2008)), which has been reported as a dry eye model, the effect of increasing tear secretion when the test compound solution was instilled was examined.

1.試驗方法 A. 試驗所使用之藥劑及動物 消旋物溶液：0.003%溶液(點眼量：50μL) 化合物1a溶液：0.003%溶液(點眼量：50μL) 化合物1b溶液：0.003%溶液(點眼量：50μL) Diquafosol Sodium溶液：3%溶液(點眼量：50μL) 實驗動物：JW系白色兔(性別：體重約2kg，雄性，一群3~4隻) 1. Test method A. Drugs and animals used in the test Racemate solution: 0.003% solution (injection volume: 50μL) Compound 1a solution: 0.003% solution (eye volume: 50 μL) Compound 1b solution: 0.003% solution (eye volume: 50 μL) Diquafosol Sodium solution: 3% solution (eye volume: 50μL) Experimental animal: JW white rabbit (gender: weight about 2kg, male, a group of 3~4 rabbits)

B：淚液之測定、點眼及評價方法 對正常JW系雄性白色兔依1日3次、共7日進行0.1%硫酸阿托品50μL點眼，使用淚液測試紙計測5分鐘內濕潤的長度。接著，將0.1%硫酸阿托品依1日3次、以及生理食鹽水(控制組)、0.01%消旋物溶液、化合物1a溶液或化合物1b溶液、或者3%Diquafosol Sodium溶液依1日4次，每次50μL、共10日進行點眼，於最終點眼1小時後，使用淚液測試紙計測5分鐘內濕潤的長度。點眼及評價係於兩眼實施，將各眼數據視為1例處理。所得數值係以被試驗化合物溶液點眼前為100%進行換算，依淚液增加率之方式表示。統計分析係依司徒頓t檢定進行。 B: Determination of tears, instillation and evaluation methods Normal JW male white rabbits were instilled with 50 μL of 0.1% atropine sulfate three times a day for 7 days, and the tear test paper was used to measure the length of wetting within 5 minutes. Then, 0.1% atropine sulfate was given 3 times a day, and normal saline (control group), 0.01% racemate solution, compound 1a solution or compound 1b solution, or 3% Diquafosol Sodium solution was given 4 times a day. Instill 50 μL each time for 10 days, and measure the length of wetting within 5 minutes using tear test paper 1 hour after the final eye instillation. Eye dotting and evaluation were carried out on both eyes, and the data of each eye was treated as one case. The obtained value is converted by taking the test compound solution in front of the eye as 100%, and expressed in the form of tear fluid increase rate. Statistical analysis was performed by Stuton's t test.

2. 結果及考察 圖5表示經被試驗化合物溶液點眼1小時後相對於點眼前之淚液增加率。控制組、0.01%消旋物溶液、化合物1a溶液及化合物1b溶液分別顯示86%、151%、157%及145%之淚液增加率，相較於控制組確認到有顯著性差異。另一方面，3%Diquafosol Sodium溶液雖確認到134%之淚液增加，但並未確認到有顯著性差異。 2. Results and investigation Fig. 5 shows the rate of increase of tear fluid relative to the eye of the eye after 1 hour of instillation of the test compound solution. The control group, 0.01% racemate solution, compound 1a solution and compound 1b solution showed 86%, 151%, 157% and 145% tear increase rate respectively, and a significant difference was confirmed compared with the control group. On the other hand, the 3% Diquafosol Sodium solution was confirmed to increase tear fluid by 134%, but no significant difference was confirmed.

[試驗例4]  對於使用眼窩外淚腺摘出模式鼠之角膜上皮障礙的效果 使用已報告為乾眼症模式之眼窩外淚腺摘出模式鼠，檢討經被試驗化合物溶液點眼時之角膜上皮障礙抑制作用。 [Experiment 4] The effect on corneal epithelial disorder using extraorbital lacrimal gland extraction model mice Using the extraorbital lacrimal gland enucleation model mouse which has been reported as a dry eye model, the corneal epithelial disorder inhibitory effect of the test compound solution was examined.

