TW200304824A - Nicotinamide derivatives useful as PDE4 inhibitors - Google Patents

Nicotinamide derivatives useful as PDE4 inhibitors Download PDF

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Publication number
TW200304824A
TW200304824A TW092102415A TW92102415A TW200304824A TW 200304824 A TW200304824 A TW 200304824A TW 092102415 A TW092102415 A TW 092102415A TW 92102415 A TW92102415 A TW 92102415A TW 200304824 A TW200304824 A TW 200304824A
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Taiwan
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group
alkyl
formula
asthma
disease
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TW092102415A
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Chinese (zh)
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Thomas Victor Magee
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Pfizer
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    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine

Abstract

The invention relates to nicotinamide derivatives and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such derivatives. The nicotinamide derivatives according to the present invention are useful in numerous diseases, disorders and conditions, in particular inflammatory, allergic and respiratory diseases, disorders and conditions as well as for wounds healing.

Description

200304824 ⑴ 玫、發明說明 本發明係關於以下通式之菸鹼醯胺衍生物：200304824 ⑴ Rose, description of the invention The present invention relates to nicotinamide derivatives of the following general formula:

(其中Ri、R2、R3、R4、X、Υ、η及m係具有以下指定的 意義），以及在製備包括這些衍生物時所使用之中間物白勺 製備方法及這些衍生物的用途。 3’，5’環系核苷酸磷酸二酯酶類（PDEs)包含區分成彼此 在結構、生物化學及藥理學上有差異的至少1 1種不同族 系的大的酵素種類。常將在每一個種族系之內的酵素稱爲 同功酵素（isoenzyme)或同功酵素（isozyme)。在該種類之 內包括總共超過1 5種基因產物，以及進一步的多樣性起 因於那些基因產物的差異倂接及後轉譯處理。本發明主要 係關於第四種PDEs的四種基因產物，即PDE4A、PDE4B 、PDE4C及PDE4D。將這些酵素統稱爲PDE4同功酵素族 系之同型體或副型態。 PDE4s係以第二信使環系核苷酸，腺苷3,35，_環系單 磷酸（cAMP)之選擇性高親和力水解降解作用及對咯利普 蘭（rolipram)抑制作用的選擇性爲特徵。最近已發現許多 PDE4s之選擇性抑制劑，並已在許多疾病模式中展現起因 於該抑制作用有利的藥理效應（參考例如Torphy等人之 (2) (2)200304824(Where Ri, R2, R3, R4, X, Υ, η, and m have the meanings specified below), as well as the preparation method of intermediates used in the preparation including these derivatives, and the use of these derivatives. 3 ', 5' loop system nucleotide phosphodiesterases (PDEs) include large enzyme species that are distinguished into at least 11 different families with structural, biochemical, and pharmacological differences. Enzymes within each ethnic group are often referred to as isoenzymes or isozymes. This category includes a total of more than 15 gene products, as well as further diversity due to differences in those gene products and subsequent translation processing. The present invention mainly relates to four gene products of the fourth PDEs, namely PDE4A, PDE4B, PDE4C and PDE4D. These enzymes are collectively referred to as isoforms or paratypes of the PDE4 isoenzyme family. PDE4s is characterized by the selective high-affinity hydrolytic degradation of the second messenger ring nucleotide, adenosine 3,35, and ring monophosphate (cAMP) and the selectivity of its inhibitory effect on rolipram. Many selective inhibitors of PDE4s have recently been discovered and have shown favorable pharmacological effects due to the inhibitory effect in many disease models (see, for example, (2) (2) 200304824 of Torphy et al.

Environ Health Perspect，1 994，102 Suppl 10，ρ 79-84, Dup 1 ant i er 等人之 J Med C hem，1 9 96，3 9，p 1 2 0- 1 2 5， Schneider 等人之 Pharmacol Biochem Behav, 1995， 50, p 211-217，Banner 及 Page 之 B r J Pharmacol，1 995, 114，p 93 -9 8，Barnette 等人之 J Pharmacol Exp Ther， 1 9 9 5，273，p 674-679，Wright 等人之 Can J Physiol Pharmacol，1 9 9 7，7 5，p 1 0 0 1 - 1 0 0 8，M a n ab e 等人之 Eu r J Pharmacol，1 9 9 7，3 3 2，p 9 7 - 1 0 7 及 Uk i t a 等人之 J Me d Chem，1999，42, p 1088-1099)。因此，在本技藝中持續 對關於更多的PDE4選擇性抑制劑的發現非常有興趣。 已在本技藝中以選擇性PDE4抑制劑的發現及發展獲 得成功的結果。PDE4抑制劑減低在活體內嗜曙紅細胞回 流至過敏原攻毒之動物的肺部，同時也減低在過敏原攻毒 之後發生的枝氣管收縮及枝氣管反應性提升。PDE4抑制 劑也抑制免疫細胞（包括CD4+ T-淋巴細胞、單細胞、大型 細胞及嗜鹼細胞）的活性、減低肺水腫、抑制興奮的非腎 上腺素能非膽鹼能神經傳遞（eNANC)、加強抑制的非腎上 腺素能非膽鹼能神經傳遞（iNANC)、降低氣道平滑肌促細 胞分裂作用及誘發支氣管擴張作用。PDE4抑制劑也抑制 許多與COPD之病理生理學有關連之炎性細胞（包括單細 胞/巨噬細胞、CD4+ T-淋巴細胞、嗜曙紅細胞及嗜中性細 胞）的活性。PDE4抑制劑也降低血管平滑肌促細胞分裂作 用及可能干擾氣道上皮細胞產生初炎性調節因子的能力。 經由中性蛋白酶的釋放及來自彼顆粒之酸水解酶和反應性 -6 - (3) 200304824 氧物種的產生使得嗜中性細胞助長與慢性發炎關連的組織 破壞及進一步與症狀病理有牽連，如氣腫。因此’ PDE4 抑制劑也特別有用於治療許多發炎、呼吸性及過敏性疾病 、異常或症狀與創傷，彼等在臨床上的發展主要係用於治 療氣喘病、COPD、枝氣管炎及氣腫。 可以使用PDE4抑制劑對各種炎性細胞反應的效應作 爲鑑定及選擇用於進一步硏究之抑制劑的基準。這些效應 包括提升cAMP及抑制超氧化物的生產作用、去顆粒作用 、向化性，以及在嗜曙紅細胞、嗜中性細胞及單細胞中釋 放腫瘤壞死因子a (TNF α )。 如以上的說明，本發明係關於菸鹼醯胺衍生物族系之 PDE4抑帋[j齊(1 。 已合成出具有PDE4抑制活性之菸鹼醯胺衍生物。例 如，專利申請案第WO 98/4 5 268號係揭示具有作爲選擇 性PDE4D同功酵素抑制劑之活性的菸鹼醯胺衍生物。由 以下的化學式代表這些選擇性PDE4D抑制劑：Environ Health Perspect, 1 994, 102 Suppl 10, ρ 79-84, Dup 1 ant i er et al. J Med C hem, 1 9 96, 39, p 1 2 0- 1 2 5, Pharmacol by Schneider et al. Biochem Behav, 1995, 50, p 211-217, Banner and Page, BR J Pharmacol, 1 995, 114, p 93 -9 8, Barnette et al. J Pharmacol Exp Ther, 1 9 9 5, 273, p 674 -679, Can J Physiol Pharmacol by Wright et al., 1 9 9 7, 7 5, p 1 0 0 1-1 0 0 8, Manab et al. Eu r J Pharmacol, 1 9 9 7, 3 3 2, p 9 7-107 and U Meda et al. J Me d Chem, 1999, 42, p 1088-1099). Therefore, there is a continuing interest in the discovery of more selective inhibitors of PDE4 in the art. Successful results have been achieved in the art with the discovery and development of selective PDE4 inhibitors. PDE4 inhibitors reduce the return of eosinophils to the lungs of allergen challenged animals in vivo, and also reduce bronchoconstriction and increased bronchial reactivity after allergen challenge. PDE4 inhibitors also inhibit the activity of immune cells (including CD4 + T-lymphocytes, single cells, large cells, and basophils), reduce pulmonary edema, inhibit excited non-adrenergic non-cholinergic neurotransmission (eNANC), and strengthen Inhibition of non-adrenergic and non-cholinergic neurotransmission (iNANC), reduction of airway smooth muscle mitogenic effect and induction of bronchiectasis. PDE4 inhibitors also inhibit the activity of many inflammatory cells (including single cells / macrophages, CD4 + T-lymphocytes, eosinophils, and neutrophils) that are related to the pathophysiology of COPD. PDE4 inhibitors also reduce the mitogenic effect of vascular smooth muscle and may interfere with the ability of airway epithelial cells to produce proinflammatory regulators. Through the release of neutral protease and the acid hydrolase and reactivity of -6-(3) 200304824, the generation of oxygen species enables neutrophils to promote the destruction of tissues associated with chronic inflammation and further implicate the pathology of symptoms, such as emphysema. Therefore, PDE4 inhibitors are also particularly useful in the treatment of many inflammations, respiratory and allergic diseases, abnormalities or symptoms and traumas. Their clinical development is mainly used to treat asthma, COPD, bronchitis and emphysema. The effects of PDE4 inhibitors on various inflammatory cell responses can be used as a basis for identifying and selecting inhibitors for further investigation. These effects include promotion of cAMP and inhibition of superoxide production, degranulation, chemotacticity, and release of tumor necrosis factor a (TNFα) in eosinophils, neutrophils, and single cells. As described above, the present invention relates to the PDE4 inhibitory family of the nicotinamide family of derivatives [j 齐 (1. Nicotinamide derivatives having PDE4 inhibitory activity have been synthesized. For example, patent application WO 98 / 4 5 268 reveals nicotinamide derivatives having activity as selective PDE4D isoenzyme inhibitors. These selective PDE4D inhibitors are represented by the following chemical formula:

R\ 3 A Λ \〆 (Β)η m ν 1 — — (D)P 0 RR \ 3 A Λ \ 〆 (Β) η m ν 1 — — (D) P 0 R

R (〇)t 其中特別是m及n可以等於〗，以及p可以等於〇，a可 以係氧’ B可以係nH，I*可以等於0，E可以係Ο、NH或 (4) 200304824 S’ R5可以係包括1至4個雜原子之飽和或不飽和環系或 雙環系（C3-C7)雜環系基及R1可以係視需要以各種取代基 取代之芳基。 專利申請案第W0 0 1/57〇36號也揭示具有以下化學 式之菸鹼醯胺衍生物，其係治療各種發炎、過敏及呼吸性 疾病及症狀有用的P D E 4抑制劑：R (〇) t where especially m and n can be equal to, and p can be equal to 0, a can be oxygen 'B can be nH, I * can be equal to 0, E can be 0, NH or (4) 200304824 S' R5 may be a saturated or unsaturated ring system or a bicyclic (C3-C7) heterocyclic group including 1 to 4 heteroatoms and R1 may be an aryl group substituted with various substituents as necessary. Patent Application No. WO 0 1 / 57〇36 also discloses nicotinamide derivatives of the following chemical formula, which are P D E 4 inhibitors useful for treating various inflammations, allergies and respiratory diseases and symptoms:

Z 其中特別是·· η係1或2，m係0至2，Y = C(RE)-或-[N-&gt; (〇)]-，W 係-〇-、-S( = 0)t-或-N(R3)-，Q 代表各種環，其 中係苯基，Z係- 〇R12、-C( = 0)R12或CN及R12係選自烷 基、焼基、環院基、苯基、苯甲基及單環系雜環部份。 但是對另外會展示經改進具有可能最低的反效果（如 例如水腫）之治療指數的PDE4抑制劑仍有極大的需求。 因此，本發明係關於通式（1)之新穎菸鹼醯胺衍生物 -8- (5) 200304824 〇Z Among them, η is 1 or 2, m is 0 to 2, Y = C (RE)-or-[N- &gt; (〇)]-, and W is -〇-, -S (= 0) t- or -N (R3)-, Q represents various rings, of which is phenyl, Z is-〇R12, -C (= 0) R12 or CN and R12 are selected from alkyl, fluorenyl, cyclohexyl, Phenyl, benzyl and monocyclic heterocyclic moieties. However, there is still a great need for PDE4 inhibitors that additionally show improved therapeutic indices with the lowest possible adverse effects (e.g., edema). Therefore, the present invention relates to a novel nicotinamide derivative of the general formula (1) -8- (5) 200304824.

R3 或右適當時，彼在醫藥上可接受之鹽類及/或異構物 、彼之互變體、媒合物、多型體、同位素變異體或代謝物 5 其中： m 係 〇、1、2 或 3， ♦ η 係 0、i、2 或 3， ♦Rl及各自係獨立選自氫原子 '鹵基、氰基、（Ci-C4) 院基及（Ci-C4)烷氧基之元件， X 係-〇-、-S-或-NH-， ♦&gt;R3係選自以下之元件， (a)苯基、萘基、雜芳基及（C3-c8)環烷基，將每一個視 需要以1至3個分別選自鹵基、氰基、（(^-(：4)烷基 、（C1-C4)院氧基、（C1-C4)院硫基、-C( = 0)NH2、 -CfCONI^CrCd烷基、羥基、-O-cpOKCpCO 烷 基、-C( = 0)-0-(Ci-C4)院基及經基（C1-C4)院基之取 代基取代，或 (b )共同形成其中一種以下結構（〗〗）至（i 4)之雙環系基 (6) 200304824R3 or R. Where appropriate, he is a pharmaceutically acceptable salt and / or isomer, his tautomer, vehicle, polymorph, isotope variant, or metabolite 5 where: m is 0, 1 , 2 or 3, ♦ η is 0, i, 2 or 3, ♦ R1 and each is independently selected from the group consisting of a hydrogen atom, a halo group, a cyano group, a (Ci-C4) group and a (Ci-C4) alkoxy group Element, X is -0-, -S- or -NH-, ♦ &gt; R3 is an element selected from (a) phenyl, naphthyl, heteroaryl and (C3-c8) cycloalkyl, Each of them is optionally selected from 1 to 3 halo, cyano, ((^-(: 4) alkyl, (C1-C4) hosoxy, (C1-C4) hosthio, -C ( = 0) NH2, -CfCONI ^ CrCd alkyl, hydroxyl, -O-cpOKCpCO alkyl, -C (= 0) -0- (Ci-C4) Substitute, or (b) together form one of the following bicyclic radicals (6) to (i 4) 200304824

其餘部位之附著點， Φ 《♦Y係選自部份的式（1 5)至（1 n)之元件： 又 ★ * 一 °v° * (15) (1.6) (17) ?\ Η N ★ °v°X V 、 〇 0 (19) (1.10) 〇、、'The attachment points of the remaining parts, Φ "Y is a component selected from the partial formulas (1 5) to (1 n): and ★ * one ° v ° * (15) (1.6) (17)? \ Η N ° v ° XV 〇0 (19) (1.10) 〇, '

(1.8)(1.8)

其中以符號” *，，表示每一個部份的式（1 5 )至（1 1 1)與式（1) 的其餘部位-NH-之附著點，以及以符號”**”表示每一個部 份的式（1 5)至（1 4)與式（I)的其餘部位-R4-之附著點， +及R4係選自以下之元件’ (a )苯基、萘基及雜芳基，將每一個視需要以1至3個 分別選自羧酸、〔（=〇)-〇-(〇-C4)烷基、鹵基、氰基 、-C( = 〇)NH2、（C1-C4)院基、（Cl-C4)j：兀氧基、（Cl- -10- (7) (7)200304824 C4)鹵烷基、羥基及羥基（Cl-C4)烷基之取代基取代， 或 (b)視需要以羥基、羧酸、¢:( = 0)-0-((:^(:4)烷基、苯基 、萘基或雜芳基取代之（Ci-CJ烷基，其中將每一個 該苯基、萘基及雜芳基視需要以1至3個分別選自 羧酸、¢:( = 0)0((^-(:4)烷基、鹵基、氰基、 -C( = 0)NH2、（CpCd 烷基、（Ci-CU)烷氧基、（Ci-Cd 鹵烷基、羥基及羥基（Ci-CJ烷基之取代基取代。 已發現這些菸鹼醯胺衍生物係展示極佳的治療實用性 及治療指數之PDE4同功酵素抑制劑，特別有用於治療發 炎、呼吸及過敏性疾病和治療創傷。 在以上的通式（1)中，以鹵基表示選自氟基、氯基、 溴基及碘基之鹵素原子，特別係氟基或氯基。 以（Ci-C4)烷基表示包括1、2、3或4個碳原子之直 鏈或支鏈基。如果彼等攜帶或以其它的基之取代基出現時 也適用，例如’在（Ci-Cd烷氧基、（Q-C4)烷硫基' (Ci-C4)鹵烷基、羥基（CrCd烷基、（:（ = 0)0((^-04)烷基等之中 。適合的（C!-C4)烷基實例係甲基、乙基、正丙基、異丙 基、正丁基、異丁基、第二丁基及特丁基。適合的（Ci-C4)院氧基實例係甲氧基、乙氧基、正丙氧基、異丙氧基 、正丁氧基、異丁氧基、第二丁氧基及特丁氧基。適合的 (Ci-C4)烷硫基實例係甲硫基、乙硫基、正丙硫基、異丙 硫基、正丁硫基、異丁硫基、第二丁硫基及特丁硫基。適 合的（C^C：4)鹵烷基係以鹵基取代之烷基。如果沒有另外 (8) (8)200304824 的說明，則彼等可以包括1、2、3、4、5、6或7個鹵素 原子。該鹵基係以赢基、氣基、溴基或硕基較佳，特別裹 氟基或氯基。例如，在以氟基取代之烷基中，可將甲基以 三氟甲基存在。同樣適用於羥基（K4)烷基，除了彼係 以羥基（-OH)取代之烷基之外。根據本發明較佳的具體實 施例，這些基包括一個羥基取代基。適合的羥基（Ci_c4) 烷基實例係羥甲基、1-羥乙基或2-羥乙基。 以（CpC8)環烷基代表3_員至I員飽和單環系環。適 合的（Cs-C：8)環烷基實例特別係環丙基 '環丁基、環戊基 、環己基、環庚基及環辛基。可將這些基視需要取代，如 在R3之定義中所指出的方式。經取代之（C3_C8)環烷基實 例係2-甲基環己基、甲基環己基、甲基環己基、％甲 基環己基、6 -甲基環己基、2 -羥基環己基、3_羥基環己基 、‘羥基環己基、5-羥基環己基、6-羥基環己基、2-氟基 環己基、3-氣基環己基、I氟基環己基、5_氟基環己基、 6-氟基壞己基、甲基_3_羥基環己基、2_甲基羥基環 己基、2-羥基_4_甲基環己基等。 在以上的通式（1)中，雜芳基係具有5至14環元件之 單環系或多環罕惊：t # /、方ί矢系統之基，其包括1、2、3、4或5 個雜原子，其係休墟@ 一 ^ 砍據运兀件總數量及品質而定。雜芳基實 例係氮（Ν)、氧&amp; _ k )及硫（S)。如果包括數個雜原子時，則 1 Μ 7E #同或不相同的雜原子。也可以將雜芳基不取 代，將彼經單取件卞々 Μ ^ &amp;取代，如在以上用於根據本發明之 通式（1)的R3及 4 t疋義中所指出的方式。雜芳基係以 -12- 200304824 Ο)Among them, the symbol "*" represents the attachment point of each part of the formulas (1 5) to (1 1 1) and the rest of the formula (1) -NH-, and the symbol "**" represents each part The attachment points of the formulae (15) to (14) and the rest of the formula (I) -R4-, + and R4 are selected from the following elements: (a) phenyl, naphthyl and heteroaryl, Each of them is selected from carboxylic acid, [(= 〇) -〇- (〇-C4) alkyl, halo, cyano, -C (= 〇) NH2, (C1-C4) ) Yuanji, (Cl-C4) j: oxo, (Cl--10- (7) (7) 200304824 C4) haloalkyl, hydroxy and hydroxy (Cl-C4) alkyl substituted with substituents, or (b) if necessary, substituted with a hydroxy, carboxylic acid, ¢ :( = 0) -0-((: ^ (: 4) alkyl, phenyl, naphthyl, or heteroaryl group (Ci-CJ alkyl, where Each of the phenyl, naphthyl, and heteroaryl groups is selected from carboxylic acid, ¢: (= 0) 0 ((^-(: 4) alkyl, halo, cyano, -C (= 0) NH2, (CpCd alkyl, (Ci-CU) alkoxy, (Ci-Cd haloalkyl, hydroxy, and Ci-CJ alkyl substituents. These nicotine bases have been found Amine derivatives show excellent treatment The PDE4 isoenzyme inhibitor of therapeutic utility and therapeutic index is particularly useful for treating inflammation, respiratory and allergic diseases and treating wounds. In the above general formula (1), the halogen group is selected from fluorine group and chlorine group Halogen atom of bromo and iodo, especially fluorine or chloro. (Ci-C4) alkyl represents a straight or branched chain group containing 1, 2, 3 or 4 carbon atoms. If they carry Or when it is substituted with other groups, such as 'in (Ci-Cd alkoxy, (Q-C4) alkylthio', (Ci-C4) haloalkyl, hydroxyl (CrCd alkyl, (: (= 0) 0 ((^-04) alkyl, etc. Examples of suitable (C! -C4) alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , Second butyl and tert-butyl. Examples of suitable (Ci-C4) oxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, Second butoxy and tert-butoxy. Examples of suitable (Ci-C4) alkylthio groups are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio , Second butylthio and tert-butylthio. Suitable (C ^ C: 4) Alkyl is an alkyl substituted with halo. Unless otherwise specified in (8) (8) 200304824, they may include 1, 2, 3, 4, 5, 6, or 7 halogen atoms. The halo Ethyl, bromo or bromo are preferred, especially fluoro or chloro. For example, in alkyl substituted with fluoro, methyl can be present as trifluoromethyl. The same applies to hydroxyl (K4) alkyl, except for alkyl groups which are substituted with hydroxy (-OH). According to a preferred embodiment of the present invention, these groups include a hydroxy substituent. Examples of suitable hydroxy (Ci_c4) alkyl are hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl. (CpC8) cycloalkyl represents a 3-membered to 1-membered saturated monocyclic ring. Examples of suitable (Cs-C: 8) cycloalkyl groups are particularly cyclopropyl'cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. These bases can be substituted as needed, as indicated in the definition of R3. Examples of substituted (C3_C8) cycloalkyl are 2-methylcyclohexyl, methylcyclohexyl, methylcyclohexyl,% methylcyclohexyl, 6-methylcyclohexyl, 2-hydroxycyclohexyl, 3-hydroxy Cyclohexyl, 'hydroxycyclohexyl, 5-hydroxycyclohexyl, 6-hydroxycyclohexyl, 2-fluorocyclohexyl, 3-aminocyclohexyl, Ifluorocyclohexyl, 5-fluorocyclohexyl, 6-fluoro Methylhexyl, methyl-3-hydroxycyclohexyl, 2-methylhydroxycyclohexyl, 2-hydroxy-4-methylcyclohexyl, and the like. In the above general formula (1), the heteroaryl system is a monocyclic or polycyclic system having 5 to 14 ring elements: t # /, the base of the square vector system, which includes 1, 2, 3, 4 Or 5 heteroatoms, which is the rest market @ 一 ^ Cut according to the total quantity and quality of the transport pieces. Examples of heteroaryl groups are nitrogen (N), oxygen &amp; _k) and sulfur (S). If several heteroatoms are included, 1 M 7E #same or different heteroatoms. It is also possible to replace the heteroaryl group with a single item 卞 々 ^ ^ &amp; as described above in the meanings of R3 and 4t for the general formula (1) according to the present invention. Heteroaryl is -12- 200304824 〇)

包括1、2、3或4個（特別係1、2或3個）選自n、0及S 之相同或不相同的雜原子之單環系或雙環系芳族基較佳。 雜芳基係以具有5至1〇環元件之單環系或雙環系芳族基 特別佳，特別係5 -員至6 -貝單環系方族基，其包括（i)從 1至4個雜原子或（Π)1或2個氮雜原子及i個氧原子或1 個硫原子或（iii)l或2個氧或硫雜原子。適合的雜芳基實 例係衍生自吡咯、呋喃、呋咱、噻吩、咪唑、吡唑、噁唑 、異噁唑、噻唑、異噻唑、四唑、三阱、吡啶、吡阱、嘧 啶、噠嗪、吲哚嗪、吲哚、異吲哚、吲唑、嘌呤、萘啶、 酞嗪、Π奎啉、異喹啉、喹唑啉、喹噁啉、噌啉及以苯並稠 合之這些雜環基衍生物之基，如例如苯並呋喃、苯並噻吩 、苯並噁唑及苯並噻唑。以選自吡咯基、吡唑基、1，2,3 -三唑基、1，2，4 -三唑基、四唑基、噁唑基、異噁唑基、噻 唑基、異噻唑基、1，2，4 -噁二唑基、1，3，4 -噁二唑基、呋喃 基、噻嗯基、吡啶基、噠嗪基、嘧啶基及吡阱基之雜芳基 特別佳。氮雜芳基也可以N-氧化物或四級鹽類存在。 在根據本發明的通式（1)中，在將基經單-或多-取代時 ，則該取代基可位於任何預期的位置。也在將基經多取代 時，該取代基可以相同或不相同。 可以使用慣用的步驟（如以下例證的方法）製備式（1)之 菸鹼醯胺衍生物，其中Ri、R2、R3、R4、X、Y、η及m 係如先前用於式（1)之菸鹼醯胺衍生物之定義，除非有其 它另外的說明。 可自式（2)化合物開始製備式（1)之菸鹼醯胺衍生物： (10) 200304824 〇A monocyclic or bicyclic aromatic group comprising 1, 2, 3 or 4 (particularly 1, 2 or 3) heteroatoms selected from n, 0 and S which are the same or different is preferred. Heteroaryl is particularly preferably a monocyclic or bicyclic aromatic group having 5 to 10 ring elements, particularly a 5-membered to 6-belt monocyclic square group group, which includes (i) from 1 to 4 One heteroatom or (Π) 1 or 2 nitrogen heteroatom and i oxygen atom or 1 sulfur atom or (iii) 1 or 2 oxygen or sulfur heteroatom. Examples of suitable heteroaryl groups are derived from pyrrole, furan, furazine, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, triple well, pyridine, pyridine, pyrimidine, pyridazine , Indazine, indole, isoindole, indazole, purine, naphthyridine, phthalazine, quinoline, isoquinoline, quinazoline, quinoxaline, oxoline, and benzo-fused Cyclic derivative groups such as, for example, benzofuran, benzothiophene, benzoxazole, and benzothiazole. Selected from pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, Heteroaryl groups of 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furyl, thienyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazolyl are particularly preferred. Azaaryl may also be present as an N-oxide or a quaternary salt. In the general formula (1) according to the present invention, when a group is mono- or poly-substituted, the substituent may be located at any desired position. When a group is further substituted, the substituents may be the same or different. Conventional procedures (such as the method exemplified below) can be used to prepare nicotinamide derivatives of formula (1), where Ri, R2, R3, R4, X, Y, η, and m are as previously used in formula (1) Definition of nicotinamide derivatives unless otherwise stated. The nicotinamide derivative of formula (1) can be prepared from the compound of formula (2): (10) 200304824

其中Rl、R2、r3、r4、X、Υ、η及m係如先前用於式（1) 之菸鹼醯胺衍生物之定義。 在Y代表部份的式（1 7)、（1 8)或（1 10)之基時，則可 將式（2)化合物與對應之R4-磺醯氯衍生物（r4S02C1或 R4NHS〇2或 R4C( = 0)NHS02C1)在適合的溶劑中（例如，二 氯甲烷）及在有機鹼的存在下（例如，三乙胺）在從〇°C至室 溫之溫度範圍下（約20 °C )反應。 在Y代表部份的式（1 5)、（1 9)或（1 1 1)之基時，則可 將式（2)化合物與對應之 R4-羧酸衍生物（R4COOH或 r4so2nh-ch2cooh 或 r4c(o)nh-ch2-cooh)使用在適合 的溶劑（例如，二甲基甲醯胺）及有機鹼（例如，N-甲基嗎 啉）存在下的活化劑在室溫下反應。使用例如： a) 1-羥基苯並三唑及1-(3-二甲基胺丙基）-3-乙基碳化二 醯胺鹽酸， b )羰基二咪唑，或 c )草醯氯及二甲基甲醯胺（以二氯甲烷作爲溶劑） 可以達成酸的活化作用。 在Y代表部份的式（1 6)之基時，則可將式（2)化合物 與羰基二咪唑在適合的溶劑中（如二氯甲烷）反應及將所獲 -14- (11) 200304824 得的中間物與攜帶取代基r4之胺反應。 必須強調的是在式（1)之菸鹼醯胺衍生物中的R3及r4 代表以烷氧基取代之苯基環時，則可將這些結構使用熟練 本技藝的人熟知的特定的去保護條件轉化成羥基類似物。 使用熟練本技藝的人熟知的去保護條件除去通式（3 ) 化合物之去保護基”prot”，可以製備通式（2)化合物·· 〇Wherein R1, R2, r3, r4, X, Υ, η and m are as defined for the nicotinamide derivative used in formula (1). When Y represents a part of the base of the formula (1 7), (1 8) or (1 10), the compound of formula (2) and the corresponding R4-sulfonyl chloride derivative (r4S02C1 or R4NHS〇2 or R4C (= 0) NHS02C1) in a suitable solvent (for example, dichloromethane) and in the presence of an organic base (for example, triethylamine) in a temperature range from 0 ° C to room temperature (about 20 ° C )reaction. When Y represents a part of the base of formula (1 5), (1 9) or (1 1 1), the compound of formula (2) and the corresponding R4-carboxylic acid derivative (R4COOH or r4so2nh-ch2cooh or r4c (o) nh-ch2-cooh) is reacted at room temperature using an activator in the presence of a suitable solvent (for example, dimethylformamide) and an organic base (for example, N-methylmorpholine). Examples of use: a) 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiamidate hydrochloride, b) carbonyldiimidazole, or c) oxadiazine and diamine Methylformamide (with dichloromethane as solvent) can achieve acid activation. When Y represents part of the group of formula (16), the compound of formula (2) can be reacted with carbonyldiimidazole in a suitable solvent (such as dichloromethane) and the obtained -14- (11) 200304824 can be obtained. The resulting intermediate is reacted with an amine carrying the substituent r4. It must be emphasized that when R3 and r4 in the nicotinamide derivative of formula (1) represent a phenyl ring substituted with an alkoxy group, these structures can be subjected to specific deprotection known to those skilled in the art. Conditions are converted to hydroxy analogs. The deprotection group "prot" of the compound of the general formula (3) can be removed using deprotection conditions well known to those skilled in the art, and the compound of the general formula (2) can be prepared ...

