CN108727344A - A kind of compound and its synthetic method and application - Google Patents

A kind of compound and its synthetic method and application Download PDF

Info

Publication number
CN108727344A
CN108727344A CN201810457269.0A CN201810457269A CN108727344A CN 108727344 A CN108727344 A CN 108727344A CN 201810457269 A CN201810457269 A CN 201810457269A CN 108727344 A CN108727344 A CN 108727344A
Authority
CN
China
Prior art keywords
compound
reaction
hours
lower structure
molar ratio
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201810457269.0A
Other languages
Chinese (zh)
Inventor
曹小冬
陆丰平
樊毅超
毛晨
王增全
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
JIAXING TEKELUO BIOTECHNOLOGY Co Ltd
Original Assignee
JIAXING TEKELUO BIOTECHNOLOGY Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by JIAXING TEKELUO BIOTECHNOLOGY Co Ltd filed Critical JIAXING TEKELUO BIOTECHNOLOGY Co Ltd
Priority to CN201810457269.0A priority Critical patent/CN108727344A/en
Publication of CN108727344A publication Critical patent/CN108727344A/en
Priority to PCT/CN2019/081450 priority patent/WO2019218797A1/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three 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
    • C07D253/075—Two hetero atoms, in positions 3 and 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/5004—Acyclic saturated phosphines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6568—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms
    • C07F9/65683—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms the ring phosphorus atom being part of a phosphine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6568—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms
    • C07F9/65685—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms the ring phosphorus atom being part of a phosphine oxide or thioxide

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Dermatology (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)

Abstract

The present invention provides a kind of compounds, which is characterized in that for such as lower structure compound represented：A kind of novel micromolecular compound that the present invention synthesizes smears the regrowth that external application can be used for promoting hair, treats alopecia caused by alopecia caused by the alopecia of male sex hormone genotype or alopecia seborrheica or chemotherapy and various factors.