1.試驗方法 A. 試驗所使用之藥劑及動物 化合物1溶液：0.003%溶液、0.01%溶液(點眼量：5μL) Diquafosol Sodium溶液： 3%溶液(點眼量：5μL) 實驗動物：SD系鼠(性別：6週齡，雄性，一群5隻) B：淚液之測定、點眼及評價方法 SD系雄性鼠係於藉由戊巴比妥鈉40mg/kg及甲苯噻嗪(xylazine)10mg/kg之腹腔內投予進行的麻醉下，摘除兩側之眼窩外淚腺。由摘除隔日起，將生理食鹽水(控制組)、0.003%或0.01%濃度之化合物1溶液、或者3%Diquafosol Sodium溶液依1日6次，每次5μL、共11日進行點眼，於最終點眼24小時後，於藉由戊巴比妥鈉40mg/kg及甲苯噻嗪(xylazine)10mg/kg之腹腔內投予進行的麻醉下，藉由0.1%螢光異硫氰酸鹽溶液點眼2μL將角膜障礙部位染色，將角膜分割為9份之各部位的染色像分數化為4階段，以9部位之分數之合計作為各眼之角膜障礙分數。各分數之基準如以下。 0：未染色 1：染色稀疏，各點狀之染色部分呈分離 2：染色程度中等，點狀之染色部分有一部分鄰接 3：染色密集，各點狀之染色部分鄰接。 點眼及評價係於兩眼實施，將各眼數據視為1例處理。統計分析係依杜納德(Dunnet)之多重比較檢定進行。 1. Test method A. Drugs and animals used in the test Compound 1 solution: 0.003% solution, 0.01% solution (eye volume: 5 μL) Diquafosol Sodium solution: 3% solution (eye volume: 5μL) Experimental animals: SD mice (gender: 6 weeks old, male, a group of 5) B: Determination of tears, instillation and evaluation methods SD male mice were anesthetized by intraperitoneal administration of pentobarbital sodium 40 mg/kg and xylazine 10 mg/kg, and the extraorbital lacrimal glands on both sides were excised. From the next day after the removal, normal saline (control group), 0.003% or 0.01% compound 1 solution, or 3% Diquafosol Sodium solution was instilled 6 times a day, 5 μL each time, for a total of 11 days. 24 hours after instillation, under anesthesia by intraperitoneal administration of pentobarbital sodium 40mg/kg and xylazine (xylazine) 10mg/kg, by 0.1% fluorescent isothiocyanate solution 2 μL of the eye was used to stain the corneal disorder site, and the stained image of each part of the cornea divided into 9 parts was divided into 4 stages, and the total of the scores of the 9 parts was used as the corneal disorder score of each eye. The basis of each score is as follows. 0: uncolored 1: The dyeing is sparse, and the dyed parts of each point are separated 2: The degree of dyeing is medium, and the dyed parts of the dots are partly adjacent 3: Dyeing is intensive, and the dot-shaped dyed parts are adjacent to each other. Eye dotting and evaluation were carried out on both eyes, and the data of each eye was treated as one case. Statistical analysis was performed according to Dunnet's multiple comparison test.

2. 結果及考察 圖6表示經被試驗化合物溶液點眼1小時後相對於點眼前之角膜障礙分數。角膜障礙分數係控制組為18.0，0.003%及0.01%之化合物1溶液分別為13.0及10.5，3%Diquafosol Sodium溶液為11.9；相較於控制組，0.01%濃度之化合物1溶液、及3%Diquafosol Sodium溶液確認到有顯著性差異。 (產業上之可利用性) 2. Results and investigation Fig. 6 shows the fraction of corneal disturbance with respect to the anterior eye of the test compound solution 1 hour after instillation. The corneal disorder score was 18.0 for the control group, 13.0 and 10.5 for 0.003% and 0.01% Compound 1 solutions, and 11.9 for 3% Diquafosol Sodium solution; compared with the control group, 0.01% Compound 1 solution and 3% Diquafosol A significant difference was confirmed for the Sodium solution. (industrial availability)

本發明之化合物係具有顯著之淚液分泌促進作用，且可有效作為新穎乾眼症治療劑，因此具有產業上之可利用性。The compound of the present invention has remarkable lacrimal secretion promoting effect, and can be effectively used as a novel dry eye treatment agent, so it has industrial applicability.

