CN1345309A - 二芳基衍生物及其作为药物的用途 - Google Patents
二芳基衍生物及其作为药物的用途 Download PDFInfo
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- CN1345309A CN1345309A CN00805693A CN00805693A CN1345309A CN 1345309 A CN1345309 A CN 1345309A CN 00805693 A CN00805693 A CN 00805693A CN 00805693 A CN00805693 A CN 00805693A CN 1345309 A CN1345309 A CN 1345309A
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- Prior art keywords
- dimethylphenyl
- hydroxyl
- group
- acid
- hydroxyphenoxy
- Prior art date
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- 238000003304 gavage Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
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- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
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- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000011147 magnesium chloride Nutrition 0.000 description 1
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- 235000010355 mannitol Nutrition 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000000633 nuclear envelope Anatomy 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960005453 strychnine Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000004454 trace mineral analysis Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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- C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
- C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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Abstract
本发明公开了式(I)的化合物,其中W是O、S、S(O)或S(O)2;X是-SR4、-S(O)R4或-S(O)2R4、-S(O)2NR5R6;或者X是-C(O)NR5R6,条件是-C(O)NR5R6位于3’、4’或5’位;Y是O或H2;Z是氢、卤素、羟基、选择性取代的烷氧基、芳烷氧基、酰氧基或烷氧基羰基氧基;R是氢、卤素、三氟甲基、低级烷基或环烷基;R1是羟基、选择性取代的烷氧基、芳氧基、杂芳氧基、芳烷氧基、环烷氧基、杂芳烷氧基或-NR5R6;R2是氢、卤素或烷基;R3是卤素或烷基;R4是选择性取代的烷基、芳基、芳烷基、杂芳烷基或杂芳基;R5、R6和R7彼此独立地是氢、选择性取代的烷基、环烷基、芳基、芳烷基、杂芳基或杂芳烷基;或者R5和R6合在一起是选择性地被O、S、S(O)、S(O)2或NR7间断的亚烷基,该亚烷基与它们所连接的氮原子合在一起形成5至7元环;n表示0或1至4的整数;其可药用盐;含有所述化合物的药物组合物;治疗和预防与甲状腺激素失调有关的疾病例如甲状腺机能减退和甲状腺机能亢进、肥胖、骨质疏松症和抑郁症的方法;以及用所述化合物在哺乳动物中降低LDL胆固醇和Lp(a)水平的方法。
Description
本发明涉及式I的新化合物及其可药用盐其中
W是O、S、S(O)或S(O)2;
X是-SR4、-S(O)R4、-S(O)2R4、或-S(O)2NR5R6;或者X是-C(O)NR5R6,条件是-C(O)NR5R6位于3’、4’-或5’-位;
Y是O或H2;
Z是氢、卤素、羟基、选择性取代的烷氧基、芳烷氧基、酰氧基或烷氧基羰基氧基;
R是氢、卤素、三氟甲基、低级烷基或环烷基;
R1是羟基、选择性取代的烷氧基、芳氧基、杂芳氧基、芳烷氧基、环烷氧基、杂芳烷氧基或-NR5R6;
R2是氢、卤素或烷基;
R3是卤素或烷基;
R4是选择性取代的烷基、芳基、芳烷基、杂芳烷基或杂芳基;
R5、R6和R7彼此独立地是氢、选择性取代的烷基、环烷基、芳基、芳烷基、杂芳基或杂芳烷基;或者R5和R6合在一起是选择性地被O、S、S(O)、S(O)2或NR7间断的亚烷基,该亚烷基与它们所连接的氮原子合在一起形成5至7元环;
n表示0或1至4的整数。
本发明的化合物是拟甲状腺剂,可用于预防和/或治疗与甲状腺激素失调有关的疾病,例如甲状腺机能减退和甲状腺机能亢进、肥胖、骨质疏松症和抑郁症。具体地讲,本发明的化合物是降血脂剂,它可以增强胆固醇从血液循环中的清除,特别是低密度脂蛋白(LDL)形式的胆固醇的清除。它们还可以向上调节哺乳动物肝脏的LDL受体功能。因此,它们可用于降低哺乳动物的血浆总胆固醇水平,特别是降低LDL-胆固醇的水平。此外,该化合物还可以在哺乳动物中降低升高了的脂蛋白(a)[Lp(a)]的水平,它是一个独立的心血管危险因素。因此,本发明的化合物可用于在哺乳动物中预防和/或治疗涉及高脂血症和高脂蛋白血症的阻塞性心血管疾病,例如动脉粥样硬化和冠心病。
本发明提供了式I化合物、含有所述化合物的药物组合物以及使用所述化合物的方法。
以下列出的是描述本发明化合物所用的各种术语的定义。这些定义适用于整个说明书中所用的术语(除非在特定的情况下单独地或作为更大基团的一部分对其另行限定)。
术语“选择性取代的烷基”是指未取代或取代的含有1至20个碳原子、优选1至7个碳原子的直链或支链的烃基。未取代的烷基的例子包括甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基、异己基、庚基、4,4-二甲基戊基、辛基等。取代的烷基包括但不仅限于,被一个或多个(例如两个或三个)下列基团取代的烷基:卤素、低级链烯基、羟基、环烷基、链烷酰基、烷氧基、烷氧基烷氧基、链烷酰氧基、氨基、烷基氨基、二烷基氨基、二烷基氨基羰基、链烷酰基氨基、巯基、烷硫基、烷基硫羰基、烷基磺酰基、芳基磺酰基、杂芳基磺酰基、磺酰氨基、硝基、氰基、羧基、烷氧基羰基、芳基、芳烷基、芳烷氧基、胍基和杂环基,所述杂环基包括吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基、哌啶基、吗啉基等。取代的烷基、特别是当变量R1是取代的烷氧基时,变量R1的取代烷基的取代基优选是低级烷基、环烷基、低级链烯基、苄基、单或二取代的低级烷基,例如ω-(氨基、单或二-低级烷基氨基、羧基、低级烷氧基羰基)-低级烷基、α-(低级链烷酰氧基、低级烷氧基羰基或二-低级烷基氨基羰基)-低级烷基,例如新戊酰氧基烷基-甲基。
术语“低级烷基”是指含有1至7个、优选1至4个碳原子的上述。
术语“卤素”或“卤素”是指氟、氯、溴和碘。
术语“链烯基”是指含有至少两个碳原子并且还含有至少一个碳碳双键的上述烷基。优选含有2至4个碳原子的基团。
术语“亚烷基”是指通过单键连接的1至6个碳原子的直链的桥(例如-(CH2)x-,其中x是1至6),其可以被1至3个低级烷基所取代。
术语“环烷基”是指3至8个碳原子的环状烃基。
术语“烷氧基”是指烷基-O-。
术语“酰基”是指链烷酰基、芳酰基、杂芳酰基、芳基链烷酰基或杂芳基链烷酰基。
术语“链烷酰基”是指烷基-C(O)-。
术语“链烷酰氧基”是指烷基-C(O)-O-。
术语“烷基氨基”和“二烷基氨基”分别是指(烷基)NH-和(烷基)2N-。
术语“链烷酰基氨基”是指烷基-C(O)-NH-。
术语“烷硫基”是指烷基-S-。
术语“烷基硫羰基”是指烷基-S(O)-。
术语“烷基磺酰基”是指烷基-S(O)2-。
术语“烷氧基羰基”是指烷基-O-C(O)-。
术语“烷氧基羰基氧基”是指烷基-O-C(O)O-。
以上定义中所提到的术语“烷基”涉及以上所定义的选择性取代的烷基。
术语“芳基”是指在环的部分含有6至12个碳原子的单环或二环芳香族烃基,例如苯基、萘基、四氢萘基和联苯基,这些基团均可以选择性地被1至4个取代基例如烷基、卤素、羟基、烷氧基、链烷酰基、链烷酰氧基、氨基、烷基氨基、二烷基氨基、链烷酰基-氨基、巯基、烷硫基、硝基、氰基、羧基、羧基烷基、烷氧基羰基、烷基硫羰基、烷基-磺酰基、磺酰氨基、杂环基等所取代。
术语“单环芳基”是指选择性取代的在芳基中所定义的苯基。
术语“芳烷基”是指直接通过烷基结合的芳基,例如苄基。
术语“芳烷氧基”是指通过烷氧基结合的芳基。
术语“芳基磺酰基”是指芳基-S(O)2-。
术语“芳酰基”是指芳基-C(O)-。
术语“杂环基”是指选择性取代的、完全饱和或不饱和的芳香族或非芳香族环状基团,例如4至7元的单环、7至11元的二环或10至15元的三环环系,该环状基团在至少一个含碳原子的环中含有至少一个杂原子。含有杂原子的杂环基团的各环可以含有1、2或3个选自氮原子、氧原子和硫原子的杂原子,其中的氮和硫杂原子还可以选择性地被氧化。杂环基团可以连接在杂原子或碳原子上。
