CN114702543A - Clascoterone derivative or pharmaceutically acceptable salt thereof, and preparation method and application thereof - Google Patents
Clascoterone derivative or pharmaceutically acceptable salt thereof, and preparation method and application thereof Download PDFInfo
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- CN114702543A CN114702543A CN202210413506.XA CN202210413506A CN114702543A CN 114702543 A CN114702543 A CN 114702543A CN 202210413506 A CN202210413506 A CN 202210413506A CN 114702543 A CN114702543 A CN 114702543A
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- 150000003839 salts Chemical class 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- GPNHMOZDMYNCPO-PDUMRIMRSA-N clascoterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CC)[C@@]1(C)CC2 GPNHMOZDMYNCPO-PDUMRIMRSA-N 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- 239000003814 drug Substances 0.000 claims abstract description 13
- 208000002874 Acne Vulgaris Diseases 0.000 claims abstract description 8
- 201000004384 Alopecia Diseases 0.000 claims abstract description 8
- 206010000496 acne Diseases 0.000 claims abstract description 8
- 201000002996 androgenic alopecia Diseases 0.000 claims abstract description 7
- -1 4-fluorophenylmethyl Chemical group 0.000 claims description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 239000007821 HATU Substances 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 206010068168 androgenetic alopecia Diseases 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000006288 3,5-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(C([H])=C1F)C([H])([H])* 0.000 claims description 3
- 125000006495 3-trifluoromethyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1[H])C([H])([H])*)C(F)(F)F 0.000 claims description 3
- 125000001318 4-trifluoromethylbenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])*)C(F)(F)F 0.000 claims description 3
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 3
- WHBHBVVOGNECLV-UHFFFAOYSA-N 11-deoxy-17-hydroxy-corticosterone Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 WHBHBVVOGNECLV-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical group NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 2
- 150000003939 benzylamines Chemical class 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 230000002333 acnegenic effect Effects 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 238000004896 high resolution mass spectrometry Methods 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 7
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229940121540 clascoterone Drugs 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 102000004142 Trypsin Human genes 0.000 description 3
- 108090000631 Trypsin Proteins 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 239000002299 complementary DNA Substances 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 239000012588 trypsin Substances 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- 125000006284 3-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(F)=C1[H])C([H])([H])* 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
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- 238000000338 in vitro Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
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- 125000001424 substituent group Chemical group 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- VJNGGOMRUHYAMC-UHFFFAOYSA-N (3,5-difluorophenyl)methanamine Chemical compound NCC1=CC(F)=CC(F)=C1 VJNGGOMRUHYAMC-UHFFFAOYSA-N 0.000 description 1
- QVSVMNXRLWSNGS-UHFFFAOYSA-N (3-fluorophenyl)methanamine Chemical compound NCC1=CC=CC(F)=C1 QVSVMNXRLWSNGS-UHFFFAOYSA-N 0.000 description 1
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- 101150029129 AR gene Proteins 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 229940123407 Androgen receptor antagonist Drugs 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 108091092584 GDNA Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- CGNLCCVKSWNSDG-UHFFFAOYSA-N SYBR Green I Chemical compound CN(C)CCCN(CCC)C1=CC(C=C2N(C3=CC=CC=C3S2)C)=C2C=CC=CC2=[N+]1C1=CC=CC=C1 CGNLCCVKSWNSDG-UHFFFAOYSA-N 0.000 description 1
- 206010041250 Social phobia Diseases 0.000 description 1
- YKNZTUQUXUXTLE-UHFFFAOYSA-N [3-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=CC(C(F)(F)F)=C1 YKNZTUQUXUXTLE-UHFFFAOYSA-N 0.000 description 1
- PRDBLLIPPDOICK-UHFFFAOYSA-N [4-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=C(C(F)(F)F)C=C1 PRDBLLIPPDOICK-UHFFFAOYSA-N 0.000 description 1
- LACURGWEZCFLBO-UHFFFAOYSA-N [4-(trifluoromethylsulfanyl)phenyl]methanamine Chemical compound NCC1=CC=C(SC(F)(F)F)C=C1 LACURGWEZCFLBO-UHFFFAOYSA-N 0.000 description 1
- 238000011481 absorbance measurement Methods 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 239000003936 androgen receptor antagonist Substances 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
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- 230000003828 downregulation Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
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- 239000013641 positive control Substances 0.000 description 1
- 230000003651 pro-proliferative effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- ZQBVUULQVWCGDQ-UHFFFAOYSA-N propan-1-ol;propan-2-ol Chemical compound CCCO.CC(C)O ZQBVUULQVWCGDQ-UHFFFAOYSA-N 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000003716 rejuvenation Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0066—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by a carbon atom forming part of an amide group
-
- 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
- A61P17/10—Anti-acne agents
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a Clascoterone derivative or pharmaceutically acceptable salt thereof, a preparation method and application thereof, and a compound shown as a general formula (I) or pharmaceutically acceptable salt thereof. The compounds of the invention or pharmaceutically acceptable salts thereof can be used in the preparation of a medicament for the treatment of acne and androgenic alopecia.