圖1係表示由化合物1a(立體配置：R體，比旋光度：(+)體)之手性管柱所得之光學純度的色譜圖。 圖2係表示由化合物1b(立體配置：S體，比旋光度：(-)體)之手性管柱所得之光學純度的色譜圖。 圖3係表示對正常兔進行化合物1溶液或Diquafosol Sodium溶液之單次點眼時，對淚液分泌的效果；數值為點眼1小時後之淚液量，以點眼前為100%進行換算，以相對於點眼前之淚液增加率計，由平均值±標準誤差表示；✽表示p值未滿0.05。 圖4係表示對正常兔進行消旋物溶液、化合物1a溶液或化合物1b溶液之單次點眼時，對淚液分泌的效果；數值為點眼1小時後之淚液量，以點眼前為100%進行換算，以相對於點眼前之淚液增加率計，由平均值±標準誤差表示；✽✽表示p值未滿0.01。 圖5係表示對阿托平誘發乾眼症模式兔進行生理食鹽水(控制組)、0.01%之消旋物溶液、化合物1a溶液或化合物1b溶液、或3%Diquafosol Sodium溶液1日4次、每次50μL且共10日的點眼時，對淚液分泌的效果；數值為點眼1小時後之淚液量，以點眼前為100%進行換算，以相對於點眼前之淚液增加率計，由平均值±標準誤差表示；✽及✽✽分別表示p值未滿0.05及未滿0.01。 圖6係表示對眼窩外淚腺摘出乾眼症模式鼠進行生理食鹽水(控制組)、0.003%或0.01%濃度之化合物1溶液、或3%Diquafosol Sodium溶液1日6次、每次5μL且共11日的點眼時的角膜障礙抑制作用；數值為由角膜障礙分數之平均值±標準誤差表示，✽及✽✽分別表示p值未滿0.05及未滿0.01。 Fig. 1 is a chromatogram showing the optical purity obtained from the chiral column of compound 1a (stereoconfiguration: R form, specific rotation: (+) form). Fig. 2 is a chromatogram showing the optical purity obtained from the chiral column of compound 1b (stereoconfiguration: S body, specific rotation: (-) body). Figure 3 shows the effect of compound 1 solution or Diquafosol Sodium solution on normal rabbits for a single eye drop, the effect on tear secretion; the value is the amount of tear fluid 1 hour after the eye drop, converted with 100% before the point, and relative The tear increase rate meter in front of the point is expressed by the mean ± standard error; ✽ indicates that the p value is less than 0.05. Figure 4 shows the effect on tear secretion when the racemate solution, compound 1a solution or compound 1b solution is instilled on normal rabbits once; the value is the amount of tear fluid 1 hour after the eye is instilled, and it is 100% in front of the eye The conversion is carried out in terms of the increase rate of tears relative to the point of the eye, expressed by the mean ± standard error; ✽✽ means that the p value is less than 0.01. Figure 5 shows that atropine-induced dry eye model rabbits were treated with normal saline (control group), 0.01% racemate solution, compound 1a solution or compound 1b solution, or 3% Diquafosol Sodium solution 1 day 4 times, The effect on tear secretion when 50 μL is instilled each time for a total of 10 days; the value is the tear volume 1 hour after the eye is instilled, and it is converted with the eye in front of the eye as 100%, and is calculated by the increase rate of tears relative to the eye in the eye The mean value ± standard error is shown; ✽ and ✽✽ mean that the p-value is less than 0.05 and less than 0.01, respectively. Figure 6 shows that normal saline (control group), compound 1 solution of 0.003% or 0.01% concentration, or 3% Diquafosol Sodium solution was administered to mice with dry eye syndrome after lacrimal gland extraction outside the orbit, 6 times a day, 5 μL each time and a total of The inhibitory effect on corneal disorder during instillation on the 11th; the value is represented by the mean ± standard error of the corneal disorder score, and ✽ and ✽✽ represent p values less than 0.05 and less than 0.01, respectively.