单环杂环基团的例子包括吡咯烷基、吡咯基、吡唑基、氮杂环丁烷基、吡唑啉基、咪唑基、咪唑啉基、咪唑烷基、噁唑基、噁唑烷基、异噁唑啉基、异噁唑基、噻唑基、噻二唑基、噻唑烷基、异噻唑基、异噻唑烷基、呋喃基、四氢呋喃基、噻吩基、噁二唑基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代吖庚因基、吖庚因基、4-哌啶酮基、吡啶基、2-吡啶酮、N-低级烷基-吡啶酮,例如N-低级烷基-2-吡啶酮、吡嗪基、嘧啶基、哒嗪基、四氢吡喃基、吗啉基、硫吗啉基、S-氧代-硫吗啉基、S,S-二氧代-硫吗啉基、1,3-二氧戊环和四氢-1,1-二氧代噻吩基等。
二环杂环基团的例子包括吲哚基、苯并噻唑基、苯并噁唑基、苯并噻吩基、奎宁环基、喹啉基、四氢异喹啉基、异喹啉基、苯并咪唑基、苯并吡喃基、吲嗪基、苯并呋喃基、苯并吡喃酮基(chromonyl)、香豆素基、苯并吡喃基、噌啉基、喹喔啉基、吲唑基、吡咯并吡啶基、呋喃并吡啶基(例如呋喃并[2,3-c]吡啶基、呋喃并[3,2-b]吡啶基]或呋喃并[2,3-b]吡啶基)、二氢异吲哚基、二氢喹唑啉基(例如3,4-二氢-4-氧代-喹唑啉基)等。
三环杂环基团的例子包括咔唑基、苯并吲哚基、菲咯啉基、吖啶基、菲啶基、呫吨基等。
术语“杂环基”包括取代的杂环基团。取代的杂环基团是指被1、2或3个如下基团取代的杂环基团:
(a)烷基;
(b)羟基(或保护的羟基);
(c)卤素;
(d)氧代(即=O);
(e)氨基、烷基氨基或二烷基氨基;
(f)烷氧基;
(g)环烷基;
(h)羧基;
(i)杂环氧基;
(j)烷氧羰基、例如未取代的低级烷氧基羰基;
(k)巯基;
(l)硝基;
(m)氰基;
(n)磺酰氨基、磺酰氨基烷基或磺酰氨基二烷基;
(o)芳基;
(p)烷基羰基氧基;
(q)芳基羰基氧基;
(r)芳硫基;
(s)芳氧基;
(t)烷硫基;
(u)甲酰基;
(v)芳烷基;或
(w)被烷基、环烷基、烷氧基、羟基、氨基、烷基氨基、二烷基氨基或卤素取代的芳基。
术语“杂环氧基”是指通过氧桥结合的杂环基团。
术语“杂芳基”是指芳香族杂环,例如单环或二环芳基,例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、呋喃基、噻吩基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吲哚基、苯并噻唑基、苯并噁唑基、苯并噻吩基、喹啉基、异喹啉基、苯并咪唑基、苯并呋喃基等,其选择性地被一个或多个在取代的芳基中所述的取代基所取代,例如被低级烷基、低级烷氧基或卤素取代。
术语“杂芳氧基”是指杂芳基-O-。
术语“杂芳基磺酰基”是指杂芳基-S(O)2-。
术语“杂芳酰基”是指杂芳基-C(O)-。
术语“杂芳烷基”是指通过烷基结合的杂芳基。
本发明还包括前药衍生物,例如本发明的羧酸(COR1是羧基)的可药用前药酯衍生物,该衍生物可以通过溶剂分解作用或在生理条件下转化成游离的羧酸。
所述羧酸酯的例子包括由COR1所定义的酯,优选低级烷基酯、环烷基酯、低级链烯基酯、苄酯、单或二取代的低级烷基酯,例如ω-(氨基、单或二-低级烷基氨基、羧基、低级烷氧羰基)-低级烷酯、α-(低级链烷酰氧基、低级烷氧羰基或二-低级烷基氨基羰基)-低级烷基酯,例如新戊酰氧基-甲酯等本领域中常用的酯。
R优选表示氢或低级烷基;
R1优选表示羟基、低级烷氧基或芳氧基。
R2优选表示氢、卤素或低级烷基。
R3优选表示卤素或低级烷基。
R4优选表示苯基或被一个或多个选自低级烷基、低级烷氧基、卤素和三氟甲基的取代基取代的苯基。
R5优选表示氢。
R6优选表示苯基或被一个或多个选自低级烷基、低级烷氧基、卤素和三氟甲基的取代基取代的苯基。
W优选是O。
X优选是-S(O)2R4或-S(O)2NR5R6。
Y优选是O。
Z优选是氢或羟基。
整数“n”优选是0、1或2。
根据取代基的性质,本发明的化合物可以具有一个或多个不对称中心。所形成的非对映体、对映体和几何异构体均包括在本发明的范围内。
优选以上所定义的式I化合物,条件是当X是-C(O)NR5R6时,Z不是氢。
优选如式I化合物及其可药用盐,其中
W是O或S;
X是-S(O)2R4;R4是低级烷基、苯基或被一个或多个选自低级烷基、低级烷氧基、卤素和三氟甲基的取代基取代的苯基;或者X是-S(O)2NR5R6或-C(O)NR5R6;其中R5是氢或低级烷基,R6是氢、低级烷基、被NR5R6取代的低级烷基、3至7元环烷基、苯基、被一个或多个选自低级烷基、低级烷氧基、卤素和三氟甲基的取代基取代的苯基;吡啶基或N-低级烷基-2-吡啶酮;或者
R5和R6合在一起是亚烷基或被O或S(O)2间断的亚烷基,所述亚烷基与它们所连接的氮原子合在一起形成5至7元环;
Y是O或H2;
Z是氢或羟基;
R是氢;
R1是羟基、低级烷氧基或NR5R6;R5是氢或低级烷基,R6是氢、低级烷基、低级烷氧基,或者R5和R6合在一起是亚烷基或被O间断的亚烷基,所述亚烷基与它们所连接的氮原子合在一起形成5至7元环;
R2是氢、卤素或低级烷基;
R3是卤素或低级烷基;
n表示0、1或2。
优选式IA的化合物及其可药用盐;其中
W是O或S;
X是-SR4、-S(O)R4、-S(O)2R4、-S(O)2NR5R6或-C(O)NR5R6;
Y是O或H2;
Z是氢、卤素、羟基、烷氧基、芳烷氧基、酰氧基或烷氧基羰基氧基;
R1是羟基、低级烷氧基或芳氧基;
R2是氢、卤素或低级烷基;
R3是卤素或低级烷基;
R4是选择性取代的烷基、芳基、芳烷基、杂芳基或杂芳烷基;
R5、R6和R7彼此独立地是氢、选择性取代的烷基、环烷基、芳基、芳烷基、杂芳基或杂芳烷基;或者R5和R6合在一起是选择性地被O、S、S(O)、S(O)2或NR7间断的亚烷基,所述亚烷基与它们所连接的氮原子合在一起形成5至7元环;
n表示0、1或2。
X是-S(O)2R4、-S(O)2NR5R6或-C(O)NR5R6;
Z是羟基、低级链烷酰氧基或低级烷氧基;
R1是羟基或低级烷氧基;
R2和R3是低级烷基;
R4是芳基;
R5、R6和R7彼此独立地是氢、选择性取代的烷基、环烷基、芳基、芳烷基、杂芳基、或杂芳烷基;或者R5和R6合在一起是选择性地被O、S、S(O)、S(O)2或NR7间断的亚烷基,所述亚烷基与它们所连接的氮原子合在一起形成5至7元环。
X是-S(O)2R4或-S(O)2NR5R6;
R4是单环芳基;
R5、R6和R7彼此独立地是氢、选择性取代的烷基或芳基;或者R5和R6合在一起是CH2CH2-Q-CH2CH2,其中Q是CH2、O、NR7、S、S(O)或S(O)2,所述CH2CH2-Q-CH2CH2与它们所连接的氮原子合在一起形成6元环。
特别优选其中X是S(O)2R4并且R4是选择性地被低级烷基、卤素、低级烷氧基或三氟甲基取代的苯基的式IC化合物、其可药用盐及其前药衍生物。
本发明的任何酸性化合物的可药用盐是与碱形成的盐,即阳离子盐,例如碱金属盐和碱土金属盐,例如钠、锂、钾、钙、镁盐,以及铵盐,例如铵、三甲基铵、二乙基铵和三-(羟基甲基)-甲基-铵盐。
当在结构中存在碱性基团如吡啶基时,还可以形成无机酸、有机酸和有机磺酸例如盐酸、甲磺酸、马来酸等的酸加成盐。
式I化合物可以从式II的适当取代的苯酚化合物(按照文献中公知的方法制备)制备:其中R2和R3具有本文中所定义的含义,W是氧,制备方法如下:首先将其转化成例如三氟甲基磺酰基酯,然后将该酯用氯化锂在惰性溶剂例如N-甲基-吡咯烷酮、N,N-二甲基甲酰胺或二甲亚砜中处理形成式III化合物可将式III化合物通过如下方法转化成式IV化合物:将式III化合物与式V的适当取代的苯酚化合物或苯硫酚化合物在碱例如氢化钠或碳酸钾的存在下在惰性溶剂例如N-甲基吡咯烷酮、N,N-二甲基甲酰胺或二甲亚砜中在室温或升高的温度下反应,其中R具有本文所定义的含义,X’和Z’表示本文所定义的X和Z,或者X’和Z’分别是可以转化成X和Z的基团。式V化合物可以用本文或本领域中记载的方法制得。
或者,式IV化合物可以通过将式VI的二芳基碘鎓四氟硼酸盐与其中W是氧或硫的式II的苯酚或苯硫酚化合物缩合制得,其中R、X’和Z’如上所定义,缩合反应按照本领域中描述的方法进行,例如,在铜催化剂和碱例如三乙胺的存在下在惰性溶剂例如二氯甲烷中进行。
其中Z’是烷氧基或芳烷氧基的式IV化合物可以按照本领域公知的方法转化成其中Z’是羟基的式IV化合物,例如,当Z’是甲氧基时,使用酸如氢溴酸或三卤化硼,例如三氯化硼或三溴化硼;或者当Z’是苄氧基时,使用氢气在催化剂如钯碳的存在下进行转化。
其中X是S(O)2NR5R6的本发明化合物可以通过如下方法制备:例如,首先将其中R和X’是氢并且X’位于3’位,Z’是羟基、烷氧基或芳烷氧基并且Z’位于4’位的式IV化合物与氯磺酸在有机溶剂例如二氯甲烷中反应生成式VII化合物其中Z’如上所定义。其中Z’是羟基的式VII化合物可以用本领域公知的方法和条件转化成其中Z’是保护的羟基例如链烷酰氧基、烷氧羰基氧基或三烷基甲硅烷氧基的式VII化合物。
其中Z’是烷氧基、芳烷氧基、链烷酰氧基、烷氧羰基氧基或三烷基甲硅烷氧基的式VII化合物可以通过与氯化试剂例如草酰氯或亚硫酰氯在惰性溶剂例如二氯甲烷或四氢呋喃中、在催化量的N,N-二甲基甲酰胺的存在下反应转化成式VIII化合物,其中Z’如上所定义。
其中的Z’如上所定义的式IX化合物可以用本领域公知的方法和条件或按照本文的描述转化成Z’是羟基的式IX化合物。
所形成的胺,例如式X的化合物,可以用酰化试剂例如乙基草酰氯、乙基丙二酰氯、乙基琥珀酰氯或溴乙酸乙酯在碱例如N-甲基吗啉或三乙胺的存在下在有机溶剂例如二氯甲烷、四氢呋喃或N,N-二甲基甲酰胺中处理形成式I化合物,例如式XI的化合物其中R1是烷氧基,Y是氧或H2,Z’表示本文中所定义的Z或者Z’是可以转化成Z的基团,n表示0至4的整数。其中R1是烷氧基的式I化合物还可以通过将例如式X的化合物与酰化试剂例如草酸二甲酯或草酸二乙酯在升高的温度下缩合来制备,其中的酰化试剂同时作为反应物和溶剂。
其中R1是例如烷氧基或芳氧基的式I化合物可以按照常规方法,例如用含水的碱例如碱金属碳酸盐或氢氧化物在有机溶剂例如乙醇或四氢呋喃中水解成其中R1是羟基的式I化合物。
同样,其中X’和Z’表示本文中所定义的X和Z或者X’和Z’分别是可以转化成X和Z的基团的其它式IV化合物可以按照本文中所描述的方法或其改变形式转化成式XII化合物:如需要,可以通过将X’和Z’分别转化成X和Z将所述化合物转化成相应的式I化合物。例如,其中X’=COOH的化合物可以按照本领域公知的方法转化成其中X是C(O)NR5R6的相应的式I的酰胺。其中COR1是COOH的类似化合物可以转化成其中COR1是CONR5R6的化合物。
在用于按照本文所述的方法转化成本发明化合物的原料化合物和中间体中所存在的功能基例如氨基、巯基、羧基和羟基可以选择性地用制备有机化合物中常用的常规保护基进行保护。保护的氨基、疏基、羧基和羟基是那些可以在温和的条件下转化成游离的氨基、疏基、羧基和羟基而不会破坏分子结构或引起其它不想要的副反应的基团。
