WO2016023510A1 - 一种小分子化合物及其合成方法和应用 - Google Patents

一种小分子化合物及其合成方法和应用 Download PDF

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WO2016023510A1
WO2016023510A1 PCT/CN2015/086908 CN2015086908W WO2016023510A1 WO 2016023510 A1 WO2016023510 A1 WO 2016023510A1 CN 2015086908 W CN2015086908 W CN 2015086908W WO 2016023510 A1 WO2016023510 A1 WO 2016023510A1
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dichloro
group
alkyl
substituted
phenyl
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PCT/CN2015/086908
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French (fr)
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王增全
曹晓东
毛晨
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嘉兴特科罗生物科技有限公司
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Priority to EP15831295.9A priority Critical patent/EP3181556B1/en
Priority to DK15831295.9T priority patent/DK3181556T5/da
Priority to JP2017502885A priority patent/JP6444487B2/ja
Publication of WO2016023510A1 publication Critical patent/WO2016023510A1/zh
Priority to US15/431,779 priority patent/US9920022B2/en

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    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
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Definitions

  • the present invention relates to the field of chemical synthesis, and in particular to a small molecule compound and a synthesis method and application thereof.
  • the hair follicle is a tiny organ that repeats three growth stages: the anagen (growth phase), the middle anagen phase (degeneration phase), and the telogen phase (dormant phase).
  • growth phase the middle anagen phase
  • telogen phase the telogen phase
  • HBK hair keratinocytes
  • Minoxidil was first used in the treatment of hypertension, and almost all patients who used minoxidil developed symptoms of hirsutism during treatment.
  • 2% of minoxidil solution It is passed as an over-the-counter drug for alopecia caused by androgen.
  • Finasteride is the only drug approved by the FDA for clinical treatment of alopecia and is a 5 ⁇ -reductase inhibitor. It inhibits the activity of 5 ⁇ -reductase (type II), thereby preventing the conversion of testosterone in the hair to dihydrotestosterone (DHT), reducing the amount of DHT in the hair loss zone (promoting hair growth).
  • the present invention aims to study a new drug that can be applied to hair growth.
  • R 1 is selected from hydrogen, halogen, C 0 -C 6 alkyl or it is optionally substituted with one to three substituents, cyano, isocyanate, amide, isosulfonyl, isosulfonamide, sulfonate Amido, sulfinamido, S-alkyl, S-aryl, S-aryl,
  • substituent is selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl, O-alkyl, O-aryl, O-aryl, N-alkyl, N-aryl, N- Heteroaryl
  • R 2 is selected from the group consisting of hydrogen, halogen, C 0 -C 6 alkyl or substituted alkyl, alkoxy, aryl, substituted aryl, benzyl, substituted benzyl;
  • R 3 is selected from the group consisting of hydrogen, halogen, C 0 -C 6 alkyl or substituted alkyl, alkoxy, aryl, substituted aryl, benzyl, substituted benzyl;
  • R 4 is selected from hydrogen, C 1 -C 6 alkyl or substituted alkyl
  • R 5 is selected from hydrogen, C 0 -C 6 alkyl or substituted alkyl
  • X is selected from an alkyl or substituted alkyl group, an amine group or a substituted amine group;
  • Y is selected from an alkyl group or a substituted alkyl group, an oxygen group, a sulfur group, an amino group, a carbonyl group, a sulfoxide group, and a sulfone group.
  • the alkyl group involved may be a substituted or unsubstituted linear alkyl group, a branched alkyl group, a cycloalkyl group; when it is a cycloalkyl group, an alkyl group
  • the carbon atom on the ring may be optionally substituted by oxygen, sulfur or nitrogen, and any one or several bonds of the cyclic structure may be an aromatic group or a heteroaryl group in parallel.
  • the small molecule compound provided by the present invention may preferably be represented by the following structural formula:
  • R is a mono- or poly-substituted halogen, an alkylsulfonyl group, an alkyl group, a methoxy group, a nitro group, an amino group, a carboxyl group, an ester group, a hydroxyl group, an aryl group, a benzyl group, or a hydrogen.
  • the small molecule compound provided by the present invention may also preferably be represented by the following structural formula:
  • R is a mono- or poly-substituted halogen, alkylsulfonyl, alkyl, methoxy, nitro, amino, carboxy, ester, hydroxy, aryl, benzyl, hydrogen, O-alkyl, O -aryl, O-arylhetero, N-alkyl, N-aryl, N-heteroaryl;
  • X is carbon and nitrogen
  • Z 1 , Z 2 , Z 3 , Z 4 and Z 5 are carbon, oxygen, sulfur, nitrogen, carbonyl (ie, forming an aromatic or non-aromatic lactam lactam).
  • the small molecule compound provided by the present invention may also preferably be represented by the following structural formula:
  • R is a mono- or poly-substituted halogen, alkylsulfonyl, alkyl, methoxy, nitro, amino, carboxy, ester, hydroxy, aryl, benzyl, hydrogen, O-alkyl, O -aryl, O-arylhetero, N-alkyl, N-aryl, N-heteroaryl;
  • X is carbon and nitrogen
  • Z 1 , Z 2 , Z 3 and Z 4 are carbon, oxygen, sulfur, nitrogen, carbonyl (ie, forming an aromatic or non-aromatic lactam lactam).
  • the alkyl group involved may be a substituted or unsubstituted linear alkyl group, a branched alkyl group, a cycloalkyl group; when it is a polysubstituted group, a substituent bonded to Z 1 -Z 5 may also be aroma in parallel with any or any of Z 1 and Z 2 , Z 2 and Z 3 , Z 3 and Z 4 , Z 4 and Z 5 , heteroaryl or cycloalkyl group.
  • the small molecule compound provided by the present invention is:
  • the invention also provides a method for synthesizing the above small molecule compound, characterized in that: 4- Methoxyphenol and 1,2,3-trichloro-5-nitrobenzene are the starting materials.
  • Step 1 The reaction of 4-methoxyphenol with 1,2,3-trichloro-5-nitrobenzene to form 1,3-dichloro-2-(4-methoxyphenoxy)-5-nitrate Base benzene
  • Step 2 reacting 1,3-dichloro-2-(4-methoxyphenoxy)-5-nitrobenzene with a benzoic acid derivative to form (5-(2,6-dichloro-4-nitrogen) Phenoxy)-2-methoxyphenyl)(substituted phenyl)methyl ketone;
  • Step 3 Reduction of the carbonyl group of (5-(2,6-dichloro-4-nitrophenoxy)-2-methoxyphenyl)(substituted phenyl)methyl ketone to methylene and nitro After reduction to amino group, 3,5-dichloro-4-(3-(substituted benzyl)-4-methoxyphenoxy)phenylamine is obtained;
  • Step 4 Reaction of 3,5-dichloro-4-(3-(substituted benzyl)-4-methoxyphenoxy)phenylamine with oxalyl chloride monoethyl ester to give 2-((3,5-dichloro) 4-(3-(substituted benzyl)-4-methoxyphenoxy)phenyl)amino)-oxalyl ethyl ester;
  • Step 5 Reaction of 2-((3,5-dichloro-4-(3-(substituted benzyl)-4-methoxyphenoxy)phenyl)amino)-oxalyl ethyl ester with hydroxylamine hydrochloride Producing N1-(3,5-dichloro-4-(3-(substituted benzyl)-4-methoxyphenoxy)phenyl)-N2-oxalyl hydroxylamine;
  • Step 6 Demethoxymethylation of N1-(3,5-dichloro-4-(3-(substituted benzyl)-4-methoxyphenoxy)phenyl)-N2-oxalylhydroxylamine
  • the target small molecule compound is obtained after the base.
  • benzoic acid derivative can also be replaced with an acid of the following structure:
  • R may be a C0-C6 alkyl group or optionally substituted with one to three substituents
  • the substituent is selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl, O-alkyl, O-aryl, O-aryl, N-alkyl, N-aryl, N-hetero Base, S-alkyl, S-aryl, S-arylhetero.
  • the first step is carried out under a strong base condition, and the molar ratio of the strong base to the 4-methoxyphenol is from 1.5 to 2:1.
  • the strong base may be selected from various organic/inorganic various types of strong base reagents which can be applied to the ether-forming reaction. Preferred from potassium amide, sodium amide, sodium cyanide, potassium cyanide, butyl lithium, lithium diisopropylamide, benzyl lithium, Grignard reagent, alkyl copper lithium, sodium methoxide, sodium ethoxide, potassium ethoxide, uncle Any one of sodium butoxide, sodium hydroxide, potassium hydroxide and the like, the reaction temperature is 120-160 ° C, and the reaction time is 1-6 hours.