(3) \prot Ra 其中Ri、R2、X、R3、η及m係如先前用於式（1)之菸鹼醯 胺衍生物之定義及Prot係適合的保護基，其包括（但不限 於此）苯甲基、胺基甲酸酯（例如，特丁氧羰基）、醯胺（例 如，三氟乙醯胺）或醯亞胺（例如，酞醯亞胺）。(3) \ prot Ra wherein Ri, R2, X, R3, η and m are the same as the definition of nicotinamide derivative used in formula (1) and Prot is a suitable protecting group, including (but not limited to) This) benzyl, carbamate (for example, t-butoxycarbonyl), amidine (for example, trifluoroacetamide) or amidine (for example, phthalimide).

可以如流程1的展示製備式（3)化合物·· -15- (12) (12)200304824Compounds of formula (3) can be prepared as shown in Scheme 1 -15- (12) (12) 200304824

流程1Flow 1

宜中 R 、 1、R2、X、R3、η、m及Prot係如先前的說明及R， 代表（cvC4)烷基。 在典型的步驟中，可將式（6)之菸酸酯與適當的醇、 硫赶或式R3XH(7)之胺在包括鹼（如碳酸鉋）的適當的溶劑 中（例如，二甲基甲醯胺或二噁烷）在從室溫至10(KC之溫 度範圍下反應，以得到式（5 1)化合物。可將其以鹼金屬氫 氧化物皂化，以得到式（4 1)之酸，接著將其與式（8)之經 單保護之二胺： -16- (13) (13)200304824Preferably, R, 1, R2, X, R3, η, m and Prot are as described above and R represents a (cvC4) alkyl group. In a typical procedure, a nicotinic acid ester of formula (6) and an appropriate alcohol, sulfur, or amine of formula R3XH (7) can be used in a suitable solvent including a base (such as carbon shavings) (for example, dimethyl Formamidine or dioxane) is reacted at a temperature ranging from room temperature to 10 (KC) to obtain a compound of formula (5 1). It can be saponified with an alkali metal hydroxide to obtain a compound of formula (4 1) Acid, followed by a monoprotected diamine of formula (8): -16- (13) (13) 200304824

使用活化劑（如那些在以上陳述的其中一種活化法中說明 的試劑，即a)l -經基苯並三哗及1-(3 -二甲基胺丙基）-3 -乙 基碳化二醯胺鹽酸或b)羰基二咪唑或c)草醯氯及二甲基 甲醯胺，以二氯曱烷作爲溶劑）反應，可以轉化成式（3)化 合物。 根據另一個替代法，可以如流程2的展示製備式（3) 化合物：Use activators (such as those described in one of the activation methods stated above), i.e. a) l-benzotriazole and 1- (3-dimethylaminopropyl) -3 -ethylcarbodicarbonate Amidamine hydrochloride or b) carbonyldiimidazole or c) oxadiazine and dimethylformamide are reacted with dichloromethane as a solvent to convert the compound into formula (3). According to another alternative, the compound of formula (3) can be prepared as shown in Scheme 2:

•17- (14) 20030482417- (14) 200304824

Y、R3、n、m、R’及Prot係如先前的說明 其中Ri、R2、x 八3 ο 在典型的步驟中’可將式（6)之薛酸1旨使用驗金 氧化物水解成式（5 2)之薛酸，將其與式（8)之經單保護之 二胺使用以上陳述的其中一種活化法反應。可將在之前的 步驟所獲得的式（4 2 )之氯基卩比卩定與適當的醇、硫赶或式 R 3 X Η ( 7 )之胺在包括鹼（如碳酸鉋）的適當的溶劑中（例如， 二甲基甲醯胺或二噁烷）在從室溫至l〇0°C之溫度範圍下 -18- (15) 200304824 反應。 式（6)及（7)化合物係市售商品或可以熟練本技藝的人 熟悉的慣用步驟製得。 以超過量的式（9)之二胺：Y, R3, n, m, R 'and Prot are as described previously. Among them, Ri, R2, x 8 3 ο In a typical step, the Xue acid 1 of formula (6) can be hydrolyzed to gold oxide using Xue acid of formula (5 2) is reacted with the monoprotected diamine of formula (8) using one of the activation methods stated above. The chloro group of formula (4 2) obtained in the previous step can be combined with a suitable alcohol, sulfur or amine of formula R 3 X Η (7) in a suitable compound including a base such as carbon shavings. The reaction in a solvent (for example, dimethylformamide or dioxane) is performed at a temperature ranging from room temperature to 100 ° C -18- (15) 200304824. The compounds of the formulae (6) and (7) are commercially available products or are prepared by customary procedures familiar to those skilled in the art. In excess of the diamine of formula (9):

⑼⑼

(其中m及η係如以上的定義）與適合的衍生劑（如二羧酸 二特丁酯，以得到特丁氧羰基衍生物）在適合的溶劑中（如 二氯甲烷）及在室溫下反應，可以製備式（8)之經單保護之 二胺。 式（9)化合物係巾售商品或可以熟練本技藝的人熟悉 的慣用步驟輕易製得。(Where m and η are as defined above) and a suitable derivatizing agent (such as di-tert-butyl dicarboxylic acid to obtain a t-butoxycarbonyl derivative) in a suitable solvent (such as dichloromethane) and at room temperature In the next reaction, a monoprotected diamine of formula (8) can be prepared. The compound of formula (9) is a commercially available towel or can be easily prepared by customary procedures familiar to those skilled in the art.

在之前的方法中使用的所有以上的反應及原料的製備 作用係慣用且適當的試劑，以及就其性能或製備作用之反 應條件與分離預期產物之步驟係那些熟練本技藝的人以參 考文獻先例及其實例和製備作用所熟知的。 關於一些以本文所說明的式（1 )之菸鹼醯胺衍生物的 製備法步驟’可能有必要保護不希望反應的潛在的反應性 官能基。在這種情況下，可以使用任何可相容的保護基。 牛寸別可以使用如那些以T W GREENE (Protective Groups in Organic Synthesis, A W i 1 e y -1 n t e r s c i e n c e Publication, 1981)或以 McOMlE (Protective Groups in Organic -19- (16) 200304824All the above reactions and the preparation of raw materials used in the previous method are conventional and appropriate reagents, and the reaction conditions and the steps of separating the expected products in terms of their performance or preparation are those who are skilled in the art to reference the precedent. Its examples and preparation are well known. Regarding some of the steps of the method for preparing a nicotinamide derivative of the formula (1) described herein, it may be necessary to protect potentially reactive functional groups that are not expected to react. In this case, any compatible protecting group can be used. For example, you can use products such as T W GREENE (Protective Groups in Organic Synthesis, A W i 1 e y -1 n t e r s c i e n c e Publication, 1981) or McOMlE (Protective Groups in Organic -19- (16) 200304824

Chemisti*y，PlenumPi*ess，1973)所說明之方法。 - 也可以根據各種熟知的方法（如例如結晶作用或色層 _ 分離法）純化式（1 )之菸鹼醯胺衍生物與用於彼之製備作用 的中間物。 根據本發明一般的觀點，以如先前說明的式（1}之菸 驗醯胺衍生物較佳，除了以下之外的化合物： 1 ) m不是0，同時以Y代表部份的式（丨5 )及&amp;代表 未經取代之（C!-C4)烷基， φ 2) m等於0，同時以Y代表部份的式〇 5)及R4代表 苯基、萘基或雜芳基，將每一個視需要以1至3 個獨立選自羧酸、鹵基、氰基、（Ci-C4)院基、 (C1-C4)院氧基、（C1-C4)鹵院基、經基及經其（。1_ C4)院基之取代基取代’或R4代表視需要以經基 、羧酸或雜芳基（將其視需要以〗至3個獨立選自 竣酸、鹵基、氰基、（Ci-co烷基、（Ci-c4)院氧基 、經基及羥基（C「C4)院基之取代基取代）取代之 馨 (C1-C4)院基’及 6)及R4代表 ^ 3個獨立選 、（c i - C 4)院氧 -C4)烷基之取 3) m等於0，同時以Y代表部份的式（1 苯基或萘基，將每一個視需要以1至 自羧酸、鹵基、氰基、（Ci-C4)烷基、 基、（Ci-cj鹵烷基、羥基及羥基（Ci_ 代基取代。 以其中： ❖ m及η等於1， •20- (17) (17)200304824 + 及r2各自係獨立選自氫原子、鹵基、氰基、（Cl_C4) 烷基及（Cl-C4)烷氧基之元件， ❖ X 係-〇·， ♦R3係選自以下之元件， (a) 苯基、萘基、雜芳基及（C3_c8)環烷基，將每一個視 需要以1至3個分別選自鹵基、氰基、（Cl-C4)烷基 、（C”C4)烷氧基、（C”C4)烷硫基、-C( = 0)NH2、 •C^C^Nl^CVCd烷基、羥基、-O-CbOMCrC^)烷基 ' -C ( = 4)烷基及羥基（Ci-Cd烷基之取代基 取代，或 (b) 共同形成其中一種以下結構（1 1)至（I4)之雙環系基Chemisti * y, PlenumPi * ess, 1973). -Nicotinamide derivatives of formula (1) and intermediates used for their preparation can also be purified according to various well-known methods, such as crystallization or chromatographic separation. According to the general point of view of the present invention, the nicotinamide derivative of formula (1) as described above is preferred, except for the following compounds: 1) m is not 0, and Y is a partial formula (5) ) And &amp; represent unsubstituted (C! -C4) alkyl, φ 2) m is equal to 0, and Y represents a part of the formula 05) and R4 represents phenyl, naphthyl or heteroaryl, and Each one is independently selected from 1 to 3 selected from carboxylic acid, halo, cyano, (Ci-C4), radical (C1-C4), oxygen, (C1-C4), halogen, radical, and Substituted by its substituent (.1_C4) 'or R4 represents a radical, a carboxylic acid, or a heteroaryl group as needed (if necessary, it may be from 3 to 3 independently selected from the group consisting of carboxylic acid, halo, and cyano , (Ci-co alkyl, (Ci-c4) oxo, substituted by radicals and hydroxy groups (C "C4) oxo substituted by C)) (C1-C4) oxo 'and 6) and R4 represent ^ 3 independently selected, (ci-C 4) oxygen-C4) alkyl 3) m is equal to 0, while Y represents a part of the formula (1 phenyl or naphthyl, each 1 as needed From carboxylic acid, halo, cyano, (Ci-C4) alkyl, radical, (Ci-cj haloalkyl, hydroxy And hydroxy (Ci_ substituted group. In which: ❖ m and η are equal to 1, • 20- (17) (17) 200304824 + and r2 are each independently selected from a hydrogen atom, a halogen group, a cyano group, a (Cl_C4) alkyl group And (Cl-C4) alkoxy elements, ❖ X is -0 ·, ♦ R3 is an element selected from (a) phenyl, naphthyl, heteroaryl, and (C3_c8) cycloalkyl, each One is optionally selected from 1 to 3 selected from halo, cyano, (Cl-C4) alkyl, (C "C4) alkoxy, (C" C4) alkylthio, -C (= 0) NH2 , • C ^ C ^ Nl ^ CVCd alkyl, hydroxyl, -O-CbOMCrC ^) alkyl '-C (= 4) alkyl and hydroxyl (Ci-Cd alkyl substituent substitution, or (b) together One of the bicyclic radicals of the following structures (1 1) to (I4)

(11) (12) (13) (1.4) 其中以符號” ”表示每一個部份的式（1 1)至（1 4)與式（I)的 其餘部位之附著點， ❖ Y係選自由部份的式（1 5)之基- C( = 0)- ’ ❖及R4係選自以下之元件’ (a )苯基、萘基及雜芳基’將每一個視需要以Ϊ至3個 分別選自续酸、[( = 0)-0-(^4)燒基、鹵基、氰基 -21 - (18) 200304824 、-C( = 0)NH2、（CpCd烷基、（CrCd烷氧基、 (C 1 一 C4)鹵烷基、羥基及羥基（CrC4)烷基之取代基耳 ' V ’ 或 (b )以羥基、羧酸、¢:( = 0)-0-((^-(:4)烷基、苯基、％ 奈_ 或雜芳基取代之（CrC4)烷基，其中將每一個該苯# 、萘基及雜芳基視需要以1至3個分別選自_ _(11) (12) (13) (1.4) Where the symbol “” represents the attachment points of each part of the formula (1 1) to (1 4) and the rest of the formula (I), ❖ Y is selected from Part of the group of the formula (1 5)-C (= 0)-'❖ and R4 are selected from the following elements' (a) phenyl, naphthyl and heteroaryl' will each be Ϊ to 3 if necessary Are selected from the group consisting of a continuous acid, [(= 0) -0-(^ 4) alkyl, halo, cyano-21-(18) 200304824, -C (= 0) NH2, (CpCd alkyl, (CrCd Alkoxy, (C 1 -C4) haloalkyl, hydroxyl and hydroxy (CrC4) alkyl substituents ear 'V' or (b) with hydroxyl, carboxylic acid, ¢: (= 0) -0-(( ^-(: 4) alkyl, phenyl,% naphthalene, or heteroaryl substituted (CrC4) alkyl, wherein each of the benzene #, naphthyl, and heteroaryl is selected from 1 to 3 as needed Since _ _

C (= Ο) Ο ( C 1 - C 4)院基、鹵基、氰基、-c (= 〇 ) ]si JJC (= Ο) Ο (C 1-C 4) courtyard, halo, cyano, -c (= 〇)] si JJ

(G-C4)院基、（Cl-C4)院氧基、（Cl-C4)鹵烷基、键基 及羥基（Ci-C4)烷基之取代基取代， 之式（1)之菸鹼醯胺衍生物，或若適當時，彼在醫趨 接受之鹽類及/或異構物、彼之互變體、媒合物、多型體 、同位素變異體或代謝物特別佳。 以其中： ❖ m及n等於1， ♦&gt;Ri及R2各自係獨立選自氫原子、鹵基及甲基之元件，(G-C4) substituents, (Cl-C4), oxo, (Cl-C4) haloalkyl, bond groups, and hydroxy (Ci-C4) alkyl substituents, nicotine of formula (1) Derivatives of amidine, or, where appropriate, salts and / or isomers, tautomers, mediators, polymorphs, isotopic variants or metabolites that are acceptable in medical practice. In which: ❖ m and n are equal to 1, ♦ &gt; Ri and R2 are each independently selected from the group consisting of a hydrogen atom, a halogen group and a methyl group,