Description
Technical Field
The invention relates to a chemical drug, a preparation method and application thereof, in particular to a Clascoterone derivative or pharmaceutically acceptable salt thereof, and a preparation method and application thereof.
Background
Acne and alopecia occur widely, the external image of a patient is seriously affected, and even serious people can cause social phobia, self-esteem decline, depression and the occurrence of light birth behaviors. Clascoterone is a novel steroid topical androgen receptor antagonist developed by Cassiopia SpA, Italy, mainly used for the treatment of acne and androgenetic alopecia without causing systemic side effects. Currently, the FDA in the united states has approved Clascoterone (1% cream) for the treatment of acne in patients 12 years of age and older at month 8 of 2020.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a Clascoterone derivative or a pharmaceutically acceptable salt thereof, and aims to find a candidate drug with better curative effect. Another object of the present invention is to provide a process for the preparation of the above compound or a pharmaceutically acceptable salt thereof. It is a further object of the present invention to provide the use of said compounds or pharmaceutically acceptable salts thereof for the manufacture of a medicament for the treatment of acne, androgenetic alopecia.
The technical scheme is as follows: the invention relates to a compound shown as a general formula (I) or a medicinal salt thereof:
wherein,
R1selected from alkoxy with 1-6 carbon atoms, alkyl with 1-3 carbon atoms, hydrogen, hydroxyl, amino and substituted or unsubstituted benzylamine group;
R2selected from acyl with 1-6 carbon atoms, alkyl with 1-3 carbon atoms, hydrogen and trifluoromethyl.
The compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
n- (4-fluorophenylmethyl) -3-oxo-androst-4-ene-17 a- (1-oxopropoxy) -17 ss-carboxamide (XHZ1701)
N- (3-fluorobenzyl) -3-oxo-androst-4-ene-17 α - (oxopropoxy) -17 β -carboxamide (XHZ1702)
N- (3, 5-difluorobenzyl) -3-oxo-androst-4-ene-17 a- (1-oxopropoxy) -17 ss-carboxamide (XHZ1703)
N- (4-trifluoromethylsulfanyl-benzyl) -3-oxo-androst-4-ene-17 α - (1-oxopropoxy) -17 β -carboxamide (XHZ1704)
N- (4-trifluoromethylbenzyl) -3-oxo-androst-4-ene-17 α - (1-oxopropoxy) -17 β -carboxamide (XHZ1705)
N- (3-trifluoromethylbenzyl) -3-oxo-androst-4-ene-17 α - (1-oxopropoxy) -17 β -carboxamide (XHZ1706)
A pharmaceutical composition comprising one or more of said compounds or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
The preparation method of the compound or the pharmaceutically acceptable salt thereof comprises the following steps:
the preparation method of the compound or the pharmaceutically acceptable salt thereof comprises the following steps:
taking a compound 1 as a raw material, firstly carrying out oxidation reaction with periodic acid to obtain a compound 2; then carrying out esterification reaction on the compound 2 and propionic anhydride to obtain a compound 3, and finally carrying out condensation reaction on the compound 3 and various benzylamines under the catalysis of a condensing agent HATU and triethylamine to obtain a compound of a general formula (I); or also through salt-forming reaction to obtain the medicinal salt of the compound.
A process for the preparation of said compound or a pharmaceutically acceptable salt thereof, wherein compound 1 is 17 α, 21-dihydroxy-pregn-4-ene-3, 20-dione, compound 2 is 3-oxo-androst-4-ene-17 α -hydroxy-17 β -carboxylic acid, and compound 3 is 3-oxo-androst-4-ene-17 α - (1-oxopropoxy) -17 β -carboxylic acid.
The use of said compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of acne.
The application of the compound or the medicinal salt thereof in preparing the medicament for treating androgenetic alopecia.
Has the advantages that: compared with the prior art, the invention has the following advantages: the compound or the medicinal salt thereof has different degrees of proliferation promoting effects on human hair papilla cells (HHDPC), can be used for preparing medicaments for treating human acne and androgenetic alopecia, and has good application prospects.
Drawings
FIG. 1 shows the effect of XHZ1703 compound and Clascoterone as a positive drug on the inhibition of the transcription level of the AR gene.