Description

A kind of compound and its synthetic method and application
Technical field
The present invention relates to the field of chemical synthesis, are to be related to a kind of chemical compound and its synthetic method and application particularly.
Background technology
Hair growth is one and constantly repeats three growth phases：Anagen (growth period), catagen The process that moves in circles of (catagen) and telogen (rest period).In growth period, ball top keratinocyte (HBK) is violent Increment and differentiation, cause the growth of hair shaft to extend.However, by environment, spontaneous metabolism, stress, operating pressure, immunity drop The influence of many factors such as low and inherent cause, these factors may result in the degeneration of hair follicle cell, cause hair by It gradually stops growing, hair attenuates or even falls off in turn.For example, the stimulation of the pathology of pressure or male sex hormone may result in hair Capsule cycle disorder, includes the shortening in growth period, and hair follicle cell is degenerated, the extension of growth medium, the problems such as so as to cause alopecia It generates.
Alopecia is broadly divided into male sex hormone genotype baldness (androgenetic alopecia), commonly referred to as seborrhea Property baldness, alopecia areata (Alopecia areata), whole alopecia send out (Alopecia totalis), baldness caused by chemotherapy (Chemo-therapy induced alopecia) and traumatic scar are bald.Baldness is most commonly that male sex hormone baldness (Male Pattern hair loss).This kind of baldness (pattern hair loss) has generation in male and female, with man The most about 50% male had different degrees of baldness, about 25% women to have hair gradually to become to property before 50 years old Sparse phenomenon.Literature research report many biological factors to the adjusting of hair cycle with synchronize have effect.These factors It can be divided into different classifications, for example, hormone, growth factor, enzyme and transcription factor.Specifically, as, utilize clpp gene Except the research with trangenic mice is indicated, the beginning of Sonic hedgehog and keratinocyte growth factor promotion anagen turns Change growth factor-beta, fibroblast growth factor-5 and nerve growth factor by inducing hair follicle keratinocyte apoptosis, adds Fast hair follicle is converted from early growth period to growth medium, hair can be caused to stop growing.Theoretically we can by these because Son is regulated and controled, and promotes hair growth or hair growth inhibition well to reach.In fact, having had in experimental study Countless reported literatures can successfully induce hair regeneration or hair growth inhibition.
The means for treating baldness are very limited, are only limitted to drug therapy and hair transplantation.So far, baldness specific aim is treated Drug only have FDA by two medicines：(Finasteride is non-by Rogaine (Minoxidil minoxidils) and Propecia That department carries).Minoxidil is used for the treatment of hypertension earliest, and nearly all patient using minoxidil is found in therapeutic process All there is the symptom of hirsutism.2% tinctures of Rogaine were ratified the baldness of external curing male in 1988 by FDA. 1996,2% minoxidil solution was by the external application non-prescribed medicine of the alopecia by being used as androgenic.Then, various The minoxidil of dosage form and dosage is approved by the fda in the United States for the alopecia for the treatment of sex successively.Tamsulosin is current In city FDA by only there are one the prescription drug for clinical treatment alopecia, be 5α-reductase inhibitor.It can press down 5α-reductase (II types) activity processed, to prevent stosterone in hair from being converted into dihydrotestosterone (DHT), reduces alopecia area The amount of DHT, to promote hair growth.However, the two hair regeneration drugs are all because hair-growing effects are undesirable and its drug Side effect makes patient's utilization rate relatively low, cannot meet the needs of hair loss patient.
It however as the development in epoch, is increasingly shown especially about the illness on hair, therefore, in order to meet the need of modern It asks, the diversification for related drug and multifarious research, hair regeneration therapeutical and the drug development for controlling baldness is promoted to have It waits for further going deep into and expansion, patient needs more efficient, Small side effects, hair regeneration external used medicine easy to use.
Invention content
The present invention is directed to synthesize and study one kind can be applied to trichogenous compound drug of new generation.
A kind of compound provided by the invention, which is characterized in that for such as lower structure compound represented：
Or
OrOr
Wherein, the Y is any on phenyl ring or times several substituted alkyl, hydroxyl, halogen and hydrogen；
The X be carbon, nitrogen, phosphorus, wherein carbon can also be carbonyl (), phosphorus can also be
The G1 is five-, six- or seven-membered ring；
The five-membered ring can be the ring of following structure：
The S1, S2, S3, S4Carbon, oxygen, nitrogen, sulphur can be selected from；
The X-S1, X-S4, S1-S2, S2-S3, S3-S4Between chemical bond can be singly-bound or double bond.
The hexatomic ring can be the ring of following structure：
The L1, L2, L3, L4, L5Carbon, oxygen, nitrogen, sulphur can be selected from；
The X-L1, X-L5, L1-L2, L2-L3, L3-L4, L4-L5Between chemical bond can be singly-bound or double bond.
The heptatomic ring can be the ring of following structure：
The K1, K2, K3, K4, K5, K6Carbon, oxygen, nitrogen, sulphur can be selected from；
The X-K1, X-K6, K1-K2, K2-K3, K3-K4, K4-K5, K5-K6Between chemical bond can be singly-bound or double bond.
The Z be carbon, nitrogen, phosphorus, wherein carbon can also be represented as carbonyl () form, phosphorus can also be represented asForm；
The R be monosubstituted or polysubstituted hydrogen, halogen, alkyl sulphonyl, alkyl, alkoxy, nitro, amino, carboxyl, Ester group, hydroxyl, aryl, benzyl, O- alkyl, O- aryl, O- heterocyclic bases, N- alkyl, N- aryl, N- heteroaryls.
The alkyl group in groups, alkoxy in abovementioned alkyl, alkyl sulphonyl, the alkyl group in O- alkyl, Alkyl group in N- alkyl, involved alkyl be substituted or unsubstituted straight chained alkyl, branched alkyl, naphthenic base, it is excellent It is 1-16 to select carbon chain lengths, and substituent group thereon can be alkyl, hydroxyl, halogen, aromatic radical etc..
Above-mentioned ester group can be Arrcostab or aromatic ester.
Further, a kind of compound provided by the invention, also has a structure in which feature：I.e., it is such as lower structure institute The compound shown：
Wherein, Z1、Z2、Z3、Z4For carbon, oxygen, sulphur, nitrogen；The X-Z1Key, X-Z4Key, Z1-Z2Key, Z2-Z3Key, Z3-Z4Key is Singly-bound or double bond.I.e., at the ring group of aroma type or non-aromatic odor type, such as：Lactams lactams etc..