X 係-0-， ♦&gt;R3係視需要以1至3個分別選自鹵基、氰基、（C^C4) 烷基、（G-C4)烷氧基、（Cl_C4)烷硫基、-C( = 〇)NH2、· c( = o)nh(Ci-c4)烷基、羥基、-0_c( = 〇)(Ci-C4)烷基、· c( —〇)·0-(Κ4)燒基及羥基（C「C4)焼基之取代基取代之 苯基， ❖ γ係選自部份的式（1 5)之基_c( = 0)_， +及R4係選自以下之元件， (〇視需要以；1至3個分別選自羧酸、c( = 〇)_0-(Ci_C4) -22- v (19) (19)200304824 院基、鹵基、氰基、-C( = 0)NH2、（CpCd烷基、（Cr 烷氧基、（Ci-CU)鹵烷基、羥基及羥基（Cl-C4)烷基 之取代基取代之苯基，或 (b )以羥基或苯基取代之（Cl_C4)烷基，其中將該苯基視 需要以1至3個分別選自羧酸、C( = 0)0(Cl-C4)烷基 、鹵基、氰基、-C( = 0)NH2、（κ4)烷基、（CrCd 燒氧基、（G-C4)鹵烷基、羥基及羥基（Cl-C4)烷基之 取代基取代， 之式（1)之菸鹼醯胺衍生物，或若適當時，彼在醫藥上可 接受之鹽類及/或異構物、彼之互變體、媒合物、多型體 、同位素變異體或代謝物更特別佳。 以其中： m及n等於J， ♦&gt;Rl係氫原子或氟基及R2係氫原子， ❖ X係-0… 々R3係視需要以選自鹵基及_c( = 0)-(MCi_C4)烷基之取代 基取代之苯基， γ係選自部份的式（i 5)之基_ C (= 〇) _， ❖及R4係選自以下之元件， (a )視需要以1至3個分別選自鹵基、（Q-C4)烷基及 經基之取代基取代之苯基，或 (b )以淫基或苯基取代之（Ci_c4)烷基，其中將該苯基 視需要以1至3個分別選自鹵基、（Q-C4)烷基及羥 基之取代基取代， (20) (20)200304824 之式（1)之菸鹼醯胺衍生物，或若適當時，彼在醫藥上可 接受之鹽類及/或異構物、彼之互變體、媒合物、多型體 、同位素變異體或代謝物還更特別佳。 特別佳的式（1)之菸鹼醯胺衍生物係如以下實例節段 中的說明，即： 2- (4-氟基苯氧基）-1^-{4-[(2-羥基-3-甲基苯醯基胺基） 甲基]苯甲基}菸鹼醯胺， 3- (3-{4-[(3-羥基苯醯基胺基）甲基]苯甲基胺甲醯基} 吡啶-2-氧基）苯甲酸乙酯， 2-(4-氟基苯氧基）-N-{4-[(6-氟基-2-羥基苯醯基胺基） 甲基]苯甲基}菸鹼醯胺， 2_(4_赢基苯氧基）-N-{4-[(5-氧基-2-經基苯釀基胺基） 甲基]苯甲基}菸鹼醯胺， 2-(4-氟基苯氧基）-1{4-[(3-羥基-4-甲基苯醯基胺基） 甲基]苯甲基}菸鹼醯胺， 2-(4-氟基苯氧基）-N-{4-[(3-羥基苯醯基胺基）甲基]苯 曱基}菸鹼醯胺， 2-(4-氟基苯氧基）-N-{4-[(2-羥基苯醯基胺基）甲基]苯 甲基}菸鹼醯胺， 2-(4-氟基苯氧基）-N-{ 4-[(4-羥基苯醯基胺基）甲基]苯 甲基}菸鹼醯胺， 2-(4-氟基苯氧基）-N-{4-[(2-羥基-4-甲基苯醯基胺基） 甲基]苯甲基}菸鹼醯胺， 2-(4-氟基苯氧基）-N-{4-[(3-羥基-2-甲基苯醯基胺基） -24- (21) (21)200304824 甲基]苯甲基}菸鹼醯胺， 2- (4-氟基苯氧基）-N-{4-[(2-羥基-5-甲基苯醯基胺基） 甲基]苯甲基}菸鹼醯胺， 5-氟基-2-(4-氟基苯氧基）-N-{4-[(2-羥基苯醯基胺基） 甲基]苯甲基}菸鹼醯胺， 5-氟基-2-(4-氟基苯氧基）-N-{4-[(2-羥基乙醯基胺基） 甲基]苯甲基}菸鹼醯胺， 5-氟基-2-(4-氟基苯氧基）-N-{4-[(4-羥基苯醯基胺基） 曱基]苯甲基}薛鹼醯胺， 3- (3-{4-[(3-羥基苯醯基胺基）甲基]苯曱基胺甲醯基} 吡啶-2 -氧基）苯甲酸乙酯， 3-(3-{4-[(2-羥基苯乙醯基胺基）甲基]苯甲基胺甲醯基 }吡啶-2-氧基）苯甲酸乙酯， 3-(3-{4-[(3-羥基苯乙醯基胺基）甲基]苯甲基胺甲醯基 }吡啶氧基）苯甲酸乙酯， 3-(3_{4-[(4-羥基苯乙醯基胺基）甲基]苯甲基胺甲醯基 }吡啶-2-氧基）苯甲酸乙酯。 也可將式（1)之菸鹼醯胺衍生物視需要轉變成在醫藥 上可接受之鹽類。式（1)之菸鹼醯胺衍生物的這些在醫藥 上可接受之鹽類特別包括其酸加成鹽及鹼鹽類。 以形成無毒性鹽類之無機或有機無毒性酸形成適合的 酸加成鹽類。適合的這些酸加成鹽類實例係氫氯酸鹽、氫 溴酸鹽、氫碘酸鹽、硫酸鹽、硫酸氫鹽、硝酸鹽、磷酸鹽 、磷酸氫鹽、醋酸鹽、馬來酸鹽、富馬酸鹽、酒石酸鹽、 -25- (22) (22)200304824 檸檬酸鹽、葡糖酸鹽、琥珀酸鹽、葡糖二酸鹽、苯甲酸鹽 、甲烷磺酸鹽、乙烷磺酸鹽、苯磺酸鹽、對-甲苯磺酸鹽 及雙羥萘酸鹽類。 以形成無毒性鹽類之鹼形成適合的鹼鹽類，如鹼金屬 鹽、鹼土金屬鹽或與氨及生理上的受耐性有機胺之加成鹽 類。適合的這些鹼鹽類實例係鈉、鉀、鋁、鈣、鎂、鋅或 銨鹽及與三乙胺、乙醇胺、二乙醇胺、三甲胺、甲胺、丙 胺、二異丙胺、N，N-二甲基乙醇胺、苯甲胺、二環己胺、 N-苯甲基-石·苯乙胺、N，N，-二苯甲基乙撐二胺、二苯撐 二胺、奎寧、膽鹼、精胺酸、賴胺酸、半胱胺酸、二苯甲 胺、參（2-羥乙基）胺或ααα -參（羥甲基）甲胺之加成鹽 類。 包括酸性基及鹼性基之化合物也可以內鹽或甜菜鹼形 式存在，其也在本發明的範圍內。以參考Berge等人之J Pharm Sci，1 977，66, p 1-19 檢視適合的鹽類。 通常可以根據熟練本技藝的人已知的慣用步驟自式 (1)之菸鹼醯胺衍生物獲得鹽類，例如，與有機或無機酸 或鹼溶劑或分散劑組合，或另一選擇係自其它鹽類的陰離 子交換或陽離子交換作用。可自溶液沉澱出鹽及以過濾或 以溶劑的蒸發作用回收鹽。 式（1)之菸鹼醯胺衍生物也可以立體異構物形式存在 。如果式（1)之菸鹼醯胺衍生物包括一或多個不對稱中心 時，則這些可以彼此獨立具有組態或（R)組態°本發明 包括式（1 )之菸鹼醯胺衍生物所有可能的立體異構物’例 -26- (23) (23)200304824 如，對映異構物及非對映異構物，以及二或多種立體異構 · 物形式之混合物，例如，對映異構物及/或非對映異構物 以所有比例之混合物。本發明因此係關於具有對映異構純 形式，同時成爲左旋性及右旋性異構體、外消旋物形式及 兩種對映異構物以所有比例之混合物形式的對映異構物。 在順式/反式異構現象的存在下，本發明係關於順式與反 式兩種形式及這些形式以所有比例之混合物。若必要時， 在合成作用中以使用立體化學均一性原料、以立體選擇性 · 合成作用或根據慣用的方法（例如，以色層分離法、結晶 作用或以對掌相之色層分離法）可以製備各個立體異構物 。若適當時，可在分離立體異構物之前進行衍生化作用。 可在式（1)之菸鹼醯胺衍生物階段或在合成期間的原料或 中間物階段分離出立體異構物混合物。 而且，根據本發明的式（1)化合物包括移動式氫原子 ，即以各種互變體形式存在。本發明也關於式（1 )化合物 的所有互變體。 鲁 本發明更包括其它型態的式（1)之菸鹼醯胺衍生物， 例如，媒合物（如水合物及多型體），即各種不同的結晶結 構之根據本發明的菸鹼醯胺衍生物。 本發明也包括式（1)之菸鹼醯胺衍生物或其在醫藥上 ’ 可接受之鹽的所有適合的同位素變異體。將式（1 )之菸鹼 · 醯胺衍生物或其在醫藥上可接受之鹽定義成一種將其中至 少一個原子以具有相同的原子數，但是原子量與經常發現 的自然原子量不同的原子代替之變異體。可以倂入式（1) -27- (24) (24)200304824 之菸鹼醯胺衍生物及其在醫藥上可接受之鹽類的同位素異 實例包括氫、碳、氮、氧、硫、氟及氯之同位素，如分別 是 2H、3H、13C、14C、15N、17〇、18〇、35s、18f 及 36ci 。式（1)之菸鹼醯胺衍生物及其在醫藥上可接受之鹽類特 定的同位素變異體（例如，那些其中倂入放射活性同位素（ 如3H或14c)之變異體）可用於藥物及/或基質組織分布硏 究。以氘化（及3H)及碳-14(即14c)同位素特別佳，因爲彼 等容易的製備作用及偵測能力。而且，以同位素（如氚， 即2 H)的取代作用可以提供以更高的代謝穩定性得到特定 的治療利益，例如，增加在活體內的半衰期或減少劑量需 求，並在一些環境下可能因此較佳。通常可以使用適合的 試劑的適當的同位素變異體以慣用的步驟製備式（1)之菸 鹼醯胺衍生物及其在醫藥上可接受之鹽類，如在以下的實 例及製備作用節段中說明的例證方法及製備作用。 若適當時，本發明也關於式（1 )之菸鹼醯胺衍生物的 活性代謝物，即在細胞代謝作用期間及在有機體具有活性 之衍生物。例如，這些代謝物可以是式（1 )化合物之葡糖 苷酸衍生物、N-氧化物衍生物或磺酸鹽衍生物。 根據進一步的觀點，本發明係關於式（1)之菸鹼醯胺 衍生物的混合物及其與彼在醫藥上可接受之鹽、媒合物、 多型體、異構物型式、代謝物及/或同位素型式之混合物 〇 根據本發明，將除了其在醫藥上可接受之鹽類（即該 媒合物 '多型體、異構物形式、互變體、代謝物及同位素 •28- (25) (25)200304824 型式）之外的所有本文以上說明的式（1)之菸鹼醯胺衍生物 型式在以下（包括申請專利範圍）定義成式（1)之菸鹼醯胺衍 生物的”衍生型式”。 式（1)之菸鹼醯胺衍生物、彼在醫藥上可接受之鹽類 及/或衍生型式係有價値之醫藥活性化合物，其適合於許 多以PDE4涉入之異常的治療法及預防法，特別適用於發 炎性異常、過敏性異常、呼吸性疾病及創傷。可將作爲治 療法或預防法的醫藥物之如上述之式（1)之菸鹼醯胺衍生 物、彼在醫藥上可接受之鹽類及/或衍生型式根據本發明 投予動物，以晡乳類較佳，以及特別是人類。可將彼以其 本身，或彼此的混合物或醫藥製品型式投藥，允許彼經腸 (胃）或非經腸投藥，以及其包括以有效劑量之至少一種式 (1)之菸鹼醯胺衍生物、其在醫藥上可接受之鹽類及/或衍 生型式作成活性成份（除了慣用的無醫藥毒害性之賦形劑 及/或添加劑之外）。 因此，本發明也關於包括式（1)之菸鹼醯胺衍生物及/ 或彼在醫藥上可接受之鹽類及/或衍生型式與慣用的無醫 藥毒害性之賦形劑及/或添加劑一起的組成物。可以根據 與標準的醫藥實用性相容的熟知的方法製備這些組成物。 該組成物通常包括從〇 5至6 0重量％之活性化合物及從 4〇至9 9 5重量％之賦形劑及/或添加劑。根據本發明，該 賦形劑及/或添加劑係專家熟知的試劑，以提供最終的醫 藥組成物有利的特性。典型的賦形劑及/或添加劑包括（但 不以任何方式限於此）酸化及鹼化劑、氣霧推進劑、抗微 -29- (26) (26)200304824 生物劑（包括抗細菌劑、抗黴菌劑及抗原蟲劑）、抗氧化劑 、緩衝劑、螯合劑、皮膚活性劑、分散劑、懸浮劑、潤膚 劑、乳化劑、穿透加強劑、保存劑、分離劑、溶劑、穩定 劑、硬化劑、糖、界面活性劑及調味劑。而且，將該組成 物製備成與希望的投藥途徑相容的型式，供任何既定的病 患使用與適合於欲治療之任何既定的病患之疾病、異常或 症狀。可以想像的適合的投藥途徑係經腸及非經腸投藥途 徑，如例如局部、經口、鼻內、肺部、直腸、靜脈內、動 脈內、腹膜內、椎管內、心室內、尿導管內、胸骨內、顱 內、肌肉內、皮下或眼內途徑。 在希望以經口途徑投藥時，則將式（1)之菸鹼醯胺衍 生物、彼在醫藥上可接受之鹽類及/或彼之衍生型式以立 即-、延緩-、改良-、持續-、間續-或控制-釋放應用之藥 片、膠囊、多重微粒、凝膠、薄膜、胚珠、酏劑、溶液或 懸浮液劑型投藥，其可以包括調味劑或著色劑。也可將式 (1)之菸鹼醯胺衍生物、彼在醫藥上可接受之鹽類及/或彼 之衍生型式以快分散或快溶解劑型或高能量分散或塗佈之 粒子投藥。若必要時，式（υ之菸鹼醯胺衍生物、彼在醫 藥上可接受之鹽類及/或彼之衍生型式的適合的調配物可 以具有經塗佈或未經塗佈之劑型。 這些固體醫藥組成物（例如，藥片）可以包括賦形劑（ 如微結晶纖維素、乳糖、檸檬酸鈉、碳酸鈣、磷酸二鈣、 甘胺酸及源粉（以玉米、馬鈴薯或樹薯澱粉較佳））、崩散 劑（如澱粉乙醇酸鈉、交聯羧甲基纖維素鈉及特定的複合 -30- (27) (27)200304824 矽酸鹽）及粒化結合劑（如聚乙烯環吡啶酮、羥丙基甲基纖 維素（HPMC)、羥丙基纖維素（HPC)、蔗糖、白明膠及阿拉 伯膠）。此外，可以包括潤滑劑，如硬脂酸鎂、硬脂酸、 山嵛酸甘油酯及滑石粉）。 作爲一般實例之藥片調配物典型係可以包括介於約 〇 〇 1毫克至5 〇 〇毫克之活性化合物，同時藥片塡充重量可 在從5〇毫克至1〇〇〇毫克之範圍內。可以標準的方法製造 藥片，例如，以直接壓縮或以濕式或乾式粒化法。可將藥 片核心以適當的罩層塗佈。 也可以使用固態組成物或類似型態作爲在白明膠或 HPMC膠囊中的塡充劑。就此而論，較佳的賦形劑包括乳 糖、澱粉、纖維素、牛奶糖或高分子量聚乙二醇。關於水 懸浮液及/或酏劑，可將式（1)之菸鹼醯胺衍生物、彼在醫 藥上可接受之鹽類及/或彼之衍生型式與各種甜味劑、著 色劑或染料，與乳化及/或懸浮劑及與稀釋劑（如水、乙醇 、丙二醇及甘油）組合和彼之組合物組合。 也可將式（1)之菸鹼醯胺衍生物、彼在醫藥上可接受 之鹽類及/或彼之衍生型式以注射（例如，經靜脈內、動脈 內、腹膜內、椎管內、心室內、尿導管內、胸骨內、顱內 、肌肉內或皮下）投藥或可將彼以灌入或無針注射技術投 藥。最好使用可以包括其它物質（例如，足以使溶液與血 液具有等滲性之鹽類或葡萄糖）之無菌水溶液形式用於這 種投藥。若必要時，應將水溶劑經適合的方式緩衝（以從 3至9之PH較佳）。以那些熟練本技藝的人熟知的標準的 -31 - (28) (28)200304824 醫藥技術可輕易完成在無菌條件下的這些調配物製備作用 〇 經常將式（1)之菸鹼醯胺衍生物、彼在醫藥上可接受 之鹽類及/或彼之衍生型以從0 001毫克/公斤至100毫克/ 公斤（單次或多次服用）之日劑量以口服投予或注射人類病 患。 也可將式（1)之菸鹼醯胺衍生物、彼在醫藥上可接受 之鹽類及/或彼之衍生型式經鼻內或吸入投藥，並方便以 乾散劑吸入器形式輸送，或以來自使用或不使用適合的推 進劑（例如，二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷 、氫氟鏈烷（如1，1，1，2-四氟乙烷（HFA 134A[商標])或 1，1，1，2,3,3,3-七氟丙烷（HFA 227EA [商標]))、二氧化碳或 其它適合的氣體）之加壓容器、泵、噴灑器、霧化器或噴 霧器之氣霧形式輸送。在加壓之氣膠案例中，以提供輸送 以儀表計量的量之閥可以測定劑量單位。加壓容器、泵、 噴灑器、霧化器或噴霧器可以包括活性化合物之溶液或懸 浮液，例如，使用乙醇與推進劑之混合物作爲溶劑，其可 以另外包括潤滑劑（例如，花椒聚糖三油酸酯）。可以調配 在吸入器或吹入器使用的膠囊或匣（以例如白明膠製得的） ’使其包括式（1)之菸鹼醯胺衍生物與適合的散劑鹼（如乳 糖或澱粉）之散劑混合物。 氣霧或乾散劑調配物的分配係每一次輸予病患的以儀 表計量的劑量或，，吹噗量，，包括從1微克至4000微克之式 (1)之菸鹼醯胺衍生物較佳。整日的氣霧服用量係在從1 (29) (29)200304824 微克至20微克之範圍內，可將其以單次服用量投藥，或 更常以整天經多次服用。 也可將式（1)之菸鹼醯胺衍生物、彼在醫藥上可接受 之鹽類及/或彼之衍生型式以乳膏、凝膠、懸浮液、乳液 、軟膏、粉劑、散劑、噴劑、泡沬、慕斯、倂入藥物之繃 帶、溶液、海棉、織物、微乳液、薄膜、皮膚貼片、軟膏 (如凡士林或以白色軟石鱲爲主之軟膏或經由皮膚貼片或 其它裝置）形式經局部或皮膚投藥。可以使用穿透加強劑 ，並可以使用與環糊精組合之化合物。此外，可以使用離 子導入術、電子導入術、電泳療法或超聲波導入術輸送化 合物。可將彼直接在創傷位置上投藥。可將彼倂入塗佈的 縫線中。例如，可將彼倂入由無機油、花椒聚糖單硬脂酸 酯、聚山梨酸酯60、黥鱲酯鱲、十八烷醇、2-辛基十二 烷醇、苯甲醇、水、聚乙二醇及/或液態石蠟之水性或油 狀懸浮液所組成的乳液或乳膏，或可將彼倂入適合的軟膏 中，該軟膏係由一或多種以下：無機油、液態凡士林、白 凡士林、丙二醇、聚氧乙烯聚氧丙烯化合物、乳化蠟及水 所組合的，或與纖維素或聚丙烯酸酯衍生物或其它黏度改 良劑成爲水凝膠，或與丁烷/丙烷、UFA、CFC、C02或其 它適合的推進劑成爲乾散劑或液態噴劑或氣膠’也視需包 括潤滑劑（如花椒聚糖三油酸酯），或與白軟石鱲或以聚乙 二醇浸漬之紗布繃帶或與水凝膠、水膠體、藻酸酯成爲藥 膏繃帶或成爲膜繃帶之倂入藥物之繃帶。 可將以懸浮液或其它調配物之化合物以從〇 〇 1至5 0 -33- (30) (30)200304824 毫克/毫升（以從0 3至3〇毫克/毫升較佳）之日劑量經局部 投予具有急性/手術創傷之人類病患。該劑量可隨創傷尺 寸、創傷是否是開放式 '閉合式或部份閉合式創傷及皮膚 是否完整而改變。 或者可將式（1 )之菸鹼醯胺衍生物、彼在醫藥上可接 受之鹽類及/或彼之衍生型式經直腸投藥，例如，以凝膠 的栓劑型式，雖然也可以考慮其它型式。 也可將彼經由眼部投藥，特別是眼部瘢痕。關於眼睛 的應用，可將化合物調配成在pH經調整之等滲性無菌食 鹽水中的微粒懸浮液，或以調配成視需要與保存劑（如氯 苯甲烷銨）組合之在pH經調整之等滲性之無菌食鹽水中的 溶液較佳。或者可將彼調配成軟膏，如凡士林。 也在A Lehir之” Pharmacie galenique”中詳細說明如 本文上述的各種醫藥調配物（Mason編輯的第2版，1992 年）。 醫師將在任何情況下決定最適合於任何各個病患實際 的劑量，並將隨病患的年齡、重量、健康狀況及性別與欲 治療之疾病嚴重性、異常或症狀、與其它治療（等）視需要 的組合療法、特殊病患的反應及通常任何獨特的相關疾病 、異常或症狀和病患的因素而改變。因此，男人用之日劑 量經常可以包括從5 0毫克至5公克，若適當時，以單次 投藥或同時以2或多次投藥。當然可以有値得更高或更低 的劑量範圍的案例，以及該範圍係在本發明的範圍內。 根據本發明，也可以使用式（1)之菸鹼醯胺衍生物、 -34- (31) (31)200304824 彼在醫藥上可接受之鹽類及/或彼之衍生型式與環糊精組 合。以已知的環糊精形成具有藥物分子之包含及非包含複 合物。以藥物-環糊精複合物的形成作用可以變更藥物分 子的溶解度、分解速度、生物利用率及/或穩定特性。藥 物-環糊精複合物通常適用於大部份的劑型及投藥途徑。 可以作爲與藥物直接複合的替代物之環糊精作爲輔助添加 劑使用，例如，作爲載體、稀釋劑或溶解劑。最常使用 α-、/3-及 環糊精，以及在 WO-A-91/11172、WO-A-94/02418及WO-A-98/55148中說明適合的實例。 根據本發明的另一個具體實施例，也可將式（1)之菸 鹼醯胺衍生物、其在醫藥上可接受之鹽類、其衍生型式或 組成物作爲與一或多種添加的治療劑共同投予病患之組合 物使用，以獲得一些特殊預期的治療及結果。第二個或更 多的添加治療劑也可以是式（1)之菸鹼醯胺衍生物、或其 在醫藥上可接受之鹽類、其衍生型式或組成物，或是一或 多種本技藝已知的PDE4抑制劑。更典型的是第二或更多 的治療劑將選自不同的治療劑種類。 如本文所使用之與如本文提及之式（1)之菸鹼醯胺衍 生物及一或多種其它的治療劑”共同治療”、”共同-治療” 及”組合”術語希望代表，以及確實提及和包括以下： •將菸鹼醯胺衍生物（類）及治療劑（類）的這種組合物同時 投予需要治療之病患，其係在將這些組份一起調配成 單一劑型，接著使這些組份同時釋予該病患的時候， •將菸鹼醯胺衍生物（類）及治療劑（類）的這種組合物幾乎 -35· (32) (32)200304824 同時投予需要治療之病患，其係在將這些組份各自調 · 配成單獨的劑型，使該病患在幾乎同時服用，使這些 - 組份在幾乎同時釋予該病患的時候， •將菸鹼醯胺衍生物（類）及治療劑（類）的這種組合物依次 投予需要治療之病患，其係在將這些組份各自調配成 單獨的劑型，使該病患在每一次明顯的投藥間隔下依 次服用，使這些組份在依次不同的時間釋予該病患的 時候，及 © •將菸鹼醯胺衍生物（類）及治療劑（類）的這種組合物依次 投予需要治療之病患，這是在將這些組份一起調配成 單一劑型，以受控制的方式釋放這些組份，使彼在相 同及/或不相同的時間同時、連續及/或重複投予該病患 的時候。 可與式（1)之菸鹼醯胺衍生物、其在醫藥上可接受之 鹽類、其衍生型式或組成物組合使用的其它適合的治療劑 實例包括(但不任何方式受限於此）： ^ (a ) 5-脂肪氧合酶（5-LO)抑制劑或5-脂肪氧合酶活化蛋 白質（FLAP)拮抗劑， (b )白三烯素拮抗劑（LTRAs)，包括LTB4、LTC4、LTD4 及LTE4拮抗劑， (c )組胺系受體拮抗劑，包括Η 1及H3拮抗劑， ~ (d)用於解除充血的^ 1 -及^ 2 -腎上腺素受體劑' 血管收 縮劑、交感神經刺激劑， (e )蠅蕈鹼系M3受體拮抗劑或抗膽鹼能劑’ -36- (33) (33)200304824 (f)々2-腎上腺素受體激動劑， (g )茶驗， (h )色甘酸鈉， (i ) COX-1抑制劑（NSAIDs)及COX-2選擇性抑制劑， (j )經口或吸入之糖皮質類固醇， (k )抗內源發炎體之單株抗體活性， (1 )抗腫瘤壞死因子（抗-TNF- α )劑， (m )黏著分子抑制劑，包括VLA-4拮抗劑， (η)激肽-B!-及B2-受體拮抗劑， (〇 )免疫抑制劑， (p )基質金屬蛋白酶抑制劑（MMPs)， (q)速激肽NKi、NK2及NK3受體拮抗劑， (I·)彈性蛋白酶抑制劑， (s)腺苷A2a受體激動劑， (t )尿激酶抑制劑， (U )在多巴胺受體上起作用之化合物，例如，D2激動劑 ，及 (v ) NF κ yS路徑之調節劑，例如，IKK抑制劑。 根據本發明，以式（1)之菸鹼醯胺衍生物與以下之組 合物較佳： -蠅覃鹼系M 3受體激動劑或抗膽鹼能劑，特別包括 異丙托銨（ipratropium)鹽類（即溴化物）、噻托胺 (tiotropium)鹽類（即溴化物）、歐系托鹽類（即溴化 物）、皮若日平（perenzepine)及泰令日平 (34) (34)200304824 (t elenzepine)， -Θ 2 -腎上腺素受體激動劑，包括舒喘寧（a 1 b u t e r o 1) 、沙 丁胺醇（s a 1 b u t a m o 1)、福莫特若（f 〇 r m o t e r o 1)及 沙美特羅（salmeterol)， -糖皮質類固醇，特別是減少系統反效果之吸入式糖 皮質類固醇，包括脫氫可的松、脫氫皮甾醇、氟 尼縮松（flunisolide)、曲安奈德（triamcinolone acetonide)、倍氯美松雙丙酸酯 beclomethasone dipropionate)、布地萘德（budesonide)、氟替卡松 丙酸酯（fluticasone propionate)及莫美他松糠酸酯 (mometasone furoate)， -腺苷A2a受體激動劑。 應認知的是以本文所提及之治療包括治病、減輕及預 防性治療。隨後的說明係關於可施予式（1)之菸鹼醯胺衍 生物之治療應用。 以式（1)之菸鹼醯胺衍生物抑制PDE4同功酵素及因此 具有廣泛的治療應用，如以下進一步的說明，因爲同功酵 素之PDE4族系在所有的哺乳類生理學中扮演基本角色。 以PDE4同功酵素執行的酵素角色係腺苷3，，5，_環系單磷 酸（cAMP)在初炎性白細胞內的細胞內水解作用，依次負 有調節許多在體內的激素效應之責任及因此以PDE4抑制 劑在各種生理處理中扮演重要的角色。在本技藝中有多方 面的文獻說明PDE4抑制劑在各種抑制細胞反應上的效應 ，除了增加cAMP之外，其包括抑制超氧化物的生產作用 (35) (35)200304824 、去顆粒作用、向化性及在嗜曙紅細胞、嗜中性細胞及單 細胞中釋放腫瘤壞死因子a (TNF α )。 因此，本發明進一步的觀點係關於以式（1)之菸鹼醯 胺衍生物、其在醫藥上可接受之鹽類、其衍生型式或組成 物治療其中涉及PDE4同功酵素之疾病、異常及症狀之應 用。本發明也特別關於以式（1)之菸鹼醯胺衍生物、彼在 醫藥上可接受之鹽類、彼之衍生型或組成物治療由以下所 組成的群組之疾病、異常及症狀之用途： •不論什麼型式、發病原因或致病機制之氣喘病，特別係 選自異位性氣喘病、非異位性氣喘病、過敏性氣喘病 、以異位性枝氣管IgE-介入之氣喘病、枝氣管氣喘病 、本質型氣喘病、實質型氣喘病、由病理生理阻礙引 起的內因性氣喘病、由環境因子引起的外因性氣喘病 、未知或不明原因之本質型氣喘病、枝氣管氣喘病、 氣腫性氣喘病、以運動誘發之氣喘病、以過敏原誘發 之氣喘病、以冷空氣誘發之氣喘病、職業性氣喘病、 以細菌、黴菌、原蟲或病毒感染之感染性氣喘病、非 過敏性氣喘病、初期氣喘病及陣發性哮喘性嬰兒徵候 群之氣喘病， •慢性或急性枝氣管收縮、慢性枝氣管炎、小氣道阻塞及 氣腫， •不論什麼型式、發病原因或致病機制之阻塞性或發炎性 氣道疾病，特別係選自慢性嗜曙紅細胞肺病、慢性阻 塞性肺部疾病（COPD)、包括慢性枝氣管炎、肺水腫或 (36) (36)200304824 與其有關連之呼吸困難的COPD、以不可逆、漸進式氣 道阻塞、成人呼吸性壓迫徵候群（ARDS)爲特徵之 COPD及對其它的藥物治療法的氣道高反應性而發生的 病情加劇之阻塞性或發炎性氣道疾病， •不論什麼型式、發病原因或致病機制之肺塵沉著病，特 別係選自礬土沉著病或鋁礬土工人沉著病、炭末沈著 症或礦工氣喘病、石棉沉著症或蒸氣維修工氣喘病、 霰粒腫或石末沉著症、以吸入駝鳥毛塵所以引起的禿 睫、以吸入鐵粒子所引起的鐵沈著肺病、矽肺病或碾 石工病、棉肺症或棉塵氣喘病及滑石粉塵沉著病之肺 塵沉著病， •不論什麼型式、發病原因或致病機制之枝氣管炎，特別 係選自急性枝氣管炎、急性喉氣管枝氣管炎、花生枝 氣管炎、卡他性枝氣管炎、格魯布性（croupus)枝氣管 炎、乾性枝氣管炎、感染性枝氣管炎、氣喘性枝氣管 炎、產生性枝氣管炎、葡萄球菌或鏈球菌性枝氣管炎 及豬丹毒性枝氣管炎之枝氣管炎， •不論什麼型式、發病原因或致病機制之枝氣管炎擴張症 ，特別係選自圓筒狀枝氣管炎擴張症、成囊性枝氣管 炎擴張症、紡綞狀梭形枝氣管炎擴張症、微血管型枝 氣管炎擴張症、肺囊性枝氣管炎擴張症、乾性枝氣管 炎擴張症及濾泡枝氣管炎擴張症之枝氣管炎擴張症， •不論什麼型式、發病原因或致病機制之季節的過敏性鼻 炎或常年的過敏性鼻炎或鼻竇炎，特別係選自化膿性 -40- (37) (37)200304824 或未化膿性鼻竇炎、急性或慢性鼻竇炎及篩竇炎、額 竇炎、上頜竇炎或蝶竇炎之鼻竇炎， •不論什麼型式、發病原因或致病機制之類風濕性關節炎 ’特別係選自急性關節炎、急性痛風性關節炎、慢性 發炎性關節炎、退化性關節炎、感染性關節炎、萊姆 (Lyme)關節炎、增殖性關節炎、牛皮癖性關節炎及脊 柱性關節炎之類風濕性關節炎， •與發炎有關的痛風及感冒和疼痛， 春 •不論什麼型式、發病原因或致病機制之與嗜曙紅細胞有 關之異常，特別係選自嗜曙紅白血球增高症、肺腫瘤 溶解嗜曙紅白血球增高症、勞弗勒氏（L〇ffier，s)徵候群 、慢性嗜曙紅細胞肺炎、熱帶肺嗜曙紅白血球增高症 '枝氣管肺炎性麴菌病、麴菌腫、肉芽腫（包括嗜曙紅 細胞、過敏性肉牙腫血管炎或丘-施氏（C h u r g - S t r a u s s) 徵候群）、結節性多動脈炎（PAN)及全身壞死性血管炎 之與嗜曙紅細胞有關之異常， ® •異位性皮膚炎、過敏性皮膚炎、接觸性皮膚炎或過敏性 或異位性濕疹， •不論什麼型式、發病原因或致病機制之蓴麻疹，特別係 5¾自以免疫性介入之尋麻疼、以補體介入之尋麻參、 致蓴麻疹物質誘發之蓴麻疹、以物理劑誘發之蓴麻疹 ‘ 、以壓力誘發之蓴麻疹、特發性蓴麻疹、急性蓴麻疹 、慢性奪麻疼、血管性水腫、膽鹼能蓴麻瘆、體染色 體顯性形式及後天性形式之寒冷性蓴麻疹、接觸性蓴 -41 - (38) (38)200304824 麻疹、嚴重性蓴麻疹及丘疹性奪麻疹之蓴麻疹， •不論什麼型式、發病原因或致病機制之結膜炎，特別係 選自光化性結膜炎、急性卡它性結膜炎、急性傳染性 結膜炎、過敏性結膜炎、異位性結膜炎、慢性卡它性 結膜炎、膿性結膜炎及春季型結膜炎之結膜炎， •不論什麼型式、發病原因或致病機制之葡萄膜炎，特別 係選自全部或部份葡萄膜發炎、前段葡萄膜炎、虹彩 炎、睫狀體炎、虹膜睫狀體炎、肉芽腫型葡萄膜炎、 非肉芽腫型葡萄膜炎、晶狀體抗原葡萄膜炎、後端葡 萄膜炎、脈絡膜炎及脈絡視網膜炎之葡萄膜炎， •牛皮癬， •不論什麼型式、發病原因或致病機制之多發性硬化症， 特別係選自初發性多發性硬化症及復發型多發性硬化 症之多發性硬化症， •不論什麼型式、發病原因或致病機制之自身免疫/發炎 性疾病，特別係選自自身免疫血液治療異常、溶血性 貧血、再生不良性貧血、純紅細胞性貧血、特發性血 小板低下性紫斑、全身性紅斑狼瘡症、多發性軟骨炎 、硬皮症、韋格納氏肉芽腫（Wegener’s)、皮膚肌炎、 慢性活動性肝炎、重症肌無力、史蒂芬-詹森（St even s-John son)徵候群、特發性脂肪瀉、自身免疫發炎性腸病 、潰瘍性結腸炎、內分泌眼病變 '格雷氏疾病 (Grave's)、結節病、肺泡炎、慢性過敏性肺炎、原發 性膽汁性肝硬化、青少年糖尿病或I型糖尿病、乾燥性 -42- (39) (39)200304824 角膜結膜炎、流行性角膜結膜炎、擴散性肺 (p u 1 m ο n a r y)間纖維病變或肺（1 u n g)間纖維病變、特發性 _ 肺纖維病變、囊性纖維病變、具有或不具有腎病徵候 群之腎絲球腎炎、急性腎絲球腎炎、特發性腎病徵候 群、微小變化腎病變、發炎性/高增殖性皮膚病、良性 家族性天疱瘡、紅斑型天疱瘡、葉狀天疱瘡及尋常型 天疱瘡之自身免疫/發炎性疾病， •預防在器官移植之後的異體接枝排斥， 鲁 •不論什麼型式、發病原因或致病機制之發炎性腸病 (IBD)，特SU係選自膠狀性大腸炎、大腸炎性息肉、腸 道壁整層大腸炎、潰瘍性結腸炎及克隆氏疾病（CD)之 發炎性腸病， •不論什麼型式、發病原因或致病機制之敗血性休克，特 別係選自腎衰竭、急性腎衰竭、惡病質、瘧疾性惡病 質、低體質惡病質、尿毒症惡病質、心因性惡病質、 腎上腺惡病質或阿狄森氏病（Addison’s)、癌性惡病質 鲁 及由於以人類免疫性不全病毒（HIV)感染之惡病質之敗 血性休克， •肝臟傷害， •不論什麼型式、發病原因或致病機制之肺高壓症，包括 ’ 原發性肺高壓症/自發性高壓症、對充血性心臟衰竭之 - 續發性肺高壓症、對慢性阻塞性肺部疾病之續發性肺 高壓症、肺靜脈高壓症、肺動脈高壓症及以缺氧誘發 之肺高壓症， -43- (40) (40)200304824 •骨質流失症、原發性骨質疏鬆症及續發性骨質疏鬆症， •不論什麼型式、發病原因或致病機制之中樞神經系統異 常’特別係選自抑鬱症、阿茲海默氏病、巴金生氏病 、學習及記憶損傷、遲發的運動異常、藥物成癮、動 脈硬化性癡呆症及連同亨丁頓氏（Huntington’s)舞蹈病 之癡呆症 '威爾森氏症（Wilson’s)、震顫麻痺及丘腦萎 縮症之中樞神經系統異常， •感染，尤其係病毒的感染，其中這些病毒會增加在彼宿 主中的TNF- α生產作用或其中這些病毒對在彼宿主中 的TNF- α向上調節作用具有敏感性，所以對彼之複製 作用或其它的病毒活性有不利的衝擊性，包括選自 HIV-1、HIV-2及HIV-3、巨細胞病毒（CMV)、流行性 感冒病毒、腺病毒及疱疹病毒（包括帶狀疱疹及單純疱 性）之病毒， •酵母菌及黴菌感染，其中該酵母菌及黴菌對TNF-α之 向上調節作用具有敏感性及誘出在彼之宿主中的TNF-α生產作用（例如，黴菌性腦膜炎），特別係在連同以治 療全身性酵母菌及黴菌感染所選擇之其它藥物（包括（但 不限於此）多黏菌素（例如，多黏菌素Β)、咪唑（例如， 克黴唑（clotrimazole)、益康唑（econazole)、咪康唑 (miconazole)及酮康卩坐（ketoconazole))、三 Π坐（例如，赢 康唑（fluconazle)及易退唑（itranazole))與兩性黴素（例 如，兩性黴素B及粒質體兩性黴素B)—起投藥時， •缺血-再灌流傷害、缺血性心臟疾病、自身免疫性糖尿 -44 - (41) (41)200304824 病、視網膜自身免疫症、慢性淋巴細胞白血病、HIV 感染、紅斑性狼瘡、腎及輸尿管疾病、尿生殖和胃腸 道異常及攝護腺疾病， •減低在人體或動物體內的瘢痕成形作用，如在急性創傷 的復原時的瘢痕成形作用，及 •牛皮癖、其它的皮膚及化妝用品，包括減輕發炎現象、 皮膚軟化、皮膚彈性及增加濕度的活性。 本發明還有進一步的觀點也關於以式（1 )之菸鹼醯胺 衍生物、或其在醫藥上可接受之鹽類、其衍生型式或組成 物製造具有PDE4抑制活性之藥物的用途。本發明特別係 關於以式（1)之菸鹼醯胺衍生物、或其在醫藥上可接受之 鹽類、其衍生型式或組成物製造用於治療發炎、呼吸、過 敏及瘢痕成形疾病、異常及症狀之藥物及更精確的是治療 在以上陳列的疾病、異常及症狀之藥物的用途。 因此，本發明係提供用於治療哺乳類（包括人類）特別 有利的方法’包括以有效劑量之式（1)之菸鹼醯胺衍生物 、或其在醫藥上可接受之鹽類、其衍生型式或組成物治療 該哺乳類。更精確的是本發明係提供用於治療哺乳類（包 括人類）特別有利的方法，以治療發炎、呼吸、過敏及瘢 痕成形疾病、異常或症狀，該方法包括以有效劑量之式 (1)之菸鹼醯胺衍生物、其在醫藥上可接受之鹽類及/或衍 生型式治療該哺乳類。 以下的實例係例證式（1)之菸鹼醯胺衍生物之製備作 用： -45- (42) 200304824 實例1 : 2_(4-氟基苯氧基）-N-{4_[(2-羥基_3-甲基苯醯基胺 基）甲基]苯甲基}菸鹼醯胺 〇X is -0-,  ♦ &gt; R3 is optionally selected from halo, Cyano, (C ^ C4) alkyl, (G-C4) alkoxy, (Cl_C4) alkylthio, -C (= 〇) NH2, C (= o) nh (Ci-c4) alkyl, Hydroxyl, -0_c (= 〇) (Ci-C4) alkyl, · C (—〇) · 0- (Κ4) alkynyl and hydroxy (C “C4) fluorenyl substituted phenyl,  ❖ γ is selected from the base _c (= 0) _ of partial formula (1 5),  + And R4 are elements selected from  (〇 as needed; 1 to 3 are selected from carboxylic acids, c (= 〇) _0- (Ci_C4) -22- v (19) (19) 200304824 Halo, Cyano, -C (= 0) NH2, (CpCd alkyl, (Cr alkoxy, (Ci-CU) haloalkyl, A phenyl group substituted by a hydroxy group and a hydroxy (Cl-C4) alkyl group, Or (b) a (Cl_C4) alkyl substituted with a hydroxy or phenyl group, Wherein the phenyl group is optionally selected from carboxylic acid, C (= 0) 0 (Cl-C4) alkyl, Halo, Cyano, -C (= 0) NH2, (Κ4) alkyl, (CrCd alkoxy, (G-C4) haloalkyl, Substituted by hydroxy and hydroxy (Cl-C4) alkyl,  A nicotinamide derivative of formula (1), Or if appropriate, He is pharmaceutically acceptable salts and / or isomers, Other tautomorphs, Vehicle Polymorphism, Isotope variants or metabolites are particularly preferred.  With which:  m and n are equal to J,  ♦ &gt; Rl is a hydrogen atom or a fluorine group and R2 is a hydrogen atom,  ❖ X is -0 ... 々R3 is a phenyl substituted with a substituent selected from halo and _c (= 0)-(MCi_C4) alkyl, if necessary,  γ is selected from the group _ C (= 〇) _ of the formula (i 5),  ❖ and R4 are components selected from the following,  (a) if necessary, 1 to 3 selected from halo, (Q-C4) alkyl and phenyl substituted with a substituent of the group, Or (b) a (Ci_c4) alkyl group substituted with phenyl or phenyl, Wherein the phenyl is optionally selected from halo, (Q-C4) alkyl and hydroxy substituents,  (20) (20) 200304824 The nicotinamide derivative of formula (1), Or if appropriate, He is pharmaceutically acceptable salts and / or isomers, Other tautomorphs, Vehicle Polymorphism, Isotope variants or metabolites are also particularly preferred.  Particularly preferred nicotinamide derivatives of formula (1) are as described in the following example sections, which is:  2- (4-fluorophenylphenoxy) -1 ^-{4-[(2-hydroxy-3-methylphenylfluorenylamino) methyl] benzyl} nicotinamide,  3- (3- {4-[(3-hydroxyphenylfluorenylamino) methyl] benzylaminomethylmethyl} pyridine-2-oxy) benzoate,  2- (4-fluorophenylphenoxy) -N- {4-[(6-fluoroyl-2-hydroxyphenylfluorenylamino) methyl] benzyl} nicotinamide  2_ (4_vinylphenoxy) -N- {4-[(5-oxy-2-merylphenylamino) methyl] benzyl} nicotinamide,  2- (4-fluorophenylphenoxy) -1 {4-[(3-hydroxy-4-methylphenylfluorenylamino) methyl] benzyl} nicotinamide,  2- (4-fluorophenylphenoxy) -N- {4-[(3-hydroxyphenylfluorenylamino) methyl] phenylfluorenyl} nicotinamide,  2- (4-fluorophenylphenoxy) -N- {4-[(2-hydroxyphenylfluorenylamino) methyl] benzyl} nicotinamide,  2- (4-fluorophenylphenoxy) -N- {4-[(4-hydroxyphenylfluorenylamino) methyl] benzyl} nicotinamide,  2- (4-fluorophenylphenoxy) -N- {4-[(2-hydroxy-4-methylphenylfluorenylamino) methyl] benzyl} nicotinamide,  2- (4-fluorophenylphenoxy) -N- {4-[(3-hydroxy-2-methylphenylfluorenylamino) -24- (21) (21) 200304824 methyl] benzyl} Nicotinamide,  2- (4-fluorophenoxy) -N- {4-[(2-hydroxy-5-methylphenylmethylamino) methyl] benzyl} nicotinamide,  5-fluoro-2- (4-fluorophenoxy) -N- {4-[(2-hydroxyphenylfluorenylamino) methyl] benzyl} nicotinamide,  5-fluoro-2- (4-fluorophenoxy) -N- {4-[(2-hydroxyethylamidoamino) methyl] benzyl} nicotinamide,  5-fluoro-2- (4-fluorophenylphenoxy) -N- {4-[(4-hydroxyphenylfluorenylamino) fluorenyl] benzyl} chelinamine,  3- (3- {4-[(3-hydroxyphenylfluorenylamino) methyl] phenylfluorenylaminomethylmethyl} pyridine-2-oxy) benzoate,  3- (3- {4-[(2-hydroxyphenethylamidoamino) methyl] benzylaminomethylamido} pyridine-2-oxy) benzoate,  3- (3- {4-[(3-hydroxyphenethylamidoamino) methyl] benzylaminomethylamido} pyridyloxy) benzoate,  3- (3_ {4-[(4-hydroxyphenethylamidoamino) methyl] benzylaminomethylamido} pyridine-2-oxy) benzoate.  The nicotinamide derivative of formula (1) can also be converted into a pharmaceutically acceptable salt if necessary. These pharmaceutically acceptable salts of the nicotinamide derivative of the formula (1) include, in particular, acid addition salts and alkali salts thereof.  Inorganic or organic non-toxic acids forming non-toxic salts form suitable acid addition salts. Examples of suitable acid addition salts are hydrochloride, Hydrobromide, Hydroiodate, Sulfate, Bisulfate, Nitrate, Phosphate Hydrogen phosphate, Acetate, Maleate, Fumarate, Tartrate,  -25- (22) (22) 200304824 citrate, Gluconate, Succinate, Gluconate, Benzoate Methane sulfonate, Ethane sulfonate, Besylate, P-toluenesulfonate and parabens.  To form suitable base salts with bases that form non-toxic salts, Such as alkali metal salts, Alkaline earth metal salts or addition salts with ammonia and physiologically tolerable organic amines. Examples of suitable alkali salts are sodium, Potassium, aluminum, calcium, magnesium, Zinc or ammonium salts and with triethylamine, Ethanolamine, Diethanolamine, Trimethylamine, Methylamine, Propylamine, Diisopropylamine, N, N-dimethylethanolamine, Benzylamine, Dicyclohexylamine,  N-benzyl-stone · phenethylamine, N, N, -Diphenylmethyl ethylene diamine, Diphenylene diamine, Quinine, choline, Arginine, Lysine, Cysteine, Benzidine, Addition salts of ginseng (2-hydroxyethyl) amine or ααα-ginseng (hydroxymethyl) methylamine.  Compounds including acidic and basic groups can also exist as internal salts or betaines. It is also within the scope of the present invention. With reference to J Pharm Sci of Berge and others, 1 977, 66,  p 1-19 Check for suitable salts.  Salts can usually be obtained from nicotinamide derivatives of formula (1) according to the usual procedures known to those skilled in the art, E.g, In combination with organic or inorganic acids or alkali solvents or dispersants, Or another option is anion exchange or cation exchange from other salts. Salts can be precipitated from the solution and recovered by filtration or by evaporation of the solvent.  The nicotinamide derivative of formula (1) may also exist as a stereoisomer. If the nicotinamide derivative of formula (1) includes one or more asymmetric centers, These may have configurations or (R) configurations independently of each other. The present invention includes all possible stereoisomers of nicotinamide derivatives of formula (1). Examples -26- (23) (23) 200304824 For example, Enantiomers and diastereomers, And mixtures of two or more stereoisomeric forms, E.g, Enantiomers and / or diastereomers are mixtures in all proportions. The present invention is therefore related to having enantiomerically pure forms, At the same time, it becomes a left-handed and a right-handed isomer, Enantiomers as racemates and as mixtures of the two enantiomers in all proportions.  In the presence of cis / trans isomerism, The invention relates to both cis and trans forms and mixtures of these forms in all proportions. If necessary,  Use of stereochemically homogeneous raw materials in the synthesis, Stereoselective · Synthetic or according to customary methods (for example, Chromatographic separation, Crystallization or chromatographic separation of the palm phase) can prepare individual stereoisomers. If appropriate, The derivatization can be performed before the stereoisomers are separated.  Stereoisomer mixtures can be separated at the nicotinamide derivative of formula (1) or at the raw material or intermediate stage during synthesis.  and, The compound of formula (1) according to the present invention includes a mobile hydrogen atom, That is, it exists in various tautomeric forms. The invention also relates to all tautomers of the compound of formula (1).  The present invention further includes other forms of nicotinamide derivatives of formula (1),  E.g, Vehicle compounds (such as hydrates and polymorphs), That is, the nicotinamide derivatives according to the present invention have various crystal structures.  The invention also includes all suitable isotopic variants of the nicotinamide derivative of formula (1) or a pharmaceutically acceptable salt thereof. Defining a nicotine · amidine derivative of formula (1) or a pharmaceutically acceptable salt thereof as a type in which at least one atom therein has the same atom number, But a variant in which the atomic weight is different from the atomic weight often found in natural atoms. Nicotinamide derivatives of the formula (1) -27- (24) (24) 200304824 and their pharmaceutically acceptable isotopes can be incorporated. Examples include hydrogen, carbon, nitrogen, oxygen, sulfur, Isotopes of fluorine and chlorine, Such as 2H, 3H, 13C, 14C, 15N, 17〇, 18〇, 35s, 18f and 36ci. Nicotinamide derivatives of formula (1) and their pharmaceutically acceptable salts specific isotope variants (eg, Those in which radioactive isotopes are incorporated (such as 3H or 14c) can be used for drug and / or matrix tissue distribution studies. Deuterated (and 3H) and carbon-14 (ie 14c) isotopes are particularly preferred, Because of their easy preparation and detection capabilities. and, With isotopes (such as 氚,  That is, the substitution effect of 2 H) can provide specific therapeutic benefits with higher metabolic stability, E.g, Increase half-life in vivo or reduce dose requirements, And may be better in some circumstances. The nicotinamide derivatives of formula (1) and their pharmaceutically acceptable salts can usually be prepared by conventional procedures using appropriate isotopic variants of suitable reagents, Exemplary methods and preparations are illustrated in the following Examples and Preparations section.  If appropriate, The present invention also relates to an active metabolite of a nicotinamide derivative of formula (1), That is, derivatives that are active during cell metabolism and in the organism. E.g, These metabolites can be glucuronide derivatives of compounds of formula (1), N-oxide derivative or sulfonate derivative.  According to a further point, The present invention relates to a mixture of a nicotinamide derivative of formula (1) and a pharmaceutically acceptable salt thereof, Vehicle  Polymorphism, Isomer type, Mixtures of metabolite and / or isotopic patterns. According to the invention, Except for its pharmaceutically acceptable salts (i.e. the Isomeric forms, Tautomers, Metabolites and isotopes • 28- (25) (25) 200304824) All nicotine amide derivatives of formula (1) described above are defined below (including the scope of patent applications) as formula (1) "Derivatives" of nicotinamide derivatives.  A nicotinamide derivative of formula (1), Their pharmaceutically acceptable salts and / or derivative forms are valuable pharmaceutically active compounds, It is suitable for the treatment and prevention of many abnormalities involved in PDE4. Especially suitable for inflammatory abnormalities, Allergic abnormalities, Respiratory diseases and trauma. The nicotinamide derivative of the formula (1) described above as a therapeutic or preventive medicine, He pharmaceutically acceptable salts and / or derivative forms are administered to animals according to the invention, Breast milk is better, And especially humans. You can think of it as itself, Or a mixture of each other or a pharmaceutical product type, Allow him to enter the stomach (stomach) or parenterally, And it includes at least one nicotinamide derivative of formula (1) in an effective dose, Its pharmaceutically acceptable salts and / or derivative forms are used as active ingredients (except conventional excipients and / or additives that are not toxic to medicines).  therefore, The present invention also relates to a nicotinamide derivative of formula (1) and / or a pharmaceutically acceptable salt and / or derivative thereof together with conventional excipients and / or additives that are not toxic to medicine.组合 物。 Composition. These compositions can be prepared according to well-known methods compatible with standard medical utility.  The composition usually includes from 55 to 60% by weight of the active compound and from 40 to 995% by weight of excipients and / or additives. According to the invention, The excipients and / or additives are reagents well known to experts, To provide the beneficial properties of the final medicinal composition. Typical excipients and / or additives include (but are not limited in any way) acidifying and basifying agents, Aerosol propellant, Anti-micro--29- (26) (26) 200304824 Biological agents (including antibacterial agents, Antimycotics and antiprotozoal agents), Antioxidants , Buffer, Chelating agents, Skin actives, Dispersant, Suspending agent, Emollients, Emulsifier, Penetration enhancer, Preservative, Separating agent, Solvents, stabilizer, hardener, sugar, Surfactants and flavoring agents. and, Prepare the composition in a form compatible with the desired route of administration, For use by any established patient and disease suitable for any established patient to be treated, Anomalies or symptoms. Conceivable suitable routes of administration are enteral and parenteral routes, Such as local, By mouth, Intranasal, Lungs, rectum, Intravenous, Intra-pulse, Intraperitoneally, Spinal canal, Intraventricular, In the urine catheter, Intrasternal, Intracranial, Intramuscularly, Subcutaneous or intraocular route.  