  • reaction is preferably carried out in a solvent similar to DMF and its physical/chemical properties, and the molar ratio of the reactant 4-methoxyphenol to 1,2,3-trichloro-5-nitrobenzene is 1:1. -2. 1,2,3-trichloro-5-nitrate
  • the benzene is preferably added after the 4-methoxyphenol is mixed with the alkaline agent and stirred uniformly (generally 30-60 minutes).
  • Step 2 is carried out in an Eaton reagent at a reaction temperature of 80-130 ° C and a reaction time of 2-8 hours.
  • the molar ratio of 1,3-dichloro-2-(4-methoxyphenoxy)-5-nitrobenzene to the benzoic acid derivative is 1:1.25-2;
  • the purpose of the third step is to reduce the carbonyl group to a methylene group.
  • Dichloro-4-nitrophenoxy)-2-methoxyphenyl)(substituted phenyl)methyl ketone trifluoroacetic acid: triethyl silane in a molar ratio of 1:4-6:3-5
  • the solvent is preferably dichloromethane, chloroform, tetrachloromethane or the like, and the reaction is carried out at room temperature, preferably for a period of from 1 to 6 hours.
  • the purpose of the fourth step is to reduce the nitro group to an amine group.
  • the reducing agent may be a preparation for reduction such as stannous chloride, iron, zinc, Pt or Ni.
  • the molar ratio of 5-(2,6-dichloro-4-nitrophenoxy)-2-methoxyphenyl)(substituted phenyl)methyl ketone to the reducing agent is 1:10-20.
  • the reaction was refluxed for 1-6 hours.
  • the molar ratio of 3,5-dichloro-4-(3-(substituted benzyl)-4-methoxyphenoxy)phenylamine to oxalyl chloride monoethyl ester in step 5 is 1:1.5-3; oxalyl chloride single
  • the molar ratio of ethyl ester to triethylamine is 1:1.3-2.3. The reaction is carried out for 0.5-3 hours.
  • Step 6 2-((3,5-Dichloro-4-(3-(substituted)benzyl)-4-methoxyphenoxy)phenyl)amino)-oxalyl ethyl ester and hydroxylamine hydrochloride
  • the ratio is 1:5-10, and the molar ratio of hydroxylamine hydrochloride to base (such as sodium hydroxide) is 1:1.
  • the reaction is carried out for 8-14 hours.
  • the demethylation in the step 7 can be carried out using aluminum trichloride, zinc chloride or boron tribromide.
  • the demethylating agent used per 50 mg of the raw material is 1-5 drops (about 1-20 mg), and the reaction is carried out for 1-5 hours.
  • the solvent used in the above steps may be chloroform, dichloromethane, tetrachloromethane, ethyl acetate, methyl acetate, toluene, benzene, chlorobenzene, DMF, dioxane, ethanol, acetone or the like.
  • any conventional synthetic means can be used to synthesize the substance.
  • the above specific synthetic route is only one of the means.
  • the above-mentioned one kind of small molecule compound provided by the invention is characterized in that it can be applied to diseases such as hair growth, osteoporosis, obesity, etc., especially for hair regrowth, and can be used for targeted treatment of androgen type alopecia. problem.
  • the present invention synthesizes a novel substance which can be used for hair regrowth.
  • mice in each group changed in body weight slowly, indicating that the test compound did not cause weight loss in the animals.
  • FIG. 1 TDM-001-1 photo of mouse hair growth
  • Figure 17 a graph showing changes in body weight during administration
  • Figure 18 is a graph of hair growth score during administration
  • Figure 19 is a graph showing the dandruff score during administration
  • Figure 20 is a graph of erythema score during administration.
  • Step 2 Synthesis of (5-(2,6-dichloro-4-nitrophenoxy)-2-methoxyphenyl)(4-fluorophenyl)methyl ketone
  • 1,3-Dichloro-2-(3-(4-fluorobenzyl)-4-methoxyphenoxy)-5-nitrobenzene (3.5 g, 8.3 mmol) was dissolved in ethyl acetate (50 mL) Among them, stannous chloride (18.7 g, 83 mmol) was added, followed by heating under reflux for three hours. The reaction solution was cooled to room temperature, adjusted to pH-8 with aqueous sodium bicarbonate, and then filtered. The extract was concentrated to give the product (2.6 g, 81%).
  • Step 5 Synthesis of 2-((3,5-dichloro-4-(3-(4-fluorobenzyl)-4-methoxyphenoxy)phenyl)amino)-oxalyl ethyl ester
  • reaction conditions different reaction conditions were chosen.
  • Step 6 Synthesis of N1-(3,5-dichloro-4-(3-(4-fluorobenzyl)-4-methoxyphenoxy)phenyl)-N2-oxalylhydroxylamine
  • Step 7 Synthesis of N1-(3,5-dichloro-4-(3-(4-fluorobenzyl)-4-hydroxyphenoxy)phenyl)-N2-oxalylhydroxylamine
  • reaction conditions were chosen. Such as: boron tribromide (1mg, 5mg, 10mg, 15mg, 20mg, etc.), the solvent is (chlorobenzene, chloroform, tetrachloromethane, etc.), reaction time (1 hour, 2 hours, 5 hours, etc.), the obtained product Yields range from 4-30%.
  • test compound (TMI-105795) was loaded from the pharmaceutical portion and stored in a refrigerator at -20 °C. All test compounds (including solvents) were labeled as TDM-001-1, TDM-001-2, TDM-001-3, TDM-001-4.
  • mice Female C3H mice (35-39 days old) were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. Healthy and clean mice were selected as experimental mice. Prior to grouping, 5 random mice were housed in a cage, and all mice were conditioned at least one week in the animal house, and the animals were labeled on the tail and on the cage.
  • mice single per cage
  • soft stuffing corn cob or sawdust
  • test compound was TMI-105795 (the solvent was polyethylene glycol/ethanol (30/70)), and it was dispensed into a daily dose and stored in a refrigerator at -20 °C. It is administered twice daily with the solvent at 9:30 am and 4:00 pm.
  • mice The abnormal behavior and hair growth of the mice were checked daily and carefully recorded.
  • each mouse was weighed before daily administration.
  • Hair growth levels, peripheral hair growth, dandruff, and erythema were scored on Monday, Wednesday, and Friday from the first day of the experiment to the end.
  • Test object (TMI-105795)
  • mice All mice were subjected to hair growth scores on Monday, Wednesday and Friday from the first day to the last day of the experiment according to the following criteria:
  • Peripheral hair growth ( hair growth in the shaved area, not hair growth in the dosing area):
  • the hair growth rate of the mice in different concentrations was significantly different. Among them, the growth rate of TDM-001-2 was much lower than that of TDM-001-3 and TDM-001-4.
  • mice in TDM-001-2 were transdermally treated, and the skin color of the mice turned black on the 12th day. After 16 days, the hair began to grow and continued to grow.
  • the growth rate and growth level of the mice at the low concentration are significantly lower than those of the high-concentration mice, and when the concentration reaches 0.01%, although the hair growth process exists. There is a certain difference, but when the hair growth reaches a certain level, the difference in hair growth and state is no longer obvious.
  • mice in each group gained very slowly, indicating that the test compound did not cause weight loss in the animals.
  • mice in each group showed no dandruff and erythema.
  • test compound including the lowest dose showed positive hair growth promoting effects.
  • mice b. No dandruff and erythema appeared in all mice.
  • mice showed normal skin color and symptom manifestations.
  • test substance TMI-105795 significantly promoted hair growth in C3H mice.
  • the back hair of C3H mice is known to have a time-corresponding hair growth cycle, ie, 2.5 to 3.5 weeks old and 5 to 14 weeks old, the back hair is at the end of telogen (dormant), 0 to 2.0 weeks old and 4.0 to 4.5 Zhou Ling's back hair is in the early stage of hair growth.
  • test object (TMI-105795) can significantly change the hair growth cycle and promote hair growth.
  • TR ⁇ thyroid receptor
  • TRE thyroid hormone response element
  • test compound dilution The test compound is gradually subjected to semi-log dilution in DMEM medium (containing 0.1% dimethyl sulfoxide) containing 10% activated carbon for fetal bovine serum. The highest concentration of the test compound is 10 ⁇ M. .