Further, a kind of compound provided by the invention, also has a structure in which feature：I.e., when it is polysubstituted When, R is and Z1-Z5The substituent group or R of bonding be and Z1And Z2、Z2And Z3、Z3And Z4、Z4And Z5Any or in parallel several keys Fragrance, heteroaryl or naphthene group.
In addition, the present invention also provides a kind of above-mentioned synthetic methods of compound, it is characterised in that：4, using 4- methoxyl groups Phenol and to halogen nitrobenzene derivative be initial feed, carry out the addition compound product of addition reaction arrived, obtained through hexa-atomic annulation To after pyrrolotriazine derivatives, be substituted on phenol ring and the alkane containing active reactive group be obtained by the reaction for derivative, the compound with Target product is obtained by the reaction in amine or acid.
Further, the present invention also provides a kind of above-mentioned synthetic method of compound, also have the characteristics that such：I.e., Specific process step is as follows：
Step 1: reacting generation such as lower structure compound represented with to halogen nitrobenzene derivative by 4- metoxyphenols I：
Step 2: being reduced to compound I such as lower structure compound represented II：
Step 3: by being obtained by the reaction such as lower structure institute with 2- (cyano-acetamide amino) Ethyl formate after compound II diazotising The compound III shown：
It is obtained such as lower structure compound represented IV Step 4: compound III is carried out Intra-molecular condensation：
Step 5: compound IV is hydrolyzed to obtain such as lower structure compound represented V：
Step 6: obtaining compound V decarboxylations such as lower structure compound represented VI：
Step 7: obtaining aldehyde radical on compound VI such as lower structure compound represented VII:
Step 8: by being obtained such as lower structure compound represented VIII after compound VII demethylations：
Step 9: being obtained such as lower structure compound represented IX after the aldehyde radical of compound VIII is restored：
It is obtained such as lower structure compound represented Step 10: converting after active reactive group the hydroxyl of compound IX to X：
Step 11: by compound X withOrTarget compound is obtained after reaction；
Wherein：Linker and linker ' is the group that can react and be formed chemical bond.
Above-mentioned linker can be halogen, hydroxyl, carboxyl, acid halide group, amino etc. active reactive group；
The linker ' can be halogen, hydroxyl, carboxyl, acid halide group, amino, amido, sulfenyl, methene base, benzyl isoreactivity Reactive group.
Specific reaction equation is as follows：
Most preferably, above-mentioned a kind of compound, feature is shown in following structural formula：
2- (3,5- bis- chloro- 4- (3- (4- methyl-1 H- pyrazoles -2- methyl) -4- hydroxyphenoxies) phenyl) -1,2,4- tri- Piperazine -3,5 (2H, 4H)-diketone, structural formula are：
The specific synthesis step of the compound is as follows：
Step 1: by 4- metoxyphenols and 1,2,3- tri- chloro- 5- nitrobenzenes reactions generate 1,3-, bis- chloro- 2- (4- first Oxygroup phenoxy group) -5- nitrobenzenes；
Step 2: being bis- chloro- 4- (4- methoxies of 3,5- by 1,3- bis- chloro- 2- (4- methoxyphenoxies) -5- nitrobenzene reductions Phenoxyl)-aniline；
Step 3: by after bis- chloro- 4- of 3,5- (4- methoxyphenoxies)-aniline diazotising with 2- (cyano-acetamide amino) first (2- cyano -2- ((3,5- bis- chloro- 4- (4- methoxyphenoxies) phenyl) hydrazone group) acetylamino) formic acid is obtained by the reaction in acetoacetic ester Ethyl ester；
Step 4: by (2- cyano -2- ((3,5- bis- chloro- 4- (4- methoxyphenoxies) phenyl) hydrazone group) acetylamino) first Cyclization obtains 2- (3,5- bis- chloro- 4- (- 4- methoxyphenoxies) phenyl) -6- cyano -1,2 in teos molecule, triazine -3 4-, 5 (2H, 4H)-diketone；
Step 5: by 2- (3,5- bis- chloro- 4- (- 4- methoxyphenoxies) phenyl) -6- cyano -1,2,4- triazines -3,5 (2H, 4H)-diketone hydrolyzes to obtain 2- (3,5- bis- chloro- 4- (- 4- methoxyphenoxies) phenyl) -6- carboxyls -1,2, triazine -3 4-, 5 (2H, 4H)-diketone；
Step 6: by 2- (3,5- bis- chloro- 4- (- 4- methoxyphenoxies) phenyl) -6- carboxyls -1,2,4- triazines -3,5 (2H, 4H)-diketone decarboxylation obtains 2- (3,5- bis- chloro- 4- (- 4- methoxyphenoxies) phenyl) -1,2,4- triazines -3,5 (2H, 4H)-diketone；
Step 7: by 2- (3,5- bis- chloro- 4- (- 4- methoxyphenoxies) phenyl) -1,2,4- triazines -3,5 (2H, 4H) - Aldehyde radical obtains 5- (2,6- bis- chloro- 4- (3,5- dioxo -4,5- dihydros -1,2,4- triazines -2 (3H)-yl) phenoxy group)-on diketone Benzaldehyde,2-methoxy；
Step 8: by 5- (2,6- bis- chloro- 4- (3,5- dioxo -4,5- dihydros -1,2,4- triazines -2 (3H)-yl) benzene oxygen Base) obtain after methoxyl group demethylation on-Benzaldehyde,2-methoxy 5- (2,6- bis- chloro- 4- (3,5- dioxo -4,5- dihydro -1, - 2 (3H)-yl of 2,4- triazine) phenoxy group)-Benzaldehyde,2-hydroxy；
Step 9: by 5- (2,6- bis- chloro- 4- (3,5- dioxo -4,5- dihydros -1,2,4- triazines -2 (3H)-yl) benzene oxygen Base) aldehyde radical of-Benzaldehyde,2-hydroxy restores to obtain 2- (3,5- bis- chloro- 4- (3- (methylol) -4- hydroxyphenoxies) phenyl) -1, 2,4- triazines -3,5 (2H, 4H)-diketone；
Step 10: by 2- (3,5- bis- chloro- 4- (3- (methylol) -4- hydroxyphenoxies) phenyl) -1,2,4- triazines -3,5 2- (3,5- bis- chloro- 4- (3- (chloromethyl) -4- hydroxyphenoxies) phenyl) -1,2,4- is obtained after the alcohol chlorination of (2H, 4H)-diketone Triazine -3,5 (2H, 4H)-diketone；
Step 11: by 2- (3,5- bis- chloro- 4- (3- (chloromethyl) -4- hydroxyphenoxies) phenyl) -1,2,4- triazine -3, 5 (2H, 4H)-diketone obtain target compound after being reacted with amine.
It is worth noting that, in the present invention, the molecular structure of compound according to the present invention and its derivative is appointed herein What, which is conventionally synthesized means, may serve to synthesize the substance.Above-mentioned specific synthetic route is only one of means.
It is as follows about the concrete technology condition and method used in above-mentioned synthesis step：
Wherein, step 1 carries out under basic conditions, and the molar ratio of highly basic and 4- metoxyphenols is 1.5-2：1.This is strong Alkali can be selected from all kinds of of organic/inorganic and can be applied to all kinds of strong base reagents reacted at ether.Preferably be selected from potassamide, Sodamide, Cymag, potassium cyanide, butyl lithium, diisopropyl ammonia lithium, benzyl lithium, Grignard Reagent, alkyl copper lithium, sodium methoxide, sodium ethoxide, ethyl alcohol Any in potassium, sodium tert-butoxide, sodium hydroxide, potassium hydroxide etc., reaction temperature is 120-160 DEG C, reaction time 1-6 Hour.
In addition, the reaction preferably carries out in the similar solvent of DMF and its physical/chemical, reactant 4- methoxies The molar ratio of base phenol and 1,2,3- tri- chloro- 5- nitrobenzenes is 1:1-2.1,2,3- tri- chloro- 5- nitrobenzenes are preferably in 4- methoxyl groups Phenol adds after (generally 30-60 minutes) are mixed evenly with alkaline agent.
The purpose of step 2 is nitro being reduced to amido, in the present invention, reducing agent can be used stannous chloride, iron, The preparation of the reduction such as zinc, Pt, Ni.The molar ratio of bis- chloro- 2- of 1,3- (4- methoxyphenoxies) -5- nitrobenzenes and reducing agent is 1：10-20.Back flow reaction 1-6 hours.