引入保护基的目的是防止功能基与反应物在进行所需化学转化的条件下发生不想要的反应。对于具体的反应,是否需要保护基以及保护基的选择是本领域技术人员公知的,它取决于所要保护的功能基的性质(羟基、氨基等)、含有该取代基的分子的结构和稳定性以及反应条件。
满足这些条件的公知的保护基及其引入和脱除的方法记载于,例如J.F.W.McOmie,“有机化学中的保护基(Protective Groupsin Organic Chemistry)”,Plenum Press,伦敦,纽约,1973,T.W.Greene,“有机合成中的保护基(Protective Groups inOrganic Synthesis)”,Wiley,纽约,1991。
在本文所述的反应中,羧酸的活泼功能基衍生物表示,例如酸酐(特别是混合酸酐)、酰卤、酰基叠氮、低级烷基酯及其活化的酯。混合酸酐优选是新戊酸的酸酐,或是碳酸的低级烷基(乙基、异丁基)半酯;酰卤是例如酰氯或酰溴等;活化的酯是例如琥珀酰亚氨基、邻苯二甲酰亚氨基或4-硝基苯酯;低级烷酯是例如甲酯或乙酯等。
上述反应按照常规的方法,在存在或不存在稀释剂(优选对反应物惰性并且可以溶解该反应物的稀释剂)、催化剂、缩合剂或所述其它试剂和/或在惰性气氛下,在低温、室温或升高的温度(优选处于或接近所用溶剂的沸点)、在常压或高压下进行。优选的溶剂、催化剂和反应条件如随后的实施例中所述。
本发明还包括本发明方法的各种改变形式,其中,将可在其任何阶段获得的中间体产物用作原料并进行随后的步骤;或者,在反应条件下就地形成原料;或者,将反应物以其盐或旋光纯对映体的形式使用。
本发明的化合物和中间体还可以按照公知的方法相互转化。
本发明还涉及新的原料及其制备方法。
根据所选择的原料和方法,新化合物可以是可能的异构体之一或是其混合物,例如,基本上纯的几何异构体(顺或反)、旋光异构体(对映体)、外消旋体或其混合物。上述可能的异构体或其混合物均包括在本发明的范围内。
所形成的异构体混合物可以根据其各成分的物理化学差异分离成纯净的几何或旋光异构体、非对映体、外消旋体,例如,通过色谱和/或分级结晶的方法。
所形成的终产物或中间体的外消旋体可以通过已知方法拆分成旋光对映体,例如,将其与旋光性的酸或碱形成非对映体盐分离,然后释放出旋光活性的酸性或碱性化合物。因此,可以通过例如分级结晶d-或1-(α-甲基苄基胺、辛可尼丁、辛可宁、奎宁、奎尼丁、麻黄碱、脱氢枞胺、布鲁辛或***)-盐将羧酸中间体拆分成其旋光对映体。外消旋产物还可以通过手性色谱、例如使用手性吸附剂的高压液相色谱进行拆分。
最后,本发明的化合物可以以游离的形式得到,或者,如果存在成盐基团的话,以其盐的形式得到。
可将本发明的酸性化合物用可药用碱、例如含水的碱金属氢氧化物转化成盐,优选在醚或醇溶剂例如低级链烷醇的存在下进行。可将盐用醚例如***从醇溶液中沉淀出来。所得到的盐可通过用酸处理转化成游离化合物。这些以及其它的盐还可用于纯化所得到的化合物。
带有碱基的本发明化合物可以转化成酸加成盐,特别是可药用盐。这些盐可与例如无机酸如硫酸、磷酸或氢卤酸形成;或与有机羧酸例如未取代的或被卤素取代的(C1-C4)-链烷酸如乙酸,饱和或不饱和的二元羧酸如草酸、琥珀酸、马来酸或富马酸,羟基羧酸如乙醇酸、乳酸、苹果酸、酒石酸或柠檬酸,氨基酸如天冬氨酸或谷氨酸形成;或与未取代或取代(例如被卤素取代)的有机磺酸如(C1-C4)-烷基磺酸(例如甲磺酸)或芳基磺酸形成。优选与盐酸、甲磺酸和马来酸形成的盐。
考虑到游离化合物和盐形式的化合物之间的密切关系,当在本文中提到一种化合物时,也包括相应的盐,条件是这是可能的或者在该情况下是适宜的。
化合物、包括其盐,还可以其水合物的形式得到,或者包含在其结晶中所用的其它溶剂。
本发明的药物组合物适于向哺乳动物、包括人肠道给药(例如口服或直肠给药)、经皮和胃肠外给药来治疗与甲状腺激素失调有关的疾病,例如甲状腺机能减退和甲状腺机能亢进、肥胖、骨质疏松症、抑郁症,特别是用来治疗和/或预防与高血脂症和高脂蛋白血症有关的阻塞性心血管病症,该组合物含有有效量的本发明的药物活性化合物或其与一种或多种可药用载体的混合物。
本发明的药物活性化合物可用于生产药物组合物,所述药物组合物含有有效量的药物活性化合物和适用于肠道或胃肠外应用的赋形剂或载体的混合物。优选片剂和胶囊,它们含有活性成分以及a)稀释剂,例如乳糖、葡萄糖、蔗糖、甘露醇、山梨醇、纤维素和/或甘氨酸;b)润滑剂,例如二氧化硅、滑石、硬脂酸、其镁盐或钙盐和/或聚乙二醇;对于片剂,还含有c)粘合剂,例如硅酸镁铝、淀粉糊、西黄蓍胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮;如需要,还含有d)崩解剂,例如淀粉、琼脂、藻酸或其钠盐或泡腾混合物;和/或e)吸附剂、着色剂、调味剂和甜味剂。可注射的组合物优选含水的等渗溶液或悬浮液,栓剂优选用含脂肪的乳液或悬浮液制备。所述组合物可以是无菌的和/或含有防腐剂、稳定剂、湿润剂或乳化剂、溶解促进剂、用于调节渗透压的盐和/或缓冲剂等辅剂。此外,它们还可含有其它有治疗作用的物质。所述组合物按照常规的混合、制粒或包衣方法制备,并且含有约0.1至75%、优选约1至50%活性成分。
用于经皮应用的适宜制剂含有有效量的本发明化合物和载体。优选的载体包括可吸收的可药用溶剂以帮助通过宿主的皮肤。代表性的经皮装置是绷带,其包含背衬层、含有化合物以及选择性的载体的储库、用于在较长时间内以控制的和预定的速率向宿主皮肤输送化合物的选择性的速率控制层、以及将装置固定在皮肤上的工具。
用于约50至70kg的哺乳动物的单位剂量可以含有约0.01mg至10mg活性成分。活性化合物的剂量取决于恒温动物(哺乳动物)的种类、体重、年龄和个体条件、给药形式以及所用的化合物。
本发明所解决的问题是提供了可以降低哺乳动物血浆胆固醇水平的有效的降血脂剂。本发明的化合物可以有效地与三碘甲状腺氨酸(T3)中心受体结合(这是LDL受体活性向上调节的象征)并增强LDL-胆固醇从循环中的清除。因此,本发明的化合物特别适于在哺乳动物中用作降血胆固醇剂,用来通过降低血浆中总的和LDL-胆固醇水平来治疗和预防与高胆固醇血症有关的阻塞性心血管疾病。本发明还涉及本发明的化合物在制备药物中的用途,特别是用于通过降低血浆中总的和LDL-胆固醇水平来治疗和预防与高胆固醇血症有关的阻塞性心血管疾病的药物。
本发明的化合物还可降低脂蛋白(a)水平,因此可用于治疗和预防与Lp(a)有关的阻塞性心血管疾病。
优选基本上没有与甲状腺激素有关的不利心脏副作用的本发明的选择性拟甲状腺降血脂剂。
上述性质在体外和体内试验中用哺乳动物例如小鼠、大鼠、狗、猴子或离体的器管、组织及其制备物进行了证实。可将所述化合物以溶液、优选水溶液的形式体外应用;体内应用通过肠道、胃肠外,优选静脉内,例如以悬浮液或水溶液的形式来进行。体外剂量可以从约10-7摩尔至10-11摩尔浓度。体内剂量根据给药途径的不同,可以从约0.1至1000mg/kg,优选约0.5至300mg/kg,最好是从约1至100mg/kg。
本发明的化合物可与三碘甲状腺氨酸(T3)受体结合,因此可在哺乳动物中用作甲状腺激素激动剂。
与T3中心受体的体外结合按照如下描述进行测定:
按照Emmelot等描述的差速离心法(Methods in Enzymology 31:75,Part A,1974)并略作改动,从Sprague Dawley(CD)大鼠(Charles River Labs.)制得大鼠肝脏核和质膜制备物。将从275 xg沉积物得到的核部分按照Spindler等(J.Biol.Chem.250:4118,1975)描述的方法进一步纯化。
通过Spindler等(J.Biol.Chem.250:4118,1975)的方法分析新的测试化合物与核的结合。将核在22℃下与0.3nM[125I]-L-三碘甲状腺氨酸(L-T3)一起保温。用除了含有核和放射性L-T3之外还含有各种浓度的测试化合物或3μM非放射性L-T3的试管进行平行保温。后者用来测定非特异性结合。将反应混合物以800xg离心7分钟并洗涤所得到的沉积物后,测定与核结合的放射性。减去非特异性结合的量(在与过量的(3μM)非放射性L-T3一起保温后在核沉积物中所含的放射性)测得[125I]-L-T3特异性结合的量。用作图的方法从特异性结合[125I]-L-T3对测试化合物的各种浓度的倒数图中测得抑制[125I]-L-T3的特异性结合达50%时的测试化合物的浓度(IC50)。
降胆固醇活性按照如下描述在大鼠中进行测定:
在治疗前两周以及在为期7天的治疗期内,使雄性Sprague-Dawley大鼠(230-250g)(Taconic Farms)可以随意接近水和高胆固醇食物(1.5%胆固醇和0.5%胆酸)。将分组的动物通过管饲法单独用载体或测试化合物连续口服给药7天。最后一次给药后,将动物禁食18小时然后采血。将血样以2500 rpm离心10分钟以制备血浆用于测定总胆固醇以及LDL和HDL胆固醇浓度。在LDL/VLDL析出后测定HDL值(Warnick和Albers,1978)。所有样品均用诊断试剂盒(Sigma Chemical Co.,St.Louis,MO)通过酶催化分析胆固醇。分析在Bio-Mek自动工作站上进行。通过如下方式析出LDL/VLDL部分:将0.35mL血浆等分加入微量离心管中,向其中加入12μL 2M氯化镁、11.2μL肝素钠(PorcineIntestinal,5000单位/mL)和8.3μL生理盐水。将样品涡旋振荡然后在冰上放置15分钟,然后于4℃下以1300 rpm离心10分钟,然后通过酶催化分析上清液中的胆固醇。通过将上清液的胆固醇值乘以1.09计算出稀释液的HDL胆固醇浓度。从总胆固醇中减去HDL胆固醇计算出LDL/VLDL胆固醇的值。
降胆固醇活性还可以按照上述方法在喂食常规食物的血胆固醇正常的狗中通过口服给药测试化合物5天进行评估。
降胆固醇和Lp(a)活性可以按照如下方法在血脂正常的Cynomolgus猴中测定:
使用重量为3-7kg的成年雄性和雌性Cynomolgus猴(Macacafascicularis)。将动物单独饲养并用常规的猴子食物(Purina 5047)喂养,并补充新鲜水果和蔬菜。每一只动物均作为自身的对照,在每一次给药方案之后是一段洗出期。将测试化合物溶于乙醇,浸渗到水果浆中然后口服给药。每天向动物给药测试化合物一次,治疗期为8至28天。在禁食过夜后以及在研究结束时获取血样。从用机械方法约束的未服镇静剂的动物的股静脉取血并将血样(3ml)收集在Vacutainer管(含有EDTA)中。将血液于4℃下以2000 rpm离心20分钟。将血浆样品等分然后于-70℃下保存直至进行分析。通过酶催化方法用商业试剂盒(Sigma Diagnostics)测定总胆固醇(TC)和甘油三酯(TG)的血浆浓度。在析出含apoB的脂蛋白后测定高密度脂蛋白胆固醇(HDL-C)浓度。由于食用食物的Cynomolgus猴的禁食血浆中含有可忽略不计量的极低密度脂蛋白,因此可以通过从TC中减去HDL-C计算出低密度脂蛋白胆固醇(LDL-C)浓度。试验在96孔微滴定板中进行,将其在微量板分光光度计(Dynatech MR 5000)中读数。Lp(a)的血浆浓度通过商业Lp(a)ELISA(Perlmmune,Inc.)来测定,使用试剂盒对照并参照Lp(a)标准物。Lp(a)ELISA采用抗载脂蛋白(a)的单克隆抗体进行捕获并采用抗载脂蛋白B的多克隆抗体进行检测。该试验对于Lp(a)是特异性的,不会测定游离的apo(a)、apoB或纤溶酶原。对Lp(a)的定量不受apo(a)大小的影响。Lp(a)血浆浓度用总Lp(a)物质的毫克数来表示。各研究的样品只分析一次。
作为本发明的例子,在T3核受体结合试验中,实施例26的化合物显示约0.17nM的IC50值,实施例28的化合物显示约0.13nM的IC50值,实施例35的化合物显示约1.00nM的IC50值,实施例39的化合物显示约0.04nM的IC50值。此外,所述实施例26的化合物还可以在大约20微克(μg)/kg口服(大鼠)和约10μg/kg口服(狗)的每日剂量下显著降低血清胆固醇。此外,在用所述实施例26的化合物以75μg/kg的每日剂量治疗4周后,可以使血脂正常的Cynomolgus猴的Lp(a)水平下降约40%。
以下实施例是用来说明本发明的,本发明并不仅限于此。所给出的温度为摄氏度。若无另外说明,所有的蒸发均在减压条件下进行,优选在约15和100 mmHg(=20-133毫巴)之间进行。最终产物、中间体和原料的结构通过常规的分析方法证实,例如微量分析和光谱学特征(例如MS、IR、NMR)。所用的缩写是本领域中的常规缩写。
实施例1
将氢化钠(NaH;60%矿物油分散液;64.11g,1.603mol)在350mLN-甲基吡咯烷酮(NMP)中的悬浮液冷却至0℃然后在30分钟内加入4-甲氧基苯酚(208.4g,1.679mol)溶液。将混合物升温至室温(RT),30分钟后,一次性加入4-氯-3,5-二甲基硝基苯(283.2g,1.526mol;通过Yokoyama等在EP580550中描述的方法制备)并将反应液于120℃加热2小时。将反应液冷却至室温(RT)并用水(1500ml)终止反应。将悬浮液冷却至0℃,搅拌30分钟,过滤,将滤饼用水洗涤然后真空干燥。将粗产物、乙酸乙酯(EtOAc;2100ml)和木炭(42.6g)加热回流,然后用硅藻土趁热过滤除去固体。将滤液减压浓缩至约800mL,将得到的悬浮液冷却至0℃并搅拌30分钟。通过真空过滤收集产物,用冷的EtOAc洗涤然后真空干燥得到3,5-二甲基-4-(4’-甲氧基苯氧基)硝基苯:NMR(CDCl3)2.22(s,6H),3.78(s,3H),6.68(d,2H,J=8.7),6.82(d,2H,J=8.7),8.02(s,2H)。B.3,5-二甲基-4-(4’-羟基苯氧基)硝基苯
将标题A的化合物,3,5-二甲基-4-(4’-甲氧基苯氧基)硝基苯(16.4g,60mmol)、乙酸(AcOH;100ml)和48%氢溴酸水溶液(HBr;100ml)的混合物于120℃加热16小时。将混合物冷却至室温,用水(200mL)稀释,真空过滤收集析出的产物,用水和己烷洗涤然后真空干燥得到3,5-二甲基-4-(4’-羟基苯氧基)硝基苯:NMR(CDCl3)2.22(s,6H),6.62(d,2H,J=8.7),6.77(d,2H,J=8.7),8.0(s,2H)。C.5-(2,6-二甲基-4-硝基苯氧基)-2-羟基苯磺酸
将标题B的化合物,3,5-二甲基-4-(4’-羟基苯氧基)硝基苯(7.86g,30.35mmol)的150mL二氯甲烷(CH2Cl2)溶液用氯磺酸(2.4ml,36.42mmol)在室温下处理。16小时后,将反应混合物浓缩并将残余物溶于少量二氯甲烷(约5ml)。加入盐水(100mL)析出产物,真空过滤进行收集,用水、己烷和***(Et2O)洗涤然后真空干燥得到5-(2,6-二甲基-4-硝基苯氧基)-2-羟基-苯磺酸:NMR(DMSO-d6)2.18(s,6H),6.67-6.83(m,3H),8.1(s,2H),10.07(s,1H)。D.2-苄氧基-5-(2,6-二甲基-4-硝基苯氧基)苯磺酸,铯盐
将标题C的化合物,5-(2,6-二甲基-4-硝基苯氧基)-2-羟基-苯磺酸(6.78g,20mmol)在100mL四氢呋喃(THF)和50mL N,N-二甲基甲酰胺(DMF)中的溶液用碳酸铯(15.6g,48mmol)和苄基溴(7.1ml,60mmol)在室温下处理,然后于75℃加热48小时。将反应混合物冷却至室温然后用1N盐酸水溶液(HCl;100ml)终止反应,然后蒸除THF。真空过滤收集析出的产物,用水、Et2O、EtOAc和CH2Cl2洗涤然后干燥得到2-苄氧基-5-(2,6-二甲基-4-硝基苯氧基)苯磺酸铯盐:NMR(DMSO-d6)2.18(s,6H),5.10(s,2H),6.74(dd,1H,J=8.7,3.8),6.97(d,1H,J=8.7),7.11(d,1H,J=3.8),7.23-7.39(m,3H),7.59(d,2H,J=7.5),8.12(s,2H)。E.2-苄氧基-5-(2,6-二甲基-4-硝基苯氧基)苯磺酰氯
将标题D的化合物,2-苄氧基-5-(2,6-二甲基-4-硝基苯氧基)-苯磺酸铯盐(9.9g,20mmol)的200mL二氯甲烷溶液用DMF(3.1ml,40mmol)处理,然后在室温下于30分钟内加入草酰氯(3.5ml,40mmol)。将反应混合物继续搅拌1小时,然后用***(200ml)稀释并用水和盐水洗涤,用无水硫酸钠(Na2SO4)干燥然后浓缩。将产物用***(5ml)洗涤然后真空干燥得到2-苄氧基-5-(2,6-二甲基-4-硝基-苯氧基)苯磺酰氯:NMR(CDCl3)2.24(s,6H),5.31(s,2H),7.02(dd,1H,J=8.7,3.8),7.10(d,1H,J=8.7),7.32-7.47(m,4H),7.52(d,2H,J=7.5),8.05(s,2H)。F.2-苄氧基-5-(2,6-二甲基-4-硝基苯氧基)-N-(2,2-二甲基丙基)苯磺酰胺
将标题E的化合物,2-苄氧基-5-(2,6-二甲基-4-硝基苯氧基)-苯磺酰氯(1.12g,2.5mmol)的20mL二氯甲烷溶液依次用N-甲基吗啉(NMM;550ml,5mmol)和新戊基胺(442ml,3.75mmol)在室温下处理。6小时后,将混合物在水和乙酸乙酯之间进行分配,将有机溶液用1N盐酸水溶液和盐水洗涤,用无水硫酸钠干燥然后浓缩得到2-苄氧基-5-(2,6-二甲基-4-硝基苯氧基)-N-(2,2-二甲基丙基)苯磺酰胺:NMR(CDCl3)0.78(s,9H),2.22(s,6H),2.58(d,2H,J=7.5),4.82(t,1H,J=7.5),5.18(s,2H),6.88(dd,1H,J=9,3.7),7.03(d,1H,J=9),7.33-7.51(m,6H),8.04(s,2H)。G.5-(4-氨基-2,6-二甲基苯氧基)-2-苄氧基-N-(2,2-二甲基丙基)苯磺酰胺
将标题F的化合物,2-苄氧基-5-(2,6-二甲基-4-硝基苯氧基)-N-(2,2-二甲基丙基)苯磺酰胺(1.22g,2.45mmol)和钯/活性碳(10 wt%;250mg)在40mL THF中的混合物在氢气氛(H2,1atm)下搅拌8小时。用硅藻土真空过滤除去催化剂,用THF洗涤并将合并的滤液和洗涤液浓缩。将残余物悬浮在二氯甲烷中,真空过滤收集产物,用二氯甲烷洗涤然后干燥得到5-(4-氨基-2,6-二甲基-苯氧基)-2-苄氧基-N-(2,2-二甲基丙基)苯磺酰胺:NMR(DMSO-d6)0.80(s,9H),1.90(s,6H),2.55(d,2H,J=7.5),4.90(br s,2H),6.31(s,2H),6.87 (br s,1H),6.93(br s,2H),6.97(t,1H,J=7.5),10.13(s,1H)。H.N-{4-[3-(2,2-二甲基丙基氨磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}-草氨酸
将标题G的化合物,5-(4-氨基-2,6-二甲基苯氧基)-2-苄氧基-N-(2,2-二甲基丙基)苯磺酰胺(750mg,1.98mmol)的10mL THF溶液冷却至0℃然后依次用NMM(545ml,4.96mmol)和乙基草酰氯(442ml,3.96mmol)处理。将反应液升温至室温并在1小时后用水终止反应。将混合物在水和乙酸乙酯之间进行分配,将有机溶液用1N盐酸和盐水洗涤,用无水硫酸钠干燥然后浓缩。将残余物溶于10mL THF,用1N氢氧化锂(LiOH;1.8ml,1.8mmol)在室温下处理。1小时后,用1N盐酸终止反应并将产物加入乙酸乙酯中,用盐水洗涤,用无水硫酸钠干燥然后浓缩。将产物依次用己烷和***研制,然后真空干燥得到N-{4-[3-(2,2-二甲基丙基氨磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}草氨酸:NMR(CDCl3)0.89(s,9H),2.13(s,6H),2.70(d,2H,J=7.5),5.22(t,1H,J=7.5),6.84(d,1H,J=3.7),7.04(d,1H,J=8.7),7.15(dd,1H,J=8.7,3.7),7.33(s,2H),8.54(br s,1H),9.18(s,1H);IR(KBr)1759,1693;ESI-MS 449[M-1]-。可以按照类似方法制得如下化合物。
6R=H,R6=p-MeOC6H4- | (DMSO-d6):1.90(s,6H),3.67(s,3H),6.68(d,1H,J=3),6.73(d,2H,J=9.00),6.89-6.99(m,4H),7.54(s,2H),9.58(s,1H),10.45(s,1H),10.64(s,1H) | 1209,1475,1514,1688 | 485[M-1]- |