  • DMEM medium containing 0.1% dimethyl sulfoxide
  • activated carbon for fetal calf serum was added.
  • TMI-105905 399.5 TMI-105965 95.97 TMI-105966 61.13 TMI-105906 925.4 TMI-105956 6521 TMI-105957 8757 TMI-105958 9701 TMI-105959 617.2 TMI-105960 6.478E7 TMI-105961 9243 TMI-105962 3719 TMI-105963 9577

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Abstract

本发明提供了一种小分子化合物，其特征在于，由结构式（I）所示。本发明产品的各种浓度剂量均能明显的改变毛发生长周期，促进毛发生长。表现出了明显的毛发生长促进效果。此外，每组中的小鼠体重变化的都很缓慢，表明受试化合物不会引起动物体重减少。

Description

一种小分子化合物及其合成方法和应用 技术领域
本发明涉及化学合成领域，特别地，是涉及一种小分子化合物及其合成方法和应用。
背景技术
毛囊是一个不断重复三个生长阶段：毛发生长初期(生长期)、毛发生长中期(退化期)和毛发生长终期(休眠期)的微小器官。在生长期，毛球角化细胞(HBK)剧烈的增值和分化，导致毛干的生长延长。
目前，研究报道了许多生物学因子对毛发周期的调节和同步有作用。这些因子可以被划分为不同的类别，例如，激素，生长因子，酶和转录因子。具体地说，如、利用基因敲除和转基因鼠的研究标明，音猬因子和角质化细胞生长因子促进毛发生长初期的开始，转化生长因子-β，成纤维细胞生长因子-5和神经生长因子通过诱导HBK凋亡，加速毛囊由生长初期向生长中期转化。正常状态下，毛囊周期可以被这些因子很好的调控。
然而，研究表明，针对有压力或者雄性激素的病理学刺激可能会导致毛囊周期紊乱，包括生长初期的缩短，生长终期的延长，从而导致脱发等问题的产生。
迄今为止，市场上也出现了部分针对性的药剂，尤其是FDA通过的两个药：米诺地尔和非那司提。米诺地尔最早用于高血压的治疗，治疗过程中发现几乎所有使用米诺地尔的患者都出现了多毛症的症状。1996年，2％的米诺地尔溶液 被通过作为雄性激素引起的秃发症的非处方药。非那司提是FDA通过的唯一一个用于临床的治疗秃发症的药物，是5α-还原酶抑制剂。它能抑制5α-还原酶(II型)活性，从而阻止毛发中睾丸酮转化为二氢睾丸酮(DHT)，降低了脱发区DHT的量(促进毛发生长)。
然而随着时代的发展，关于毛发上的病症越来越凸现，因此，为了符合现代人的需求，对于相关药品的多元化和多样性的研究，有待进一步的深入和展开。
发明内容
本发明旨在研究一种能够应用于毛发生长的新药品。
一种小分子化合物，其特征由如下结构式所示：
Figure PCTCN2015086908-appb-000001
R1选自氢、卤素、C0-C6的烷基或其任意地被一个到三个取代基取代、氰基、异氰酸酯基、酰胺基、异磺酰胺基、异亚磺酰胺基、磺酰胺基、亚磺酰胺基、S-烷基、S-芳基、S-芳杂基，
其中，所述取代基选自于卤素、芳基、取代芳基、杂芳基、O-烷基、O-芳基、O-芳杂基、N-烷基、N-芳基、N-杂芳基；
R2选自氢、卤素、C0-C6的烷基或取代烷基、烷氧基、芳基、取代芳基、苄基、取代苄基；
R3选自氢、卤素、C0-C6的烷基或取代烷基、烷氧基、芳基、取代芳基、苄基、取代苄基；
R4选自氢、C1-C6的烷基或取代烷基；
R5选自氢、C0-C6的烷基或取代烷基；
X选自烷基或取代烷基、胺基或取代胺基；
Y选自烷基或取代烷基、氧、硫、氨基、羰基、亚砜基、砜基。
在上述R1-R5的可选基团中，所涉及的烷基可以为取代或未取代的直链烷基、支链烷基、环烷基；当其为环烷基时，烷基环上的碳原子可以为氧、硫、氮任意取代，其环状结构的任意一条或几条键可以为芳香基团或杂芳基团并联。
本发明所提供的小分子化合物，可优选地由如下结构式所示：
Figure PCTCN2015086908-appb-000002
其中，R为单取代或多取代的卤素、烷基磺酰基、烷基、甲氧基、硝基、氨基、羧基、酯基、羟基、芳基、苄基、氢。
本发明所提供的小分子化合物，还可优选地由如下结构式所示：
Figure PCTCN2015086908-appb-000003
其中，R为单取代或多取代的卤素、烷基磺酰基、烷基、甲氧基、硝基、氨基、羧基、酯基、羟基、芳基、苄基、氢、O-烷基、O-芳基、O-芳杂基、N-烷基、N-芳基、N-杂芳基；
X为碳、氮；
Z1、Z2、Z3、Z4、Z5为碳、氧、硫、氮、羰基(即、形成芳香型或非芳香型内酰胺内酰胺)。
本发明所提供的小分子化合物，还可优选地由如下结构式所示：
Figure PCTCN2015086908-appb-000004
其中，R为单取代或多取代的卤素、烷基磺酰基、烷基、甲氧基、硝基、氨基、羧基、酯基、羟基、芳基、苄基、氢、O-烷基、O-芳基、O-芳杂基、N-烷基、N-芳基、N-杂芳基；
X为碳、氮；
Z1、Z2、Z3、Z4为碳、氧、硫、氮、羰基(即、形成芳香型或非芳香型内酰胺内酰胺)。
在上述三种优选结构中，R的可选基团中，所涉及的烷基可以为取代或未取 代的直链烷基、支链烷基、环烷基；当其为多取代时，可以为与Z1-Z5成键的取代基，也可以为与Z1和Z2、Z2和Z3、Z3和Z4、Z4和Z5任一或任几根键并联的芳香、杂芳或环烷基团。
本发明提供的小分子化合物更优选为：
N1-(3,5-二氯-4-(3-(4-氟苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺，其结构式为：
Figure PCTCN2015086908-appb-000005
N1-(3,5-二氯-4-(3-(4-甲磺酰基苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺，其结构式为：
Figure PCTCN2015086908-appb-000006
N1-(3,5-二氯-4-(3-(4-甲基苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺，其结构式为：
Figure PCTCN2015086908-appb-000007
N1-(3,5-二氯-4-(3-(3，4-二氯苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺，其结构式为：
Figure PCTCN2015086908-appb-000008
N1-(3,5-二氯-4-(3-(3-氟苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺，其结构式为：
Figure PCTCN2015086908-appb-000009
N1-(3,5-二氯-4-(3-(2-氟苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺，其结构式为：
Figure PCTCN2015086908-appb-000010
N1-(3,5-二氯-4-(4-羟基-3-(甲基吗啉)苯氧基)苯基)-N2-草酰羟胺，其结构式为：
Figure PCTCN2015086908-appb-000011
N1-(3,5-二氯-4-(4-羟基-3-(4-羟基哌啶-1-基)苯氧基)苯基)-N2-草酰羟胺，其结构式为：
Figure PCTCN2015086908-appb-000012
N1-(3,5-二氯-4-(4-羟基-3-(4-甲基哌嗪-1-甲基)苯氧基)苯基)-N2-草酰羟胺，其结构式为：
Figure PCTCN2015086908-appb-000013
N1-(3,5-二氯-4-(4-羟基-3-(吡咯烷-1-甲基)苯氧基)苯基)-N2-草酰羟胺，其结构式为：
Figure PCTCN2015086908-appb-000014
N1-(4-(3-((4-苄基哌啶-1-甲基)-4-羟基苯氧基)-3，5-二氯苯基)N2-草酰羟胺，其结构式为：
Figure PCTCN2015086908-appb-000015
N1-(3,5-二氯-4-(4-羟基-3-((4-羟基-4-苯基哌啶-1-甲基)苯氧基)苯基)N2-草酰羟胺，其结构式为：
Figure PCTCN2015086908-appb-000016