When you want to administer it orally, The nicotine amidine derivative of formula (1), His pharmaceutically acceptable salts and / or his derivative forms are immediately-, Postpone-, Improvement-, continued-, Intermittent- or controlled-release applications, capsule, Multiple particles, gel, film, Ovule, Tincture, Dosing in solution or suspension, It may include flavoring or coloring agents. The nicotinamide derivative of formula (1), They are pharmaceutically acceptable salts and / or their derivatives are administered as fast-dispersing or fast-dissolving dosage forms or high-energy dispersed or coated particles. If necessary, Formula (υ of nicotine amidine derivatives, Suitable formulations of their pharmaceutically acceptable salts and / or their derivatives may be in coated or uncoated dosage forms.  These solid pharmaceutical compositions (for example, Tablets) can include excipients such as microcrystalline cellulose, lactose, Sodium citrate, Calcium carbonate, Dicalcium phosphate,  Glycine and source flour (with corn, Potato or tapioca starch is preferred)), Disintegrating agents (such as sodium starch glycolate, Croscarmellose sodium and specific compound -30- (27) (27) 200304824 silicate) and granulated binders (such as polyvinylcyclopyridone, Hydroxypropyl methylcellulose (HPMC), Hydroxypropyl cellulose (HPC), sucrose, White gelatin and arabic gum). In addition, Can include lubricants, Such as magnesium stearate, Stearic acid,  Glyceryl behenate and talc).  As a general example, a tablet formulation may typically include between about 0.001 mg to 5,000 mg of the active compound, At the same time, the filling weight of the tablets can range from 50 mg to 10,000 mg. Tablets can be made in a standard way, E.g, Direct compression or wet or dry granulation. The core of the tablet can be coated with a suitable overlay.  It is also possible to use a solid composition or the like as an elixir in gelatin or HPMC capsules. In this connection, Preferred excipients include lactose, starch, Cellulose, Milk sugar or high molecular weight polyethylene glycol. For water suspensions and / or tinctures, The nicotinamide derivative of formula (1), He is pharmaceutically acceptable salts and / or his derivative types and various sweeteners, Colorants or dyes, With emulsifying and / or suspending agents and with diluents (such as water, Ethanol Propylene glycol and glycerol) combination and their composition combination.  The nicotinamide derivative of formula (1), He pharmaceutically acceptable salts and / or his derivative forms by injection (e.g., Intravenously, Intra-arterial, Intraperitoneally, Spinal canal, Intraventricular, In the urine catheter, Intrasternal, Intracranial They can be administered intramuscularly or subcutaneously, either by infusion or needleless injection. It is best to use other substances (for example, A sterile aqueous solution (salts or glucose) sufficient to render the solution isotonic with blood is used for this administration. If necessary, The aqueous solvent should be buffered in a suitable manner (preferably at a pH from 3 to 9). The preparation of these formulations under aseptic conditions can be easily accomplished by standard -31-(28) (28) 200304824 pharmaceutical techniques well known to those skilled in the art. Nicotinamide derivatives of formula (1) are often used , His pharmaceutically acceptable salts and / or his derivatives are administered orally to human patients orally at a daily dose from 0.001 mg / kg to 100 mg / kg (single or multiple administrations).  The nicotinamide derivative of formula (1), His pharmaceutically acceptable salts and / or his derivatives are administered intranasally or by inhalation, And easily delivered in the form of a dry powder inhaler, Or with or without the use of suitable propellants (for example, Dichlorodifluoromethane, Trichlorofluoromethane, Dichlorotetrafluoroethane, Hydrofluoroalkanes (such as 1, 1, 1, 2-tetrafluoroethane (HFA 134A [trademark]) or 1, 1, 1, 2, 3, 3, 3-Heptafluoropropane (HFA 227EA [Trademark])), Carbon dioxide or other suitable gas) Pump, Sprayer, Nebulizer or nebulizer is delivered in aerosol form. In the case of pressurized aerosol, A valve that provides a metered amount to measure the dosage unit. Pressurized container, Pump,  Sprayer, Nebulizers or nebulizers may include solutions or suspensions of the active compounds, E.g, Using a mixture of ethanol and propellant as a solvent, It may additionally include a lubricant (e.g., Zanthoxylan trioleate). Capsules or cartridges (made with, for example, gelatin) for use in an inhaler or insufflator can be formulated to include a nicotine amide derivative of formula (1) and a suitable powder base such as lactose or starch Powder mixture.  The aerosol or dry powder formulation is dispensed at a metered dose or, , Blow volume, , It is preferred to include a nicotinamide derivative of formula (1) from 1 microgram to 4000 micrograms. The daily aerosol dose ranges from 1 (29) (29) 200304824 micrograms to 20 micrograms. It can be administered in a single dose, Or more often with multiple doses throughout the day.  The nicotinamide derivative of formula (1), They are pharmaceutically acceptable salts and / or their derivative types are creams, gel, suspension, Emulsion ointment, powder, Powder, Spray, Bubble Mousse, Bandages with drugs, Solution, Sponge, Fabric, Microemulsion, film, Skin patches, Ointments (such as petroleum jelly or white soft ochre-based ointments or via skin patches or other devices) are administered topically or dermal. Can use penetration enhancers, Compounds combined with cyclodextrin can also be used. In addition, You can use ionization, Electron introduction, Electrophoresis or ultrasound delivery delivers the compound. He can be administered directly on the wound site. They can be pulled into the coated suture. E.g, You can mix it with inorganic oil, Xanthanan monostearate, Polysorbate 60, 黥 鱲 ester 鱲, Stearyl alcohol, 2-octyldodecanol, Benzyl alcohol, water, Emulsions or creams of aqueous or oily suspensions of polyethylene glycol and / or liquid paraffin, Or you can put it in a suitable ointment, The ointment consists of one or more of the following: Inorganic oil, Liquid vaseline, White vaseline, Propylene glycol, Polyoxyethylene polyoxypropylene compound, Combination of emulsifying wax and water, Or hydrogels with cellulose or polyacrylate derivatives or other viscosity modifiers, Or with butane / propane, UFA, CFC, C02 or other suitable propellants to become dry powder or liquid spray or aerosol ’also include lubricants (such as xanthan trioleate), Or with white soft rock or polyethylene glycol impregnated gauze bandages or with hydrogels, Hydrocolloid, Alginate becomes an ointment bandage or a drug-encapsulated bandage.  Compounds in suspension or other formulations may be administered at a daily dose of from 0.001 to 50-33- (30) (30) 200 304 824 mg / ml (preferably from 0.3 to 30 mg / ml). Local administration to human patients with acute / surgical trauma. This dose can vary with the size of the wound, Whether the wound is an open 'closed or partially closed wound and whether the skin is intact has changed.  Alternatively, a nicotinamide derivative of formula (1), He is pharmaceutically acceptable salts and / or his derivative forms are administered rectally, E.g, In the form of a gel suppository, Although other types can be considered.  He can also be administered through the eye, Especially eye scars. Regarding the application of the eye, Compounds can be formulated as microparticle suspensions in isotonic sterile saline with adjusted pH, Or, it is better to prepare a solution in a sterile saline solution with adjusted pH and isotonicity in combination with a preservative (such as ammonium chlorobenzyl chloride) if necessary. Or you can mix it into an ointment, Such as vaseline.  Also described in detail in A Lehir's "Pharmacie galenique" various pharmaceutical formulations as described herein (2nd edition edited by Mason, 1992).  The physician will in any case decide the actual dosage that is most suitable for any individual patient, And will vary with the age of the patient, weight, Health status and gender and severity of the disease to be treated, Abnormalities or symptoms, Combination therapy with other treatments (etc.) as needed, The response of a particular patient and usually any unique related disease, Abnormalities or symptoms and patient factors. therefore, The daily dose for men can often include from 50 mg to 5 g, If appropriate, In a single dose or 2 or more doses at the same time. There can of course be cases of higher or lower dose ranges, And this range is within the scope of the present invention.  According to the invention, Nicotinamide derivatives of formula (1),  -34- (31) (31) 200304824 They are pharmaceutically acceptable salts and / or their derivatives combined with cyclodextrin. Inclusion and non-inclusion complexes with drug molecules are formed with known cyclodextrins. The formation of drug-cyclodextrin complex can change the solubility of drug molecules, Decomposition speed, Bioavailability and / or stability characteristics. Drug-cyclodextrin complexes are generally suitable for most dosage forms and routes of administration.  Cyclodextrin, which can be used as a substitute for direct compounding with drugs, as an auxiliary additive, E.g, As a carrier, Thinner or dissolving agent. Most commonly used α-, / 3- and cyclodextrin, And in WO-A-91 / 11172, Suitable examples are described in WO-A-94 / 02418 and WO-A-98 / 55148.  According to another specific embodiment of the present invention, The nicotinamide derivative of formula (1), Its pharmaceutically acceptable salts, Its derivative or composition is used as a composition to be administered to a patient together with one or more added therapeutic agents, To get some special expected treatments and results. The second or more added therapeutic agent may also be a nicotinamide derivative of formula (1), Or a pharmaceutically acceptable salt thereof, Its derivative or composition, Or it is one or more PDE4 inhibitors known in the art. More typically, the second or more therapeutic agents will be selected from different classes of therapeutic agents.  As used herein, "co-treatment" with a nicotinamide derivative of formula (1) and one or more other therapeutic agents as mentioned herein, The terms "common-treatment" and "combination" are intended to represent, And does mention and include the following:  • simultaneous administration of this composition of nicotinamide derivatives (classes) and therapeutic agents (classes) to patients in need of treatment, It's about formulating these components together into a single dosage form. When these components are released to the patient at the same time,  • The composition of nicotinamide derivatives (classes) and therapeutic agents (classes) is almost -35 · (32) (32) 200304824 at the same time to patients in need of treatment, It consists in formulating each of these components into a separate dosage form, So that the patient takes it at about the same time, So that when the components are released to the patient almost simultaneously,  • administer this composition of nicotinamide derivatives (classes) and therapeutic agents (classes) to patients in need of treatment, It consists in formulating each of these components into a separate dosage form, So that the patient takes it sequentially at each obvious dosing interval, When these components are released to the patient at different times in sequence, And © • administer this composition of nicotinamide derivatives (classes) and therapeutic agents (classes) to patients in need, This is to mix these components together into a single dosage form, Release these components in a controlled way, Make him at the same and / or different time at the same time, Continuous and / or repeated administrations to the patient.  Compatible with nicotinamide derivatives of formula (1), Its pharmaceutically acceptable salts, Examples of other suitable therapeutic agents for which derivative forms or composition combinations are used include (but are not limited in any way):  ^ (a) a 5-lipoxygenase (5-LO) inhibitor or a 5-lipoxygenase activated protein (FLAP) antagonist,  (b) leukotriene antagonists (LTRAs), Including LTB4, LTC4, LTD4 and LTE4 antagonists,  (c) a histamine receptor antagonist, Including Η1 and H3 antagonists,  ~ (d) ^ 1-and ^ 2-adrenergic receptor agents' vasoconstrictors for decongestion, Sympathetic nerve stimulants,  (e) a muscarinic M3 receptor antagonist or an anticholinergic agent '-36- (33) (33) 200304824 (f) a 2-adrenergic receptor agonist,  (g) tea test,  (h) sodium cromoglycate,  (i) COX-1 inhibitors (NSAIDs) and COX-2 selective inhibitors,  (j) oral or inhaled glucocorticosteroids,  (k) the activity of a single antibody against an endogenous inflammator,  (1) an anti-tumor necrosis factor (anti-TNF-α) agent,  (m) an adhesion molecule inhibitor, Including VLA-4 antagonists,  (η) Kinin-B! -And B2-receptor antagonists,  (0) an immunosuppressive agent,  (p) matrix metalloproteinase inhibitors (MMPs),  (q) tachykinin NKi, NK2 and NK3 receptor antagonists,  (I ·) an elastase inhibitor,  (s) adenosine A2a receptor agonist,  (t) a urokinase inhibitor,  (U) a compound acting on a dopamine receptor, E.g, D2 agonist, And (v) a regulator of the NF κ yS pathway, E.g, IKK inhibitor.  According to the invention, The nicotinamide derivative of formula (1) and the following composition are preferred:  -Thymine base M 3 receptor agonist or anticholinergic agent, In particular, ipratropium salts (ie, bromides), Tiotropium salts (i.e. bromides), Europa salt (ie bromide), Perenzepine and Thai Lingyin (34) (34) 200304824 (t elenzepine),  -Θ 2 -adrenergic receptor agonist, Including Shuchuanning (a 1 b u t e r o 1), Albuterol (s a 1 b u t a m o 1), Formoterol (f 〇 r m o t e r o 1) and salmeterol (salmeterol),  -Glucocorticosteroids, Especially inhaled glucocorticosteroids that reduce systemic effects, Including dehydrocortisone, Dehydrosteroids, Flunisolide, Triamcinolone acetonide, Beclomethasone dipropionate), Budesonide, Fluticasone propionate and mometasone furoate,  -Adenosine A2a receptor agonist.  It should be recognized that the treatments referred to herein include treatment, Relief and preventive treatment. The ensuing description is about the therapeutic application of nicotinamide derivatives of formula (1).  The nicotinamide derivative of formula (1) inhibits PDE4 isoenzymes and therefore has a wide range of therapeutic applications. As further explained below, Because the PDE4 family of isoenzymes plays a fundamental role in all mammalian physiology.  The enzyme role is adenosine 3, which is performed by the PDE4 isoenzyme. , 5, _Intracellular hydrolysis of cyclic monophosphoric acid (cAMP) in primary inflammatory leukocytes, In turn it is responsible for regulating many of the hormonal effects in the body and therefore PDE4 inhibitors play an important role in various physiological processes. There are many literatures in this technology explaining the effect of PDE4 inhibitors on various cellular responses. In addition to increasing cAMP, It includes inhibition of the production of superoxide (35) (35) 200304824, De-granulation, Chemotaxis and in eosinophils, Neutrophils and single cells release tumor necrosis factor-a (TNFα).  therefore, A further aspect of the present invention relates to a nicotinamide amine derivative of formula (1), Its pharmaceutically acceptable salts, Derivatives or compositions for the treatment of diseases involving PDE4 isoenzymes, Application of abnormalities and symptoms. The present invention also particularly relates to nicotinamide derivatives of formula (1), He is a pharmaceutically acceptable salt, Its derivatives or compositions treat diseases of the group consisting of, Use of abnormalities and symptoms:  • No matter what type, Asthma due to onset or pathogenesis, Particularly selected from the group consisting of atopic asthma, Non-ectopic asthma, Allergic asthma Ectopic bronchial IgE-interventional asthma, Bronchial asthma Essential asthma, Parenchymal asthma, Endogenous asthma caused by pathophysiology, Exogenous asthma caused by environmental factors, Essential asthma of unknown or unknown origin, Bronchial asthma,  Emphysema asthma, Exercise-induced asthma, Allergen-induced asthma, Asthma induced by cold air, Occupational asthma,  With bacteria, Mold, Protozoal or viral infections, infectious asthma, Non-allergic asthma, Early asthma and paroxysmal asthma in infants  • chronic or acute bronchoconstriction, Chronic bronchitis, Small airway obstruction and emphysema,  • No matter what type, Obstructive or inflammatory airway disease of the cause or pathogenesis, Especially selected from chronic eosinophilic lung disease, Chronic obstructive pulmonary disease (COPD), Including chronic bronchitis, Pulmonary edema or (36) (36) 200304824 COPD associated with dyspnea, With irreversible, Progressive airway obstruction, Obstructive or inflammatory airway diseases that are exacerbated by COPD characterized by adult respiratory compression syndrome (ARDS) and airway hyperresponsiveness to other medications,  • No matter what type, Pneumoconiosis due to the cause or mechanism, Especially selected from bauxite disease or bauxite worker disease, Charcoal deposition or asthma in miners, Asbestosis or asthma due to steam repair,  Phyllostoma or lithiasis, By inhaling ostrich hair dust, Iron inhalation caused by inhalation of iron particles, Silicosis or masonry, Cotton pneumonia or cotton dust asthma and talcum dust deposits,  • No matter what type, Bronchitis of pathogenesis or pathogenesis, Especially selected from acute bronchitis, Acute laryngotracheal bronchitis, Peanut branch tracheitis, Catarrhal bronchitis, Croupus bronchitis, Dry bronchitis, Infectious bronchitis, Asthmatic bronchitis, Producing bronchitis, Staphylococcal or streptococcal bronchitis and bronchial bronchitis due to porcine toxic bronchitis,  • No matter what type, Bronchial dilatation of pathogenesis or pathogenesis, Especially selected from the group consisting of cylindrical bronchitis and dilatation, Cystic bronchitis and dilatation, Spindle-like spindle bronchiectasis, Microvascular branch bronchiectasis, Pulmonary cystic bronchitis dilatation, Dry bronchitis dilatation and follicular bronchitis dilatation  • No matter what type, Allergic rhinitis or perennial allergic rhinitis or sinusitis during the season of the cause or pathogenesis, Especially selected from purulent -40- (37) (37) 200304824 or non-purulent sinusitis, Acute or chronic sinusitis and ethmoid sinusitis, Frontal sinusitis, Sinusitis of maxillary sinusitis or sphenoid sinusitis,  • No matter what type, Rheumatoid arthritis, such as the cause or pathogenesis, is particularly selected from the group consisting of acute arthritis, Acute gouty arthritis, Chronic inflammatory arthritis, Degenerative arthritis, Infectious arthritis, Lyme arthritis, Proliferative arthritis, Rheumatoid arthritis like psoriatic arthritis and spinal arthritis,  • gout and colds and pain associated with inflammation,  Spring • No matter what type, Abnormalities related to the cause or mechanism of eosinophils, Especially selected from eosinophilia, Lung tumors Dissolved eosinophilia, Laufer s) syndrome group, Chronic eosinophilic pneumonia, Tropical lung eosinophilia 'bronchopneumoniae rickets, Mycosis, Granulomas (including eosinophils, Allergic Sarcoma vasculitis or Qiu-Shi's (C h u r g-S t r a u s s) syndrome), Eosinophilic abnormalities associated with nodular polyarteritis (PAN) and systemic necrotizing vasculitis,  ® • Atopic Dermatitis, Allergic dermatitis, Contact dermatitis or allergic or atopic eczema,  • No matter what type, The cause or mechanism of measles, Special Department 5¾ Seeking numbness with self-immunity intervention, Finding ginseng with complement intervention,  Rash measles induced by rash measles, Physical measles-induced measles ‘, Stress-induced measles, Idiopathic measles, Acute measles, Chronic numbness pain, Angioedema, Cholinergic mochi, Body Staining Cold Dominant Measles in Dominant and Acquired Forms, Contact 莼 -41-(38) (38) 200304824 Measles, Severe measles and pimples measles  • No matter what type, Conjunctivitis, the cause or pathogenesis, Especially selected from actinic conjunctivitis, Acute catarrhal conjunctivitis, Acute infectious conjunctivitis, Allergic conjunctivitis, Atopic conjunctivitis, Chronic catarrhal conjunctivitis, Conjunctivitis of purulent conjunctivitis and spring-type conjunctivitis,  • No matter what type, Uveitis, the cause or pathogenesis, Especially selected from all or part of uveal inflammation, Anterior uveitis, Iridescent inflammation, Ciliary body inflammation, Iridocyclitis, Granulomatous uveitis,  Non-granulomatous uveitis, Lens antigen uveitis, Posterior uveitis, Uveitis of choroiditis and chorioretinitis,  • psoriasis,  • No matter what type, Multiple sclerosis, the cause or mechanism of the disease,  Especially selected from multiple sclerosis of primary multiple sclerosis and relapsing multiple sclerosis,  • No matter what type, Autoimmune / inflammatory diseases due to the cause or pathogenesis, Especially selected from autoimmune blood therapy abnormalities, Hemolytic anemia, Aplastic anemia, Pure red blood cell anemia, Idiopathic blood Systemic lupus erythematosus, Multiple chondritis, Scleroderma, Wegener ’s, Dermatomyositis,  Chronic active hepatitis, Myasthenia gravis, Steven even s-John son syndrome, Idiopathic fatty diarrhea, Autoimmune inflammatory bowel disease, Ulcerative colitis, Endocrine eye disease 'Grave's disease, Sarcoidosis, Alveolitis, Chronic allergic pneumonia, Primary biliary cirrhosis, Juvenile diabetes or type 1 diabetes, Dryness -42- (39) (39) 200304824 Keratoconjunctivitis, Keratoconjunctivitis, Diffuse pulmonary (p u 1 m ο n a r y) fibrous disease or pulmonary (1 u n g) fibrous disease, Idiopathic _ pulmonary fibropathy, Cystic fibrosis, Glomerulonephritis with or without symptoms of nephropathy, Acute glomerulonephritis, Idiopathic nephropathy symptoms Minor changes in kidney disease, Inflammatory / hyperproliferative skin diseases, Benign familial pemphigus, Erythematous pemphigus, Pemphigus and Pemphigus vulgaris autoimmune / inflammatory diseases,  • prevent allograft rejection after organ transplantation,  Lu • No matter what type, Inflammatory bowel disease (IBD), the cause or pathogenesis, Special SU is selected from the group consisting of colloidal colitis, Colitis polyps, Intestinal wall full-thickness colitis, Ulcerative colitis and Crohn's disease (CD)  • No matter what type, Septic shock due to the cause or mechanism, Specially selected from renal failure, Acute renal failure, Cachexia, Malaria cachexia, Low constitution cachexia, Uremia cachexia, Psychogenic cachexia,  Adrenal cachexia or Addison ’s, Cancer cachexia Lu and the failure of cachexia due to infection with human immunodeficiency virus (HIV), hemorrhagic shock,  • liver damage,  • No matter what type, Pulmonary hypertension due to the cause or mechanism, Including ’Pulmonary Hypertension / Spontaneous Hypertension, For congestive heart failure-secondary pulmonary hypertension, For the secondary pulmonary hypertension of chronic obstructive pulmonary disease, Pulmonary hypertension Pulmonary hypertension and hypotension-induced pulmonary hypertension,  -43- (40) (40) 200304824Bone loss, Primary osteoporosis and secondary osteoporosis,  • No matter what type, Central nervous system abnormalities', the cause or pathogenesis, is selected from depression, Alzheimer's disease, Parkinson's disease, Learning and memory impairment, Delayed onset of movement, Drug addiction, Arteriosclerotic dementia and dementia with Huntington ’s dance disease 'Wilson ’s, Tremor paralysis and thalamic atrophy central nervous system abnormalities,  •infection, Especially virus infections, Where these viruses increase TNF-α production in the host or where these viruses are sensitive to the up-regulation of TNF-α in the host, So it has an adverse impact on their replication or other viral activities. Including selected from HIV-1, HIV-2 and HIV-3, Cytomegalovirus (CMV), Epidemic cold virus, Adenoviruses and herpesviruses (including shingles and herpes simplex),  • Yeast and mold infections, The yeast and mold are sensitive to the up-regulation of TNF-α and induce the production of TNF-α in their host (for example, Fungal meningitis), Specifically formulated in conjunction with other drugs (including, but not limited to) polymyxins (e.g., but not limited to) selected to treat systemic yeast and mold infections (e.g., Polymyxin B), Imidazole (for example,  Clotrimazole, Econazole, Miconazole and ketoconazole), Three Π sitting (for example, Fluconazle and itranazole) and amphotericin (for example, Amphotericin B and granulosome amphotericin B) —When administered,  Ischemia-reperfusion injury, Ischemic heart disease, Autoimmune Diabetes -44-(41) (41) 200304824 Disease, Retinal autoimmune disease, Chronic lymphocytic leukemia, HIV infection, Lupus erythematosus, Kidney and ureter diseases, Urogenital and gastrointestinal disorders and prostate disease,  • reduce scar formation in the human or animal body, Such as scar formation during the recovery of acute trauma, And • psoriasis, Other skin and cosmetics Including reducing inflammation,  Skin softening, Skin elasticity and activity to increase humidity.  The present invention also has a further aspect that relates to a nicotinamide derivative of formula (1), Or a pharmaceutically acceptable salt thereof, Use of a derivative or composition thereof to manufacture a medicament having PDE4 inhibitory activity. The present invention particularly relates to nicotinamide derivatives of formula (1), Or a pharmaceutically acceptable salt thereof, Derivatives or compositions are made to treat inflammation, Breathe, Hypersensitivity and scarring disease, Abnormal and symptomatic drugs and more precisely the treatment of the diseases listed above, Use of abnormal and symptomatic drugs.  therefore, The present invention provides a particularly advantageous method for treating mammals (including humans) 'comprising an effective dose of a nicotinamide derivative of formula (1), Or a pharmaceutically acceptable salt thereof, Its derived form or composition treats the mammal. More precisely, the present invention provides a particularly advantageous method for treating mammals, including humans, To treat inflammation, Breathe, Allergies and scar forming diseases, Abnormalities or symptoms, The method includes an effective dose of a nicotinamide derivative of formula (1), It treats the mammal in a pharmaceutically acceptable salt and / or derivative form.  The following examples illustrate the preparation of nicotinamide derivatives of formula (1):  -45- (42) 200304824 Example 1:  2_ (4-fluorophenoxy) -N- {4 _ [(2-hydroxy_3-methylphenylfluorenylamino) methyl] benzyl} nicotinamide 〇