The purpose of step 3 is to be coupled with 2- (cyano-acetamide amino) Ethyl formate after amino diazotising, in the present invention In, diazo reagent preferably is selected from nitrite, nitrous acid ester etc., when using above-mentioned diazo reagent, 3,5- bis- chloro- 4- (4- Methoxyphenoxy)-aniline：Nitrite：The molar ratio of 2- (cyano-acetamide amino) Ethyl formate is 1:1-4:1-4, solvent It is preferable to use dilute hydrochloric acid, tetrahydrofuran, DMF etc., and the reaction is in ice-water bath, and room temperature, flow back lower progress, and preferred reaction time is 0.5-6 hours.
The purpose of step 4 is 1,2,4- triazine -3,5 (2H, 4H) of pass-diketone ring, and in the present invention, solvent preferably makes With acetic acid, formic acid, propionic acid, butyric acid, hydrochloric acid solution, sulfuric acid solution, DMF, toluene etc..Alkali in reaction be preferable over sodium acetate, Potassium acetate, sodium formate, sodium propionate, sodium butyrate.(2- cyano -2- ((3,5- bis- chloro- 4- (4- methoxyphenoxies) phenyl) hydrazone group) Acetylamino) molar ratio of Ethyl formate and alkali is 1：1-2.Back flow reaction 4-18 hours.
Purpose in step 5 is that cyan-hydrolysis, in the present invention, it is preferable to use hydrochloric acid solution, sulfuric acid are molten for solvent Liquid, NaOH solution, KOH solution etc..Back flow reaction 1-18 hours.
Purpose in step 6 is decarboxylation, and in the present invention, it is preferable to use thioacetic acid, mercaptopropionic acid, salt for solvent Acid solution, sulfuric acid solution etc..Back flow reaction 1-5 hours.
Purpose in step 7 is that hexamethylenetetramine, 1,1- dichlormethyl ethers, DMF etc. can be used in aldehyde radical, upper aldehyde radical. 2- (3,5- bis- chloro- 4- (- 4- methoxyphenoxies) phenyl) -1,2,4- triazines -3,5 (2H, 4H)-diketone and hexamethylenetetramine Molar ratio 1：1.5-2.Reaction temperature is 0-120 DEG C, is reacted 2-18 hours.
The purpose of step 8 is that demethylation, demethylation can be used alchlor, zinc chloride, Boron tribromide and carry out.Often The piptonychia base that 50mg raw materials use is 1-5 drops (about 1-20mg), is reacted 1-5 hours.
The purpose of step 9 is that sodium borohydride, lithium borohydride, lithium aluminium hydride etc. can be used in reduction aldehyde radical, go back original reagent. The molar ratio of aldehyde radical and reducing agent is 1：1-2.Reaction 1-5 hours.
The purpose of step 10 is hydroxyhalide, reagent can be used thionyl chloride, chlorination sulfone, phosphorus oxychloride, phosphorus trichloride, Without phosphorus chloride etc..The molar ratio of hydroxyl and halide reagent is 1：1-2.Reaction 1-5 hours.
The purpose of step 11 is the substitution reaction of chloride and amine, which carries out under alkaline conditions, alkali and chlorination The molar ratio of object is 1.2-3：1.Alkali can be selected from all kinds of all kinds of base reagents that can be applied to the reaction of organic/inorganic.It preferably is selected from Potassamide, Sodamide, butyl lithium, diisopropyl ammonia lithium, benzyl lithium, Grignard Reagent, alkyl copper lithium, sodium methoxide, sodium ethoxide, ethyl alcohol It is any in potassium, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate etc..Reaction temperature is 50-120 DEG C. Reaction 1-5 hours.
In above steps, the solvent used can be chloroform, dichloromethane, tetrachloromethane, ethyl acetate, acetic acid first Ester, toluene, benzene, chlorobenzene, DMF, dioxane, ethyl alcohol, acetone etc..
In addition, the present invention also provides a kind of above-mentioned applications of compound, it is characterised in that：As Thyroid Hormone Receptors The agonist of β.
In addition, the present invention also provides a kind of above-mentioned applications of compound, it is characterised in that：Above compound can apply to Baldness caused by various factors or hair loss disorder promote the growth of hair.It can be especially useful for targetedly treating heredity and hero All kinds of alopecias caused by the problem of sex hormone type baldness (Androgenetic Alopecia), or the other causes of disease for the treatment of.
Further, the present invention also provides a kind of compositions that promotion hair increases, it is characterised in that：Including quality hundred Divide the above compound for 0.001%-5% than content.
In addition, the present invention also provides a kind of trichogenous compounds, it is characterised in that：Using above-mentioned chemical combination Object and the hair regeneration compound of other known mechanism are used in combination, and can remarkably promote hair regeneration.
The function and effect of the present invention
The present invention has synthesized a kind of novel chemical substance, which smears the regeneration that external application can be used for promoting hair It is long.
In cell experiment, transfected into HEK-293 with the fluoreporter gene plasmid controlled by TR- β transcription factors Cell adds agonist activation experiment to prove that product of the present invention can dramatically increase Thyroid hormone receptor β (thyroid receptor β, TR β) Gene Transcription in vitro, half-maximal effect concentration (concentration for 50%of maximal effect, EC50) it is 6.738nM.The compound is the agonist of TR β.
Percutaneous administration mouse hair growth test of smearing finds that product of the present invention can be apparent in a certain concentration dosage range Change growth cycle of hair, promote hair growth, and there is apparent dosage correlation effect, higher concentration can largely promote Into hair growth.In addition, in every group mouse weight variation all very slowly, showing will not using test-compound in this dosage The weight of animals is caused to reduce.The mouse skin of medicine-feeding part does not occur the skins such as irritation, damage or erythema in all experiments The adverse reaction of skin part.
From the above it is recognised that the substance has no toxic side effect, and promote hair regeneration with obvious effects.
Description of the drawings
Attached drawing 1, TDM-105842 promote TR β transcriptional activity experimental results；
Mouse hair growth photo in attached drawing 2 (a), control group；
Mouse hair growth photo in attached drawing 2 (b), 0.05%TDM-105842；
Mouse hair growth photo in attached drawing 2 (c-1), 0.01%TDM-105842；
Mouse hair growth photo in attached drawing 2 (c-2), 0.01%TDM-105842；
Mouse hair growth photo in attached drawing 2 (d), 0.005%TDM-105842；
Mouse hair growth photo in attached drawing 2 (e), 0.001%TDM-105842；
The change curve of each processing group mouse weight in attached drawing 3, administration process；
Each processing group mouse hair grows score curve figure in attached drawing 4, administration process；
Each processing group mouse skin Injury score curve graph in attached drawing 5, administration process；
Each processing group mouse scores of erythema curve graph in attached drawing 6, administration process.