N1-(3,5-二氯-4-(4-羟基-3-(异吲哚啉-2-甲基)苯氧基)苯基)-N2-草酰羟胺，其结构式为：
Figure PCTCN2015086908-appb-000017
N1-(3,5-二氯-4-(3-(3，4-二氢异喹啉-2(1H)-甲基)-4-羟基苯氧基)苯基)-N2-草酰羟胺，其结构式为：
Figure PCTCN2015086908-appb-000018
N1-(3,5-二氯-4-(4-羟基-3-(3-哌嗪酮-1-甲基)苯氧基)苯基)-N2-草酰羟胺，其结构式为：
Figure PCTCN2015086908-appb-000019
本发明还提供了上述一种小分子化合物的合成方法，其特征在于：采用4- 甲氧基苯酚和1，2，3-三氯-5-硝基苯为初始原料。
具体的合成步骤如下所示：
步骤一、通过4-甲氧基苯酚与1，2，3-三氯-5-硝基苯反应生成1,3-二氯-2-(4-甲氧基苯氧基)-5-硝基苯；
步骤二、将1,3-二氯-2-(4-甲氧基苯氧基)-5-硝基苯与苯甲酸衍生物反应生成(5-(2,6-二氯-4-硝基苯氧基)-2-甲氧基苯基)(取代苯基)甲基酮；
步骤三、将(5-(2,6-二氯-4-硝基苯氧基)-2-甲氧基苯基)(取代苯基)甲基酮的羰基还原为亚甲基、硝基还原为氨基后得到3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯胺；
步骤四、将3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯胺与草酰氯单乙酯反应生成2-((3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯基)胺基)-草酰乙酯；
步骤五、将2-((3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯基)胺基)-草酰乙酯与盐酸羟胺反应生成N1-(3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯基)-N2-草酰羟胺；
步骤六、将N1-(3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯基)-N2-草酰羟胺上的甲氧基脱甲基后获得目标小分子化合物。
上述工艺步骤的反应方程式如下所示：
Figure PCTCN2015086908-appb-000020
为获得结构相似的其他化合物，苯甲酸衍生物还可以被替换为如下结构的酸：
Figure PCTCN2015086908-appb-000021
其中，R可以为C0-C6的烷基或其任意地被一个到三个取代基取代；
所述取代基选自于卤素、芳基、取代芳基、杂芳基、O-烷基、O-芳基、O-芳杂基、N-烷基、N-芳基、N-杂芳基、S-烷基、S-芳基、S-芳杂基。
其中，步骤一在强碱条件下进行，强碱与4-甲氧基苯酚的摩尔比为1.5-2：1。该强碱可选自有机/无机的各类可应用于该成醚反应的各类强碱试剂。优选自氨基钾、氨基钠、氰化钠、氰化钾、丁基锂、二异丙基氨锂、苄基锂、格氏试剂，烷基铜锂、甲醇钠、乙醇钠、乙醇钾、叔丁醇钠、氢氧化钠、氢氧化钾等中的任一一种，反应温度为120-160℃，反应时间为1-6小时。
此外，该反应优选在DMF及其物理/化学性质相类似的溶剂中进行，反应物4-甲氧基苯酚与1，2，3-三氯-5-硝基苯的摩尔比为1:1-2。1，2，3-三氯-5-硝 基苯优选在4-甲氧基苯酚与碱剂混合搅拌均匀(一般为30-60分钟)后再加入。
步骤二在伊顿试剂中进行，反应温度为80-130℃，反应时间为2-8小时。1,3-二氯-2-(4-甲氧基苯氧基)-5-硝基苯与苯甲酸衍生物的摩尔比为1:1.25-2；。
步骤三的目的在于将羰基还原为亚甲基，在本发明中，优选采用三氟乙酸和三乙基硅烷将羰基还原为亚甲基，当使用上述还原剂时，5-(2,6-二氯-4-硝基苯氧基)-2-甲氧基苯基)(取代苯基)甲基酮：三氟乙酸：三乙基硅烷的摩尔比为1:4-6:3-5，溶剂优选使用二氯甲烷、三氯甲烷、四氯甲烷等，该反应在室温下进行，优选反应时间为1-6小时。
步骤四的目的在于将硝基还原为胺基，在本发明中，还原剂可使用氯化亚锡、铁、锌、Pt、Ni等还原用的制剂。5-(2,6-二氯-4-硝基苯氧基)-2-甲氧基苯基)(取代苯基)甲基酮与还原剂的摩尔比为1：10-20。回流反应1-6小时。
步骤五中3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯胺与草酰氯单乙酯的摩尔比为1:1.5-3；草酰氯单乙酯和三乙胺的摩尔比为1:1.3-2.3。反应0.5-3小时。
步骤六中2-((3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯基)胺基)-草酰乙酯与盐酸羟胺的摩尔比为1:5-10，盐酸羟胺与碱(如：氢氧化钠)的摩尔比为1:1。反应8-14小时。
步骤七中的脱甲基可采用三氯化铝、氯化锌、三溴化硼进行。每50mg原料使用的脱甲基剂为1-5滴(约1-20mg)，反应1-5小时。
上述各步骤中，采用的溶剂可以为氯仿、二氯甲烷、四氯甲烷、乙酸乙酯、乙酸甲酯、甲苯、苯、氯苯、DMF、二氧六环、乙醇、丙酮等。
此处值得指出的是，在本发明中，根据本发明的化合物及其衍生物的分子结构，任何常规合成手段都可以用来合成该物质。上述具体合成路线仅为手段之一。
本发明提供的上述一种小分子化合物，其特征在于：可应用于毛发生长、骨质疏松症、肥胖等病症，特别是针对毛发的再生长，可用于针对性的治疗雄性激素型秃发的问题。
本发明的作用和效果
本发明合成了一种新型的物质，可以用于毛发的再生长。
经皮给药小鼠毛发生长试验发现，本发明产品的各种浓度剂量均能明显的改变毛发生长周期，促进毛发生长。表现出了明显的毛发生长促进效果。此外，每组中的小鼠体重变化的都很缓慢，表明受试化合物不会引起动物体重减少。
从上述结果可以知道，该物质无毒副作用，且增毛效果明显。
附图说明
附图1(a)、TDM-001-1中小鼠毛发生长照片；
附图1(b)、TDM-001-2中小鼠毛发生长照片；
附图1(c)、TDM-001-3中小鼠毛发生长照片；
附图1(d)、TDM-001-4中小鼠毛发生长照片；
附图2、TMI-105795的试验结果；
附图3、TMI-105902的试验结果；
附图4、TMI-105903的试验结果；
附图5、TMI-105905的试验结果；
附图6、TMI-105965的试验结果；
附图7、TMI-105966的试验结果；
附图8、TMI-105906的试验结果；
附图9、TMI-105956的试验结果；
附图10、TMI-105957的试验结果；
附图11、TMI-105958的试验结果；
附图12、TMI-105959的试验结果；
附图13、TMI-105960的试验结果；
附图14、TMI-105961的试验结果；
附图15、TMI-105962的试验结果；
附图16、TMI-105963的试验结果；
附图17、给药过程中体重的变化曲线图；
附图18、给药过程中毛发生长评分曲线图；
附图19、给药过程中皮屑评分曲线图；
附图20、给药过程中红斑评分曲线图。
具体实施例
实施例一、产品编号TMI-105795
命名：
N1-(3,5-二氯-4-(3-(4-氟苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺
结构式：
Figure PCTCN2015086908-appb-000022
合成路线：
Figure PCTCN2015086908-appb-000023
具体合成方法：
步骤1:1,3-二氯-2-(4-甲氧基苯氧基)-5-硝基苯的合成
Figure PCTCN2015086908-appb-000024
把4-甲氧基苯酚(5.5克,44mmol)溶于DMF(100mL)加入NaH(2.64克,66mmol)，搅拌半个小时后加入1，2，3-三氯-5-硝基苯(10克,44mmol)。反应液加热到120℃三个小时。反应结束和冷却到室温，然后浓缩。剩余物用水淬灭后用乙酸乙酯萃取。有机层干燥浓缩后得到粗产品，然后柱层析(0-10％乙酸乙酯和石油醚)得到产物(5.0克,36％)。
在本步骤中，尝试选用了不同的反应条件。如：原料比(4-甲氧基苯酚：NaH：1，2，3-三氯-5-硝基苯＝1：2：1或1：1.8：1.5等不同比例)、溶剂(氯苯，二氧六环等)、碱剂(NaH、NaOH、叔丁醇纳等)、反应的温度(130℃，160℃)，反应时间(1小时、2小时、4小时、5小时、6小时等)，得到的产品得率从31％-68％不等。