將在N，N-二甲基甲醯胺（6毫升）中的2-羥基-3-甲基 苯甲酸（118毫克，0 773毫莫耳）、1-羥基苯並三唑（157毫 克，1 16毫莫耳）、1-(3-二甲基胺基丙基）-3-乙基碳化二 醯亞胺鹽酸（193毫克，1 01毫莫耳）、N-(4-胺基甲基苯甲 基氟基-2_(4 -氟基苯氧基）菸鹼醯胺鹽酸（300毫克， 0 7 73毫莫耳）（參考製備法3)及N-甲基嗎啉（0 17毫升，Add 2-hydroxy-3-methylbenzoic acid (118 mg, 0 773 mmol), 1-hydroxybenzotriazole (157 mg, 1 16 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (193 mg, 101 mmol), N- (4-aminomethyl) Benzylfluoro-2- (4-fluorophenoxy) nicotinamide hydrochloride (300 mg, 0 7 73 mmol) (see Preparation Method 3) and N-methylmorpholine (0 17 ml ,

1 55毫莫耳）之溶液在氮氣下及在室溫下攪拌18小時。接 著將混合物分溶在醋酸乙酯（1 0毫升）與水（1 0毫升）之間。 將有機相分開，以氯化鈉飽和水溶液（1 0毫升）淸洗及經無 水硫酸鎂乾燥。接著在真空中除去溶劑，並將殘餘物以二 乙醚（3 X 1 0毫升）濕磨，以得到成爲灰白色泡沫之2 - (4 ·氟 基苯氧基）-N-{4_[(2-羥基-3-甲基苯醯基胺基）甲基]苯甲基 }蔽驗醯胺（8〇毫克）。 'H NMR(3 00MHz, DMSO-d6) 5 =13 1 1(1H? s)， 8 3 2- 8 42(lH，m)，8 15-8 21(lH，m)，8 08-8 1 4(lH，d)，7 66-7 7 5 ( 1 H，m)5 7 10· 7 60( 1 0H，m)，6 73 -6 81(1H，t)，4 3 7- -46- (43) 200304824 4 5 6(4H，m)，2 16(3H，s)ppm。 LRMS(熱噴灑）m/z [M + H]+ 48 6，[M + NH4]+ 503 實例2-15 以類似於實例1的方法，使用適當的胺及羧酸作爲原 料，以製備以下製成表列的以下通式之化合物（表1):1 55 mmol) was stirred under nitrogen at room temperature for 18 hours. The mixture was then partitioned between ethyl acetate (10 ml) and water (10 ml). The organic phase was separated, washed with a saturated aqueous solution of sodium chloride (10 ml) and dried over anhydrous magnesium sulfate. The solvent was then removed in vacuo, and the residue was triturated with diethyl ether (3 X 10 ml) to obtain 2- (4.fluorofluorophenoxy) -N- {4 _ [(2- Hydroxy-3-methylphenylamidinoamino) methyl] benzyl} pyrimidine (80 mg). 'H NMR (3 00MHz, DMSO-d6) 5 = 13 1 1 (1H? S), 8 3 2- 8 42 (lH, m), 8 15-8 21 (lH, m), 8 08-8 1 4 (lH, d), 7 66-7 7 5 (1 H, m) 5 7 10 · 7 60 (1 0H, m), 6 73 -6 81 (1H, t), 4 3 7- -46- (43) 200304824 4 5 6 (4H, m), 2 16 (3H, s) ppm. LRMS (thermal spray) m / z [M + H] + 48 6, [M + NH4] + 503 Example 2-15 In a similar manner to Example 1, using the appropriate amine and carboxylic acid as raw materials, the following preparations were prepared Tabulated compounds of the following formula (Table 1):

表1 實例編號 月安原料製備 編號 Ri R4 2 3 Η Ιη 3 3 Η F &quot;Τ 4 3 Η 双 5 3 Η 众Table 1 Example No. Yuean raw material preparation No. Ri R4 2 3 Η Ιη 3 3 Η F &quot; Τ 4 3 Η double 5 3 众

-47 - (44) 200304824 6 3 Η OH 7 3 Η ^σ0Η 8 3 Η ^rMe OH 9 3 Η Me 10 3 Η Me OH 1112 6 F OH 121 6 F 131,2 6 F 乂Γ-47-(44) 200304824 6 3 Η OH 7 3 Η σ0Η 8 3 Η ^ rMe OH 9 3 Η Me 10 3 Η Me OH 1112 6 F OH 121 6 F 131,2 6 F 乂 Γ

-48- 1 將有機相在整理步驟中依次以水及碳酸氫鈉飽和水溶液 淸洗。 2 將化合物在以戊烷.·醋酸乙酯（以體積計之9 5 5改變至 7 0 3 0)之溶劑梯度溶離之砂膠上以閃蒸管柱色層分離法 純化。 (45) 200304824 實例2 : ln NMR(3 00MHz, DMSO-d6) δ =11 28(1H, s), 8 8 6- 8 92(lH，m)，8 7 3 -8 8 5 (lH，m)，8 10-8 22(2H，m)，7 16-7 3 6 ( 1 0H，m)，6 6 3 -6 76(2H，m)，4 47-4 5 6(2H，d)，4 40-4 46(2H，d)ppm。 LRMS(熱噴灑）m/z [M + H]+ 490，[M + NH4]+ 507-48- 1 During the finishing step, the organic phase is washed with water and a saturated aqueous solution of sodium bicarbonate in this order. 2 The compound was purified by flash column chromatography on a sand gel dissolving in a solvent gradient of pentane ·· ethyl acetate (from 9 5 5 to 70 3 0 by volume). (45) 200304824 Example 2: ln NMR (300 MHz, DMSO-d6) δ = 11 28 (1H, s), 8 8 6- 8 92 (lH, m), 8 7 3 -8 8 5 (lH, m ), 8 10-8 22 (2H, m), 7 16-7 3 6 (1 0H, m), 6 6 3 -6 76 (2H, m), 4 47-4 5 6 (2H, d), 4 40-4 46 (2H, d) ppm. LRMS (thermal spray) m / z [M + H] + 490, [M + NH4] + 507

實例3 : lH NMR(3 00MHz, DMSO-d6) δ =1 2 20( 1H? s)， 9 23- 9 11(lH，m)，8 8 3 - 8 92(lH，m)，8 17-8 21(2H，m)，8 10-8 15(2H，m)，7 67-7 75(lH，m)57 1 8-7 3 3 ( 1 0H，m)，6 86-6 96(2H, m)，4 42-4 5 1 (4H，m)ppmo LRMS(熱噴灑）m/z [M + H]+ 490，[M + NH4]+ 507 實例4 :Example 3: lH NMR (300 MHz, DMSO-d6) δ = 1 2 20 (1H? S), 9 23- 9 11 (lH, m), 8 8 3-8 92 (lH, m), 8 17- 8 21 (2H, m), 8 10-8 15 (2H, m), 7 67-7 75 (lH, m) 57 1 8-7 3 3 (1 0H, m), 6 86-6 96 (2H , m), 4 42-4 5 1 (4H, m) ppmo LRMS (thermal spray) m / z [M + H] + 490, [M + NH4] + 507 Example 4:

NMR(3 0 0MHz, DMSO-d6) δ =9 46( 1 H， s)， 8 83 - 8 92(lH，t)，8 7 5 - 8 82(lH，t)，8 1 6-8 20(lH，d)，8 09-8 14(1H, d), 7 1 5-7 3 2 ( 1 1 H? m)5 7 06- 7 1 4( 1 H, d)5 4 4 3 -4 51(2H，d)，4 3 4-4 42(2H，d)，2 13(3H，s)ppm。 LRMS(熱噴灑）m/z [M + H]+ 4 8 6，[M + NH4]+ 503 實例5 · lH NMR(3 00MHz, CDC13) 5 = 8 5 4- 8 6 1 ( 1 H? d)? 8 23 -8 3 2 ( 1 H5 m)5 8 1 7 - 8 2 3 ( 1 H, m)5 7 6 1 - 7 8 0 ( 1 H, m)5 7 3 5 - -49- (46) 200304824 7 40 (2H，m)5 7 02- 7 3 0(9H，m)，6 90-7 00( 1 H，m)，6 70-6 7 8 ( 1 H，m)5 4 60-4 70(2H，d)，4 48-4 5 9(2H，d)ppm。 LRMS(熱噴灑）m/z [M + H]+ 472，[M + NH4]+ 489 實例6 : lU NMR(3 00MHz? CDC13) 5 = 1 2 02- 1 2 50( 1 H, brs)? 8 5 3 -8 70( 1 H， brs)， 8 1 0- 8 26(2H， brs)， 6 92-7 5 0( 1 2H， m)， 6 63 -6 8 8 (2H，m)3 4 5 6-4 77(4H，2xm)ppm ° · LRMS(熱噴灑）m/z [M + H]+ 472，[M + NH4]+ 489 實例7 : lU NMR(3 00MHz, DMSO- d6) (5 =9 93(1H， s)， 8 84- 8 91(1H， t)， 8 68-8 76(1H， 8 17-8 21(1H， m)， 8 10- 8 15(1H， d)， 7 69-7 76(2H， d), 7 18-7 33(9H， m)， 6 74-NMR (3 0 0MHz, DMSO-d6) δ = 9 46 (1 H, s), 8 83-8 92 (lH, t), 8 7 5-8 82 (lH, t), 8 1 6-8 20 (lH, d), 8 09-8 14 (1H, d), 7 1 5-7 3 2 (1 1 H? m) 5 7 06- 7 1 4 (1 H, d) 5 4 4 3 -4 51 (2H, d), 4 3 4-4 42 (2H, d), 2 13 (3H, s) ppm. LRMS (thermal spray) m / z [M + H] + 4 8 6, [M + NH4] + 503 Example 5 · lH NMR (3 00MHz, CDC13) 5 = 8 5 4- 8 6 1 (1 H? D )? 8 23 -8 3 2 (1 H5 m) 5 8 1 7-8 2 3 (1 H, m) 5 7 6 1-7 8 0 (1 H, m) 5 7 3 5--49- ( 46) 200304824 7 40 (2H, m) 5 7 02- 7 3 0 (9H, m), 6 90-7 00 (1 H, m), 6 70-6 7 8 (1 H, m) 5 4 60 -4 70 (2H, d), 4 48-4 5 9 (2H, d) ppm. LRMS (thermal spray) m / z [M + H] + 472, [M + NH4] + 489 Example 6: lU NMR (3 00MHz? CDC13) 5 = 1 2 02- 1 2 50 (1 H, brs)? 8 5 3 -8 70 (1 H, brs), 8 1 0- 8 26 (2H, brs), 6 92-7 5 0 (1 2H, m), 6 63 -6 8 8 (2H, m) 3 4 5 6-4 77 (4H, 2xm) ppm ° · LRMS (thermal spray) m / z [M + H] + 472, [M + NH4] + 489 Example 7: lU NMR (3 00MHz, DMSO- d6) (5 = 9 93 (1H, s), 8 84- 8 91 (1H, t), 8 68-8 76 (1H, 8 17-8 21 (1H, m), 8 10- 8 15 (1H, d ), 7 69-7 76 (2H, d), 7 18-7 33 (9H, m), 6 74-

6 8 1 (2H, d)，4 44-4 52(2H, d)，4 3 7-4 43 (2H，d)ppm° LRMS(熱噴灑）m/z [M + H]+ 472，[M + NH4]+ 489 實例8 : H NMR(3 00MHz? DMSO-d6) 5 =12 45-12 60(1H5 b rs)5 17-9 25(1H? t)， 8 84-8 92(1H， t)， 8 1 6-8 20( 1 H， d)， 09-8 14(1H? d)， 7 72-7 78(1H， d)， 7 16-7 34(9H， m)， 67-6 73(2H， m)， 4 40-4 5 8(4H, 2xd)， 2 2 5 ( 3 H? s)ppm o LRMS(熱噴灑）m/z [M + H]+ 48 6，[M + NH4]+ 503 -50- (47) 200304824 實例9 : ]H NMR(3 00MHz, DMSO-d6) δ =9 43 ( 1 H? s), 8 96( 1 H, t)， 8 60-8 67( 1 H，t)， 8 16-8 21(1H， d)? 8 15(1H，d)，7 28-7 3 4( 1 H，d)，7 20-7 28(8H，m)， 7 03 ( 1 H，t)，6 80-6 8 6( 1 H，d)? 6 73-6 77( 1 H，d)3 4 5 4(2H，d)，4 34-4 4 0 ( 2 H，d )，2 0 7 ( 3 H，s)ppm。 LRMS(熱噴灑）m/z [M + H]+ 486，[M + NH4]+ 503 8 8 7-8 10-6 96-4 47-6 8 1 (2H, d), 4 44-4 52 (2H, d), 4 3 7-4 43 (2H, d) ppm ° LRMS (thermal spray) m / z [M + H] + 472, [ M + NH4] + 489 Example 8: H NMR (3 00MHz? DMSO-d6) 5 = 12 45-12 60 (1H5 b rs) 5 17-9 25 (1H? T), 8 84-8 92 (1H, t), 8 1 6-8 20 (1 H, d), 09-8 14 (1H? d), 7 72-7 78 (1H, d), 7 16-7 34 (9H, m), 67- 6 73 (2H, m), 4 40-4 5 8 (4H, 2xd), 2 2 5 (3 H? S) ppm o LRMS (thermal spray) m / z [M + H] + 48 6, [M + NH4] + 503 -50- (47) 200304824 Example 9:] H NMR (3 00MHz, DMSO-d6) δ = 9 43 (1 H? S), 8 96 (1 H, t), 8 60-8 67 (1 H, t), 8 16-8 21 (1H, d)? 8 15 (1H, d), 7 28-7 3 4 (1 H, d), 7 20-7 28 (8H, m) , 7 03 (1 H, t), 6 80-6 8 6 (1 H, d)? 6 73-6 77 (1 H, d) 3 4 5 4 (2H, d), 4 34-4 4 0 (2 H, d), 2 7 (3 H, s) ppm. LRMS (thermal spray) m / z [M + H] + 486, [M + NH4] + 503 8 8 7-8 10-6 96-4 47-

實例1 0 : NMR(3 00MHz， DMSO-d6) 6 = 1 2 23 ( 1H, s)， 9 26( 1 H, t)， 8 82-8 92( 1 H，t)， 8 1 5 -8 20( 1 H, d)， 8 15(1H， d)， 7 69( 1 H， s)， 7 1 2-7 3 4( 1 0H， m)， 6 81(1H, d)，4 42-4 54(4H，2xd)，2 20(3H，s)ppm。 LRMS(熱噴灑）m/z [M + H]+ 486，[M + NH4]+ 503 實例1 1 : lH NMR(400MHz? DMSO-d6) 5 = 9 2 4 - 9 3 1 ( 1 H? m), 9 00( 1 H，m)5 8 1 8 - 8 2 0 ( 1 H，d)，8 02-8 07( 1 H，dd)， 7 8 7( 1 H5 d)，7 3 5 -7 40( 1 H，t)，7 1 8 -7 3 5 (8H，m)， 6 92(2H，t)5 4 42 -4 5 6(4H，m)ppm。 LRMS(電噴灑）m/z [M + Na]+ 512，[M-H]+ 488 實例1 2 : ]H NMR(400MHz，DMSO-d6) 5 =8 93 -9 00( 1 H，m)， 9 18-8 10-6 77-Example 10: NMR (300 MHz, DMSO-d6) 6 = 1 2 23 (1H, s), 9 26 (1 H, t), 8 82-8 92 (1 H, t), 8 1 5 -8 20 (1 H, d), 8 15 (1H, d), 7 69 (1 H, s), 7 1 2-7 3 4 (1 0H, m), 6 81 (1H, d), 4 42- 4 54 (4H, 2xd), 2 20 (3H, s) ppm. LRMS (thermal spray) m / z [M + H] + 486, [M + NH4] + 503 Example 1 1: lH NMR (400MHz? DMSO-d6) 5 = 9 2 4-9 3 1 (1 H? M ), 9 00 (1 H, m) 5 8 1 8-8 2 0 (1 H, d), 8 02-8 07 (1 H, dd), 7 8 7 (1 H5 d), 7 3 5- 7 40 (1 H, t), 7 1 8 -7 3 5 (8H, m), 6 92 (2H, t) 5 4 42-4 5 6 (4H, m) ppm. LRMS (electrospray) m / z [M + Na] + 512, [MH] + 488 Example 1 2:] H NMR (400MHz, DMSO-d6) 5 = 8 93 -9 00 (1 H, m), 9 18-8 10-6 77-

92-83 -83- 13- -51 - (48) 200304824 8 22(2H, m), 8 02- 8 08 ( 1 H，m)，7 1 4-7 27(8H，m)，5 3 8 -5 4 3 ( 1 H，t)，4 43 -4 5 1 (2H，d)，4 2 1 -4 27(2H，d)，3 79-3 8 4 (2H，d)ppm 〇 LRMS(電噴灑）m/z [M-H]+ 426 實例1 3 :92-83 -83- 13- -51-(48) 200304824 8 22 (2H, m), 8 02- 8 08 (1 H, m), 7 1 4-7 27 (8H, m), 5 3 8 -5 4 3 (1 H, t), 4 43 -4 5 1 (2H, d), 4 2 1 -4 27 (2H, d), 3 79-3 8 4 (2H, d) ppm 〇LRMS ( Electrospray) m / z [MH] + 426 Example 1 3:

lR NMR(400MHz， DMSO-d6) δ =9 89( 1 H, s)? 8 90-8 9 8( 1 H， 〇， 8 64- 8 73 ( 1 H， t)? 8 19-8 21(1H， d), 8 02-8 06( 1 H，dd)，7 70-7 77(2H，d)，7 24-7 3 0(2H，d)，7 17-7 23 (6H，d)，6 73 -6 79(2H，d), 4 42-4 48(2H，d)，4 3 6- 4 40(2H，d)ppm。 LRMS(電噴灑）m/z [M + Na]+ 512，[M-H]+ 488 實例14 : 3-(3-{4-[(3-羥基苯醯基胺基）甲基]苯甲基胺甲 醯基}吡啶-2-氧基）苯甲酸乙酯lR NMR (400MHz, DMSO-d6) δ = 9 89 (1 H, s)? 8 90-8 9 8 (1 H, 〇, 8 64- 8 73 (1 H, t)? 8 19-8 21 ( 1H, d), 8 02-8 06 (1 H, dd), 7 70-7 77 (2H, d), 7 24-7 3 0 (2H, d), 7 17-7 23 (6H, d) , 6 73 -6 79 (2H, d), 4 42-4 48 (2H, d), 4 3 6- 4 40 (2H, d) ppm. LRMS (electrospray) m / z [M + Na] + 512, [MH] + 488 Example 14: 3- (3- {4-[(3-Hydroxyphenylamidinoamino) methyl] benzylaminomethylmethyl} pyridine-2-oxy) benzoate ethyl ester

將3-羥基苯甲酸（27毫克，0 19毫莫耳）、1-羥基苯並 三唑（31毫克，0 23毫莫耳）及1-(3-二曱基胺基丙基）-3- 乙基碳化二醯亞胺鹽酸（45毫克，0 23毫莫耳）加入在 -52- (49) (49)200304824 N，N-二甲基甲醯胺（15毫升）中的3_[3-(4_胺基甲基苯甲基 胺甲醯基）吡啶-2-氧基]苯甲酸乙酯鹽酸（100毫克，0 19 毫莫耳）（參考製備法9)及N-甲基嗎啉（〇 11毫升，097毫 莫耳）之溶液中。將反應混合物在室溫下及在氮氣下攪拌 1 8小時，在真空中濃縮，並將殘餘物分溶在二氯甲烷（2〇 毫升）與水（2〇毫升）之間。將有機相分開，以氯化鈉飽和 水溶液（2 0毫升）淸洗，經無水硫酸鎂乾燥及在減壓下濃縮 。接著將殘餘物在以二氯甲烷：甲醇（以體積計之9 9 1改 變至98 1)之溶劑梯度溶離之矽膠上以閃蒸管柱色層分離 法純化，以得到成爲灰白色泡沬之3-(3-{4-[(3-羥基苯醯 基胺基）甲基]苯甲基胺甲醯基}吡啶-2-氧基）苯甲酸乙酯 (45毫克）。 1H NMR(400MHz3 CDC13) δ =8 54-8 60( 1 Η， d), 8 2 1- 8 3 8(2Η， t + brs)， 8 1 7-8 20( 1Η， d)5 7 86-7 92( 1 Η， d)， 7 7 8( 1 Η? s)? 7 4 1 -7 48( 1 Η, t)5 7 2 8 - 7 3 7(2Η, m), η 〇8- 7 26(6Η，m)，6 86-6 9 5 (2Η，m)，4 6 1 -4 67(2Η，d)，4 45- 4 5 3 (2Η，d)，4 3 0-4 3 7(2Η，quart)，1 31-1 38(3Η，t)ppm〇 LRMS(電噴灑）m/Z [Μ + Η]+ 526，[M + Na]+ 548，[M.H] + 524 實例1 5 - 1 8 以類似於實例1 4的方法，使用適當的羧酸原料製備 以下製成表列的以下通式之化合物（表2): -53- (50)200304824Add 3-hydroxybenzoic acid (27 mg, 0 19 mmol), 1-hydroxybenzotriazole (31 mg, 0 23 mmol) and 1- (3-diamidoaminopropyl) -3 -Ethylcarbodiimide hydrochloride (45 mg, 0 23 mmol) added to -52- (49) (49) 200304824 N, N-dimethylformamide (15 ml) 3_ [3 -(4-Aminomethylbenzylaminomethylamidinyl) pyridine-2-oxy] benzoic acid ethyl ester hydrochloride (100 mg, 0 19 mmol) (see Preparation Method 9) and N-methyl? (0,11 ml, 097 mmol). The reaction mixture was stirred at room temperature under nitrogen for 18 hours, concentrated in vacuo, and the residue was partitioned between dichloromethane (20 mL) and water (20 mL). The organic phase was separated, washed with a saturated aqueous solution of sodium chloride (20 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was then purified on a silica gel with a solvent gradient of dichloromethane: methanol (9 9 1 to 98 1 by volume) and purified by flash column chromatography to obtain an off-white foam. -(3- {4-[(3-hydroxyphenylfluorenylamino) methyl] benzylaminomethylmethyl} pyridine-2-oxy) benzoate (45 mg). 1H NMR (400MHz3 CDC13) δ = 8 54-8 60 (1 Η, d), 8 2 1- 8 3 8 (2Η, t + brs), 8 1 7-8 20 (1Η, d) 5 7 86- 7 92 (1 Η, d), 7 7 8 (1 Η? S)? 7 4 1 -7 48 (1 Η, t) 5 7 2 8-7 3 7 (2Η, m), η 〇8- 7 26 (6Η, m), 6 86-6 9 5 (2Η, m), 4 6 1 -4 67 (2Η, d), 4 45- 4 5 3 (2Η, d), 4 3 0-4 3 7 (2Η, quart), 1 31-1 38 (3Η, t) ppm 0 LRMS (electrospray) m / Z [M + Η] + 526, [M + Na] + 548, [MH] + 524 Example 1 5 -1 8 In a manner similar to Example 14, using the appropriate carboxylic acid raw materials to prepare the following compounds of the following formula (Table 2): -53- (50) 200304824

實例編號 胺原料製備編號 R4 15 9 XT〇H 16 9 OH 17 9 18 9 ^Xr〇HExample number Amine raw material preparation number R4 15 9 XT〇H 16 9 OH 17 9 18 9 ^ Xr〇H