Specific embodiment
Embodiment one, product identification TDM-105842
2- (3,5- bis- chloro- 4- (3- (4- methyl-1 H- pyrazoles -2- methyl) -4- hydroxyphenoxies) phenyl) -1,2,4- tri- Piperazine -3,5 (2H, 4H)-diketone
Structural formula：
Synthetic route：
Specific synthetic method：
Step 1:The synthesis of 1,3- bis- chloro- 2- (4- methoxyphenoxies) -5- nitrobenzenes
4- metoxyphenols (5.5 grams, 44mmol) are dissolved in DMF (100mL), NaH (2.64 grams, 66mmol), stirring is added 1,2,3- tri- chloro- 5- nitrobenzenes (10 grams, 44mmol) are added after half an hour.Reaction solution is heated to 120 DEG C of three hours.Reaction Terminate and be cooled to room temperature, then concentrates.Residue is extracted with ethyl acetate after being quenched with water.It is obtained after organic layer drying concentration Crude product, then column chromatography (0-10% ethyl acetate and petroleum ether) obtain product (5.0 grams, 36%).
In this step, it attempts to have selected different reaction conditions.Such as：Raw material ratio (4- metoxyphenols：NaH：1,2,3- Three chloro- nitrobenzene=1 5-：2：1 or 1：1.8：1.5 equal different proportions), solvent (chlorobenzene, dioxane etc.), alkaline agent (NaH, NaOH, the tert-butyl alcohol are received), the temperature (130 DEG C, 160 DEG C) of reaction, the reaction time (1 hour, 2 hours, 4 hours, 5 hours, it is 6 small When etc.), obtained product yield is from 31%-68% etc..
Step 2:3,5- bis- chloro- 4- (4- methoxyphenoxies)-aniline
1,3-, bis- chloro- 2- (4- methoxyphenoxies) -5- nitrobenzenes (5 grams, 15.9mmol) are dissolved in ethyl acetate Stannous chloride dihydrate (35.8 grams, 159mmol) is added in (50mL).Reaction solution is heated to three hours of reflux.Reaction terminates It is cooled to room temperature, the aqueous solution of sodium bicarbonate is added, adjusts pH~8.Mixed liquor filters, and filtrate is extracted with ethyl acetate.It is organic Product (4 grams, 90%) is obtained after the dry concentration of layer.
In this step, it attempts to have selected different reaction conditions.Such as：Raw material ratio (bis- chloro- 2- (4- methoxybenzenes of 1,3- Oxygroup) -5- nitrobenzenes：Stannous chloride=1：10,1：15,1：20 etc.), solvent is (methyl acetate, acetone, benzene etc.), reducing agent (Zn/HCl, Pt/H2, Ni/H2 etc.), in the reaction time (1 hour, 2 hours, 6 hours etc.), obtained product yield is from 80%- 99% differs.
Step 3:(2- cyano -2- ((3,5- bis- chloro- 4- (4- methoxyphenoxies) phenyl) hydrazone group) acetylamino) formic acid Ethyl ester
3,5-, bis- chloro- 4- (4- methoxyphenoxies)-aniline (4.0 grams, 14mmol) is added to 50mL water and 4mL concentrated hydrochloric acids In.Heating makes aniline dissolve, and then cools to 0 DEG C.NaNO2 (1.04 grams, 15mmol) is added dropwise；Then (2- (cyano-acetamides are added Amino)) Ethyl formate (2.4 grams, 15.4mmol) is dissolved in 20mL water and 4mL pyridines).It reacts and half an hour is stirred at room temperature, first All over mixture is obtained by filtration, sterling (5.5 grams, 87%) is obtained by filtration second time.
In this step, it attempts to have selected different reaction conditions.Such as：Raw material ratio (bis- chloro- 4- (4- methoxybenzenes of 3,5- Oxygroup)-aniline：NaNO2：(2- (cyano-acetamide amino)) Ethyl formate=1：1：1 or 1：4：4 equal different proportions), solvent it is (dilute Hydrochloric acid, dioxane, DMF etc.), reaction temperature (0 DEG C, 30 DEG C, 60 DEG C), the reaction time (0.5 hour, 1 hour, 3 hours, 6 Hour etc.), obtained product yield is from 41%-92% etc..
Step 4:
2- (3,5- bis- chloro- 4- (- 4- methoxyphenoxies) phenyl) -6- cyano -1,2,4- triazines -3,5 (2H, 4H)-two Ketone
(2- cyano -2- ((3,5- bis- chloro- 4- (4- methoxyphenoxies) phenyl) hydrazone group) acetylamino) Ethyl formate (5.5 grams, 12.2mmol) are dissolved in acetic acid (40mL), and sodium acetate (1.65 grams, 12.2mmol) is added.Reaction solution is heated to 120 DEG C eight hours.Reaction solution is cooled to room temperature, and water is added, product (4 grams, 81%) is then obtained by filtration.
In this step, it attempts to have selected different reaction conditions.Such as：Raw material ratio (2- cyano -2- ((3,5- bis- chloro- 4- (4- methoxyphenoxies) phenyl) hydrazone group) acetylamino) Ethyl formate：Sodium acetate=1：1 or 1：2 equal different proportions), solvent (acetic acid, formic acid, propionic acid, butyric acid, hydrochloric acid solution, sulfuric acid solution, DMF, toluene etc.), alkali (sodium acetate, sodium formate, sodium propionate, fourth Sour sodium etc.), reaction temperature (100 DEG C, 130 DEG C), the reaction time (4 hours, 6 hours, 8 hours etc.), obtained product yield From 64%-95% etc..
Step 5:
2- (3,5- bis- chloro- 4- (- 4- methoxyphenoxies) phenyl) -6- carboxyls -1,2,4- triazines -3,5 (2H, 4H)-two Ketone
2- (3,5- bis- chloro- 4- (- 4- methoxyphenoxies) phenyl) -6- cyano -1,2,4- triazines -3,5 (2H, 4H) - Diketone (4 grams, 9.8mmol) is dissolved in acetic acid (150mL), and concentrated hydrochloric acid (15mL) is added.Reaction solution is heated to 90 DEG C five hours.Then It cools down, is quenched with sodium bicarbonate solution, product (3.8 grams, 91%) is obtained by filtration.
In this step, it attempts to have selected different reaction conditions.Such as：Sour (hydrochloric acid, sulfuric acid, phosphoric acid etc.), sour (hydroxide Sodium, potassium hydroxide etc.), solvent (acetic acid, water, DMF etc.), reaction temperature (80 DEG C -130 DEG C), the reaction time (3 hours, it is 5 small When, 18 hours etc.), obtained product yield is from 56%-91% etc..
Step 6:
2- (3,5- bis- chloro- 4- (- 4- methoxyphenoxies) phenyl) -1,2,4- triazines -3,5 (2H, 4H)-diketone
2- (3,5- bis- chloro- 4- (- 4- methoxyphenoxies) phenyl) -6- carboxyls -1,2,4- triazines -3,5 (2H, 4H) - Diketone (3.8 grams, 8.96mmol) is dissolved in thioacetic acid (30mL), and reaction solution is heated to 120 DEG C two hours.Reaction solution is cooled to room Temperature is added ethyl acetate, is then washed with hypo solution.Organic layer is concentrated to give product (3.4 grams, 100%).
In this step, it attempts to have selected different reaction conditions.Such as：Solvent (acetic acid, thioacetic acid, mercaptopropionic acid, two Phenylate etc.), reaction temperature (120 DEG C, 180 DEG C), in the reaction time (0.5 hour, 1 hour, 2 hours etc.), obtained product obtains Rate is from 52%-100% etc..
Step 7:
5- (2,6- bis- chloro- 4- (3,5- dioxo -4,5- dihydros -1,2,4- triazines -2 (3H)-yl) phenoxy group) -2- methoxies Benzaldehyde
2- (3,5- bis- chloro- 4- (- 4- methoxyphenoxies) phenyl) -1,2,4- triazines -3,5 (2H, 4H)-diketone (3.4 Gram, 8.9mmol) it is dissolved in tetrahydrofuran, hexamethylenetetramine (2.04 grams, 14.6mmol) is added.Reaction solution is heated to 70 DEG C five A hour is cooled to room temperature, then concentration is quenched with water.Residue is extracted with ethyl acetate, dry, is concentrated to give product (3.5 grams, 96%).
In this step, it attempts to have selected different reaction conditions.Such as：Raw material ratio 2- (bis- chloro- 4- (- 4- methoxyl groups of 3,5- Phenoxy group) phenyl) -1,2,4- triazines -3,5 (2H, 4H)-diketone：Hexamethylenetetramine=1：1.5 or 1：2 equal different proportions), Solvent (acetic acid, formic acid, trifluoroacetic acid etc.), the temperature (50 DEG C -120 DEG C) reacted, (2 hours, 5 hours, 18 hours reaction time Deng), obtained product yield is from 76%-97% etc..