步骤2:(5-(2,6-二氯-4-硝基苯氧基)-2-甲氧基苯基)(4-氟苯基)甲基酮的合成
Figure PCTCN2015086908-appb-000025
把1,3-二氯-2-(4-甲氧基苯氧基)-5-硝基苯(5.0克,16mmol)，4-氟苯甲酸(2.8克,20mmol)分散在伊顿试剂中(30mL)，然后把这个混合物加热到80℃四个小时。反应液冷却到室温，用碳酸氢钠的水溶液淬灭。水相用乙酸乙酯萃取，无水Na2SO4干燥后浓缩。剩余物柱层析(10％乙酸乙酯和石油醚)后 得到产物(4.5克,64％)。
在本步骤中，尝试选用了不同的反应条件。如：原料比(1,3-二氯-2-(4-甲氧基苯氧基)-5-硝基苯：4-氟苯甲酸＝1：1、1：1.5、1：2等)，反应温度(100℃、110℃、130℃等)，反应时间(2小时，5小时，8小时等)，得到的产品得率从56％-78％不等。
步骤3:1,3-二氯-2-(3-(4-氟苄基)-4-甲氧基苯氧基)-5-硝基苯的合成
Figure PCTCN2015086908-appb-000026
把(5-(2,6-二氯-4-硝基苯氧基)-2-甲氧基苯基)(4-氟苯基)甲基酮(4.4克,10mmol)溶于二氯甲烷(50mL)加入三氟乙酸(6.0克,40mmol)和三乙基硅烷(3.5克,30mmol).反应液在室温搅拌三个小时，然后用碳酸氢钠的水溶液淬灭。水相用乙酸乙酯萃取，无水Na2SO4干燥后浓缩。剩余物柱层析后(10％乙酸乙酯和石油醚)得到产物(3.5克,83％)。
在本步骤中，尝试选用了不同的反应条件。如：原料比((5-(2,6-二氯-4-硝基苯氧基)-2-甲氧基苯基)(4-氟苯基)甲基酮：三氟乙酸：三乙基硅烷＝1：4：3、1：5：4、1：6：5等)，溶剂为(氯仿、氯苯、甲苯等)，反应时间(1小时，2小时，6小时等)，得到的产品得率从80％-96％不等。
步骤4:3,5-二氯-4-(3-(4-氟苄基)-4-甲氧基苯氧基)苯胺的合成
Figure PCTCN2015086908-appb-000027
把1,3-二氯-2-(3-(4-氟苄基)-4-甲氧基苯氧基)-5-硝基苯(3.5克，8.3mmol)溶于乙酸乙酯(50mL)中，加入氯化亚锡(18.7克,83mmol)，然后加热回流三个小时。反应液冷却到室温，用碳酸氢钠的水溶液调节到pH-8，然后过滤萃取。萃取液浓缩后得到产品(2.6克，81％)。
在本步骤中，尝试选用了不同的反应条件。如：原料比(1,3-二氯-2-(3-(4-氟苄基)-4-甲氧基苯氧基)-5-硝基苯：氯化亚锡＝1：10、1：15、1：20等)，溶剂为(乙酸甲酯、丙酮、苯等)，还原剂(Zn/HCl、Pt/H2、Ni/H2等)，反应时间(1小时，2小时，6小时等)，得到的产品得率从80％-99％不等。
步骤5:2-((3,5-二氯-4-(3-(4-氟苄基)-4-甲氧基苯氧基)苯基)胺基)-草酰乙酯的合成
Figure PCTCN2015086908-appb-000028
把3,5-二氯-4-(3-(4-氟苄基)-4-甲氧基苯氧基)苯胺(200毫克,0.51mmol)溶于二氯甲烷，加入草酰氯单乙酯(120毫克，0.76mmol)和三乙胺(100毫克，1.02mmol)。反应液搅拌一个小时后，用碳酸氢钠的水溶液淬灭。水相用二氯甲烷萃取，有机层用饱和食盐水洗，然后用Na2SO4干燥浓缩后得到产品 (250毫克，100％)。
在本步骤中，尝试选用了不同的反应条件。如：原料比(3,5-二氯-4-(3-(4-氟苄基)-4-甲氧基苯氧基)苯胺：草酰氯单乙酯的摩尔比＝1：1.5、1：2、1：2.3、1：3等，草酰氯单乙酯：三乙胺的摩尔比＝1：1.5、1：2、1：2.3)，溶剂为(氯仿、乙酸乙酯、氯苯等)，反应时间(0.5小时，2小时，3小时等)，得到的产品得率从90-100％不等。
步骤6:N1-(3,5-二氯-4-(3-(4-氟苄基)-4-甲氧基苯氧基)苯基)-N2-草酰羟胺的合成
Figure PCTCN2015086908-appb-000029
把2-((3,5-二氯-4-(3-(4-氟苄基)-4-甲氧基苯氧基)苯基)胺基)-草酰乙酯(50毫克，0.10mmol)，盐酸羟胺(35毫克，0.5mmol)和氢氧化钠(20毫克，0.5mmol)溶于乙醇(10mL)中，反应液在室温搅拌过夜。反应液浓缩后用乙酸乙酯萃取，干燥浓缩后得到产品(50毫克，100％)。
在本步骤中，尝试选用了不同的反应条件。如：原料比(2-((3,5-二氯-4-(3-(4-氟苄基)-4-甲氧基苯氧基)苯基)胺基)-草酰乙酯：盐酸羟胺：氢氧化钠的摩尔比＝1：4：4、1：6：6、1：8：8、1：10：10等)，溶剂为(乙酸乙酯、甲醇等)，反应时间(8小时，10小时，12小时，14小时，16小时，18小时等)，得到的产品得率从90-100％不等。
步骤7:N1-(3,5-二氯-4-(3-(4-氟苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺的合成
Figure PCTCN2015086908-appb-000030
把N1-(3,5-二氯-4-(3-(4-氟苄基)-4-甲氧基苯氧基)苯基)-N2-草酰羟胺(50毫克，0.1mmol)溶于二氯甲烷，加入两滴三溴化硼。反应液搅拌三个小时，用甲醇淬灭后浓缩。剩余物分散在乙酸乙酯和水中，乙酸乙酯层浓缩后加入正己烷析出产品(6毫克，12％)。
在本步骤中，尝试选用了不同的反应条件。如：三溴化硼(1mg、5mg、10mg、15mg、20mg等)，溶剂为(氯苯、氯仿、四氯甲烷等)，反应时间(1小时，2小时，5小时等)，得到的产品得率从4-30％不等。
产物谱图数据：
核磁氢谱(氘代甲醇)δ7.92(s,2H),7.19(dd,J＝8.7,5.5Hz,2H),6.96(t,J＝8.9Hz,2H),6.71(d,J＝9.1Hz,1H),6.44-6.51(m,2H),3.87(s,2H)
质谱:m/z 465.3[M+H]+
下述实施例二至六所采用的合成方法与实施例一相似或相近，故，此处不再做冗余的描述。
实施例二、产品编号TMI-105902
命名：
N1-(3,5-二氯-4-(3-(4-甲磺酰基苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺
结构式：
Figure PCTCN2015086908-appb-000031
产物谱图数据：
核磁氢谱(氘代甲醇)δ7.92(s,2H),7.83(d,J＝8.6Hz,2H),7.47(d,J＝8.3Hz,2H),6.73(d,J＝9.4Hz,1H),6.49-6.57(m,2H),4.02(s,2H),3.10(s,3H)
质谱:m/z 523.6[M-H]-
实施例三、产品编号TMI-105903
命名：
N1-(3,5-二氯-4-(3-(4-甲基苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺
结构式：
Figure PCTCN2015086908-appb-000032
产物谱图数据：
核磁氢谱(氘代甲醇)δ7.90(s,2H),7.05(s,4H),6.70(d,J＝8.6Hz, 1H),6.43-6.49(m,1H),6.39(d,J＝3.0Hz,1H),3.84(s,2H),2.29(s,3H)
质谱:m/z 459.6[M-H]-
实施例四、产品编号TMI-105905
命名：
N1-(3,5-二氯-4-(3-(3，4-二氯苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺
结构式：
Figure PCTCN2015086908-appb-000033
产物谱图数据：
核磁氢谱(氘代甲醇)δ7.93(s,2H),7.38(d,J＝8.1Hz,1H),7.32(d,J＝1.9Hz,1H),7.12(dd,J＝8.2,2.0Hz,1H),6.73(d,J＝8.6Hz,1H),6.52-6.58(m,1H),6.50(d,J＝3.0Hz,1H),3.87(s,2H)
质谱:m/z 513.5[M-H]-
实施例五、产品编号TMI-105965
命名：
N1-(3,5-二氯-4-(3-(3-氟苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺
结构式：