實例1 5 : 1HNMR(400MHz，CDCl3)(5=8 90-9 1 0(lH，brs)，8 49-8 5 3 ( 1 H? d)5 8 2 8 - 8 3 4 ( 1 H? m)? 8 13-8 16(1H, d), 7 8 7- 7 92( 1 H，d)，7 77( 1 H5 s)5 7 5 3 -7 5 9(2H，d)，7 40-7 47( 1 H， t)，7 2 8 - 7 3 3 ( 1 H，m)5 7 1 4 -7 2 6( 5 H，m5 部份以溶劑遮蔽）， -54- (51) 200304824 7 0 8 - 7 1 3 ( 1 H， t)， 6 75 -6 8 1 ( 1 H， t)， 6 66-6 73 (2H， d)， 4 5 8-4 66(2H， d)， 4 46-4 52(2H? d)， 4 2 8-4 34(2H, quartet), 1 3 1-1 38(3H，t)ppmo LRMS(電噴灑）m/z [M + H]+ 526，[M + Na]+ 5 48，[M-H] + 524 實例1 6 :Example 15: 1HNMR (400MHz, CDCl3) (5 = 8 90-9 1 0 (lH, brs), 8 49-8 5 3 (1 H? D) 5 8 2 8-8 3 4 (1 H? M )? 8 13-8 16 (1H, d), 7 8 7- 7 92 (1 H, d), 7 77 (1 H5 s) 5 7 5 3 -7 5 9 (2H, d), 7 40- 7 47 (1 H, t), 7 2 8-7 3 3 (1 H, m) 5 7 1 4 -7 2 6 (5 H, m5 partially covered with solvent), -54- (51) 200304824 7 0 8-7 1 3 (1 H, t), 6 75 -6 8 1 (1 H, t), 6 66-6 73 (2H, d), 4 5 8-4 66 (2H, d), 4 46-4 52 (2H? D), 4 2 8-4 34 (2H, quartet), 1 3 1-1 38 (3H, t) ppmo LRMS (electrospray) m / z [M + H] + 526, [M + Na] + 5 48, [MH] + 524 Example 1 6:

]H NMR(400MHz? CDC13) 5 =9 61(1H? s)? 8 54-8 60( 1 H? d), 8 14-8 2 1 (2H, m)，7 9 1 -7 96( 1 H，d)，7 72-7 74( 1H? m)， 7 4 3 - 7 4 9( 1 H, t)， 7 29-7 3 3 ( 1 H， d), 7 1 9-7 24(2H, m), 7 0 8-7 1 8(4H， m)， 6 90-7 00(2H，m)， 6 73 -6 8 0(2H，m)， 4 5 8-4 63 (2H，d)，4 29-4 3 9(4H，m)，3 5 6(2H，s)5 1 35- 1 4 1 ( 3 H , t)ppmo LRMS(電噴灑）m/z [M + H]+ 540，[M + Na]+ 5 62，[M-H] + 53 8] H NMR (400MHz? CDC13) 5 = 9 61 (1H? S)? 8 54-8 60 (1 H? D), 8 14-8 2 1 (2H, m), 7 9 1 -7 96 (1 H, d), 7 72-7 74 (1H? M), 7 4 3-7 4 9 (1 H, t), 7 29-7 3 3 (1 H, d), 7 1 9-7 24 ( 2H, m), 7 0 8-7 1 8 (4H, m), 6 90-7 00 (2H, m), 6 73 -6 8 0 (2H, m), 4 5 8-4 63 (2H, d), 4 29-4 3 9 (4H, m), 3 5 6 (2H, s) 5 1 35- 1 4 1 (3 H, t) ppmo LRMS (electrospray) m / z [M + H] + 540, [M + Na] + 5 62, [MH] + 53 8

實例1 7 : lH NMR(400MHz, CDC13) 5 =8 5 2- 8 5 9 ( 1 H, d), 8 19- 8 2 5 ( 1 H, m), 8 16-8 19(1H，d)，7 90-7 94( 1 H? d)，7 78 ( 1 H， s)，7 44-7 49(1H，t)，7 28-7 3 2( 1 H，d)，7 1 8 -7 23 (2H，d)， 7 04-7 1 8(4H，m), 6 64-6 7 3 ( 3 H，m)， 6 2 8 - 6 3 5 ( 1 H，m)， 4 5 8 -4 6 6(2H，d)，4 26-4 3 8 (4 H，m)，3 4 2 ( 2 H，s )， 1 3 3-1 3 8(3H，t)ppm。 LRMS(電噴灑）m/z [M-H]+ 538 -55- (52) 200304824 實例1 8 : 1HNMR(400MHz，CDCl3)5= 8 5 5 - 8 6 1 (lH，d)，8l8- 8 2 3 ( 1 H，m)，8 15-8 18(1H，d)，7 90-7 94( 1H，d)，7 78( 1 H， s)，7 43 -7 49( 1 H，t)，7 26-7 3 0( 1 H，d)5 7 1 8 - 7 2 5 (2H，m)5 7 04- 7 1 7(3H，m)，6 95 -7 0 1 (2H，d)5 6 64-6 75 (3 H，m)，Example 17: lH NMR (400MHz, CDC13) 5 = 8 5 2- 8 5 9 (1 H, d), 8 19- 8 2 5 (1 H, m), 8 16-8 19 (1H, d) , 7 90-7 94 (1 H? D), 7 78 (1 H, s), 7 44-7 49 (1H, t), 7 28-7 3 2 (1 H, d), 7 1 8- 7 23 (2H, d), 7 04-7 1 8 (4H, m), 6 64-6 7 3 (3 H, m), 6 2 8-6 3 5 (1 H, m), 4 5 8 -4 6 6 (2H, d), 4 26-4 3 8 (4 H, m), 3 4 2 (2 H, s), 1 3 3-1 3 8 (3H, t) ppm. LRMS (electrospray) m / z [MH] + 538 -55- (52) 200304824 Example 1 8: 1HNMR (400MHz, CDCl3) 5 = 8 5 5-8 6 1 (lH, d), 8l8- 8 2 3 (1 H, m), 8 15-8 18 (1H, d), 7 90-7 94 (1H, d), 7 78 (1 H, s), 7 43 -7 49 (1 H, t), 7 26-7 3 0 (1 H, d) 5 7 1 8-7 2 5 (2H, m) 5 7 04- 7 1 7 (3H, m), 6 95 -7 0 1 (2H, d) 5 6 64-6 75 (3 H, m),

6 1 7-6 24( 1H，m)，4 5 8 -4 68(2H，d)，4 3 0-4 40(4H，m)， 3 46(2H, s)，1 3 2- 1 40(3 H，t)ppm。 LRMS(電噴灑）m/z [M + H]+ 540，[M + Na]+ 5 62，[M-H] + 53 8 以下的製備法係說明在先前的實例中使用的特定的中 間物之製備作用。 製備法1 : (4-胺基甲基苯甲基）胺基甲酸特丁酯6 1 7-6 24 (1H, m), 4 5 8 -4 68 (2H, d), 4 3 0-4 40 (4H, m), 3 46 (2H, s), 1 3 2- 1 40 (3 H, t) ppm. LRMS (electrospray) m / z [M + H] + 540, [M + Na] + 5 62, [MH] + 53 8 The following preparation method illustrates the preparation of specific intermediates used in previous examples effect. Preparation method 1: (4-Aminomethylbenzyl) tetrabutylaminoformate

H2NH2N

π Me Y YMe 〇 Me 將溶解在二氯甲烷（5 〇毫升）中的二羧酸二特丁酯 (462公克，212毫莫耳）之溶液加入在〇°C及氮氣下在二 氯甲烷（50毫升）中的4-胺基甲基苯甲胺（14 4公克，106 毫莫耳）之溶液中。允許反應混合物溫熱至室溫及攪拌1 8 小時。接著將反應混合物依次以水（100毫升）及10%檸檬 酸水溶液（2 0 0毫升）淸洗，並將有機相棄置。接著將水相 -56- (53) 200304824 之pH以加入的088氨調整至大於8之pH，並以二氯甲 烷（3x2 0 0毫升）萃取。接著將合倂的有機萃取液經無水硫 酸鎂乾燥及在真空中除去溶劑，以得到成爲白色固體之 (4 -胺基甲基苯甲基）胺基甲酸特丁酯（4 29公克）。 'H NMR(400MHz? CDC13) (5 =7 22-7 26(4H? d), 4 80- 4 90( 1H，brs)，4 23 -4 3 0(2H，m)，3 82(2H，s)，1 43(2H，s)， 1 38 (2H，s)ppmo LRMS(電噴灑）m/z[M-H]+237。 籲 製備法2· [4-({[2-(4 -截基本與基）卩比d疋-3-類基]胺基}甲基 )苯甲基]胺基甲酸特丁酯 〇π Me Y YMe 0 Me A solution of ditert-butyl dicarboxylate (462 g, 212 mmol) dissolved in dichloromethane (50 ml) was added at 0 ° C under nitrogen in dichloromethane ( 50 ml) of 4-aminomethylbenzylamine (14 4 g, 106 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was then washed with water (100 ml) and 10% aqueous citric acid solution (200 ml) in this order, and the organic phase was discarded. The pH of the aqueous phase -56- (53) 200304824 was then adjusted to a pH greater than 8 with the addition of 088 ammonia, and extracted with dichloromethane (3 x 2000 ml). The combined organic extract was then dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to obtain (4-aminomethylbenzyl) tert-butyl carbamate (4 29 g) as a white solid. 'H NMR (400MHz? CDC13) (5 = 7 22-7 26 (4H? D), 4 80- 4 90 (1H, brs), 4 23 -4 3 0 (2H, m), 3 82 (2H, s), 1 43 (2H, s), 1 38 (2H, s) ppmo LRMS (electrospray) m / z [MH] +237. Call for the preparation method 2. [4-({[2- (4-cut Basic and base) 卩 ratio d 疋 -3-type group] amino group} methyl) benzyl] amino butyl formate.

將2-(4 -氟甲苯氧基）菸酸（參考專利申請案 WO 98/45268)(6 20公克，26毫莫耳）、丨·羥基苯並三唑（5 39 公克，40毫莫耳）及1-(3-二甲基胺基丙基）-3-乙基碳化二 醯亞胺鹽酸（6 62公克，34毫莫耳）在室溫下溶解在N，N-二甲基甲醯胺（50毫升）中’並加入（4·胺基甲基苯甲基）胺 基甲酸特丁酯（6 28公克’ 26毫莫耳）（參考製備法1)，接 著加入Ν-甲基嗎啉（4 4毫升’ 40毫莫耳）。將反應混合物 -57- (54) 200304824 在氮氣下及在室溫下攪拌1 8小時，並接著分溶在醋酸乙 酯（100毫升）與水（100毫升）之間，將有機層分開。接著將 有機相以氯化鈉飽和水溶液（1 00毫升）淸洗，經無水硫酸 鎂乾燥及在真空中除去溶劑。將殘餘物以二乙醚（〗5毫升） 濕磨，以得到成爲灰白色固體之[4-({[2-(4-氟基苯氧基）吡 啶-3-羰基]胺基}甲基）苯甲基]胺基甲酸特丁酯（9 52公克） 〇 NMR(3 00MHz, CDC13) δ =8 5 6- 8 76( 1 Η, m)? 8 06- 8 14(2Η，m)，6 96-7 40(9Η，m，部份以溶劑遮蔽），々μα 95(3Η， m)， 4 20_4 40(2Η， brs)， 1 56(9Η， s)ppm。 LRMS(熱噴灑）m/z [Μ + ΝΗ4]+ 469。 製備法3 : Ν-(4·胺基甲基苯甲基）-5_氟基_2_(4_氟基苯氧 基）菸鹼醯胺鹽酸Add 2- (4-fluorotolyloxy) nicotinic acid (refer to patent application WO 98/45268) (6 20 g, 26 mmol), hydroxybenzotriazole (5 39 g, 40 mmol) ) And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (6 62 g, 34 mmol) are dissolved in N, N-dimethylformamide at room temperature Amidine (50 ml) was added and (4. aminomethylbenzyl) tert-butyl carbamate (6 28 g '26 mmol) was added (see Preparation Method 1), followed by the addition of N-methyl Morpholine (4 4 ml '40 mmol). The reaction mixture -57- (54) 200304824 was stirred under nitrogen at room temperature for 18 hours, and then partitioned between ethyl acetate (100 ml) and water (100 ml), and the organic layer was separated. The organic phase was then washed with a saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The residue was triturated with diethyl ether (5 ml) to obtain [4-({[2- (4-fluorophenoxy) pyridine-3-carbonyl] amino} methyl) benzene as an off-white solid. Methyl] tert-butyl aminoformate (9 52 g) NMR (3 00 MHz, CDC13) δ = 8 5 6- 8 76 (1 Η, m)? 8 06- 8 14 (2 Η, m), 6 96 -7 40 (9Η, m, partially covered with solvent), 々μα 95 (3Η, m), 4 20_4 40 (2Η, brs), 1 56 (9Η, s) ppm. LRMS (thermal spray) m / z [Μ + ΝΗ4] + 469. Preparation method 3: Ν- (4 · aminomethylbenzyl) -5_fluoro group_2_ (4_fluorophenylphenoxy) nicotinamine hydrochloride

將 [4-(U2_(4-氟基苯氧基）吡啶-3-羰基]胺基}甲基） 苯甲基]胺基甲酸特丁酯（9 51公克，21毫莫耳）（參考製備 法2)溶解在二氯甲烷（60毫升）中及以氯化氫起泡流經在〇 °C下的溶液中，直到溶液變飽和爲止（3 〇分鐘）。接著將反 -58- (55) 200304824 應混合物在氮氣下及在室溫下再攪拌1小時，然後在真空 中除去溶劑。將所得白色沉澱物以二乙醚（3x10毫升）濕磨 ，以得到成爲白色固體之N-(4-胺基甲基苯甲基）_5-氟基-2-(4 -氟基苯氧基）菸鹼醯胺鹽酸（7 92公克）。 lU NMR(3 00MHz5 DMSO-d6) δ =8 96-9 07( 1 Η? m)? 8 40- 8 60(2H，m)，8 1 7-8 22(lH，d)，8li-8 16(lH，m)，7 3 6-7 44(4Η，m)，7 18-7 33(5Η，m)，4 43·4 58(2Η，m,部份以溶 劑遮蔽），3 86-3 99(2H，m)ppm。 LRMS(熱噴灑）m/z[M + H]+ 352。 製備法4· (4·{[(2 -氯基氟基吡啶·3_羰基）胺基]甲基}苯 甲基）胺基甲酸特丁酯[4- (U2_ (4-Fluorophenoxy) pyridine-3-carbonyl] amino} methyl) benzyl] aminobutyrate (9 51 g, 21 mmol) (reference preparation Method 2) Dissolve in dichloromethane (60 ml) and bubble through the solution at 0 ° C with hydrogen chloride until the solution becomes saturated (30 minutes). The anti-58- (55) 200304824 reaction mixture was then stirred for an additional hour at room temperature under nitrogen and the solvent was removed in vacuo. The resulting white precipitate was triturated with diethyl ether (3x10 ml) to give N- (4-aminomethylbenzyl) _5-fluoro-2- (4-fluorophenoxy) as a white solid. Nicotinamide hydrochloride (7.92 g). lU NMR (3 00MHz5 DMSO-d6) δ = 8 96-9 07 (1 Η? m)? 8 40- 8 60 (2H, m), 8 1 7-8 22 (lH, d), 8li-8 16 (lH, m), 7 3 6-7 44 (4Η, m), 7 18-7 33 (5Η, m), 4 43 · 4 58 (2Η, m, partially covered with solvent), 3 86-3 99 (2H, m) ppm. LRMS (thermal spray) m / z [M + H] + 352. Preparation method 4 · (4 · {[(2-chlorofluoropyridine · 3-carbonyl) amino] methyl} benzyl) aminobutyrate

VVMe 〇 Me 將2-氯基-5-氟基蘇酸（參考製備法ι〇)(2 〇公克， 11 4笔吴耳）、1-經基苯並二卩坐 平亚一 85公克，137毫莫耳） 及 1-(3 - 一甲基i女基丙基）·〗7其呢/| 土）3-乙基礙化二醯亞胺鹽酸（2 62VVMe 〇Me will be 2-chloro-5-fluorothreonic acid (reference preparation method ι〇) (20 grams, 114 pen Wu Er), 1-based benzobispyrene zirconia 85 grams, 137 Mol) and 1- (3-monomethyl i-propyl propyl) · 7 7 its / | soil) 3-ethyl hindered diamidine hydrochloride (2 62

公克，13 7毫莫耳）在宰卢下龙 N */血下在N，i二甲基甲醯胺（5〇毫 升）中攬拌’並加入（4 -胳其田其衆① 月女$甲S本：甲基）胺基甲酸特丁酯 (269公克，114毫莫耳考製倫 斗）（&gt; 考衣備法1)，接著加入N-甲 基嗎啉（2 5毫升，22 8高苗η、 ^ 毛旲耳）°每著將反應混合物在氮 氣下及在室溫下攪拌1 8小時，分檢 」時力洛在二氯甲烷（1〇〇毫升） -59、 (56) 200304824 與水（1 00毫升）之間，並將有機層分開。接著將有機層以 氯化鈉飽和水溶液（1 00毫升）淸洗，經無水硫酸鎂乾燥及 在真空中除去溶劑，以得到成爲白色固體之（4-{[(2_氯基_ 5 -氟基吡啶-3 -羰基）胺基]甲基}苯甲基）胺基甲酸特丁酯 (4 0 8公克）。 lB NMR(400MHz5 DMSO-d6) 5 =9 10-9 17(1H5 t)5 8 5 2- 8 5 4(lH，d)，7 99-8 04(lH，dd)，7 26-7 3 5 (3H，m)，7 18-7 22(2H，d)，4 3 9-4 44(2H，d)，4 06-4 1 1 (2H，d)，1 38(9H， s ) p p m ° LRMS(電噴灑）m/z [M + Na]+ 416，[M-H]+ 3 92。 製備法5: [4·({[5·氟基-2-(4-氟基苯氧基）吡啶羰基]胺 基}甲基）苯甲基]胺基甲酸特丁酯 〇G, 13 7 mmol) under Zal Ha Ha Long N * / blood in N, i dimethylformamide (50 ml) and add (4-tick its field and its people ① month girl $ Formazan: Methyl) tetrabutyl carbamate (269 g, 114 millimoles) (&Co; Preparation Method 1), followed by N-methylmorpholine (25 ml, 22 8 high seedlings η, 旲）) ° each time the reaction mixture was stirred under nitrogen and at room temperature for 18 hours, sorted "Lilo in dichloromethane (100 ml) -59, (56 200304824 and water (100 ml), and the organic layer was separated. The organic layer was then washed with a saturated aqueous solution of sodium chloride (100 ml), dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo to obtain (4-{[(2_chloro- 5 -fluoro Pyridyl-3 -carbonyl) amino] methyl] benzyl) tetrabutyl carboxylate (408 g). lB NMR (400MHz5 DMSO-d6) 5 = 9 10-9 17 (1H5 t) 5 8 5 2- 8 5 4 (lH, d), 7 99-8 04 (lH, dd), 7 26-7 3 5 (3H, m), 7 18-7 22 (2H, d), 4 3 9-4 44 (2H, d), 4 06-4 1 1 (2H, d), 1 38 (9H, s) ppm ° LRMS (electrospray) m / z [M + Na] + 416, [MH] + 3 92. Preparation method 5: [4 · ({[5 · Fluoro-2- (4-fluorophenoxy) pyridinecarbonyl] amino} methyl) benzyl] aminobutyrate

將（4-{[(2-氯基-5·氟基吡啶-3-羰基）胺基]甲基}苯甲 基）胺基甲酸特丁酯（1〇0毫克，0 29毫莫耳）（參考製備法 4)、4-氟酚（28毫克，029毫莫耳）及碳酸鉋（80〇毫克， 2 5毫莫耳）在60 °C下及在氮氣下在N，N-二甲基甲醯胺（10 毫升）中攪拌1 8小時。接著將反應混合物分溶在醋酸乙酯 -60- (57) 200304824 (20毫升）與水（20毫升）之間，並將有機層分開。接著將有 機層以氯化鈉飽和水溶液（3x10毫升）淸洗，在真空中除去 溶劑及將殘餘物在以醋酸乙酯：戊烷（以體積計之5 9 5改 變至3 0 70)之溶劑梯度溶離之矽膠上以閃蒸管柱色層分離 法純化，以得到成爲白色泡沬之[4-({[5_氟基-2-(4-氟基苯 氧基）吡啶-3-羰基]胺基}甲基）苯甲基]胺基甲酸特丁酯（57 毫克）。 2H NMR(400MHz? DMSO-d6) 5 =8 97-9 02( 1 H, t), 8 19- 寒 8 21(lH，d)，8 03 - 8 08 (lH，dd)，7 3 0-7 3 6(lH，m)，7l9-7 3 0(6H，m)，7 1 卜7 16(2H，d)，4 44·4 50(2H，d)，4 03 -4 〇8(2H，d)，1 36(9H，s)ppm。 LRMS(電噴灑）m/z [M + Na]+ 492，[M-H]+ 468。 製備法 6 ·Ν-(4-胺基甲基苯甲基）-5-氟基- 2-(4-氟基苯氧 基）菸鹼醯胺鹽酸 〇Tert-Butyl (4-{[(2-chloro-5 · fluoropyridine-3-carbonyl) amino] methyl} benzyl) carbamate (100 mg, 0.29 mmol) (Reference Production Method 4), 4-fluorophenol (28 mg, 029 mmol) and carbon shavings (80 mg, 25 mmol) at 60 ° C and under nitrogen at N, N-dimethylformamide Methylformamide (10 ml) was stirred for 18 hours. The reaction mixture was then partitioned between ethyl acetate-60- (57) 200304824 (20 ml) and water (20 ml), and the organic layer was separated. The organic layer was then rinsed with a saturated aqueous solution of sodium chloride (3x10 ml), the solvent was removed in vacuo and the residue was taken up in a solvent of ethyl acetate: pentane (5 9 5 to 3 0 70 by volume) Gradient-dissolved silica gel was purified by flash chromatography column chromatography to obtain [4-({[5_fluoroyl-2- (4-fluorophenoxy) pyridine-3-carbonyl ] Amino} methyl) benzyl] tetrabutyl carbamate (57 mg). 2H NMR (400MHz? DMSO-d6) 5 = 8 97-9 02 (1 H, t), 8 19- cold 8 21 (lH, d), 8 03-8 08 (lH, dd), 7 3 0- 7 3 6 (lH, m), 7l9-7 3 0 (6H, m), 7 1 1 7 16 (2H, d), 4 44 · 4 50 (2H, d), 4 03 -4 〇8 (2H , D), 1 36 (9H, s) ppm. LRMS (electrospray) m / z [M + Na] + 492, [M-H] + 468. Production method 6 · N- (4-aminomethylbenzyl) -5-fluoro- 2- (4-fluorophenoxy) nicotinamine hydrochloride 〇

將[4 - ({[ 5 -氟基-2 - (4 -氟基苯氧基）吡啶-3 -幾基]胺基} 甲基）苯甲基]胺基甲酸特丁酯（1 62公克’ 3 44毫莫耳）（參 考製備法5 )溶解在甲醇中的2 2 5克分子量氫氯酸溶液 -61 - (58) (58)200304824 (100毫升）中，並將混合物在室溫下及在氮氣下攪拌4小 時，然後在真空中除去溶劑。將殘餘物溶解在水（5〇毫升） 中，將pH以加入的碳酸氫鈉調整至大於8之PH，並以二 氯甲烷（3x50毫升）萃取。接著將合倂的有機萃取液經無水 硫酸鎂乾燥及在真空中濃縮，以得到成爲膠之N-(4-胺基 甲基苯甲基）-%氟基(4-氟基苯氧基）菸鹼醯胺鹽酸（1 25 毫克）。 製備法7: (4-{[(2-氯基吡啶-3-羰基）胺基]甲基丨苯甲基）胺 基甲酸特丁酯 、N Cl Ύ rMe 〇 Me 將2-氯基菸酸（2 86公克，182毫莫耳）、1-羥基苯並 三唑（3 0公克，21 8毫莫耳）及1-(3-二甲基胺基丙基）-3- · 乙基碳化二醯亞胺鹽酸（4 18公克，21 8毫莫耳）在室溫下 溶解在N，N-二甲基甲醯胺（50毫升）中，並加入（4_胺基甲 基苯甲基）胺基甲酸特丁酯（4 29公克，182毫莫耳）（參考 製備法1)，接著加入N-甲基嗎啉（4毫升，3 6 3毫莫耳）。 ’ 將反應混合物在氮氣下及在室溫下攪拌1 8小時，接著分 · 溶在醋酸乙酯（100毫升）與水（100毫升）之間，並將有機層 分開。接著將有機層以氯化鈉飽和水溶液（1 〇〇毫升）淸洗 ’經無水硫酸鎂乾燥及在真空中除去溶劑。接著將殘餘物 -62- (59) 200304824 以二乙醚（2x10毫升）濕磨，以得到成爲白色固體之（4-{[(2_氯基吡啶-3-羰基）胺基]甲基}苯甲基）胺基甲酸特丁酯 (6 71公克）。 ln NMR(400MHz? DMSO-d6) δ =9 0 1 -9 08( 1 Η? t)? 8 43 - 8 47( 1 Η，m)，7 89-7 93 ( 1 Η，d)，7 45 -7 5 0( 1 Η，m)，7 3 0-7 3 7 (lH5m)，7 26-7 3 1 (2H，d)，7l7-7 21(2H，d)，4 3 9- 4 43 (2Η，d)，4 03 -4 1 0(2Η，d)，1 37(9Η，s)PPm〇 LRMS(電噴灑）m/z[M-H]+374。 籲 製備法8 : 3-(3-[(4-特丁氧基羰基胺基甲基）苯甲基胺甲醯 基]吡啶氧基}苯甲酸乙酯[4-({[5-Fluoro-2-(4-fluorophenoxy) pyridine-3 -quinyl] amino} methyl) benzyl] aminobutyrate (1 62 g '3 44 millimoles) (Reference Preparation Method 5) 2 25 grams of molecular weight hydrochloric acid solution -61-(58) (58) 200304824 (100 ml) dissolved in methanol, and the mixture at room temperature And stirred under nitrogen for 4 hours, then the solvent was removed in vacuo. The residue was dissolved in water (50 ml), the pH was adjusted to a pH greater than 8 with the addition of sodium bicarbonate, and extracted with dichloromethane (3 x 50 ml). The combined organic extract was dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain N- (4-aminomethylbenzyl)-% fluoro (4-fluorophenoxy) as a gum. Nicotinamide hydrochloride (125 mg). Preparation method 7: (4-{[(2-chloropyridine-3-carbonyl) amino] methyl 丨 benzyl) amino butyl formate, N Cl Ύ rMe 〇Me (2 86 g, 182 mmol), 1-hydroxybenzotriazole (30 g, 21 8 mmol) and 1- (3-dimethylaminopropyl) -3- · ethyl carbonization Diamidine hydrochloride (4 18 g, 21 8 mmol) was dissolved in N, N-dimethylformamide (50 ml) at room temperature, and (4-aminomethylbenzyl) was added ) Tert-butyl aminoformate (429g, 182mmol) (refer to Preparation Method 1), followed by N-methylmorpholine (4ml, 363mmol). The reaction mixture was stirred under nitrogen and at room temperature for 18 hours, and then separated and dissolved in ethyl acetate (100 ml) and water (100 ml), and the organic layer was separated. The organic layer was then washed with a saturated aqueous solution of sodium chloride (100 ml) ', dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. The residue -62- (59) 200304824 was then triturated with diethyl ether (2x10 ml) to give (4-{[(2-chloropyridine-3-carbonyl) amino] methyl} benzene as a white solid. Tert-butyl methyl) carbamate (6 71 g). ln NMR (400MHz? DMSO-d6) δ = 9 0 1 -9 08 (1 Η? t)? 8 43-8 47 (1 Η, m), 7 89-7 93 (1 Η, d), 7 45 -7 5 0 (1 Η, m), 7 3 0-7 3 7 (lH5m), 7 26-7 3 1 (2H, d), 7l-7-7 21 (2H, d), 4 3 9- 4 43 (2Η, d), 4 03 -4 1 0 (2Η, d), 1 37 (9s, s) PPmOLRMS (electrospray) m / z [MH] +374. Method 8: 3- (3-[(4-tert-butoxycarbonylaminomethyl) benzylamine formamidine] pyridyloxy} benzoate