Claims (15)

一種4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺、或其鹽或者該等之溶媒合物。A kind of 4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formamido)phenyl]amino]nicotinamide, or a salt thereof or Such solvents. 一種淚液分泌促進劑，係以4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺、或其鹽或者該等之溶媒合物為有效成分。A tear secretion enhancer, which is based on 4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formamido)phenyl]amino]nicotine Amide, or its salt, or these solvates are active ingredients. 一種乾眼症之預防及/或治療劑，係以4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺、或其鹽或者該等之溶媒合物為有效成分。A preventive and/or therapeutic agent for dry eye syndrome, which is based on 4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formamido)phenyl ]amino]nicotinamide, or a salt thereof, or a solvate thereof is an active ingredient. 一種醫藥組成物，係含有4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺、或其鹽或者該等之溶媒合物而成。A pharmaceutical composition containing 4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formamido)phenyl]amino]nicotinyl Amines, or their salts, or their solvates. 一種用於淚液分泌促進的醫藥組成物，係含有4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺、或其鹽或者該等之溶媒合物而成。A pharmaceutical composition for promoting tear secretion, containing 4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formamido)phenyl] Amino] nicotine amide, or its salt, or a solvate thereof. 一種用於乾眼症之預防及/或治療的醫藥組成物，係含有4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺、或其鹽或者該等之溶媒合物而成。A pharmaceutical composition for the prevention and/or treatment of dry eye, containing 4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formyl Amino)phenyl]amino]nicotinamide, or a salt thereof, or a solvate thereof. 一種4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺、或其鹽或者該等之溶媒合物的使用，係用於製造乾眼症之預防及/或治療劑。A kind of 4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formamido)phenyl]amino]nicotinamide, or a salt thereof or The use of these solvents is for the manufacture of preventive and/or therapeutic agents for dry eye syndrome. 一種(S)-4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺、或其鹽或者該等之溶媒合物。A kind of (S)-4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formamido)phenyl]amino]nicotinamide, or their salts or their solvates. 一種淚液分泌促進劑，係以(S)-4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺、或其鹽或者該等之溶媒合物為有效成分。A tear secretion enhancer, based on (S)-4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formamido)phenyl]amine Base] Nicotinamide, or its salt, or the solvate thereof is the active ingredient. 一種乾眼症之預防及/或治療劑，係以(S)-4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺、或其鹽或者該等之溶媒合物為有效成分。A preventive and/or therapeutic agent for dry eye syndrome, which is based on (S)-4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-carboxamide base) phenyl] amino] nicotinamide, or a salt thereof, or a solvate thereof is an active ingredient. 一種醫藥組成物，係含有(S)-4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺、或其鹽或者該等之溶媒合物而成。A pharmaceutical composition containing (S)-4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formamido)phenyl]amino ] Nicotinamide, or its salt, or a solvate thereof. 一種用於促進淚液分泌的醫藥組成物，係含有(S)-4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺、或其鹽或者該等之溶媒合物而成。A pharmaceutical composition for promoting tear secretion, containing (S)-4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-carboxamide ) phenyl] amino] nicotinamide, or a salt thereof, or a solvate thereof. 一種用於乾眼症之預防及/或治療的醫藥組成物，係含有(S)-4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺、或其鹽或者該等之溶媒合物而成。A pharmaceutical composition for the prevention and/or treatment of dry eye, containing (S)-4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine- 3-formamido)phenyl]amino]nicotinamide, or a salt thereof, or a solvate thereof. 一種(S)-4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺、或其鹽或者該等之溶媒合物的使用，係用於製造淚液分泌促進劑。A kind of (S)-4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formamido)phenyl]amino]nicotinamide, or its salt or the use of these solvents is used for the production of lacrimal fluid secretion enhancer. 一種(S)-4-[(3,5-二氟苄基)胺基]-6-[[3-(哌啶-3-甲醯胺基)苯基]胺基]菸鹼醯胺、或其鹽或者該等之溶媒合物的使用，係用於製造乾眼症之預防及/或治療劑。A kind of (S)-4-[(3,5-difluorobenzyl)amino]-6-[[3-(piperidine-3-formamido)phenyl]amino]nicotinamide, The use of the salts thereof or the solvates thereof is used for the manufacture of a preventive and/or therapeutic agent for dry eye syndrome.