Figure PCTCN2015086908-appb-000034
产物谱图数据：
核磁氢谱(氘代甲醇)δ7.91(s,2H),7.11-7.24(m,2H),6.98-7.08(m,2H),6.71(d,J＝8.6Hz,1H),6.48(dd,J＝8.6,3.2Hz,1H),6.42(d,J＝3.0Hz,1H),3.91(s,2H)
质谱:m/z 463.5[M-H]-
实施例六、产品编号TMI-105966
命名：
N1-(3,5-二氯-4-(3-(2-氟苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺
结构式：
Figure PCTCN2015086908-appb-000035
产物谱图数据：
核磁氢谱(氘代甲醇)δ7.91(s,2H),7.12-7.24(m,2H),7.00-7.10(m,2H),6.71(d,J＝8.6Hz,1H),6.48(dd,J＝8.7,3.1Hz,1H),6.42(d,J＝3.0Hz,1H),3.91(s,2H)
质谱:m/z 463.5[M-H]-
实施例七、产品编号TMI-105906
命名：
N1-(3,5-二氯-4-(4-羟基-3-(甲基吗啉)苯氧基)苯基)-N2-草酰羟胺
结构式：
Figure PCTCN2015086908-appb-000036
产物谱图数据：
1H NMR(DMSO-d6)δ:10.99(br.s.,1H),9.83(br.s.,2H),8.95(s,1H),7.96-8.22(m,2H),7.60-7.73(m,1H),6.64-6.72(m,2H),6.51-6.60(m,1H),3.57(br.s.,4H),3.52(s,2H),2.40(br.s.,4H)
实施例八、产品编号TMI-105956
命名：
N1-(3,5-二氯-4-(4-羟基-3-(4-羟基哌啶-1-基)苯氧基)苯基)-N2-草酰羟胺
结构式：
Figure PCTCN2015086908-appb-000037
产物谱图数据：
1H NMR(DMSO-d6)δ:10.10(br.s.,1H),8.10(s,3H),6.58-6.73(m,2H),6.53(d,J＝8.3Hz,1H),4.62(br.s.,1H),3.37(br.s.,2H),2.69(br.s.,2H),2.14(br.s.,2H),1.72(d,J＝9.4Hz,2H),1.38(d,J＝9.1Hz,2H)
实施例九、产品编号TMI-105957
命名：
N1-(3,5-二氯-4-(4-羟基-3-(4-甲基哌嗪-1-甲基)苯氧基)苯基)-N2-草酰羟胺
结构式：
Figure PCTCN2015086908-appb-000038
产物谱图数据：
1H NMR(DMSO-d6)δ:11.01(br.s.,1H),8.06-8.14(m,2H),6.60-6.70(m,2H),6.54(dd,J＝8.7,3.1Hz,1H),3.34(br.s.,2H),2.42(br.s.,4H),2.18-2.38(m,4H),2.11-2.18(m,3H)
实施例十、产品编号TMI-105958
命名：
N1-(3,5-二氯-4-(4-羟基-3-(吡咯烷-1-甲基)苯氧基)苯基)-N2-草酰羟胺
结构式：
Figure PCTCN2015086908-appb-000039
产物谱图数据：
1H NMR(DMSO-d6)δ:10.90(br.s.,1H),10.77(br.s.,1H),8.11(br.s.,2H),6.87(br.s.,1H),6.64(br.s.,2H),6.53(br.s.,2H),3.45(d,J＝5.4Hz,2H),1.72(br.s.,4H),1.06(br.s.,2H)
实施例十一、产品编号TMI-105959
命名：
N1-(4-(3-((4-苄基哌啶-1-甲基)-4-羟基苯氧基)-3，5-二氯苯基)N2-草酰羟胺
结构式：
Figure PCTCN2015086908-appb-000040
产物谱图数据：
1H NMR(METHANOL-d4)δ:8.40(br.s.,1H),7.99(s,2H),7.51(d,J＝7.3Hz,2H), 7.38(t,J＝7.5Hz,2H),7.30(d,J＝7.5Hz,1H),6.87-6.98(m,2H),6.82-6.87(m,1H),4.34(s,2H),3.38-3.52(m,4H),2.28-2.41(m,2H),1.96(d,J＝14.2Hz,3H),1.27-1.39(m,2H)。
实施例十二、产品编号TMI-105960
命名：
N1-(3,5-二氯-4-(4-羟基-3-((4-羟基-4-苯基哌啶-1-甲基)苯氧基)苯基)N2-草酰羟胺
结构式：
Figure PCTCN2015086908-appb-000041
产物谱图数据：
1H NMR(DMSO-d6)δ:10.63(br.s.,1H),8.10(s,2H),7.22-7.32(m,2H),7.10-7.22(m,3H),6.57-6.68(m,2H),6.51(dd,J＝8.6,3.0Hz,1H),3.35(br.s.,2H),2.82(d,J＝10.7Hz,2H),1.96(t,J＝11.1Hz,2H),1.43-1.68(m,2H),1.09-1.26(m,2H)。
实施例十三、产品编号TMI-105961
命名：
N1-(3,5-二氯-4-(4-羟基-3-(异吲哚啉-2-甲基)苯氧基)苯基)-N2-草酰羟胺
结构式：
Figure PCTCN2015086908-appb-000042
产物谱图数据：
1H NMR(DMSO-d6)δ:8.09(s,2H),7.07-7.36(m,4H),6.64-6.82(m,4H),6.56(dd,J＝8.5,3.4Hz,2H),3.79-3.91(m,4H),1.33(d,J＝4.8Hz,2H),
实施例十四、产品编号TMI-105962
命名：
N1-(3,5-二氯-4-(3-(3，4-二氢异喹啉-2(1H)-甲基)-4-羟基苯氧基)苯基)-N2-草酰羟胺
结构式：
Figure PCTCN2015086908-appb-000043
产物谱图数据：
1H NMR(DMSO-d6)δ:10.03(br.s.,1H),8.05-8.16(m,1H),7.62(s,1H),7.08-7.17(m,2H),7.04(d,J＝5.4Hz,1H),6.49-6.76(m,4H),3.83(s,1H),3.71(s,2H),3.63(s,2H),2.79(d,J＝5.6Hz,2H),2.57-2.75(m,2H)
实施例十五、产品编号TMI-105963
命名：
N1-(3,5-二氯-4-(4-羟基-3-(3-哌嗪酮-1-甲基)苯氧基)苯基)-N2-草酰羟胺
结构式：
Figure PCTCN2015086908-appb-000044
产物谱图数据：
1H NMR(DMSO-d6)δ:8.07-8.15(m,2H),7.76(s,1H),6.66-6.76(m,2H),6.58(dd,J＝8.7,3.1Hz,1H),3.53(s,2H),3.17(s,2H),3.11(br.s.,2H),2.96(s,2H),1.06(t,J＝7.0Hz,2H)
本实施例的作用和效果：
A.小鼠试验：本实验选用的检测待测化合物为TMI-105795。
一、材料和方法
本实验根据以下描述的步骤和细节进行操作，据我们所知，在实验研究过程中，没有任何影响数据的质量和完整性的情况发生。
(1)待测物
受试化合物(TMI-105795)由药学部分装后保存于-20℃冰箱中。所有受试化合物(包括溶剂)标记成TDM-001-1,TDM-001-2,TDM-001-3,TDM-001-4。
(2)实验动物
雌性C3H小鼠(达到时35-39日龄)购买于北京维通利华实验动物技术有限公司。将健康干净的小鼠挑选出来作为实验用鼠。分组前，将随机的5只小鼠一笼饲养，所有的小鼠在动物房里至少适应性饲养一周，动物的标记分别标记在尾巴上和笼盒上。
(3)动物饲养
整个实验过程，将所有小鼠(单只每笼饲养)分别饲养在不同组别中，笼盒内垫有柔软垫料(玉米芯或木屑)，以保持饲养环境的统一。自由摄取水和食物，保持饲养间的湿度(50-70％)和温度(21-25℃)稳定，且保持12小时明暗循环周期。
(4)给药
待测化合物为TMI-105795(溶剂为聚乙二醇/乙醇(30/70)),分装成为每日给药量保存在-20℃冰箱里。和溶剂一起经皮每天上午9：30和下午4：00给药两次。