Step 8:5- (2,6- bis- chloro- 4- (3,5- dioxo -4,5- dihydros -1,2,4- triazines -2 (3H)-yl) phenoxy group) - Benzaldehyde,2-hydroxy
5- (2,6- bis- chloro- 4- (3,5- dioxo -4,5- dihydros -1,2,4- triazines -2 (3H)-yl) phenoxy group) -2- first Oxygroup benzaldehyde (3.5 grams, 8.5mmol) is dissolved in dichloromethane, and Boron tribromide (0.5mL) is added dropwise.Reaction solution stirs a hour, Then it is quenched with water.Solvent is spin-dried for, and residue is extracted with ethyl acetate.Organic layer drying concentration, residue are washed with n-hexane, are obtained To product (3.3 grams, 98%).
In this step, it attempts to have selected different reaction conditions.Such as：Boron tribromide (0.1mL, 0.5mL, 1mL), solvent For (chlorobenzene, chloroform, tetrachloromethane etc.), in the reaction time (1 hour, 2 hours, 5 hours etc.), obtained product yield is from 30- 99% differs.
Step 9:2- (3,5- bis- chloro- 4- (3- (methylol) -4- hydroxyphenoxies) phenyl) -1,2,4- triazines -3,5 (2H, 4H)-diketone
5- (2,6- bis- chloro- 4- (3,5- dioxo -4,5- dihydros -1,2,4- triazines -2 (3H)-yl) phenoxy group) -2- hydroxyls Benzaldehyde (50 milligrams, 0.12mmol) is dissolved in tetrahydrofuran (20mL), sodium borohydride (14 milligrams, 0.36mmol) is added, so 3 are added afterwards to drip, reaction solution is stirred at room temperature two hours.Reaction solution is diluted with ethyl acetate, is washed with water, and anhydrous sodium sulfate is dry It is dry.Organic phase is concentrated to give product (50 milligrams, 100%).
In this step, it attempts to have selected different reaction conditions.Such as：Raw material ratio (5- (2,6- bis- chloro- 4- (3,5- dioxies Generation -4,5- dihydros -1,2,4- triazines -2 (3H)-yl) phenoxy group)-Benzaldehyde,2-hydroxy：Sodium borohydride=1：1,1：2,1：5 Deng), solvent be (methanol, ethyl alcohol, tetrahydrofuran etc.), reducing agent (lithium borohydride, lithium aluminium hydride etc.), the reaction time (1 hour, 2 Hour, 5 hours etc.), obtained product yield is from 70%-100% etc..
Step 10:2- (3,5- bis- chloro- 4- (3- (chloromethyl) -4- hydroxyphenoxies) phenyl) -1,2,4- triazines -3,5 (2H, 4H)-diketone
2- (3,5- bis- chloro- 4- (3- (methylol) -4- hydroxyphenoxies) phenyl) -1,2,4- triazines -3,5 (2H, 4H) - Diketone (50 milligrams, 0.12mmol) is dissolved in thionyl chloride, and reaction solution is stirred at room temperature two hours.Then it is concentrated to give product (50 Milligram, 100%).
In this step, it attempts to have selected different reaction conditions.Such as：Chlorination reagent (thionyl chloride, chlorination sulfone, trichlorine Oxygen phosphorus etc.), reaction temperature (0 DEG C -50 DEG C), the reaction time (1 hour, 2 hours, 5 hours etc.), obtained product yield from 67%-100% etc..
Step 11:2- (3,5- bis- chloro- 4- (3- (4- methyl-1 H- pyrazoles -2- methyl) -4- hydroxyphenoxies) phenyl) -1, 2,4- triazines -3,5 (2H, 4H)-diketone
2- (3,5- bis- chloro- 4- (3- (chloromethyl) -4- hydroxyphenoxies) phenyl) -1,2,4- triazines -3,5 (2H, 4H) - Diketone (50 milligrams, 0.12mmol) is dissolved in DMF, and potassium carbonate (49.7 milligrams, 0.36mmol) and 3- methyl -4H- pyrazoles is added (49.2 milligrams, 0.6mmol).Reaction solution is heated to 60 DEG C of three hours.Reaction solution is cooled to room temperature, is diluted with ethyl acetate, Then it washes, anhydrous sodium sulfate drying.Organic phase concentrates, and product (15 milligrams, 27%) is obtained after column chromatography.
In this step, it attempts to have selected different reaction conditions.Such as：Alkali (potassamide, Sodamide, butyl lithium, diisopropyl Base ammonia lithium, benzyl lithium, Grignard Reagent, alkyl copper lithium, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, sodium hydroxide, hydroxide Potassium, potassium carbonate, sodium carbonate etc.), reaction temperature (30 DEG C -100 DEG C), in the reaction time (1 hour, 3 hours, 5 hours etc.), obtain Product yield from 13%-35% etc..
Product spectral data：
Nucleus magnetic hydrogen spectrum (deuterated methanol) δ 7.75 (s, 2H), 7.53 (s, 1H), 7.41 (s, 1H), 7.28 (s, 1H), 6.78 (s, 1H), 6.62-6.65 (m, 1H), 6.22 (d, J=3.0Hz, 1H), 5.22 (s, 2H), 2.02-2.09 (m, 3H)
Mass spectrum:m/z 461.3[M+H]+
Embodiment two,
2- (3,5- bis- chloro- 4- (3- (4,4 '-Difluoro-cyclohexyl -2- methyl) -4- hydroxyphenoxies) phenyl) -1,2,4- Triazine -3,5 (2H, 4H)-diketone
Structural formula：
m/z 499[M+H]+
Embodiment three,
2- (3,5- bis- chloro- 4- (3- (1P- cyclohexyl -2- methyl) -4- hydroxyphenoxies) phenyl) -1,2,4- triazines -3,5 (2H, 4H)-diketone
Structural formula：
m/z 481[M+H]+
Example IV,
2- (3,5- bis- chloro- 4- (3- (1- hydroxyl -1P- cyclohexyl -2- methyl) -4- hydroxyphenoxies) phenyl) -1,2,4- Triazine -3,5 (2H, 4H)-diketone
Structural formula：
m/z 497[M+H]+
Embodiment five,
2- (3,5- bis- chloro- 4- (3- (4- methyl -4P- cyclohexyl -2- methyl) -4- hydroxyphenoxies) phenyl) -1,2,4- Triazine -3,5 (2H, 4H)-diketone
Structural formula：
m/z 495[M+H]+
Embodiment six,
2- (3,5- bis- chloro- 4- (3- (1- phosphines-cyclohexyl -2- methyl) -4- hydroxyphenoxies) phenyl) -1,2,4- triazines - 3,5 (2H, 4H)-diketone
Structural formula：
m/z 497[M+H]+
Embodiment seven,
2- (3,5- bis- chloro- 4- (3- (3- cyclopropyl -1- cyclohexyl -2- methyl) -4- hydroxyphenoxies) phenyl) -1,2,4- Triazine -3,5 (2H, 4H)-diketone
Structural formula：
m/z 489[M+H]+
Embodiment eight,
2- (3,5- bis- chloro- 4- (3- dimethyl phosphine -4- hydroxyphenoxies) phenyl) -1,2,4- triazines -3,5 (2H, 4H)-two Ketone
Structural formula：
m/z 427[M+H]+
Embodiment nine,
Name：2- (3,5- bis- chloro- 4- (3- (dimethyl phosphine -2- methyl) -4- hydroxyphenoxies) phenyl) -1,2,4- tri- Piperazine -3,5 (2H, 4H)-diketone
Structural formula：
m/z 457[M+H]+
Cell experiment and mouse hair growth test：
In cell experiment, transfected into HEK-293 with the fluoreporter gene plasmid controlled by TR- β transcription factors Cell adds agonist activation experiment to prove that product of the present invention can dramatically increase Thyroid hormone receptor β (thyroid receptor β, TR β) Gene Transcription in vitro, half-maximal effect concentration (concentration for 50%of maximal effect, EC50) it is 6.738nM.The compound is the agonist of TR β.
Percutaneous administration mouse hair growth test of smearing finds that product of the present invention can be apparent in a certain concentration dosage range Change growth cycle of hair, promote hair growth, and there is apparent dosage correlation effect, higher concentration can largely promote Into hair growth.In addition, in every group mouse weight variation all very slowly, showing will not using test-compound in this dosage The weight of animals is caused to reduce.The mouse skin of medicine-feeding part does not occur the skins such as irritation, damage or erythema in all experiments The adverse reaction of skin part.
From the above it is recognised that the substance has no toxic side effect, and promote hair regeneration with obvious effects.