7R5=H,R6=p-FC6H4CH2- | (DMSO-d6):2.02(s,6H),4.03(d,2H,J=6.4),6.80-6.89(m,3H),7.01(t,2H,J=4.0),7.22(dd,2H,J=6.3,8.7),7.56(s,2H),7.77(t,1H,J=6.4),10.32(s,1H),10.64(s,1H) | 1224,1481,1695 | 487[M-1]- |
8R5=Me-,R6=Ph- | (CDCl3):1.96(s,6H),3.14(s,3H),6.54(d,1H,J=2.4),6.84-6.85(m,2H),6.88-7.03(m,2H),7.20-7.28(m,5H) | 1209,1230,1481,1691 | 469[M-1]- |
9R5=H,R6=n-Pr- | (CDCl3):0.87(t,3H,J=7.5),1.38-1.56(m,2H),2.11(s,6H),2.94(app q,2H,J=7.5),5.0(t,1H,J=7.5),6.84(d,1H,J=3),7.0(d,1H,J=9),7.08(dd,1H,J=9,3),7.32(s,2H),8.44(br s,1H),9.0(br s,1H) | 1214,1485,1693,1751 | 421[M-1]-440[M+NH4]+ |
10R5=H,R6=i-Pr- | (DMSO-d6):0.95(d,6H,J=7.5),2.02(s,6H),3.2-3.31(m,1H),6.86(br s,1H),6.97(br s,2H),7.06(d,1H,J=7.5),7.57(s,2H),10.32(br s,1H),10.64(br s,1H) | 1209,1485,1698,1742 | 421[M-1]- |
11R5=H,R6=n-Bu- | (DMSO-d6):0.72(t,3H,J=7.5),1.1-1.35(m,4H),2.03(s,6H),2.76(app q,2H,J=7.5),6.87(br s,1H),6.97(br s,2H),7.1(t,1H,J=7.5),7.58(s,2H) | 1321,1481,1691 | 435[M-1]-454[M+NH4]+ |
12R5=H,R6=i-Bu- | (DMSO-d6):0.75(d,6H,J=8.2),1.49-1.62(m,1H),2.03(s,6H),2.55(app t,2H,J=6.8),6.85(br s,1H),6.96(br s,2H),7.17(t,1H,J=6.8),7.57(s,2H),10.25(br s,1H),10.61(br s,1H) | 1209,1481,1693,1762 | 435[M-1]- |
13R5=H,R6=t-Bu- | (DMSO-d6):1.02(s,9H),2.03(s,6H),6.81-7.02(m,4H),7.56(s,2H),10.20(br s,1H),10.61(br s,1H) | 1204,1486,1645,1754 | 435[M-1]- |
标题化合物按照与实施例1类似的方式制备:NMR(DMSO-d6)2.21(s,6H),6.87(d,1H,J=8.3),6.95-7.12(m,6H),7.65(s,2H),9.99(s,1H),10.73(s,1H),10.97(s,1H);IR(KBr)1163,1506,1690;ESI-MS 489[M-1]-,508[M+NH4]+。
实施例24
N-{4-[3-(4-氟苯基氨磺酰基)苯氧基]-3,5-二甲基苯基}草氨酸
标题化合物按照与实施例1类似的方式制备:NMR(DMSO-d6)1.91(s,6H),6.73-6.74(m,1H),6.95-7.00(m,2H),7.04-7.10(m,2H),7.21(dd,1H,J=8.2,2.4),7.35(d,1H,J=8.0),7.52(app t,1H,J=8.0),7.59(s,2H),10.21(s,1H),10.75(s,1H);IR(KBr)1161,1223,1509,1697;ESI-MS 457[M-1]-,476[M+NH4]+。
实施例25
标题化合物按照与实施例1类似的方式制备:NMR(DMSO-d6)2.06(s,3H),6.65(d,1H,J=8.8),6.92-7.18(m,7H),7.55(m,7H),7.55(dd,1H,J=8.8,2.4),7.70(d,1H,J=2.4),9.98(s,1H),10.69(s,1H),10.72(s,1H),10.75(s,1H);IR(KBr)1326,1487,1506,1692;ESI-MS 457[M-1]-。
实施例26
A.4-氟苯亚磺酸
将4-氟苯磺酰氯(2g,10.28mmol)的50mL THF(从Na-二苯酮中蒸馏)溶液冷却至0℃然后分批加入硼氢化钠(1.9g,51.4mmol)。将反应液搅拌2小时然后升温至室温,2小时后,用水(5ml)终止反应。蒸除溶剂,加入6N盐酸将含水残余物酸化。将产物加入乙酸乙酯中,用盐水洗涤,用无水硫酸钠干燥然后浓缩得到4-氟苯亚磺酸:NMR(DMSO-d6)7.12(app t,2H,J=8.3),7.5(dd,2H,J=8.3,6);ESI-MS 159[M-1]-。
B.2-(4-氟苯磺酰基)苯-1,4-二醇
将标题A的化合物,4-氟苯亚磺酸(3g,18.75mmol)的10mL水溶液在室温下加入到1,4-苯醌(1.93g,17.86mmol)的30mL二氯甲烷溶液中。4小时后,真空过滤收集析出的产物,用冷的二氯甲烷洗涤然后真空干燥得到2-(4-氟苯磺酰基)苯-1,4-二醇:NMR(DMSO-d6)6.73(d,1H,J=9),6.92(dd,1H,J=9,3),7.31(d,1H,J=3),7.41(app t,2H,J=9),7.96(dd,2H,J=9,5),9.41(s,1H),10.05(s,1 H);ESI-MS 267[M-1]-。
C.4-(2,6-二甲基-4-硝基苯氧基)-2-(4-氟苯磺酰基)苯酚
将标题B的化合物,2-(4-氟苯磺酰基)苯-1,4-二醇(1.2g,4.48mmol)于0℃下一次性加入到NaH(60%矿物油分散液;0.39g,9.86mmol)的15mL NMP悬浮液中。将混合物升温至室温,30分钟后,加入4-氯-3,5-二甲基硝基苯(1g,5.38mmol)并将反应液于120℃加热1小时。将反应液冷却至室温并用1N盐酸水溶液终止反应。将混合物在水和乙酸乙酯之间进行分配,将有机溶液用水和盐水洗涤,用无水硫酸钠干燥然后浓缩。经硅胶色谱(洗脱剂;EtOAc/己烷-1/2/1/1)得到4-(2,6-二甲基-4-硝基苯氧基)-2-(4-氟-苯磺酰基)苯酚:NMR(CDCl3)2.11(s,6H),6.85-6.96(m,3H),7.00(app t,2H,J=9),7.88(dd,2H,J=9,5),7.98(s,2H),8.73(s,1H)。
D.4-(4-氨基-2,6-二甲基苯氧基)-2-(4-氟苯磺酰基)苯酚
将标题C的化合物,4-(2,6-二甲基-4-硝基苯氧基)-2-(4-氟-苯磺酰基)苯酚(0.69g,1.65mmol)和钯/活性碳(10wt%;69mg)在10mL乙醇和10mL二氯甲烷中的混合物在氢气氛(H2,1atm)下搅拌6小时。用硅藻土真空过滤除去催化剂,用1/1乙醇和二氯甲烷的混合物洗涤,将合并的滤液和洗涤液浓缩然后真空干燥得到4-(4-氨基-2,6-二甲基苯氧基)-2-(4-氟苯磺酰基)-苯酚:NMR(DMSO-d6)1.93(s,6H),4.92(s,2H),6.34(s,2H),6.85(d,1H,J=9),7.00(dd,1H,J=9,3),7.12(d,1H,J=3),7.43(app t,2H,J=9),7.94(dd,2H,J=9,5),9.41(s,1H),10.4(s,1H)。
E.N-{4-[3-(4-氟苯磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}草氨酸乙酯
将标题D的化合物,4-(4-氨基-2,6-二甲基苯氧基)-2-(4-氟苯磺酰基)苯酚(0.64g,1.65mmol)和2mL草酸二乙酯的混合物于180℃加热3小时。将反应液冷却至室温然后真空蒸除草酸二乙酯。经硅胶色谱(洗脱剂;EtOAc/己烷-1/3?2/3)得到N-{4-[3-(4-氟苯磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}草氨酸乙酯:NMR(CDCl3)1.46(t,3H,J=7.5),2.06(s,6H),4.42(q,2H,J=7.5),6.90-6.98(m,3H),7.22(app t,2H,J=8.3),7.40(s,2H),7.87-7.93(m,2H),8.87(br s,1H);ESI-MS 486[M-1]-。
F.N-{4-[3-(4-氟苯磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}草氨酸
将标题E的化合物,N-{4-[3-(4-氟苯磺酰基)-4-羟基-苯氧基]-3,5-二甲基苯基}草氨酸乙酯(773mg,1.58mmol)的15mL乙醇溶液用1N氢氧化钠水溶液(NaOH;4.75ml,4.75mmol)在室温下处理。1小时后,用1N盐酸水溶液(5.5ml)终止反应并将产物加入乙酸乙酯中,用盐水洗涤,用无水硫酸钠干燥然后浓缩。将产物用***研制然后真空干燥得到N-{4-[3-(4-氟苯磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}草氨酸:NMR(DMSO-d6)2.06(s,6H),6.88(d,1H,J=9),7.03(dd,1H,J=9,3),7.13(d,1H,J=3),7.43(app t,2H,J=9),7.61(s,2H),7.94(dd,2H,J=9,5),10.5(s,1H),10.69(s,1H);IR(KBr)1240,1481,1685,1764;ESI-MS 458[M-1]-。
按照类似的方式制得如下化合物。
实施例35
33R4=n-Bu- | (DMSO-d6):0.81(t,3H,J=7.2),1.24-1.36(m,2H),1.41-1.51(m,2H),2.04(s,6H),3.37(t,2H,J=7.2),6.88(d,1H,J=3),7.08(dd,1H,J=9,3),7.15(d,1H,J=3),7.00-7.10(m,2H),7.57(s,2H),10.67(s,2H) | 1205,1488,1694 | 420[M-1]-439[M+NH4]+ |