將（4 — U(2-氯基吡啶羰基）胺基]甲基}苯甲基）胺基 甲酸特丁酯（12 〇公克，3 2 2毫莫耳）（參考製備法7)、3-經基本甲酸乙酯（6 42公克，38 6毫莫耳）及碳酸絶（1 5 7 么克，48 3笔莫耳）在及在氮氣下在二噁烷（18〇毫 升)中攪拌】8小時。仍有原料的存在，所以再一起加入一 份”經基苯甲酸乙酯（6 42公克，3 8 6 _莫耳）及碳酸絶 (15 7么克，48 3毫莫耳）與二噁烷（々Μ毫升）及比&amp;二甲 -63- (60) (60)200304824 基甲醯胺（40毫升），並將反應在70 °C下再攪拌22小時。 接著在減壓下除去溶劑，將殘餘物分溶在醋酸乙酯（2〇〇 毫升）與水（200毫升）之間，並將有機層分開。接著將有機 層以氯化鈉飽和水溶液（3x100毫升）淸洗，在真空中除去 溶劑及將殘餘物在以醋酸乙酯：己烷（以體積計之〇 1 〇〇 改變至5 0 5 0)之溶劑梯度溶離之矽膠上以閃蒸管柱色層分 離法純化，以得到成爲灰白色泡沬之3-{3-[(4-特丁氧基 羰基胺基甲基）苯甲基胺甲醯基]吡啶氧基}苯甲酸乙酯 (7 42毫克）。 NMR(400MHz? DMSO-d6) δ =8 92-8 98( 1 Η? t), 8 18- 8 21(1Η，d)，8 14-8 18(1Η，d)，7 8 卜7 8 5 ( 1 Η，d)，7 77( 1Η， s)，7 5 4- 7 60( 1 Η，t)5 7 46-7 5 0( 1 Η，m)5 7 27-7 3 1 (2Η，d)5 7 22-7 26( 1 Η， m)， 7 14-7 18(3Η，d)，4 47-4 5 1 (2Η，d)， 4 29-4 3 5 (2Η? quart), 4 04-4 08(2Η? d)? 1 37(9Η, s)5 1 28-1 35(3Η，t)ppmo LRMS(電噴灑）m/z [M + Na]+ 5 2 8，[Μ-Η]+ 5 04。 製備法9: [N-(4-胺基甲基苯甲基）-2-(4-氟基苯氧基）菸鹼 醯胺鹽酸 -64- (61) 200304824Tert-butyl (4- U (2-chloropyridylcarbonyl) amino] methyl} benzyl) carbamate (120 g, 3 2 2 mmol) (refer to Preparation Method 7), 3- Stir in basic ethyl formate (6 42 g, 38.6 mmol) and carbonate (1 5 7 g, 48 3 moles) under nitrogen in dioxane (18 ml)] 8 hour. The raw materials still exist, so add another portion of "Ethyl Benzoate (6 42 g, 3 8 6 _mol) and Carbonic Acid (15 7 g, 48 3 mmol) with dioxane (々ΜmL) and dimethyl-63- (60) (60) 200304824 methylformamide (40mL), and the reaction was stirred at 70 ° C for another 22 hours. Then the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (200 mL) and water (200 mL), and the organic layer was separated. The organic layer was then rinsed with a saturated aqueous solution of sodium chloride (3 x 100 mL) and vacuumed The solvent was removed from the solution and the residue was purified by flash column chromatography on a silica gel with a solvent gradient of ethyl acetate: hexane (from 1000 to 500 by volume) in a solvent gradient. Ethyl 3- {3-[(4-tert-butoxycarbonylaminomethyl) benzylaminomethyl] pyridyloxy} benzoate (7 42 mg) was obtained as an off-white foam. NMR (400MHz DMSO-d6) δ = 8 92-8 98 (1 Η? T), 8 18- 8 21 (1Η, d), 8 14-8 18 (1Η, d), 7 8 Bu 7 8 5 (1 Η , D), 7 77 (1Η, s), 7 5 4- 7 60 (1 Η, t) 5 7 46-7 5 0 (1 Η, m) 5 7 27-7 3 1 (2Η, d) 5 7 22-7 26 (1 Η, m), 7 14-7 18 (3Η, d), 4 47- 4 5 1 (2Η, d), 4 29-4 3 5 (2Η? Quart), 4 04-4 08 (2Η? D)? 1 37 (9Η, s) 5 1 28-1 35 (3Η, t) ppmo LRMS (electrospray) m / z [M + Na] + 5 2 8, [Μ-Η] + 5 04. Preparation method 9: [N- (4-aminomethylbenzyl) -2- ( 4-fluorophenoxy) nicotinamide amine hydrochloride-64- (61) 200304824

將3-{3-[(4-特丁氧基羰基胺基甲基）苯甲基胺甲驢基] 吡啶-2-氧基}苯甲酸乙酯（7 42公克，I4 7毫莫耳）（參考製 備法8)溶解在二氯甲院（1〇〇毫升）中及以氯化氫起泡流經 在0 °C下的溶液中，直到溶液變飽和爲止（3 〇分鐘）。在真 空中除去溶劑，以得到成爲白色固體之[N-(4-胺基甲基苯 甲基）-2-(4-氟基苯氧基）菸鹼醯胺鹽酸（7 16毫克）。 JH NMR(400MHz, DMSO-d6) δ =9 48-9 54( 1 Η? m) 5 8 8 3 -Ethyl 3- {3-[(4-tert-butoxycarbonylaminomethyl) benzylaminomethyl] pyridine-2-oxy} benzoate (7 42 g, I 4 7 mmol) (Reference Preparation Method 8) Dissolved in dichloromethane (100 ml) and bubbled with hydrogen chloride and passed through the solution at 0 ° C until the solution became saturated (30 minutes). The solvent was removed in vacuo to obtain [N- (4-aminomethylbenzyl) -2- (4-fluorophenoxy) nicotinamine hydrochloride (7 16 mg) as a white solid. JH NMR (400MHz, DMSO-d6) δ = 9 48-9 54 (1 Η? M) 5 8 8 3-

9 03 (3 H，brs)，8 62- 8 66(lH，m)，8 5 7-8 63 (lH，d)，8 3 5-8 42(1Η，d)，8 22( 1 Η，s)，8 0 1 -8 0 8( 1 Η，t)，7 93 -7 98( 1 Η， d)，7 8 1 -7 9 1 (4Η，m)，7 68-7 74( 1 Η，d)，4 94-5 0 1 (2Η，d)， 4 76-4 8 1 (2Η， quart)， 4 3 6-4 42(2Η, m)， 1 7 5 - 1 8 0(3Η， t) ρ ρ m 〇 乙11乂8(電噴灑）111/2[1^ + 11]+ 406。 製備法10: 2 -氯基-5-氟基菸酸 -65- (62) (62)2003048249 03 (3 H, brs), 8 62- 8 66 (lH, m), 8 5 7-8 63 (lH, d), 8 3 5-8 42 (1Η, d), 8 22 (1Η, s), 8 0 1 -8 0 8 (1 Η, t), 7 93 -7 98 (1 Η, d), 7 8 1 -7 9 1 (4Η, m), 7 68-7 74 (1 Η , D), 4 94-5 0 1 (2Η, d), 4 76-4 8 1 (2Η, quart), 4 3 6-4 42 (2Η, m), 1 7 5-1 8 0 (3Η, t) ρ ρ m 〇 B 11 乂 8 (electric spray) 111/2 [1 ^ + 11] + 406. Preparation method 10: 2-chloro-5-fluoronicotinic acid -65- (62) (62) 200304824

將2 -氛基-5-氣基蘇酸乙醋（50 4公克，0 247莫耳）（ 參考文獻 J Med Chem 5 1993，36(18)，2676-88)溶解在四 氫呋喃（350毫升）中，並加入2克分子量氫氧化鋰水溶液 (247毫升，0 495莫耳）。將反應混合物在室溫下攪泮3天 。將溶液的pH以加入的6當量氫氯酸減低至等於1之pH ，接著以二氯曱烷萃取。將合倂的有機萃取液經無水硫酸 鎂乾燥，並在真空中除去溶劑，以得到固體，將其以二乙 醚濕磨及接著在真空中乾燥，以得到成爲白色固體之2-氯基-5-氟基菸酸（40 5 6公克）。 NMR(400MHz, DMSO-d6) δ =8 20( 1 Η? s)5 8 6 2 ( 1 Η? s ) ρ ρ m ο LRMS(電噴灑）m/z [Μ + Η]+ 174。 菸鹼醯胺衍生物的活體外活性 以化合物抑制以PDE4使cAMP水解成AMP之能力 測定式（1)之菸鹼醯胺衍生物的PDE4抑制活性（也參考文 獻1)。將以氚標記之cAMP以PDE4培育。在培育之後， 所生產之以放射標記之AMP能夠與矽酸釔SPA珠結合。 接著這些SPA珠發生可以閃爍計數定量之光線。以加入 PDE4抑制劑避免自cAMP形成AMP及使計數量減少。可 -66- (63) (63)200304824 將PDE4抑制劑之IC5〇定義成造成與只有PDE4之控制井 (沒有抑制劑）比較時減少50%計數量之化合物濃度。 以式（1)之菸鹼醯胺衍生物抑制自人類末梢血液單細 胞釋出TNF α之能力證明彼之抗發炎特性（也參考文獻2) 。自健康的自願者收集靜脈血，並以經由 H i s 〇 p a q u e (F i c ο 11)軟墊之離心作用純化單核細胞。以加入 脂肪多糖刺激這些細胞生產TNF α。在LPS的存在下培 育18小時之後，取出細胞上層淸液，並以ELISA測定在 上層淸液中的TNF α濃度。以加入PDE4抑制劑減少所生 產之TNF α量。測定IC5〇，其等於得到在與以LPS刺激 之控制井比較時抑制50%TNF α生產作用之化合物濃度。 在上述的檢定中測試所有的實例，並發現彼具有小於 5〇〇毫微克分子量之IC5〇(TNF α篩選）。以及就大部份測 試的化合物而言，發現彼具有甚至小於200毫微克分子量 之 IC5G(TNF α 篩選）。 文獻·· 1 Thhompson J W, Teraski WL, Epstein PM, Strada SJ , “Assay of nucleotidephosphodiesterase and resolution of multiple molecular forms of the isoenzyme”， Advances in cyclic nucleotides research, edited by Brooker G，Greengard P，Robinson GA，Raven Press, New York 1979，10，p 69-92。 2 Yoshimura T? Kurita C5 Nagao T5 Usami E, Nakao T, -67- (64) 200304824Ethyl 2-amino-5-aminothreonate (50 4 g, 0 247 mol) (Reference J Med Chem 5 1993, 36 (18), 2676-88) was dissolved in tetrahydrofuran (350 ml) And added 2 g of a molecular weight lithium hydroxide aqueous solution (247 ml, 0 495 moles). The reaction mixture was stirred at room temperature for 3 days. The pH of the solution was reduced to a pH of 1 with 6 equivalents of hydrochloric acid added, followed by extraction with dichloromethane. The combined organic extract was dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo to obtain a solid, which was triturated with diethyl ether and then dried in vacuo to give 2-chloro-5 as a white solid. -Fluoronicotinic acid (40 5 6 g). NMR (400MHz, DMSO-d6) δ = 8 20 (1 Η? S) 5 8 6 2 (1 Η? S) ρ ρ m ο LRMS (electrospray) m / z [Μ + Η] + 174. In vitro activity of nicotinamide derivatives The ability of compounds to inhibit the hydrolysis of cAMP to AMP with PDE4 was measured. The PDE4 inhibitory activity of nicotinamide derivatives of formula (1) was also determined (see also reference 1). The tritium-labeled cAMP was incubated with PDE4. After incubation, the radiolabeled AMP produced can be combined with yttrium silicate SPA beads. These SPA beads then produce light that can be counted and quantified. The addition of PDE4 inhibitors prevents the formation of AMP from cAMP and reduces the count. May -66- (63) (63) 200304824 The IC50 of a PDE4 inhibitor is defined as the concentration of a compound that results in a 50% reduction in counts when compared to a control well with only PDE4 (no inhibitor). The ability of the nicotinamide derivative of formula (1) to inhibit the release of TNF α from human peripheral blood single cells demonstrates its anti-inflammatory properties (see also reference 2). Venous blood was collected from healthy volunteers, and monocytes were purified by centrifugation via a HiS0 p aq u e (F i c ο 11) cushion. The addition of lipopolysaccharide stimulated these cells to produce TNFα. After 18 hours of incubation in the presence of LPS, the upper mash of the cells was removed and the TNFα concentration in the upper mash was measured by ELISA. The addition of PDE4 inhibitors reduced the amount of TNF alpha produced. The IC50 was determined, which is equivalent to the concentration of the compound that inhibits the production of TNFα by 50% when compared to control wells stimulated with LPS. All the examples were tested in the assays described above, and they were found to have an IC50 of less than 5000 nanograms molecular weight (TNFα screening). And for most of the compounds tested, they were found to have IC5G (TNFα screening) with a molecular weight of even less than 200 nanograms. Literature · 1 Thhompson JW, Teraski WL, Epstein PM, Strada SJ, "Assay of nucleotidephosphodiesterase and resolution of multiple molecular forms of the isoenzyme", Advances in cyclic nucleotides research, edited by Brooker G, Greengard P, Robinson GA, Raven Press , New York 1979, 10, p 69-92. 2 Yoshimura T? Kurita C5 Nagao T5 Usami E, Nakao T, -67- (64) 200304824

Watanabe S， Kobayashi J， Y amazaki F， Tanaka H， Nagai H， “Effects of cAMP-phosphodiesterase isozyme inhibitor on cytokine production by lipopolysaccharide-stimulated human peripheral blood mononuclear cells’’， Gen Pharmacol， 1997, 2 9(4), p 6 3 ° -68-Watanabe S, Kobayashi J, Y amazaki F, Tanaka H, Nagai H, “Effects of cAMP-phosphodiesterase isozyme inhibitor on cytokine production by lipopolysaccharide-stimulated human peripheral blood mononuclear cells '', Gen Pharmacol, 1997, 2 9 (4), p 6 3 ° -68-

Claims (1)