Claims (11)

1. a kind of compound, which is characterized in that for such as lower structure compound represented：
Wherein, the Y is any on phenyl ring or times several substituted alkyl, hydroxyl, halogen and hydrogen；
The X is carbon, nitrogen, phosphorus；
The Z is carbon, nitrogen, phosphorus；
The G1 is five-, six- or seven-membered ring；
The R is monosubstituted or polysubstituted hydrogen, halogen, alkyl sulphonyl, alkyl, alkoxy, nitro, amino, carboxyl, ester Base, hydroxyl, aryl, benzyl, O- alkyl, O- aryl, O- heterocyclic bases, N- alkyl, N- aryl, N- heteroaryls.
2. a kind of compound as described in claim 1, which is characterized in that for such as lower structure compound represented：
Wherein, Z1、Z2、Z3、Z4For carbon, oxygen, sulphur, nitrogen；
The X-Z1Key, X-Z4Key, Z1-Z2Key, Z2-Z3Key, Z3-Z4Key is singly-bound or double bond.
3. a kind of compound as described in claim 1, it is characterised in that：
When it is polysubstituted, R is and Z1-Z5The substituent group or R of bonding be and Z1And Z2、Z2And Z3、Z3And Z4、Z4And Z5It is any Or appoint fragrance, heteroaryl or the naphthene group of several key parallel connections.
4. a kind of manufacturing method of compound as described in claim 1, it is characterised in that：Using 4- metoxyphenols and to halogen Nitrobenzene derivative is initial feed, carries out the addition compound product of addition reaction arrived, and triazine derivatives are obtained through hexa-atomic annulation After object, it is substituted on phenol ring and the alkane containing active reactive group is obtained by the reaction for derivative, which reacts with amine or acid Obtain target product.
5. a kind of manufacturing method of compound as described in claim 1, which is characterized in that realized by following steps：
Step 1: reacting generation such as lower structure compound represented I with to halogen nitrobenzene derivative by 4- metoxyphenols：
Step 2: being reduced to compound I such as lower structure compound represented II：
Step 3: by being obtained by the reaction as shown in lower structure with 2- (cyano-acetamide amino) Ethyl formate after compound II diazotising Compound III：
It is obtained such as lower structure compound represented IV Step 4: compound III is carried out Intra-molecular condensation：
Step 5: compound IV is hydrolyzed to obtain such as lower structure compound represented V：
Step 6: obtaining compound V decarboxylations such as lower structure compound represented VI：
Step 7: obtaining aldehyde radical on compound VI such as lower structure compound represented VII:
Step 8: by being obtained such as lower structure compound represented VIII after compound VII demethylations：
Step 9: being obtained such as lower structure compound represented IX after the aldehyde radical of compound VIII is restored：
It is obtained such as lower structure compound represented X Step 10: converting after active reactive group the hydroxyl of compound IX to：
Step 11: by compound X withTarget compound is obtained after reaction；
Wherein：Linker and linker ' is the group that can react and be formed chemical bond.
6. a kind of manufacturing method of compound as claimed in claim 5, it is characterised in that：
In step 1, reactant 4- metoxyphenols are 1 with the molar ratio to halogen nitrobenzene:1-2；
In step 2, the molar ratio of compound I and the reducing agent for reduction reaction is 1：10-20；
In step 3, the molar ratio of compound II, diazo reagent and 2- (cyano-acetamide amino) Ethyl formate are 1:1-4: 1-4；
In step 4, the molar ratio of compound III and the alkali for ring-closure reaction is 1：1-2；
In step 7, the molar ratio of compound VI and aldehyde radical reagent is 1：1.5-2；
In step 8, the mass ratio of compound VII and demethylation reagent is 1：0.01-0.5；
In step 9, the molar ratio of compound VIII and the reducing agent for restoring aldehyde radical is 1：1-2；
In step 10, the molar ratio of compound IX and active group reagent is 1：1-2；
In step 11, compound X withMolar ratio be 1：1-2.
7. a kind of manufacturing method of compound as claimed in claim 5, it is characterised in that：
The step 1 carries out under basic conditions, is reacted 1-6 hours under conditions of being 120-160 DEG C in reaction temperature；
The molar ratio of the highly basic and 4- metoxyphenols is 1.5-2：1；
The reaction condition of the step 2 is：Back flow reaction 1-6 hours；
The reaction condition of the step 3 is：It is carried out under ice-water bath, room temperature or reflux, the reaction time is 0.5-6 hours；
The reaction condition of the step 4 is:Back flow reaction 4-18 hours；
The step 5 is hydrolyzed in acid or alkaline solution, and reaction condition is：Back flow reaction 1-18 hours；
Step 6 back flow reaction 1-5 hours in acid condition；
The reaction condition of the step 7 is:Under 0-120 DEG C of reaction temperature, react 2-18 hours；
The reaction condition of the step 8 is：Under 0-120 DEG C of reaction temperature, react 1-5 hours.
The reaction condition of the step 9 is：Under 0-120 DEG C of reaction temperature, react 1-5 hours；
The reaction condition of the step 10 is：Under 0-120 DEG C of reaction temperature, react 1-5 hours；
The step 11 under alkaline conditions, under conditions of reaction temperature is 50-120 DEG C, is reacted 1-5 hours.
8. a kind of application of compound, it is characterised in that：Compound as described in claim 1-7 is any can swash as thyroid gland The agonist of plain receptor β.
9. a kind of application of compound, it is characterised in that：Compound as described in claim 1-7 is any can apply to it is various because Baldness caused by element or hair loss disorder promote the growth of hair.
10. a kind of composition for promoting hair to increase, it is characterised in that：Including mass percentage content is 0.001%-5%'s Compound as described in claim 1-7 is any.
11. a kind of trichogenous compound, it is characterised in that：Compound as described in claim 1-7 is any and its The hair regeneration compound of its known mechanism is used in combination, and can remarkably promote hair regeneration.
CN201810457269.0A 2018-05-14 2018-05-14 A kind of compound and its synthetic method and application Pending CN108727344A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201810457269.0A CN108727344A (en) 2018-05-14 2018-05-14 A kind of compound and its synthetic method and application
PCT/CN2019/081450 WO2019218797A1 (en) 2018-05-14 2019-04-04 4-phenoxy-phenyl-2h-[1,2,4]triazine-3,5-diketone derivative and preparation method therefor and use thereof for promoting hair growth