34R4=i-Pr- | (DMSO-d6):1.11(d,6H,J=7),2.03(s,6H),3.66-3.75(m,1H),6.88(d,1H,J=3),),7.02(d,1H,J=3),7.08(dd,1H,J=9,3),7.57(s,2H),10.65(s,2H) | 1229,1354,1480,1688,1761 | 406[M-1]-425[M+NH4]+ |
标题化合物按照与实施例26类似的方式制备:NMR(DMSO-d6)2.05(s,6H),3.35(s,2H),6.89(d,1H,J=9),7.01(dd,1H,J=9,3),7.14(d,1H,J=3),7.39-7.45(m,4H,),7.93(dd,2H,J=8.8,5.2),10.18(s,1H),10.55(s,1H),12.6(br s,1H);IR(KBr)1142,1239,1485,1623,1654,1736;ESI-MS 472[M-1]-。
实施例36
标题化合物按照与实施例26类似的方式制备:NMR(DMSO-d6)2.04(s,6H),2.50-2.56(m,4H),6.87(d,1H,J=9),7.01(dd,1H,J=9,3),7.12(d,1H,J=3),7.39-7.45(m,4H),7.93(dd,2H,J=8.8,5.2),9.93(s,1H),10.5(br s,1H),12.1(s,1H);IR(KBr)1480,1659,1717;ESI-MS 486[M-1]-。
实施例37
标题化合物按照与实施例26类似的方式制备:NMR(MeOH-d4)2.06(s,6H),2.65(t,2H,J=7),3.49(t,2H,J=7),6.82(d,1H,J=9),6.85(s,2H),6.94(dd,1H,J=9,3),7.15(d,1H,J=3),7.23(app t,2H,J=9),7.88-7.93(m,2H);IR(KBr)1199,1493,1675;ESI-MS 460[M+1]+,458[M-1]-。
实施例38
标题化合物按照与实施例26类似的方式制备:NMR(DMSO-d6)2.18(s,3H),6.90(d,1H,J=9),6.92(d,1H,J=9),7.16(dd,1H,J=9,3),7.34(d,1H,J=3),7.43(app t,2H,J=9),7.61(dd,1H,J=9,3),7.74(d,1H,J=3),7.97(dd,2H,J=9,5),10.67(s,1H),10.71(s,1H);IR(KBr)1234,1495,1697;ESI-MS 444[M-1]-。
实施例39
标题化合物按照与实施例26类似的方式制备:NMR(DMSO-d6)6.91(d,1H,J=9),7.09(dd,1H,J=9,3),7.20(d,1H,J=3),7.44(app t,2H,J=8.6),7.92-7.97(m,2H),8.27(s,2H),10.74(s,1H),11.15(s,1H);IR(KBr)1290,1454,1484,1589,1695;ESI-MS 588[M-1]-。
实施例40
标题化合物按照与实施例26类似的方式制备:NMR(DMSO-d6)2.06(s,6H),6.88(d,1H,J=9),7.03(dd,1H,J=9,3),7.13(d,1H,J=3),7.42(app t,2H,J=8.9),7.66(s,2H),7.92-7.96(m,2H),8.0(br s,1H),8.29(br s,1H),10.49(s,1H),10.58(s,1H);IR(KBr)1141,1250,1481,1676;ESI-MS 497[M-1]-,475[M+NH4]+。
实施例41
标题化合物按照与实施例26类似的方式制备:ES-MS 499[M-1]-,518[M+NH4]+。
实施例42
标题化合物按照与实施例26类似的方式制备:ES-MS 499[M-1]-,518[M+NH4]+。
实施例43
标题化合物按照与实施例26类似的方式制备:ES-MS 513[M-1]-,515[M+1]+,532[M+NH4]+。
实施例44
标题化合物按照与实施例26类似的方式制备:ES-MS 517[M+1]+。
实施例45
标题化合物按照与实施例26类似的方式制备:ES-MS 527[M-1]-,529[M+1]+,546[M+NH4]+。实施例46
将NaH(60%矿物油分散液;1.32g,33mmol)的50mL NMP悬浮液冷却至0℃然后一次性加入2,5-二羟基苯甲酸(1.54g,10mmol)。将混合物升温至室温,30分钟后,一次性加入4-氯-3,5-二甲基-硝基苯(2.41g,13mmol)并将反应液于120℃加热3小时。将反应液冷却至室温并加入2-甲氧基乙氧基甲基氯化物(2.85ml,25mmol)。搅拌30分钟后,将混合物倒入水中并将产物加入***中。将有机溶液用盐水洗涤,用无水硫酸钠干燥然后浓缩。经硅胶色谱(洗脱剂;EtOAc/己烷-1/2→3/2)得到5-(2,6-二甲基-4-硝基苯氧基)-2-(2-甲氧基乙氧基甲氧基)苯甲酸2-甲氧基乙氧基甲酯:NMR(CDCl3)2.23(s,6H),3.36(s,3H),3.38(s,3H),3.54-3.60(m,4H),3.80-3.90(m,4H),5.28(s,2H),5.52(s,2H),6.82(dd,1H,J=9,3),7.17-7.23(m,2H),8.02(s,2H)。B.5-(4-氨基-2,6-二甲基苯氧基)-2-(2-甲氧基乙氧基甲氧基)苯甲酸2-甲氧基乙氧基甲酯
将标题A的化合物,5-(2,6-二甲基-4-硝基苯氧基)-2-(2-甲氧基-乙氧基甲氧基)苯甲酸2-甲氧基乙氧基甲酯(3.2g,6.68mmol)和钯/活性碳(10wt%;320mg)在50mL乙酸乙酯中的混合物在氢气氛(H2,1atm)下搅拌3小时。用硅藻土真空过滤除去催化剂,用乙酸乙酯洗涤,将合并的滤液和洗涤液浓缩然后真空干燥得到5-(4-氨基-2,6-二甲基苯氧基)-2-(2-甲氧基乙氧基甲氧基)苯甲酸2-甲氧基-乙氧基甲酯:NMR(CDCl3)2.07(s,6H),3.37(s,3H),3.40(s,3H),3.52-3.62(m,4H),3.83-3.92(m,4H),5.26(s,2H),5.52(s,2H),6.60(s,2H),6.80(dd,1H,J=8.3,3),7.13(d,1H,J=8.3),7.24(d,1H,J=3)。C.5-[4-(乙氧基草酰基氨基)-2,6-二甲基苯氧基]-2-羟基苯甲酸
将标题B的化合物,5-(4-氨基-2,6-二甲基苯氧基)-2-(2-甲氧基-乙氧基甲氧基)苯甲酸2-甲氧基乙氧基甲酯(2.83g,6.3mmol)的20mL THF溶液冷却至0℃然后依次用NMM(2.1ml,18.9mmol)和乙基草酰氯(0.915ml,8.19mmol)处理。15分钟后,将混合物在乙酸乙酯和水之间进行分配,将有机溶液用盐水洗涤,用无水硫酸钠干燥然后浓缩。将残余物溶于30mL乙醇然后加入20mL 6N盐酸。将混合物室温搅拌16小时,然后减压蒸除乙醇。将残余物用水(100ml)稀释,真空过滤收集固体,用水洗涤然后干燥。用乙腈重结晶得到5-[4-(乙氧基草酰基氨基)-2,6-二甲基苯氧基]-2-羟基苯甲酸:NMR(DMSO-d6)1.31(t,3H,J=7),2.06(s,6H),4.30(q,2H,J=7),6.88-6.97(m,2H),7.08(dd,1H,J=9,3),7.54(s,2H),10.7(s,1H)。D.N-{4-[4-羟基-3-(哌啶-1-羰基)苯氧基]-3,5-二甲基苯基}草氨酸
将标题C的化合物,5-[4-(乙氧基草酰基氨基)-2,6-二甲基苯氧基]-2-羟基苯甲酸(37mg,0.1mmol)的1mL DMF溶液用NMM(55μL,0.5mmol)和1,1’-羰基二咪唑(32mg,0.2mmol)在室温下处理。将反应混合物于60℃加热1小时,然后冷却至室温并加入哌啶(24μL),0.24mmol)。16小时后,将反应液用1.5N LiOH水溶液(333μL,0.5mmol)处理。将混合物搅拌30分钟,然后用三氟乙酸(TFA;100μL)终止反应。将产物通过HPLC纯化(流动相;乙腈-水,含0.1%三氟乙酸)得到N-{4-[4-羟基-3-(哌啶-1-羰基)苯氧基]-3,5二甲基苯基}草氨酸:NMR(DMSO-d6)1.34-1.63(m,6H),2.06(s,6H),3.30(br s,4H),6.36(d,1H,J=2.3),6.67(dd,1H,J=8.3,2.3),6.80(d,1H,J=8.3),7.53(s,2H),9.38(br s,1H),10.6(s,1H);ESI-MS 413[M+1]+。
实施例47
N-{4-[4-羟基-3-(吗啉-4-羰基)苯氧基]-3,5-二甲基苯基}草氨酸
标题化合物按照与实施例46类似的方式制备:ESI-MS 415[M+1]+。
实施例48
N-[4-(3-环己基氨基甲酰基-4-羟基苯氧基)-3,5-二甲基苯基]草氨酸
标题化合物按照与实施例46类似的方式制备:ESI-MS 427[M+1]+。实施例49
标题化合物按照与实施例46类似的方式制备:ESI-MS 403[M+1]+。
实施例50
N-{4-[4-羟基-3-(2-吗啉-4-基-乙基氨基甲酰基)苯氧基]-3,5二甲基苯基}-草氨酸
标题化合物按照与实施例46类似的方式制备:ESI-MS 458[M+1]+。
实施例51
标题化合物按照与实施例46类似的方式制备:ESI-MS 422[M+1]+。
实施例52:制剂实施例:可以按照如下描述制备含有100mg活性物质,例如N-{4-[3-(4-氟苯磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}草氨酸的硬明胶胶囊:组成(1000粒胶囊)活性成分 100.0g乳糖 250.0g微晶纤维素 30.0g十二烷基硫酸钠 2.0g硬脂酸镁 8.0g
将十二烷基硫酸钠通过筛孔尺寸为0.2mm的筛子加入到冻干的活性成分中。将两种成分充分混合。然后通过筛孔尺寸为0.6mm的筛子加入乳糖,随后通过筛孔尺寸为0.9mm的筛子加入微晶纤维素。然后将这些成分继续混合10分钟。最后通过筛孔尺寸为0.8mm的筛子加入硬脂酸镁。继续混合3分钟后,将390mg所得到的制剂填充到0号硬明胶胶囊中。