(5)实验设计
Figure PCTCN2015086908-appb-000045
Figure PCTCN2015086908-appb-000046
(6)行为学观察
每天均需检查小鼠的异常行为表现和毛发生长情况，并仔细记录下来。
(7)体重
实验过程中，每只小鼠每天给药前都要称量体重。
(8)评分
从实验开始的第一天到最终结束，每周一、周三和周五对毛发生长级别，外周毛发生长，皮屑，红斑这些现象进行评分。
二、试剂，耗材，设备
(1)待测物(TMI-105795)
(2)Eppendof移液器
(3)100μl枪头，灭菌
(4)小动物剃毛器
三、实验过程
(1)分组
用小动物剃毛器，小心仔细的将小鼠后腿背部的毛剃掉，注意避免损伤小鼠背部皮肤。再次确认小鼠背部皮肤的颜色，所有的小鼠应该是粉红色皮肤，任何皮肤有损伤的小鼠都应当从实验中剔除。随机的将小鼠分成五组，并单只饲养。
(2)给药流程
每天上午给药前，记录每只小鼠的体重。用移液器吸取20μL相应的溶液涂于小鼠背部剃毛区，然后用枪头把药液均匀涂于后腿间的背部，大约为直径1厘米的区域。确保每天给药的区域是同一个区域，并等待药液干燥之后再放入笼盒中。
(3)评分流程
所有小鼠依据以下标准，在实验开始的第一天到最后一天中的每周一、周三和周五进行毛发生长评分：
a.毛发生长等级(给药区域)：
0＝皮肤没有颜色改变，或者毛发生长；
1＝皮肤颜色均匀改变：给药区由粉红色变成灰/黑色，但无毛发生长；
2＝出现短而稀疏的毛发生长；
3＝浓密的毛发生长，同周围未剃毛区域一样。
b.外周毛发生长(剃毛区的毛发生长，而不是给药区的毛发生长)：
0＝皮肤没有颜色改变，或者毛发生长；
1＝皮肤颜色改变成灰/黑色但没有毛发生长；
2＝外周区域稀疏毛发生长；
3＝外周区域浓密毛发生长。
c.皮屑：
0＝无
1＝轻微
2＝严重或脱皮
d.红斑：
0＝无(正常皮肤)
1＝轻微
2＝严重
e.其他异常情况(待测物在给药区的沉积，杂乱的毛发生长，等等)
四、试验结果
(1)、实验过程中小鼠状态
a.如图1(a)-(d)所示,给药3周后，和溶剂的空白对照组相比，待测物(TMI-105795)的所有剂量均表现出明显的毛发生长促进作用。溶剂对照组没有发现明显的毛发生长。
b.如图1(a)-(d)所示,待测化合物的不同剂量也出现了明显的剂量依赖，高剂量的待测化合物对毛发生长的促进作用明显强于低剂量的。如图18所示，根据给药过程中各小鼠毛发生长的评分结果可以看出，空白溶剂对照组始终无变化，TDM-001-2(即、0.005％(w/v))浓度组相较于TDM-001-3(即、0.01％(w/v))浓度组和TDM-001-4(即、(0.05％(w/v))浓度组有明显的差异。
针对不同浓度的给药小鼠实验组来看，其毛发生长的速度差异明显，其中，TDM-001-2增长的速度远低于TDM-001-3和TDM-001-4的速度。
具体表现为：TDM-001-2的小鼠经皮用药后，第12天小鼠皮肤颜色变黑，16天后可见毛发开始生长，并持续生长。
TDM-001-3的小鼠经皮用药后，第2天小鼠皮肤颜色变黑，6天后可见毛发开始生长，并持续生长。
TDM-001-4的小鼠经皮用药后，第2天小鼠皮肤颜色变黑，8天后可见毛发开始生长，并持续生长。
由此可以看出，低浓度的给药小鼠的生长速度和生长水平明显低于高浓度的给药小鼠的生长速度和水平，而当浓度达到0.01％时，虽然其毛发生长的过程存在一定差异，但当其发毛的生长达到一定水平时，毛发生长的情况和状态差异不再明显。
c.如图17所示，每组中的小鼠体重增加的都很缓慢，表明受试化合物不会引起动物体重减少。
d.如图19和20所示，每组中的小鼠都未出现皮屑和红斑现象。
(2)、评价结果汇总
a.包括最低剂量的受试化合物都表现出阳性的促进毛发生长的效果。
b.所有小鼠都未出现皮屑和红斑现象。
除了以上出现的情况，所有小鼠均表现出正常的皮肤颜色和症状表现。
五、本实施例的结论
待测物TMI-105795明显地促进了C3H小鼠的毛发生长。
C3H小鼠背部毛发已知具有时间对应的毛发生长周期，即、2.5到3.5周龄和5到14周龄其背部毛发处于毛发生长终期(休眠期)，0到2.0周龄和4.0到4.5周龄其背部毛发处于毛发生长初期。
本实验中，检测了待测物(TMI-105795)对C3H小鼠毛发生长的影响。经皮给药三周后，和溶剂对照组相比，待测物(TMI-105795)的不同剂量都表现出毛发生长促进作用。同时，待测物的三个不同剂量也表现出了明显的剂量依赖。
故而，本实验结果显示待测物(TMI-105795)能明显的改变毛发生长周期，促进毛发生长。
此处值得指出，其他几种实施例中的化合物也能产生近似的效果，此处不再做冗余的描述。
B：甲状腺受体TRβ激动剂实验
一、具体试验方法：
1、细胞铺板：
1)细胞铺板之前2小时，96孔板加入40微升多聚-D-赖氨酸，室温包被。
2)移除多聚-D-赖氨酸。96孔板每孔加入4*104个HEK-293细胞，使用含10％胎牛血清的DMEM培养基在37摄氏度细胞培养箱培养过夜。
2、共转染：
1)转染之前2小时，移除细胞培养基。每孔加入100微升含10％活性炭处理胎牛血清的DMEM培养基，37摄氏度培养箱孵育2小时。
2)制备质粒DNA-XtremeGENE HP脂质体复合物。
①转染试剂X-tremeGENE HP用前室温复温，轻微涡旋混匀。
②在无菌试管中加入Opti-MEM I减血清培养基。
③每个反应体系加入50纳克甲状腺受体(TRβ)质粒DNA和50纳克甲状腺激素应答元件(TRE)质粒DNA。轻微吹打使之完全混匀。
④将0.2微升转染试剂X-tremeGENE HP加入稀释的共转DNA混合物。轻微吹打使之完全混匀。
⑤在室温中孵育20分钟，进而形成质粒DNA-XtremeGENE HP脂质体复合物。
3)96孔板每孔加入10微升复合物。轻微摇动培养板使复合物均匀分散。
4)37度培养箱孵育24小时。
3、激动剂化合物处理：
1)配制化合物稀释液：用含10％活性炭处理胎牛血清的DMEM培养基(含0.1％二甲亚砜)将待测化合物逐步进行半对数稀释，待测化合物的最高浓度为10微摩。
2)移除细胞培养基，加入配置的化合物稀释液(二甲亚砜最终浓度为0.1％)。
3)对于空白对照，加入含10％活性炭处理胎牛血清的DMEM培养基(含0.1％二甲亚砜)。
4)37摄氏度培养箱孵育24小时。
4、荧光素酶报告基因检测：
1)移除培养基，每孔加入40微升磷酸缓冲液。
2)每孔加入40微升Bright-Glo试剂，震荡30秒。避光孵育2分钟。
3)将每孔70微升细胞裂解物加入白色聚苯乙烯96孔板。
4)用EnVision检测荧光信号。
二、试验结果：(如图2-7所示)
编号 EC50(nM)
105796 179.4
TMI-105902 250.3
TMI-105903 136.4
TMI-105905 399.5
TMI-105965 95.97
TMI-105966 61.13
TMI-105906 925.4
TMI-105956 6521
TMI-105957 8757
TMI-105958 9701
TMI-105959 617.2
TMI-105960 6.478E7
TMI-105961 9243
TMI-105962 3719
TMI-105963 9577

Claims (12)

  1. 一种小分子化合物，其特征在于，由如下结构式所示：
    Figure PCTCN2015086908-appb-100001
    R1选自氢、卤素、C0-C6的烷基或其任意地被一个到三个取代基取代、氰基、异氰酸酯基、酰胺基、异磺酰胺基、异亚磺酰胺基、磺酰胺基、亚磺酰胺基、S-烷基、S-芳基、S-芳杂基，
    其中，所述取代基选自于卤素、芳基、取代芳基、杂芳基、O-烷基、O-芳基、O-芳杂基、N-烷基、N-芳基、N-杂芳基；
    R2选自氢、卤素、C0-C6的烷基或取代烷基、烷氧基、芳基、取代芳基、苄基、取代苄基；
    R3选自氢、卤素、C0-C6的烷基或取代烷基、烷氧基、芳基、取代芳基、苄基、取代苄基；
    R4选自氢、C1-C6的烷基或取代烷基；
    R5选自氢、C0-C6的烷基或取代烷基；
    X选自烷基或取代烷基、胺基或取代胺基；
    Y选自烷基或取代烷基、氧、硫、氨基、羰基、亚砜基、砜基。
  2. 如权利要求1所述的一种小分子化合物，其特征在于，由如下结构式所示：
    Figure PCTCN2015086908-appb-100002