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810457269.0A CN108727344A (en) 2018-05-14 2018-05-14 A kind of compound and its synthetic method and application

Publications (1)

Publication Number Publication Date
CN108727344A true CN108727344A (en) 2018-11-02

Family

ID=63937432

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810457269.0A Pending CN108727344A (en) 2018-05-14 2018-05-14 A kind of compound and its synthetic method and application

Country Status (2)

Country Link
CN (1) CN108727344A (en)
WO (1) WO2019218797A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019218797A1 (en) * 2018-05-14 2019-11-21 嘉兴特科罗生物科技有限公司 4-phenoxy-phenyl-2h-[1,2,4]triazine-3,5-diketone derivative and preparation method therefor and use thereof for promoting hair growth
CN111018801A (en) * 2019-12-25 2020-04-17 山东国邦药业有限公司 Preparation method of anticoccidial veterinary drug cimetiril
CN112300133A (en) * 2019-07-31 2021-02-02 深圳微芯生物科技股份有限公司 Heterocyclic compound and application thereof
WO2021043185A1 (en) * 2019-09-04 2021-03-11 Sunshine Lake Pharma Co., Ltd. A compound as a thyroid hormone beta receptor agonist and use thereof
US11091467B2 (en) 2019-05-08 2021-08-17 Aligos Therapeutics, Inc. Modulators of THR-β and methods of use thereof
WO2022037617A1 (en) 2020-08-19 2022-02-24 成都凡诺西生物医药科技有限公司 Cyanotriazine derivative, preparation method therefor, and application thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW202322824A (en) 2020-02-18 2023-06-16 美商基利科學股份有限公司 Antiviral compounds
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1088819A2 (en) * 1999-09-30 2001-04-04 Pfizer Products Inc. 6-azauracil derivatives as thyroid receptor ligands
CN1389203A (en) * 2001-05-31 2003-01-08 辉瑞产品公司 Method for treating hair-dropping using thyromimetic compound
US20050085541A1 (en) * 2002-01-30 2005-04-21 Hiroaki Shiohara Novel thyroid hormone receptor ligand, medicinal compositions containing the same and use thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108727344A (en) * 2018-05-14 2018-11-02 嘉兴特科罗生物科技有限公司 A kind of compound and its synthetic method and application

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1088819A2 (en) * 1999-09-30 2001-04-04 Pfizer Products Inc. 6-azauracil derivatives as thyroid receptor ligands
CN1389203A (en) * 2001-05-31 2003-01-08 辉瑞产品公司 Method for treating hair-dropping using thyromimetic compound
US20050085541A1 (en) * 2002-01-30 2005-04-21 Hiroaki Shiohara Novel thyroid hormone receptor ligand, medicinal compositions containing the same and use thereof

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019218797A1 (en) * 2018-05-14 2019-11-21 嘉兴特科罗生物科技有限公司 4-phenoxy-phenyl-2h-[1,2,4]triazine-3,5-diketone derivative and preparation method therefor and use thereof for promoting hair growth
US11091467B2 (en) 2019-05-08 2021-08-17 Aligos Therapeutics, Inc. Modulators of THR-β and methods of use thereof
CN114096531A (en) * 2019-05-08 2022-02-25 阿利戈斯治疗公司 THR-beta modulators and methods of use thereof
CN112300133A (en) * 2019-07-31 2021-02-02 深圳微芯生物科技股份有限公司 Heterocyclic compound and application thereof
WO2021043185A1 (en) * 2019-09-04 2021-03-11 Sunshine Lake Pharma Co., Ltd. A compound as a thyroid hormone beta receptor agonist and use thereof
CN111018801A (en) * 2019-12-25 2020-04-17 山东国邦药业有限公司 Preparation method of anticoccidial veterinary drug cimetiril
WO2022037617A1 (en) 2020-08-19 2022-02-24 成都凡诺西生物医药科技有限公司 Cyanotriazine derivative, preparation method therefor, and application thereof

Also Published As

Publication number Publication date
WO2019218797A1 (en) 2019-11-21

Similar Documents

Publication Publication Date Title
CN108727344A (en) A kind of compound and its synthetic method and application
US5750553A (en) Optionally substituted phenylimidazolidines, their preparation process and intermediates, their use as medicaments and the pharmaceutical compositions containing them
Chen et al. Gallium (III) triflate-catalyzed one-pot selective synthesis of 2, 3-dihydroquinazolin-4 (1H)-ones and quinazolin-4 (3H)-ones
EP1758869B1 (en) Pyridazin-3(2h)-one derivatives and their use as pde4 inhibitors
Tibiletti et al. One-pot synthesis of meridianins and meridianin analogues via indolization of nitrosoarenes
Li et al. An efficient construction of quinazolin-4 (3H)-ones under microwave irradiation
WO2009123967A1 (en) 5,6,7,8-tetrahydroquinazolin-2-amine derivatives and related compounds as histamine h4 receptor modulators for the treatment of asthma
FR2671348A1 (en) NOVEL PHENYLIMIDAZOLIDINES, PROCESS FOR THE PREPARATION THEREOF, THEIR USE AS MEDICAMENTS AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME.
TW200400033A (en) New pyridazin-3(2H)-one derivatives
WO2016202125A1 (en) Azd9291 intermediate and preparation method therefor
JP2003518104A (en) Method for producing triazolinethione derivative
EP2390250A2 (en) Gonadotropin releasing hormone receptor antagonists, manufacturing method thereof, and pharmaceutical composition containing same
JP5209760B2 (en) 1-N-phenylamino-1H-imidazole derivative and pharmaceutical composition containing the same
JP2011063599A (en) Method for producing heterocyclic fluoroalkenyl sulfone
RU2152934C1 (en) Substituted phenylimidazolidines, methods of their synthesis (variants) and pharmaceutical composition based on thereof
CA3158379A1 (en) 1,2,4-triazine-3,5-dione compound, preparation method therefor, and application thereof
TW200927096A (en) Derivatives of 5-amino-4,6-disubstituted indole and 5-amino-4,6-disubstituted indoline as potassium channel modulators
CN107445909A (en) A kind of preparation method of prothioconazoles intermediate
US8101624B2 (en) Quinazoline derivatives
US20240025875A1 (en) A compound as a thyroid hormone beta receptor agonist and use thereof
CA2977905A1 (en) Derivatives of 2-aminopyridine as adenosine a2b receptor antagonists and ligands of the melatonin mt3 receptors
Lange et al. Synthesis and SAR of 1, 4, 5, 6-tetrahydropyridazines as potent cannabinoid CB1 receptor antagonists
JP2017522329A (en) Small molecule compound, synthesis method thereof, and application thereof
CZ304539B6 (en) Process for preparing substituted aniline derivative
PH27023A (en) Heteroarylethylamine as production promotes in livestock

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication

Application publication date: 20181102

RJ01 Rejection of invention patent application after publication