Claims (10)
其中
W是O、S、S(O)或S(O)2;
X是-SR4、-S(O)R4、-S(O)2R4、或-S(O)2NR5R6;或者X是位于3’-、4’-或5’-位的-C(O)NR5R6;
Y是O或H2;
Z是氢、卤素、羟基、选择性取代的烷氧基、芳烷氧基、酰氧基或烷氧基羰基氧基;
R是氢、卤素、三氟甲基、低级烷基或环烷基;
R1是羟基、选择性取代的烷氧基、芳氧基、杂芳氧基、芳烷氧基、环烷氧基、杂芳烷氧基或-NR5R6;
R2是氢、卤素或烷基;
R3是卤素或烷基;
R4是选择性取代的烷基、芳基、芳烷基、杂芳烷基或杂芳基;
R5、R6和R7彼此独立地是氢、选择性取代的烷基、环烷基、芳基、芳烷基、杂芳基或杂芳烷基;或者R5和R6合在一起是选择性地被O、S、S(O)、S(O)2或NR7间断的亚烷基,该亚烷基与它们所连接的氮原子合在一起形成5至7元环;
n表示0或1至4的整数。
2.权利要求1的化合物,条件是,当X是-C(O)NR5R6时,Z不是氢。
3.权利要求1或2所述的式I化合物或其可药用盐,其中
W是O或S;
X是-S(O)2R4;R4是低级烷基、苯基或被一个或多个选自低级烷基、低级烷氧基、卤素和三氟甲基的取代基取代的苯基;或者X是-S(O)2NR5R6或-C(O)NR5R6;其中R5是氢或低级烷基,R6是氢、低级烷基、被NR5R6取代的低级烷基、3至7元环烷基、苯基、被一个或多个选自低级烷基、低级烷氧基、卤素和三氟甲基的取代基取代的苯基;吡啶基或N-低级烷基-2-吡啶酮;或者
R5和R6合在一起是亚烷基或被O或S(O)2间断的亚烷基,所述亚烷基与它们所连接的氮原子合在一起形成5至7元环;
Y是O或H2;
Z是氢或羟基;
R是氢;
R1是羟基、低级烷氧基或NR5R6;R5是氢或低级烷基,R6是氢、低级烷基、低级烷氧基,或者R5和R6合在一起是亚烷基或被O间断的亚烷基,所述亚烷基与它们所连接的氮原子合在一起形成5至7元环;
R2是氢、卤素或低级烷基;
R3是卤素或低级烷基;
n表示0、1或2。
其中
W是O或S;
X是-SR4、-S(O)R4、-S(O)2R4、-S(O)2NR5R6或-C(O)NR5R6;
Y是O或H2;
Z是氢、卤素、羟基、烷氧基、芳烷氧基、酰氧基或烷氧基羰基氧基;
R1是羟基、低级烷氧基或芳氧基;
R2是氢、卤素或低级烷基;
R3是卤素或低级烷基;
R4是选择性取代的烷基、芳基、芳烷基、杂芳基或杂芳烷基;
R5、R6和R7彼此独立地是氢、选择性取代的烷基、环烷基、芳基、芳烷基、杂芳基或杂芳烷基;或者R5和R6合在一起是选择性地被O、S、S(O)、S(O)2或NR7间断的亚烷基,所述亚烷基与它们所连接的氮原子合在一起形成5至7元环;
n表示0、1或2;
或其可药用盐。
5.权利要求1或2的化合物,该化合物为下式化合物:
其中
X是-S(O)2R4、-S(O)2NR5R6或-C(O)NR5R6;
Z是羟基、低级链烷酰氧基或低级烷氧基;
R1是羟基或低级烷氧基;
R2和R3是低级烷基;
R4是芳基;
R5、R6和R7彼此独立地是氢、选择性取代的烷基、环烷基、芳基、芳烷基、杂芳基、或杂芳烷基;或者R5和R6合在一起是选择性地被O、S、S(O)、S(O)2或NR7间断的亚烷基,所述亚烷基与它们所连接的氮原子合在一起形成5至7元环;所述环可选择性地含有另一个选自氧、氮和硫的杂原子;
或其可药用盐。
7.权利要求6的化合物,其中X是S(O)2R4并且R4是选择性地被低级烷基、卤素、低级烷氧基或三氟甲基取代的苯基;其可药用盐或其可药用的前药酯。
8.权利要求1的化合物,所述化合物选自:
N-{4-[3-(2,2-二甲基丙基氨磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}草氨酸;
N-[4-(4-羟基-3-苯基氨磺酰基苯氧基)-3,5-二甲基苯基]草氨酸;
N-{4-[3-(4-氟苯基氨磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}草氨酸;
N-{4-{3-(2-氟苯基氨磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}草氨酸;
N-{4-[3-(3-氟苯基氨磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}草氨酸;
N-{4-[4-羟基-3-(4-甲氧基苯基氨磺酰基)苯氧基]-3,5-二甲基苯基}草氨酸;
N-{4-[3-(4-氟苄基氨磺酰基)-4-羟基-苯氧基]-3,5-二甲基苯基草氨酸;
N-{4-[4-羟基-3-(甲基苯基氨磺酰基)苯氧基]-3,5-二甲基苯基}草氨酸;
N-[4-(4-羟基-3-丙基氨磺酰基苯氧基)-3,5-二甲基苯基]草氨酸
N-[4-(4-羟基-3-异丙基氨磺酰基苯氧基)-3,5-二甲基苯基]草氨酸;
N-[4-(3-丁基氨磺酰基-4-羟基苯氧基)-3,5-二甲基苯基]草氨酸
N-[4-(4-羟基-3-异丁基氨磺酰基苯氧基)-3,5-二甲基苯基]草氨酸;
N-[4-(3-叔丁基氨磺酰基-4-羟基苯氧基)-3,5-二甲基苯基]草氨酸;
N-[4-(3-环己基氨磺酰基-4-羟基苯氧基)-3,5-二甲基苯基]草氨酸;
N-[4-(3-二甲基氨磺酰基-4-羟基苯氧基)-3,5-二甲基苯基]草氨酸;
N-{4-[4-羟基-3-(吡咯烷-1-磺酰基)苯氧基]-3,5-二甲基苯基}草氨酸;
N-{4-[4-羟基-3-(哌啶-1-磺酰基)苯氧基]-3,5-二甲基苯基}草氨酸;
N-{4-[4-羟基-3-(2-甲氧基乙基氨磺酰基)苯氧基]-3,5-二甲基苯基}草氨酸;
N-{4-[4-羟基-3-(吗啉-4-磺酰基)苯氧基]-3,5-二甲基苯基}草氨酸;
N-{4-[3-(二氧代硫吗啉-4-磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基)草氨酸;
N-{4-[4-羟基-3-(吡啶-3-基氨磺酰基)苯氧基]-3,5-二甲基苯基)草氨酸;
N-{4-[4-羟基-3-(1-甲基-6-氧代-1,6-二氢吡啶-3-基氨磺酰基)苯氧基]-3,5-二甲基苯基}草氨酸;
N-{4-[3-(4-氟苯基氨磺酰基)-4-羟基苯硫基]-3,5-二甲基苯基}草氨酸;
N-{4-[3-(4-氟苯基氨磺酰基)苯氧基]-3,5-二甲基苯基}草氨酸;
N-{4-[3-(4-氟苯基氨磺酰基)-4-羟基苯氧基]-3-甲基苯基}草氨酸;
N-{4-[3-(4-氟苯磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}草氨酸;
N-[4-(3-苯磺酰基-4-羟基苯氧基)-3,5-二甲基苯基]草氨酸;
N-{4-[3-(4-氯苯磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}草氨酸;
N-{4-[4-羟基-3-(甲苯-4-磺酰基)苯氧基]-3,5-二甲基苯基}草氨酸;
N-{4-[4-羟基-3-(4-甲氧基苯磺酰基)苯氧基]-3,5-二甲基苯基}草氨酸;
N-{4-[4-羟基-3-(4-三氟甲基苯磺酰基)苯氧基]-3,5-二甲基苯基}草氨酸;
N-[4-(4-羟基-3-甲磺酰基苯氧基)-3,5-二甲基苯基]草氨酸;
N-{4-[3-(丁烷-1-磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}草氨酸;
N-{4-[4-羟基-3-(丙烷-2-磺酰基)苯氧基]-3,5-二甲基苯基}草氨酸
N-{4-[3-(4-氟苯磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}丙酰胺酸;
N-{4-[3-(4-氟苯磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}琥珀酰胺酸;
3-{4-[3-(4-氟苯磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基氨基}丙酸;
N-{4-[3-(4-氟苯磺酰基)-4-羟基苯氧基]-3-甲基苯基}草氨酸;
N-{3,5-二溴-4-[3-(4-氟苯磺酰基)-4-羟基苯氧基]苯基}草氨酸;
N-{4-[3-(4-氟苯磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}草酰胺;
N-{4-[3-(4-氟苯磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}-N’-丙基-草酰胺;
N-{4-[3-(4-氟苯磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}-N’-异丙基-草酰胺;
N-丁基-N’-{4-[3-(4-氟苯磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}-草酰胺;
N-{4-[3-(4-氟苯磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}-N’-(2-甲氧基乙基)草酰胺;
N-{4-[3-(4-氟苯磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}-2-吗啉-4-基-2-氧代乙酰胺;
N-{4-[3-(4-氟苯磺酰基)-4-羟基苯氧基]-3,5-二甲基苯基}-2-吗啉-4-基-2-氧代乙酰胺;
N-{4-[4-羟基-3-(哌啶-1-羰基)苯氧基]-3,5-二甲基苯基}草氨酸;
N-{4-[4-羟基-3-(吗啉-4-羰基)苯氧基]-3,5-二甲基苯基}草氨酸;
N-[4-(3-环己基氨基甲酰基-4-羟基苯氧基)-3,5-二甲基苯基]草氨酸;
N-{4-[4-羟基-3-(2-甲氧基乙基氨基甲酰基)苯氧基]-3,5-二甲基苯基}草氨酸;
N-{4-[4-羟基-3-(2-吗啉-4-基-乙基氨基甲酰基)苯氧基]-3,5-二甲基苯基}草氨酸;和
N-{4-[4-羟基-3-(吡啶-3-基氨基甲酰基)苯氧基]-3,5-二甲基苯基}草氨酸;
或其可药用盐。
9.权利要求1至8中任意一项所述的化合物用于制备药物的用途,其中,所述药物可用于预防和治疗与甲状腺激素失调有关的疾病,用于预防和治疗与高血脂症和高脂蛋白血症有关的阻塞性心血管疾病,用于预防和治疗甲状腺机能减退和甲状腺机能亢进、肥胖、骨质疏松症和抑郁症,用于降低总的血浆胆固醇水平和LDL-胆固醇水平以及用于预防和治疗动脉粥样硬化和冠心病。