    其中，R为单取代或多取代的卤素、烷基磺酰基、烷基、甲氧基、硝基、氨基、羧基、酯基、羟基、芳基、苄基、氢。
  3. 如权利要求1所述的一种小分子化合物，其特征在于，由如下结构式所示：
    Figure PCTCN2015086908-appb-100003
    其中，R为单取代或多取代的卤素、烷基磺酰基、烷基、甲氧基、硝基、氨基、羧基、酯基、羟基、芳基、苄基、氢、O-烷基、O-芳基、O-芳杂基、N-烷基、N-芳基、N-杂芳基；
    X为碳、氮；
    Z1、Z2、Z3、Z4、Z5为碳、氧、硫、氮、羰基。
  4. 如权利要求1所述的一种小分子化合物，其特征在于，由如下结构式所示：
    Figure PCTCN2015086908-appb-100004
    其中，R为单取代或多取代的卤素、烷基磺酰基、烷基、甲氧基、硝基、氨基、羧基、酯基、羟基、芳基、苄基、氢、O-烷基、O-芳基、O-芳杂基、N-烷基、N-芳基、N-杂芳基；
    X为碳、氮；
    Z1、Z2、Z3、Z4为碳、氧、硫、氮、羰基。
  5. 如权利要求1所述的一种小分子化合物，其特征在于：为N1-(3,5-二氯 -4-(3-(4-氟苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺；或
    N1-(3,5-二氯-4-(3-(4-甲磺酰基苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺；或
    N1-(3,5-二氯-4-(3-(4-甲基苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺；或
    N1-(3,5-二氯-4-(3-(3，4-二氯苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺；或
    N1-(3,5-二氯-4-(3-(3-氟苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺；或
    N1-(3,5-二氯-4-(3-(2-氟苄基)-4-羟基苯氧基)苯基)-N2-草酰羟胺；或
    N1-(3,5-二氯-4-4-羟基-3-(甲基吗啉)苯氧基)苯基)-N2-草酰羟胺；或
    N1-(3,5-二氯-4-(4-羟基-3-(4-羟基哌啶-1-基)苯氧基)苯基)-N2-草酰羟胺；或
    N1-(3,5-二氯-4-(4-羟基-3-(4-甲基哌嗪-1-甲基)苯氧基)苯基)-N2-草酰羟胺；或
    N1-(3,5-二氯-4-(4-羟基-3-(吡咯烷-1-甲基)苯氧基)苯基)-N2-草酰羟胺；或
    N1-(4-(3-((4-苄基哌啶-1-甲基)-4-羟基苯氧基)-3，5-二氯苯基)N2-草酰羟胺；或
    N1-(3,5-二氯-4-(4-羟基-3-((4-羟基-4-苯基哌啶-1-甲基)苯氧基)苯基)N2-草酰羟胺；或
    N1-(3,5-二氯-4-(4-羟基-3-(异吲哚啉-2-甲基)苯氧基)苯基)-N2-草酰羟胺；或
    N1-(3,5-二氯-4-(3-(3，4-二氢异喹啉-2(1H)-甲基)-4-羟基苯氧基)苯基)-N2-草酰羟胺；或
    N1-(3,5-二氯-4-(4-羟基-3-(3-哌嗪酮-1-甲基)苯氧基)苯基)-N2-草酰羟胺。
  6. 一种小分子化合物的合成方法，其特征在于：
    步骤一、通过4-甲氧基苯酚与1，2，3-三氯-5-硝基苯反应生成1,3-二氯-2-(4-甲氧基苯氧基)-5-硝基苯；
    步骤二、将1,3-二氯-2-(4-甲氧基苯氧基)-5-硝基苯与苯甲酸衍生物反应生成(5-(2,6-二氯-4-硝基苯氧基)-2-甲氧基苯基)(取代苯基)甲基酮；
    步骤三、将(5-(2,6-二氯-4-硝基苯氧基)-2-甲氧基苯基)(取代苯基)甲基酮的羰基还原为亚甲基得到1,3-二氯-2-(3-(取代苄基)-4-甲氧基苯氧基)-5-硝基苯；
    步骤四、将1,3-二氯-2-(3-(取代苄基)-4-甲氧基苯氧基)-5-硝基苯的硝基还原为氨基后得到3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯胺；
    步骤五、将3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯胺与草酰氯单乙酯反应生成2-((3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯基)胺基)-草酰乙酯；
    步骤六、将2-((3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯基)胺基)-草酰乙酯与盐酸羟胺反应生成N1-(3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯基)-N2-草酰羟胺；
    步骤七、将N1-(3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯基)-N2-草酰羟胺上的甲氧基脱甲基后获得目标小分子化合物。
  7. 如权利要求6所述的一种小分子化合物的合成方法，其特征在于：
    所述苯甲酸衍生物可以被替换为如下结构的化合物：
    Figure PCTCN2015086908-appb-100005
    其中，R可以为C0-C6的烷基或其任意地被一个到三个取代基取代；
    所述取代基选自于卤素、芳基、取代芳基、杂芳基、O-烷基、O-芳基、O-芳杂基、N-烷基、N-芳基、N-杂芳基、S-烷基、S-芳基、S-芳杂基。
  8. 如权利要求6所述的一种小分子化合物的合成方法，其特征在于：
    步骤一中4-甲氧基苯酚与1，2，3-三氯-5-硝基苯的摩尔比为1:1-2；
    步骤二中1,3-二氯-2-(4-甲氧基苯氧基)-5-硝基苯与苯甲酸衍生物的摩尔比为1:1.25-2；
    步骤四中1,3-二氯-2-(3-(取代苄基)-4-甲氧基苯氧基)-5-硝基苯与还原剂的摩尔比为1：10-20；
    步骤五中3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯胺与草酰氯单乙酯的摩尔比为1:1.5-3；
    步骤六中2-((3,5-二氯-4-(3-(取代苄基)-4-甲氧基苯氧基)苯基)胺基)-草酰乙酯与盐酸羟胺的摩尔比为1:5-10。
  9. 如权利要求6所述的一种小分子化合物的合成方法，其特征在于：
    步骤一在强碱条件下进行，
    所述强碱可选自氨基钾、氨基钠、氰化钠、氰化钾、丁基锂、二异丙基氨锂、苄基锂、格氏试剂，烷基铜锂、甲醇钠、乙醇钠、乙醇钾、叔丁醇钠、氢氧化钠、氢氧化钾，反应温度为120-160℃；
    步骤二在伊顿试剂中进行，反应温度为80-130℃。
  10. 如权利要求6所述的一种小分子化合物的合成方法，其特征在于：步骤三中采用三氟乙酸和三乙基硅烷将羰基还原为亚甲基，
    其中，5-(2,6-二氯-4-硝基苯氧基)-2-甲氧基苯基)(取代苯基)甲基酮：三氟乙酸：三乙基硅烷的摩尔比为1:4-6:3-5。
  11. 如权利要求6所述的一种小分子化合物的合成方法，其特征在于：步骤七中的脱甲基可采用三氯化铝、氯化锌、三溴化硼进行。
  12. 如权利要求1所述的一种小分子化合物，其特征在于：可应用于毛发的再生、骨质疏松症、肥胖。
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US20170158651A1 (en) 2017-06-08
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EP3181556A4 (en) 2018-01-10
JP2017522329A (ja) 2017-08-10
EP3181556B1 (en) 2021-09-29
DK3181556T3 (da) 2022-01-03
HUE057149T2 (hu) 2022-04-28
US9920022B2 (en) 2018-03-20
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JP6444487B2 (ja) 2019-01-09
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