(1) 200304824 拾、申請專利範圍 1 一種式（1)化合物： 〇(1) 200304824 Patent application scope 1 A compound of formula (1): 〇 R3R3 或其在醫藥上可接受之鹽類及/或異構物、互變體、媒合 物、多晶型體、同位素變異體或代謝物， 其中： m 係 0、1、2 或 3， ❖ η 係 0、1、2 或 3， ❖ R!及R2各自係獨立選自氫原子、鹵基、氰基、 烷基及（C^Cd烷氧基， ❖ X 係-0-、-S-或-NH-，Or a pharmaceutically acceptable salt and / or isomer, tautomer, vehicle, polymorph, isotope variant or metabolite thereof, wherein: m is 0, 1, 2 or 3, ❖ η is 0, 1, 2 or 3, ❖ R! and R2 are each independently selected from hydrogen atom, halo, cyano, alkyl and (C ^ Cd alkoxy, ❖ X is -0, -S- Or -NH-, ❖R3係選自以下者， (a)苯基、萘基、雜芳基及（C3-C8)環烷基，其各視需要 以 1至 3個分別選自鹵基、氰基、（Ci-CJ烷基、 (Ci-CJ 烷氧基、（Ci-Cd 硫烷基、-C( = 0)NH2、- 烷基、羥基、-O-CbOMCrCd 烷基 、-CbCO-O-d-Cd烷基及羥基（Ci-CJ烷基之取代基 取代，或 (b )如以下結構（1 1)至（1 4)之雙環系基： -69- (2) 200304824❖R3 is selected from the following: (a) phenyl, naphthyl, heteroaryl and (C3-C8) cycloalkyl, each of which is selected from halo, cyano, (Ci -CJ alkyl, (Ci-CJ alkoxy, (Ci-Cd sulfanyl, -C (= 0) NH2, -alkyl, hydroxyl, -O-CbOMCrCd alkyl, -CbCO-Od-Cd alkyl And a hydroxyl group (Ci-CJ alkyl substituent), or (b) a bicyclic system having the structure (1 1) to (1 4): -69- (2) 200304824 (1 1) (1.2) (1.3) (14)(1 1) (1.2) (1.3) (14) 其中以符號表示每一個部份的式（1丨）至（1 4)與式（1)的 其餘部位之附著點， ♦♦♦ Y係選自部份的式（1 5 )至（〗1 ])者： 又 ★ * A /* * / N *0、、〇◊〇 〇、/〇 X / κι Η * * ^ * Ν Η (15) (16) (17) (1.8) 〇、、 * * 〆 / \ ★ 〇 &lt;又.. Η 人1V 〇 (1.9) (1.10) (1.11)Among them, the attachment points of each part of the formulas (1 丨) to (1 4) and the rest of the formula (1) are represented by symbols. ♦♦♦ Y is selected from the partial formulas (1 5) to (〖1 ]): ★ ★ A / * * / N * 0 ,, 〇◊〇〇, / 〇X / κι Η * * ^ * Ν Η (15) (16) (17) (1.8) 〇, * * 〆 / \ ★ 〇 &lt; again: Η person 1V 〇 (1.9) (1.10) (1.11) 其中以符號” ”表示每一個部份的式（1 5 )至（1 1 i )與式（}) 的其餘部位-NH-之附著點，且以符號”**，，表示每—個部份 的式（1 5)至（1 11)與式（1)的其餘部位-R4之附著點， ※及R4係選自以下者， (a )苯基、萘基及雜芳基，其各視需要以1至3個分別 選自羧酸、CbOhCMCi-CU)烷基、鹵基、氰基、一 c( = o)nh2、（Ci-co烷基、（CrC#)烷氧基、（c^c&lt;) 鹵烷基、羥基及羥基（Ci-C4)烷基之取代基取代，$ -70- (3) (3)200304824 (b)視需要以键基、竣酸、C(，-0-(Cl_C4)烷基、苯基 i萘基或雜芳基取代之（C1_C4)院基，其中該苯基、 本基及雜方基各視需要以1至3個分別選自羧酸、 c( = 〇)〇(Cl-c4)烷基、鹵基、氰基、_c(=〇)NH2 ' (c! c4)燒基、（Ci_c4)院氧基' 歯院基、趣 基及羥基（Ci-C4)烷基之取代基取代。 2如申請專利範_ 1項之化合物，其係除了以下 之外的化合物： υ m不是0,同時Y代表部份的式(1 5)及R4代表未經取 代之（C1-C4)院基， 2) m等於0，同時Y代表部份的式（1 5)及b代表苯基、 蔡基或雜芳基’其各視需要以1$ 3個獨立選自羧酸 、鹵基、氰基、（Q-C4)烷基、（Ci-c4)烷氧基、（Cl c 鹵烷基、羥基及羥基（(^-Co烷基之取代基取代，变4) 代表視需要以羥基、羧酸或雜芳基（其視需要以丨 ~ 個獨立選自羧酸、鹵基、氰基、（Cl-C4)烷基、β 3 烷氧基、羥基及羥基（c^c：4)烷基之取代基 ^e4) 乂代）取代 之（Ci-CU)烷基，及 ^ 3 ) m等於0，同時γ代表部份的式（1 6)及R 4代 ％ 衣本_或 萘基，其各視需要以1至3個獨立選自竣酸、國 氰基、（Ci-Cd烷基、（C^Cd烷氧基、（Ci_c〇國产 羥基及羥基（c 1 - C 4)院基之取代基取代。 3 如根據申請專利範圍第1項之化合物，复+ ❖ m及η等於1， -71 (4) 200304824 ♦Ri及R2各自係獨立選自氫原子、鹵基、氰基、（CrCd 烷基及（Ci-C#)烷氧基， ❖ X 係-0 ·， ♦R3係選自以下者， (a) 苯基、奈基、雜方基及（C3_Cs)環院基，其各視需要 以1至3個分別選自鹵基、氰基、（Cl_C4)烷基、 (Ci-C4)烷氧基、（Ci-C4)硫烷基、-C( = 0)NH2、-CfCONI^CrCd烷基、羥基、-O-CbOKKd烷基 、-¢:( = 0)-0-((^-C4)烷基及羥基（Cl_C4)烷基之取代 基取代，或 (b) 如以下結構（1 1)至（1 4)之雙環系基：Among them, the symbol “” indicates the attachment point of each part of the formulas (1 5) to (1 1 i) and the rest of the formula (}) -NH-, and the symbol “**” indicates each part The attachment points of the formula (1 5) to (1 11) and the rest of the formula (1)-R4, ※ and R4 are selected from the group consisting of (a) phenyl, naphthyl, and heteroaryl, each of If necessary, 1 to 3 are respectively selected from carboxylic acid, CbOhCMCi-CU) alkyl, halo, cyano, mono-c (= o) nh2, (Ci-coalkyl, (CrC #) alkoxy, ( c ^ c &lt;) haloalkyl, hydroxy and hydroxy (Ci-C4) alkyl substituents, $ -70- (3) (3) 200304824 (b) if necessary, bond group, citric acid, C (,, -0- (Cl_C4) alkyl, phenyl i naphthyl or heteroaryl substituted (C1_C4) courtyard, wherein the phenyl, the main and the heterosquaryl groups are each selected from carboxylic acids with 1 to 3 as needed , C (= 〇) 〇 (Cl-c4) alkyl, halo, cyano, _c (= 〇) NH2 '(c! C4) alkyl, (Ci_c4) oxo' Substituted by a substituent of a hydroxy (Ci-C4) alkyl group. 2 As a compound of the patent application _1, it is a compound other than the following: υ m is not 0, and Y represents a part of the formula (1 5) and R4 represents an unsubstituted (C1-C4) base, 2) m is equal to 0, and Y represents a part of the formula (1 5) and b represents a phenyl group, and a Zeki group Or heteroaryl ', each of which is independently selected at 1 $ 3 independently selected from carboxylic acid, halo, cyano, (Q-C4) alkyl, (Ci-c4) alkoxy, (Cl c haloalkyl, Hydroxyl and hydroxy ((^ -Co alkyl substituent substitution, change 4) represents a hydroxyl group, a carboxylic acid, or a heteroaryl group (which, if necessary, is independently selected from carboxylic acid, halo, cyano, (Cl-C4) alkyl, β 3 alkoxy, hydroxyl and hydroxy (c ^ c: 4) alkyl substituents ^ e4) hydration) substituted (Ci-CU) alkyl, and ^ 3) m It is equal to 0, and γ represents a part of the formula (16) and R 4 %% of chrysene_ or naphthyl, each of which is independently selected from 1 to 3 independently selected from citric acid, cyano group, and (Ci-Cd alkane) Group, (C ^ Cd alkoxy group, (Ci_c0 domestic hydroxyl group and hydroxyl (c 1-C 4) group substituents. 3 For compounds according to item 1 of the scope of patent application, complex + ❖ m and η Equal to 1, -71 (4) 200304824 ♦ Ri and R2 are each independently selected from hydrogen atom, halo group, cyano group, (CrCd alkyl and (Ci-C #) alkoxy, ❖ X is -0 ,, ♦ R3 is selected from the group consisting of (a) phenyl, naphthyl, heterocyclyl, and (C3_Cs) cyclohexyl, If necessary, 1 to 3 are selected from halo, cyano, (Cl_C4) alkyl, (Ci-C4) alkoxy, (Ci-C4) sulfanyl, -C (= 0) NH2,- CfCONI ^ CrCd alkyl, hydroxyl, -O-CbOKKd alkyl,-¢ :( = 0) -0-((^-C4) alkyl and hydroxy (Cl_C4) alkyl substituent substitution, or (b) as Bicyclic system groups of the following structures (1 1) to (1 4): (11) (1.2)(11) (1.2) (1.3) (14) 其中以符號表示每一個部份的式（1 1)至（1 4)與式（1)的 其餘部位之附著點， ❖ Y係部份的式（1 5)之-C( = 0)-基， ❖及R4係選自以下者， (a)苯基、萘基及雜芳基’其各視需要以1至3個分別 選自殘酸、院基、鹵基、氰基、-C( = 0)NH2、（C^Cd 烷基、（CrCd 烷氧基、（Ci-CU) -72- (5) 200304824 鹵烷基、經基及經基（Cl_c4)院基 (b )丨、丨额茸 执- 取代基取代，或 殘酸、C( = 0)·0-⑹-C他基、苯其、兹其 或雜芳基取代之（C1_C4)烷基，宜 &quot;不土 _ ^ , 〃中喊苯基、萘基及 雑方基各視需要以1至 主3個分別選自羧酸、 以=〇)〇((^(：4)烷基、鹵基、 氣基、-c( = 〇)nh2、 (Cl-C4)烷基、（ci-c4)烷氧基、（c 、一 鹵烷基、羥 基及羥基（Ci-C：4)烷基之取代基取代，(1.3) (14) Where the attachment points of each part of the formulas (1 1) to (1 4) and the rest of the formula (1) are represented by symbols, ❖ Y is part of the formula (1 5)- C (= 0) -group, ❖ and R4 are selected from the group consisting of (a) phenyl, naphthyl, and heteroaryl ', each of which is selected from 1 to 3, respectively, selected from a residual acid, a phenyl group, a halide group, Cyano, -C (= 0) NH2, (C ^ Cd alkyl, (CrCd alkoxy, (Ci-CU) -72- (5) 200304824 haloalkyl, meridian and meridian (Cl_c4) (b) 丨, 丨 erinium-substituents, or (C1_C4) alkyl substituted with residual acid, C (= 0) · 0-⑹-C-tyl, benzyl, ziqi or heteroaryl, preferably &quot; 不 土 _ ^, in 〃, phenyl, naphthyl, and fluorenyl are each selected from 1 to 3 as required, respectively, selected from carboxylic acids, with = 〇) 〇 ((^ (: 4) alkyl, halogen Group, gas group, -c (= 〇) nh2, (Cl-C4) alkyl, (ci-c4) alkoxy, (c, monohaloalkyl, hydroxyl, and hydroxy (Ci-C: 4) alkyl Substituents, 或其在醫藥上可接受之鹽類及/或異構物' 互變體、媒合 勿、多晶型體、同位素變異體或代謝物。 4如申請專利範圍第1項之化合物，其中· ♦ m及η等於1， ♦1^]及R2各自係獨立選自氫原子、鹵基及甲基， + Χ 係-0-， + R3係視需要以1至3個各選自鹵基、氰基、^ 卜c4)燒Or their pharmaceutically acceptable salts and / or isomers' tautomers, catabolites, polymorphs, isotopic variants or metabolites. 4. The compound according to item 1 of the scope of patent application, wherein: ♦ m and η are equal to 1, ♦ 1 ^] and R2 are each independently selected from a hydrogen atom, a halogen group and a methyl group, + χ is -0, and + R3 is If necessary, 1 to 3 each selected from halo, cyano, and ^ c4) 基、（C2-C4)烷氧基、（Ci-Cd 硫烷基、-c〇0：)Nh C^C^NHiCi-Cd 烷基、羥基、-O-epOMC^Cd 院其 、 c ( = 0)-0-((^-(:4)烷基及羥基（CrCd烷基之取代其 、 也取代；&gt; 苯基， &lt; + Y係部份的式（1 5)之4( = 0)-基， ※及R4係選自以下者， U)視需要以1至3個分別選自羧酸、C (= 0 )、 基、鹵基、氰基、-C( = 0)NH2、（Cl-C4)烷 烷氧基、（Ci-Cd鹵烷基、羥基及羥基（c 取代基取代之苯基’或 〇、（c 卜 C, 基、 )烷 c4) C4)烷基之 -73- (6) (6)200304824 (b)以羥基或苯基取代之（C^Cd烷基，其中該苯基視需要 以1至3個分別選自殘酸、C( = 0)0(Ci-C4)院基、鹵 基、氰基、-C( = 0)NH2、（Ci-Cd烷基、（Ci-CJ烷氧基 、（Ci-CU)鹵烷基、羥基及羥基（C^Cd烷基之取代基 取代， 或其在醫藥上可接受之鹽類及/或異構物、互變體、媒合 物、多晶型體、同位素變異體或代謝物。 5 如申請專利範圍第1項之化合物，其中： ❖ m及η等於1， ♦Ri係氫原子或氟基而R2係氫原子， X 係-0 -， R3係視需要以選自鹵基及- = 4)烷基之取代 基取代之苯基， ❖ Y係部份的式（1 5 )之-c (= Ο)-基， ❖及R4係選自以下者， (a) 視需要以1至3個分別選自鹵基、（Cl_C4)烷基及羥基 之取代基取代之苯基，或 (b) 以羥基或苯基取代之（Cl_c4)烷基，其中該苯基視需要 以1至3個分別選自鹵基、（Ci-CO烷基及羥基之取 代基取代， 或其在醫藥上可接受之鹽類及/或異構物、互變體、媒合 物、多晶型體、同位素變異體或代謝物。 6 如申請專利範圍第1項之化合物，其係選自： 2-(4-氟基苯氧基）-N-{4-[(2-羥基-3-甲基苄醯基胺基） (7) (7)200304824 甲基]苯甲基}菸鹼醯胺， 3-(3-{4-[(3-羥基苄醯基胺基）甲基]苯甲基胺甲醯基} 吡啶-2-基氧）苯甲酸乙酯， 2-(4-氟基苯氧基）-1{4-[(6-氟基-2-羥基苄醯基胺基） 甲基]苯甲基}菸鹼醯胺， 2-(4-氟基苯氧基）-!^-{4-[(5-氟基-2-羥基苄醯基胺基） 甲基]苯甲基}菸鹼醯胺， 2-(4-氟基苯氧基）-1{4-[(3-羥基-4-甲基苄醯基胺基） 甲基]苯甲基}菸鹼醯胺， 2-(4-氟基苯氧基）_N-{4-[(3-羥基苄醯基胺基）甲基]苯 甲基}菸鹼醯胺， 2-(4-氟基苯氧基）-N-{4-[(2-羥基苄醯基胺基）甲基]苯 甲基}菸鹼醯胺， 2-(4-氟基苯氧基）-N-{4-[(4-羥基苄醯基胺基）曱基]苯 甲基}菸鹼醯胺， 2-(4-氟基苯氧基）-1{4-[(2-羥基-4-甲基苄醯基胺基） 甲基]苯甲基}菸鹼醯胺， 2-(4-氟基苯氧基）-N-{4-[(3-羥基-2 -甲基苄醯基胺基） 甲基]苯甲基}菸鹼醯胺， 2-(4-赢基苯氧基）-N-{4-[(2 -經基-5-甲基卡釀基胺基） 甲基]苯甲基}菸鹼醯胺， 5-氟基-2-(4-氟基苯氧基）-N-{4-[(2-羥基苄醯基胺基） 甲基]苯甲基}菸鹼醯胺， 5-氟基-2-(4-氟基苯氧基）_N-{4-[(2-羥基乙醯基胺基） -75- (8) 200304824 甲基]苯甲基}菸鹼醯胺， 5-氟基- 2-(4-氟基苯氧基）-N-{4-[(4-羥基苄醯基胺基） 甲基]苯甲基}菸鹼醯胺， 3-(3-{4-[(3-羥基苄醯基胺基）甲基]苯甲基胺甲醯基} 吡啶-2-基氧）苯甲酸乙酯， 3-(3-{4-[(2-羥基苯乙醯基胺基）甲基]苯甲基胺甲醯基 }舭卩定-2 -基氧）苯甲酸乙酯， 3-(3-{4-[(3-羥基苯乙醯基胺基）甲基]苯甲基胺甲醯基 } 口比卩定-2 -基氧）苯甲酸乙酯， 3-(3-{4-[(4-羥基苯乙醯基胺基）甲基]苯甲基胺甲醯基 }吡啶-2-基氧）苯甲酸乙酯。 7 —種(製備如申請專利範圍第1項之式（1)化合物或 其在醫藥上可接受之鹽或其衍生型式之方法，其特徵在於 其包含令下式之化合物：Group, (C2-C4) alkoxy group, (Ci-Cd sulfanyl group, -c00:) Nh C ^ C ^ NHiCi-Cd alkyl group, hydroxyl group, -O-epOMC ^ Cd group, c (= 0) -0-((^-(: 4) alkyl and hydroxy (CrCd alkyl is substituted, and also substituted; &gt; phenyl, &lt; + Y-based part of the formula (1 5) of 4 (= 0)-group, ※ and R4 are selected from the following, U) If necessary, 1 to 3 are respectively selected from the group consisting of carboxylic acid, C (= 0), a group, a halogen group, a cyano group, and -C (= 0) NH2 , (Cl-C4) alkalkoxy, (Ci-Cd haloalkyl, hydroxy and hydroxy (c-substituted phenyl 'or 0, (c, C,), alkane c4) C4) alkyl -73- (6) (6) 200304824 (b) (C ^ Cd alkyl substituted with hydroxy or phenyl, where the phenyl is optionally selected from the group consisting of a residual acid and C (= 0) 0 ( Ci-C4) courtyard, halo, cyano, -C (= 0) NH2, (Ci-Cd alkyl, (Ci-CJ alkoxy, (Ci-CU) haloalkyl, hydroxy, and hydroxy (C ^ Cd alkyl substituent substitution, or a pharmaceutically acceptable salt and / or isomer, tautomer, vehicle, polymorph, isotope variant, or metabolite. 5 If applying for a patent Compounds of scope item 1, Where: ❖ m and η are equal to 1, ♦ Ri is a hydrogen atom or a fluoro group and R2 is a hydrogen atom, X is -0-, and R3 is optionally substituted with a substituent selected from a halogen group and-= 4) alkyl group. Phenyl, ❖ The -c (= Ο)-group of the formula (1 5) in the Y system, ❖ and R4 are selected from the following, (a) 1 to 3 are respectively selected from the halogen group, ( Cl_C4) alkyl and hydroxy substituted phenyl, or (b) hydroxy or phenyl substituted (Cl_c4) alkyl, wherein the phenyl is optionally selected from halo, (Ci -CO alkyl and hydroxy substituents, or pharmaceutically acceptable salts and / or isomers, tautomers, vehicles, polymorphs, isotopic variants, or metabolites thereof. 6 Such as The compound in the scope of patent application No. 1 is selected from the group consisting of: 2- (4-fluorophenoxy) -N- {4-[(2-hydroxy-3-methylbenzylamino) (7) (7) 200304824 Methyl] benzyl} nicotinylamine, 3- (3- {4-[(3-hydroxybenzylamino) methyl] benzylaminomethylmethyl} pyridine-2- Ethyloxy) benzoate, 2- (4-fluorophenoxy) -1 {4-[(6-fluoro-2-hydroxybenzylamino) amino ] Benzyl} nicotinamide, 2- (4-fluorophenoxy)-! ^-{4-[(5-fluoro-2-hydroxybenzylamino) methyl] benzyl } Nicotinamide, 2- (4-fluorophenoxy) -1 {4-[(3-hydroxy-4-methylbenzylfluorenylamino) methyl] benzyl} nicotinamide, 2- (4-Fluorophenoxy) _N- {4-[(3-hydroxybenzylamino) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy) -N- {4-[(2-hydroxybenzylamidoamino) methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy) -N- {4-[(4- Hydroxybenzylamino) fluorenyl] benzyl} nicotinamide, 2- (4-fluorophenoxy) -1 {4-[(2-hydroxy-4-methylbenzylfluorenylamino) ) Methyl] benzyl} nicotinamide, 2- (4-fluorophenoxy) -N- {4-[(3-hydroxy-2 -methylbenzylfluorenylamino) methyl] benzene Methyl} nicotinylamine, 2- (4-benzylphenoxy) -N- {4-[(2-methyl-5-methylcarboxamino) methyl] benzyl} smoke Amidoamine, 5-fluoro-2- (4-fluorophenoxy) -N- {4-[(2-hydroxybenzylamino) methyl] benzyl} nicotinamide, 5 -Fluoro-2- (4-fluorophenoxy) _N- {4-[(2-hydroxyethylamidoamino) -75- (8) 20 0304824 methyl] benzyl} nicotinamide, 5-fluoro-2- (4-fluorophenoxy) -N- {4-[(4-hydroxybenzylamino) methyl] benzene Methyl} nicotinylamine, ethyl 3- (3- {4-[(3-hydroxybenzylfluorenylamino) methyl] benzylaminomethylmethyl} pyridin-2-yloxy) benzoate, 3- (3- {4-[(2-hydroxyphenethylamidoamino) methyl] benzylaminomethylamido} halidine-2 -yloxy) benzoate, 3- (3- {4-[(3-Hydroxyphenethylamidoamino) methyl] benzylaminomethylamido} Methylpyridine-2 -yloxy) benzoate, 3- (3- {4- [ (4-hydroxyphenethylamidoamino) methyl] benzylaminomethylamido} pyridin-2-yloxy) benzoate. 7—A method for preparing a compound of formula (1) as described in item 1 of the scope of patent application or a pharmaceutically acceptable salt thereof or a derivative thereof, characterized in that it comprises a compound of the following formula: (其中Ri、R2、X、R3、η及m係如申請專利範圍第1項 之定義）與對應之R4-磺醯氯衍生物（其中Y代表部份的式 (1 7)、（1 8)或（1 10)之基）反應， 或與對應之r4-羧酸衍生物（其中 Y代表部份的式 (1 5)、（1 9)或（1 11)之基）反應， -76- (9) (9)200304824 或與羰基二咪唑（其中Y代表部份的式（1幻之基）反應 〇 8 一種醫藥組成物，其包括如申請專利範圍第2項 之式（1)化合物或其在醫藥上可接受之鹽或其衍生型式與 慣用醫藥上無毒害性之賦形劑及/或添加劑。 9如申請專利範圍第1項之式（1)化合物或其在醫藥 上可接受之鹽或其衍生型式或組成物，其係作爲藥劑。 10如申請專利範圍第1項之式（1)化合物或其在醫 藥上可接受之鹽或衍生型式或組成物，係用於治療與 PDE4同功酵素有關之疾病 '異常及症狀。 11如申請專利範圍第1項之式（1)化合物或其在醫 藥上可接受之鹽、其衍生型式或組成物，係用於治療選自 以下的疾病、異常及症狀： •不論什麼型式、發病原因或致病機制之氣喘病，特別係 選自異位性氣喘病、非異位性氣喘病、過敏性氣喘病 、以異位性枝氣管IgE-介入之氣喘病、枝氣管氣喘病 、本質型氣喘病、實質型氣喘病、由病理生理阻礙引 起的內因性氣喘病、由環境因子引起的外因性氣喘病 、未知或不明原因之本質型氣喘病、非異位性氣喘病 、枝氣管氣喘病、氣腫性氣喘病、以運動誘發之氣喘 病、以過敏原誘發之氣喘病、以冷空氣誘發之氣喘病 、職業性氣喘病、以細菌、黴菌、原蟲或病毒感染之 感染性氣喘病、非過敏性氣喘病、初期氣喘病及陣發 性哮喘性嬰兒徵候群之氣喘病， -77- (10) (10)200304824 •慢性或急性枝氣管收縮、慢性枝氣管炎、小氣道阻塞及 氣腫， •不論什麼型式、發病原因或致病機制之阻塞性或發炎性 氣道疾病，特別係選自慢性嗜曙紅細胞肺病、慢性阻 塞性肺部疾病（COPD)、包括慢性枝氣管炎、肺水腫或 與其有關連之呼吸困難的COPD、以不可逆、漸進式氣 道阻塞、成人呼吸性壓迫徵候群（ARDS)爲特徵之 C Ο P D及對其它的藥物治療法的氣道高反應性而發生的 病情加劇之阻塞性或發炎性氣道疾病， •不論什麼型式、發病原因或致病機制之肺塵沉著病，特 別係選自礬土沉著病或鋁礬土工人沉著病、炭末沈著 症或礦工氣喘病、石棉沉著症或蒸氣維修工氣喘病、 霰粒腫或石末沉著症、以吸入駝鳥毛塵所以引起的禿 睫、以吸入鐵粒子所引起的鐵沈著肺病、矽肺病或碾 石工病、棉肺症或棉塵氣喘病及滑石粉塵沉著病之肺 塵沉著病， •不論什麼型式、發病原因或致病機制之枝氣管炎，特別 係選自急性枝氣管炎、急性喉氣管枝氣管炎、花生枝 氣管炎、卡他性枝氣管炎、格魯布性（croupiis)枝氣管 炎、乾性枝氣管炎、感染性氣喘性枝氣管炎、產生性 枝氣管炎、葡萄球菌或鏈球菌性枝氣管炎及豬丹毒性 枝氣管炎之枝氣管炎， •不論什麼型式、發病原因或致病機制之枝氣管炎擴張症 ，特別係選自圓筒狀枝氣管炎擴張症' 成囊性枝氣管 -78- (11) (11)200304824 炎擴張症、紡綞狀梭形枝氣管炎擴張症、微血管型枝 氣管炎擴張症、肺囊性枝氣管炎擴張症、乾性枝氣管 炎擴張症及瀘泡枝氣管炎擴張症之枝氣管炎擴張症， •不論什麼型式、發病原因或致病機制之季節的過敏性鼻 炎或常年的過敏性鼻炎或鼻竇炎，特別係選自化膿性 或未化膿性鼻竇炎、急性或慢性鼻竇炎及篩竇炎、額 竇炎、上頜竇炎或蝶竇炎之鼻竇炎， •不論什麼型式、發病原因或致病機制之類風濕性關節炎 ’特別係選自急性關節炎、急性痛風性關節炎、慢性 發炎性關節炎、退化性關節炎、感染性關節炎、萊姆 (Lyme)關節炎、增殖性關節炎、牛皮癬性關節炎及脊 柱性關節炎之類風濕性關節炎， •與發炎有關的痛風及發熱和疼痛， •不論什麼型式、發病原因或致病機制之與嗜曙紅細胞有 關之異常，特別係選自嗜曙紅白血球增高症、肺腫瘤 溶解嗜曙紅白血球增高症、勞弗勒氏（1^0£〖1^，3)徵候群 '慢性嗜曙紅細胞肺炎、熱帶肺嗜曙紅白血球增高症 、枝氣管肺炎性麴菌病、麴菌腫、肉芽腫（包括嗜曙紅 細胞、過敏性肉芽腫血管炎或丘-施氏（Churg-SUauss) 徵候群）、結節性多動脈炎（PAN)及全身壞死性血管炎 之與嗜曙紅細胞有關之異常， •異位性皮膚炎、過敏性皮膚炎、接觸性皮膚炎或過敏性 或異位性濕疹， •不論什麼型式、發病原因或致病機制之_麻疹，特別係 -79- (12) (12)200304824 選自以免疫性介入之蓴麻疹、以補體介入之奪麻g、 致蓴麻疹物質誘發之蓴麻疹、以物理劑誘發之奪g _ 、以壓力誘發之蓴麻疼、特發性蓴麻疼、急性奪g 0 、慢性蓴麻疹、血管性水腫、膽鹼能蓴麻疹、體g 體顯性形式或後天性形式之寒冷性_麻疹、接觸彳、生_ 麻疹、嚴重性蓴麻疹及丘疹性蓴麻疹之蓴麻疹， •不論什麼型式、發病原因或致病機制之結膜炎，特别j # 選自光化性結膜炎、急性卡它性結膜炎、急性傳染彳生 結膜炎、過敏性結膜炎、異位性結膜炎、慢性卡它性 結膜炎、膿性結膜炎及春季型結膜炎之結膜炎， •不論什麼型式、發病原因或致病機制之葡萄膜炎，特別 係選自全部或部份葡萄膜發炎、前段蔔萄膜炎、虹彩 炎、睫狀體炎、虹膜睫狀體炎、肉芽腫型葡萄膜炎、 非肉芽腫型蔔萄膜炎、晶狀體抗原葡萄膜炎、後端蔔 萄膜炎、脈絡膜炎及脈絡視網膜炎之葡萄膜炎， •牛皮癬， •不論什麼型式、發病原因或致病機制之多發性硬化症， 特別係選自初發性多發性硬化症及復發型多發性硬化 症之多發性硬化症， •不論什麼型式、發病原因或致病機制之自身免疫/發炎 性疾病’特別係選自自身免疫血液治療異常、溶血性 貧血、再生不良性貧血、純紅細胞性貧血、特發性血 小板低下性紫斑、全身性紅斑狼瘡症、多發性軟骨炎 硬皮症、卑：格納氏肉芽腫（Wegener’s)、皮膚肌炎、 -80- (13) (13)200304824 慢性活動性肝炎、重症肌無力、史蒂芬-John son)徵候群、特發性脂肪瀉、自身免疫發炎性腸病 、潰瘍性結腸炎、內分泌眼病變、格雷氏疾病 (Grave，s)、結節病、肺泡炎、慢性過敏性肺炎、原發 性膽汁性肝硬化、青少年糖尿病或1型糖尿病、乾燥性 角膜結膜炎、流行性角膜結膜炎、擴散性肺 (p U1 m ο n a r y )間纖維病變或肺（1 u n g)間纖維病變、特發性 肺纖維病變、囊性纖維病變、具有或不具有腎病徵候 群之腎絲球腎炎、急性腎絲球腎炎、特發性腎病徵候 群、微小變化腎病變、發炎性/高增殖性皮膚病、良性 家族性天疱瘡、紅斑型天疱瘡、葉狀天疱瘡及尋常型 天疱瘡之自身免疫/發炎性疾病， •預防在器官移植之後的異體接枝排斥’ •不論什麼型式、發病原因或致病機制之發炎性腸病 (IBD)，特別係選自膠狀性大腸炎、大腸炎性息肉、腸 道壁整層大腸炎、潰瘍性結腸炎及克隆氏疾病（CD)之 發炎性腸病， •不論什麼型式、發病原因或致病機制之敗血症休克，特 別係選自腎衰竭、急性腎衰竭、惡病質、瘧疾性惡病 質、低體質惡病質、尿毒症惡病質、心因性惡病質、 腎上腺惡病質或阿狄森氏病（Addison’s)、癌性惡病質 及由於以人類免疫性不全病毒（HIV)感染之惡病質之敗 血症休克， •肝臟傷害， -81 - (14) (14)200304824 •不論什麼型式、發病原因或致病機制之肺高壓症，包括 原發性肺高壓症/自發性高壓症、對充血性心臟衰竭之 續發性肺高壓症、對慢性阻塞性肺部疾病之續發性肺 高壓症、肺靜脈高壓症、肺動脈高壓症及以缺氧誘發 之肺高壓症， •骨質流失症、原發性骨質疏鬆症及續發性骨質疏鬆症， •不論什麼型式、發病原因或致病機制之中樞神經系統異 常，特別係選自抑鬱症、阿茲海默氏病、巴金生氏病 、學習及記憶損傷、遲發的運動異常、藥物成癮、動 脈硬化性癡呆症及連同亨丁頓氏（H u n t i n g t ο η ’ s )舞蹈病 之癡呆症、威爾森氏症（Wilson's)、震顫麻痺及丘腦萎 縮症之中樞神經系統異常， •感染，尤其係病毒的感染，其中這些病毒會增加在彼宿 主中的TNF- α生產作用或其中這些病毒對在彼宿主中 的TNF- α向上調節作用具有敏感性，所以對彼之複製 作用或其它的重要活性有不利的衝擊性，包括選自 HIV-1、HIV-2及HIV-3、巨細胞病毒（CMV)、流行性 感冒病毒、腺病毒及疱疹病毒（包括帶狀疱疹及單純疱 性）之病毒， •酵母菌及黴菌感染，其中該酵母菌及黴菌對TNF- α之 向上調節作用具有敏感性或誘出在彼之宿主中的TNF-α生產作用（例如，黴菌性腦膜炎），特別係在連同以治 療全身性酵母菌及黴菌感染所選擇之其它藥物（包括（但 不限於）多黏菌素（例如，多黏菌素Β)、咪唑（例如，克 •82- (15) (15)200304824 黴哗（clotrimazole)、益康唑（econazole)、咪康 u坐 (miconazole)及酮康卩坐（ketoconazole))、三 D坐（例如，氟 康_ (fluconazle)及易退嗅（itranazole))與兩性黴素（例 如，兩性黴素B及粒質體兩性黴素B)—起投藥時， •缺血-再灌流傷害、缺血性心臟疾病、自身免疫性糖尿 病、視網膜自身免疫症、慢性淋巴細胞白血病、HIV 感染、紅斑性狼瘡、腎及輸尿管疾病、尿生殖和胃腸 道異常及攝護腺疾病， 參 •減低在人體或動物體內的瘢痕成形作用，如在急性創傷 的復原時的瘢痕成形作用，及 •牛皮癬、其它的皮膚及化妝用途，包括減輕發炎現象、 皮膚軟化、1皮膚彈性及增加濕度的活性0 12 —種如申請專利範圍第1項之式（1)化合物或其 在醫藥上可接受之鹽、其衍生型式或其組成物之應用，係 用於製造具有PDE4抑制活性之藥物。 13 —種如申請專利範圍第1項之式（1)化合物或其 春 在醫藥上可接受之鹽、其衍生型式或其組成物之應用，係 用於製造用於治療發炎、呼吸及過敏性疾病、異常及症狀 以及治療創傷之藥物。 1 4 一種如申請專利範圍第1項之式（1 )化合物或其 二 在醫藥上可接受之鹽、媒合物或其組成物之應用，係用於 ▼ 製造用於治療選自申請專利範圍第1 1項所述疾病、異常 及症狀之藥物。 -83- 200304824 陸、（一）、本案指定代表圖為··第_圖 (二）、本代表圖之元件代表符號簡單說明：(Where Ri, R2, X, R3, η, and m are as defined in the first patent application scope) and the corresponding R4-sulfosulfonyl chloride derivative (where Y represents a part of the formula (1 7), (1 8 ) Or (1 10) group), or with the corresponding r4-carboxylic acid derivative (where Y represents a part of the group of formula (1 5), (1 9) or (1 11)), -76 -(9) (9) 200304824 or reacting with carbonyldiimidazole (where Y represents a part of the formula (1)) 8 A pharmaceutical composition comprising a compound of formula (1) as in item 2 of the scope of the patent application Or a pharmaceutically acceptable salt or a derivative thereof and a conventionally non-toxic excipient and / or additive. 9 For example, the compound of formula (1) in the scope of patent application 1 or its pharmaceutically acceptable The salt or derivative form or composition thereof is used as a medicament. 10 For example, the compound of formula (1) or the pharmaceutically acceptable salt or derivative form or composition thereof in item 1 of the scope of patent application is used for the treatment and PDE4 Disease abnormalities and symptoms related to work enzymes. 11 For example, the compound of formula (1) in the scope of patent application or its pharmaceutically acceptable Salt, its derivative or composition, is used to treat diseases, abnormalities and symptoms selected from the following: • Asthma, regardless of the type, etiology or pathogenesis, especially selected from heterotopic asthma, non-heterogeneous Asthmatic asthma, allergic asthma, ectopic bronchial IgE-intervened asthma, bronchial asthma, essential asthma, parenchyma asthma, endogenous asthma caused by pathophysiology, Environmental factors-induced exogenous asthma, essential or unknown asthma, non-ectopic asthma, bronchial asthma, emphysema asthma, exercise-induced asthma, allergen-induced asthma Disease, asthma induced by cold air, occupational asthma, infectious asthma infected with bacteria, mold, protozoa, or virus, non-allergic asthma, early asthma, and paroxysmal asthma syndrome Asthma, -77- (10) (10) 200304824 • Chronic or acute bronchoconstriction, chronic bronchitis, small airway obstruction, and emphysema, regardless of type, cause, or Pathogenesis of obstructive or inflammatory airway diseases, especially selected from chronic eosinophilic lung disease, chronic obstructive pulmonary disease (COPD), including chronic bronchitis, pulmonary edema, or COPD associated with dyspnea, Irreversible, progressive airway obstruction, adult respiratory compression syndrome (ARDS) characterized by COPD, and obstructive or inflammatory airway diseases that are exacerbated by airway hyperresponsiveness to other medications, regardless of whether What type, cause, or pathogenesis of pneumoconiosis is especially selected from bauxite or bauxite worker's disease, charcoal or miner's asthma, asbestosis or steam maintenance worker's asthma, Chronic swollen or lithotripsy, bald eyelashes caused by inhalation of ostrich hair dust, iron deposits lung disease caused by inhalation of iron particles, silicosis or stone milling disease, cotton pneumonia or cotton dust asthma, and talc dust deposits Pneumoconiosis, • Bronchitis regardless of the type, cause or pathogenesis, especially selected from acute bronchitis, acute laryngotracheal bronchitis Tube inflammation, peanut bronchitis, catarrhal bronchitis, croupiis bronchitis, dry bronchitis, infectious asthmatic bronchitis, bronchogenic bronchitis, staphylococcus or streptococcus Bronchial bronchitis and toxic bronchial bronchitis of porcine bronchitis, bronchial dilatation of any type, pathogenesis or pathogenic mechanism, especially selected from cylindrical bronchitis dilatation 'cystic Bronchus-78- (11) (11) 200304824 Inflammation and dilatation, fusiform spindle bronchiectasis, microvascular bronchiectasis, pulmonary cystic bronchitis dilatation, dry bronchitis dilatation And bronchiolitis dilated bronchiolitis, regardless of the type, pathogenesis or pathogenesis of allergic rhinitis or perennial allergic rhinitis or sinusitis, especially selected from purulent or non-sinusitis Sinusitis with purulent sinusitis, acute or chronic sinusitis, and ethmoid sinusitis, frontal sinusitis, maxillary sinusitis, or sphenoid sinusitis, rheumatoid arthritis, regardless of type, etiology, or pathogenesis From acute arthritis, acute gouty arthritis, chronic inflammatory arthritis, degenerative arthritis, infectious arthritis, Lyme arthritis, proliferative arthritis, psoriasis arthritis and spinal arthritis Rheumatoid arthritis, • gout and fever and pain associated with inflammation, • abnormalities associated with eosinophils, regardless of type, etiology or pathogenesis, especially selected from eosinophilia, lung tumors Dissolved eosinophilia, Lauffler's (1 ^ 0 £ 〖1 ^, 3) syndrome 'chronic eosinophilic pneumonia, tropical pulmonary eosinophilia, bronchopneumoniae rickets, Mycelia, granulomas (including eosinophils, allergic granulomatous vasculitis or Churg-SUauss syndrome), nodular polyarteritis (PAN), and systemic necrotizing vasculitis and eosinophils Related abnormalities: • Atopic dermatitis, allergic dermatitis, contact dermatitis or allergic or atopic eczema, • No matter what type, cause or mechanism of _ measles, especially -79- (12) (12) 200304824 selected from the group consisting of immune measles measles, complement measles g, measles induced by measles-causing substances, measles induced by physical agents _, induced by stress Ramie Pain, Idiopathic Ramie Pain, Acute G0, Chronic Ramie Measles, Angioedema, Cholinergic Ramie Measles, Body G Dominant Form or Acquired Form of Cold_Measles, Exposure, Health _ Measles, severe rash measles, and pimple rash measles, • No matter what type, cause or mechanism of conjunctivitis, especially j # selected from actinic conjunctivitis, acute catarrhal conjunctivitis, acute infectious diseases Conjunctivitis, allergic conjunctivitis, atopic conjunctivitis, chronic catarrhal conjunctivitis, purulent conjunctivitis, and conjunctivitis of spring-type conjunctivitis, • uveitis regardless of the type, etiology or pathogenesis, especially selected from all or parts Uveitis, anterior uveitis, iriditis, ciliary inflammation, iridocyclitis, granulomatous uveitis, non-granulomatous uveitis, lens antigen uveitis, back end Uveitis, choroiditis, and chorioretinitis, uveitis, • psoriasis, • multiple sclerosis regardless of the type, etiology, or pathogenesis, especially selected from primary multiple sclerosis and recurrent multiple sclerosis Multiple sclerosis of sexual sclerosis, no matter what type, pathogenesis or pathogenic mechanism of autoimmune / inflammatory disease 'is especially selected from autoimmune blood therapy abnormalities, hemolytic anemia, aplastic anemia, pure red blood cells Anemia, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, polychondritis scleroderma, hypodermic: Wegener's granulomatous (Wegener's), dermatomyositis, -80- (13) (13) 200304824 chronic activity Hepatitis, myasthenia gravis, Stephen-John son) syndrome, idiopathic steatosis, autoimmune inflammatory bowel disease, ulcerative colitis, endocrine eye disease, Grave's disease, sarcoidosis, alveoli Inflammation, chronic allergic pneumonia, primary biliary cirrhosis, juvenile diabetes or type 1 diabetes, dry keratoconjunctivitis, epidemic cornea Meningitis, diffuse pulmonary (p U1 m ο nary) fibrous disease or interpulmonary (1 ung) fibrotic disease, idiopathic pulmonary fibrotic disease, cystic fibrotic disease, glomerulonephritis with or without nephrotic syndrome , Acute glomerulonephritis, idiopathic nephropathy syndrome, minor changes nephropathy, inflammatory / hyperproliferative skin disease, benign familial pemphigus, erythematous pemphigus, phyllodes pemphigus and pemphigus vulgaris Immune / Inflammatory Diseases, • Prevents allograft rejection after organ transplantation '• Inflammatory bowel disease (IBD), regardless of type, etiology or pathogenesis, especially selected from colloidal colitis, colitis Sexual polyps, intestinal wall colitis, ulcerative colitis and Crohn's disease (CD), inflammatory bowel disease, regardless of the type, etiology or pathogenesis of septic shock, especially selected from renal failure, Acute renal failure, cachexia, malaria cachexia, low constitution cachexia, uremia cachexia, psychogenic cachexia, adrenal cachexia or Addison's disease, cancer cachexia And septic shock due to cachexia infected with human immunodeficiency virus (HIV), • liver damage, -81-(14) (14) 200304824 • no matter what type, cause or mechanism of pulmonary hypertension, including the original Pulmonary hypertension / spontaneous hypertension, secondary pulmonary hypertension for congestive heart failure, secondary pulmonary hypertension for chronic obstructive pulmonary disease, pulmonary venous hypertension, pulmonary hypertension and hypoxia Induced pulmonary hypertension, • Osteoporosis, primary osteoporosis, and secondary osteoporosis, • Central nervous system abnormalities, regardless of type, cause, or pathogenic mechanism, especially selected from depression, Afghanistan Zheimer's disease, Parkinson's disease, learning and memory impairment, delayed motor abnormalities, drug addiction, arteriosclerotic dementia, and dementia with Huntington's dance disease , Wilson's, tremor paralysis, and thalamus atrophy of the central nervous system abnormalities, • infections, especially those infected with viruses, in which these viruses increase TNF-α production in the host or in which these viruses are sensitive to TNF-α up-regulation in another host, and therefore have an adverse impact on their replication or other important activities, including those selected from HIV- 1. HIV-2 and HIV-3, cytomegalovirus (CMV), influenza virus, adenovirus and herpes virus (including herpes zoster and herpes simplex) viruses, • yeast and mold infections, in which the yeast Bacteria and molds are sensitive to the up-regulating effects of TNF-α or induce TNF-α production in their host (eg, mycotic meningitis), especially in conjunction with the treatment of systemic yeast and mold infections Other drugs of choice (including, but not limited to, polymyxins (eg, polymyxin B), imidazole (eg, g • 82- (15) (15) 200304824 clotrimazole, econazole (Econazole), miconazole and ketoconazole), three-D (for example, fluconazle and itranazole), and amphotericin (for example, amphoteric mold) B and Amphotericin B) At the time of administration, ischemia-reperfusion injury, ischemic heart disease, autoimmune diabetes, retinal autoimmune disease, chronic lymphocytic leukemia, HIV infection, lupus erythematosus, kidney and ureteral diseases, urogenital and gastrointestinal tract Abnormalities and prostate diseases, reduce the scar forming effect in the human or animal body, such as the scar forming effect in the recovery of acute wounds, and psoriasis, other skin and cosmetic uses, including reducing inflammation and softening the skin 1 、 Skin elasticity and humidity-increasing activity 0 12 —The application of the compound of formula (1) or its pharmaceutically acceptable salt, its derivative or its composition as described in item 1 of the scope of patent application, which is used for manufacturing Drug with PDE4 inhibitory activity. 13 —Application of a compound of formula (1) or its spring in pharmacologically acceptable salts such as item 1 of the scope of the patent application, its derivative form or its composition is used for the manufacture of treatment for inflammation, respiration and allergies Diseases, abnormalities and symptoms, and medicines for trauma. 1 4 An application of the compound of formula (1) or its two pharmaceutically acceptable salts, vehicles, or compositions as described in item 1 of the scope of the patent application, which is used for manufacturing and treatment selected from the scope of the patent application Drugs for diseases, abnormalities and symptoms described in item 11. -83- 200304824 Lu, (1), the designated representative figure in this case is ... Figure _ (2), the component representative symbols of this representative figure are simply explained: 柒、本案若有化學式時，請揭示最能顯示發明特徵的化學 式：柒 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: -3--3-
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