10.含有治疗有效量的权利要求1至8中任意一项所述化合物和可药用载体的药物组合物。
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US28010599A | 1999-03-29 | 1999-03-29 | |
US09/280,105 | 1999-03-29 |
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PL (1) | PL349355A1 (zh) |
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CZ20013117A3 (cs) | 1999-03-01 | 2002-06-12 | Pfizer Products Inc. | Oxamové kyseliny a jejich deriváty jako ligandy thyreoidního receptoru |
US6790978B2 (en) | 1999-03-29 | 2004-09-14 | Novartis Ag | Thyromimetic organic compounds |
AU2001230929B2 (en) | 2000-02-17 | 2004-09-23 | Bristol-Myers Squibb Co. | Aniline-derived ligands for the thyroid receptor |
IL151376A0 (en) * | 2000-03-31 | 2003-04-10 | Pfizer Prod Inc | Malonamic acids and derivatives thereof as thyroid receptor ligands |
US6664291B2 (en) | 2000-03-31 | 2003-12-16 | Pfizer, Inc. | Malonamic acids and derivatives thereof as thyroid receptor ligands |
AU4884701A (en) * | 2000-05-12 | 2001-11-20 | Kissei Pharmaceutical Co. Ltd. | Malonanilic acid derivatives, medicinal compositions containing the same and usethereof |
US6395784B1 (en) | 2000-06-07 | 2002-05-28 | Bristol-Myers Squibb Company | Benzamide ligands for the thyroid receptor |
DE10038007A1 (de) | 2000-08-04 | 2002-02-14 | Bayer Ag | Neue Amino-und Amido-Diphenylether für Arzneimittel |
DE10046029A1 (de) | 2000-09-18 | 2002-03-28 | Bayer Ag | Indazole |
AU2002223626A1 (en) * | 2000-10-20 | 2002-04-29 | Novartis Ag | Combinations of a thyromimetic compound and a statin |
JP2004517851A (ja) * | 2000-12-27 | 2004-06-17 | バイエル アクチェンゲゼルシャフト | 甲状腺受容体のリガンドとしてのインドール誘導体 |
US6777442B2 (en) | 2001-03-12 | 2004-08-17 | Bayer Aktiengesellschaft | Diphenyl derivatives |
DE10122443A1 (de) * | 2001-05-09 | 2002-11-14 | Bayer Ag | Amido-Diphenyl-Derivate |
US6777443B2 (en) | 2001-05-15 | 2004-08-17 | Novartis Ag | Dipeptide derivatives |
ES2267945T3 (es) * | 2001-05-31 | 2007-03-16 | Pfizer Products Inc. | Uso medico de compuestos tiromimeticos para tratar la perdida del cabello y composiciones. |
DE10131462A1 (de) * | 2001-06-29 | 2003-01-09 | Bayer Ag | Phenol-Derivate |
ATE313325T1 (de) | 2001-09-26 | 2006-01-15 | Pfizer Prod Inc | Indolcaroboxylsäure als thyroidrezeptor-liganden |
US6818766B2 (en) | 2002-10-02 | 2004-11-16 | Synthon Bv | Process for making bicalutamide and intermediates thereof |
US7829552B2 (en) * | 2003-11-19 | 2010-11-09 | Metabasis Therapeutics, Inc. | Phosphorus-containing thyromimetics |
WO2005105712A1 (en) * | 2004-05-05 | 2005-11-10 | Novo Nordisk A/S | Sulfonamide derivatives |
MX2007001215A (es) | 2004-08-06 | 2007-04-17 | Otsuka Pharma Co Ltd | Compuestos aromaticos. |
MX2007014502A (es) | 2005-05-26 | 2008-02-07 | Metabasis Therapeutics Inc | Tiromimeticos para el tratamiento de enfermedades del higado graso. |
PL1957073T3 (pl) | 2005-12-05 | 2014-09-30 | Otsuka Pharma Co Ltd | Substancja lecznicza |
UA95978C2 (ru) | 2006-10-02 | 2011-09-26 | Оцука Фармас'Ютікел Ко., Лтд. | Ингибитор активации stat3/5 |
WO2009133834A1 (ja) * | 2008-04-28 | 2009-11-05 | 塩野義製薬株式会社 | 血管内皮リパーゼ阻害活性を有するケトアミド誘導体 |
TW201512171A (zh) | 2013-04-19 | 2015-04-01 | Pfizer Ltd | 化學化合物 |
CN104193699B (zh) * | 2014-08-14 | 2016-05-25 | 嘉兴特科罗生物科技有限公司 | 一种小分子化合物及其合成方法和应用 |
KR20190104524A (ko) | 2016-11-21 | 2019-09-10 | 바이킹 테라퓨틱스 인코포레이티드 | 당원축적질환의 치료 방법 |
WO2018226604A1 (en) | 2017-06-05 | 2018-12-13 | Viking Therapeutics, Inc. | Compositions for the treatment of fibrosis |
EP3768690A4 (en) | 2018-03-22 | 2021-11-24 | Viking Therapeutics, Inc. | CRYSTALLINE SHAPES AND METHOD FOR MAKING CRYSTALLINE SHAPES OF A COMPOUND |
CN112300133A (zh) * | 2019-07-31 | 2021-02-02 | 深圳微芯生物科技股份有限公司 | 一种杂环化合物及其应用 |
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IL144637A0 (en) | 2002-05-23 |
PE20001587A1 (es) | 2001-01-31 |
JP2002540189A (ja) | 2002-11-26 |
CO5160290A1 (es) | 2002-05-30 |
TR200102225T2 (tr) | 2002-01-21 |
PL349355A1 (en) | 2002-07-15 |
NO20014702D0 (no) | 2001-09-27 |
CZ20013449A3 (cs) | 2001-12-12 |
NO20014702L (no) | 2001-09-27 |
HK1042692A1 (zh) | 2002-08-23 |
AU4290800A (en) | 2000-10-16 |
CA2361016A1 (en) | 2000-10-05 |
MXPA01009843A (es) | 2002-05-06 |
SK13812001A3 (sk) | 2002-04-04 |
RU2001126579A (ru) | 2004-02-27 |
NZ514062A (en) | 2001-09-28 |
HUP0200588A2 (hu) | 2002-07-29 |
EP1165502A1 (en) | 2002-01-02 |
WO2000058279A1 (en) | 2000-10-05 |
BR0009431A (pt) | 2002-01-08 |
KR20010105394A (ko) | 2001-11-28 |
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