Detailed Description
The results of the melting point data in the following examples were measured by X-4 type digital display micro melting point apparatus (Beijing Takker instruments, Ltd.); the nuclear magnetic spectrum data of the final product and the intermediate are DMSO-d6 or CDCl3-d3 as solvent and TMS as internal standard, measured by Bruker's 300MHz or 400MHz NMR spectrometer; high Resolution Mass Spectrometry (HRMS) was determined by an Agilent model Q-TOF 6520 mass spectrometer.
Reagents used in the synthesis, purification and isolation of the compounds are: (1) column chromatography silica gel: 200 or 300 meshes of silica gel are purchased from Qingdao ocean chemical industry; (2) HSGF254 TLC plate: purchased from the tobacco desk chemical research institute; (3) the conventional solvents used in the column chromatography elution system, such as petroleum ether, dichloromethane, ethyl acetate, methanol and the like, and chemical reagents required by the reaction are all commercially available chemical pure products or analytically pure products except for special instructions.
Example 1: preparation of 3-oxo-androst-4-ene-17 alpha-hydroxy-17 beta-carboxylic acid (2)
The compound 17 alpha, 21-dihydroxy-pregn-4-ene-3, 20-Diketone (1) (1g,2.89mmol) is dissolved in 10ml tetrahydrofuran solution and H is added5IO6(1.31g,5.78mmol) at room temperature for 2 h. After the reaction is finished, the reaction solution is concentrated under reduced pressure, added with water and stirred for 30min, filtered by suction and dried to obtain a yellow product (0.79g, the molar yield is 83%).1H NMR(300MHz,DMSO-d6)δ12.32(s,1H),5.66(d,J=1.5Hz,1H),4.87(s,1H),1.18(s,3H),0.70(s,3H).
Example 2: preparation of 3-oxo-androst-4-ene-17 alpha- (1-oxopropoxy) -17 beta-carboxylic acid (3)
The compound 3-oxo-androst-4-ene-17 α -hydroxy-17 β -carboxylic acid (2) (1.4g,4.22mmol) was dissolved in 13ml of propionic anhydride, 3ml of anhydrous pyridine was added, and the reaction was carried out at room temperature for 1 hour. After the reaction, 200mL of water was added and crystallized in an ice bath, and a white solid was obtained by suction filtration (0.92g, molar yield 65%).1H NMR(300MHz,DMSO-d6)δ12.48(s,1H),5.55(s,1H),2.71-2.56(m,1H),1.07(s,3H),0.92(t,J=7.5Hz,4H),0.63(s,3H).
Example 3: preparation of N- (4-fluorophenylmethyl) -3-oxo-androst-4-ene-17 alpha- (1-oxopropoxy) -17 beta-carboxamide (XHZ1701)
The compound 3-oxo-androst-4-ene-17 α - (1-oxopropoxy) -17 β -carboxylic acid (3) (0.26g,0.67mmol) was dissolved in 3mL dichloromethane, 0.38g HATU (1.0mmol) and 0.37mL TEA (2.68mmol) were added and the reaction was allowed to react at room temperature for 1h, followed by addition of 0.14mL 4-fluorobenzylamine (1.2mmol) and continued for 10 h. After the reaction is finished, water is added for quenching. Extraction with dichloromethane, washing of the organic phase three times with saturated ammonium chloride solution and combining the organic phases. Concentrated under reduced pressure, and separated by column chromatography to obtain a yellow-white solid (0.11g, molar yield 35%). Mobile phase system (CH)2Cl2:CH3OH=100:1)。m.p.186.4-188.4℃.1H NMR(300MHz,DMSO-d6)δ8.00(t,J=6.1Hz,1H),7.36-7.21(m,2H),7.14(t,J=8.9Hz,2H),5.67(s,1H),4.32-4.07(m,2H),2.99-2.77(m,1H),1.18(s,3H),1.02(t,J=7.5Hz,3H),0.62(s,3H).13C NMR(75MHz,CDCl3)δ199.44,173.00,170.79,169.36,160.58,134.21,129.74,123.99,115.65,92.59,77.50,77.07,76.65,53.28,50.83,47.19,42.99,38.58,35.71,33.95,32.74,31.94,30.42,30.13,28.16,23.82,20.62,17.40,14.40,9.02.19F NMR(282MHz,CDCl3)δ-114.87.HRMS(ESI)m/z calcd for[M+Na]+518.2677,found 518.2671.
Example 4: preparation of N- (3-fluorobenzyl) -3-oxo-androst-4-ene-17 alpha- (oxopropoxy) -17 beta-carboxamide (XHZ1702)
Synthetic methods for compound XHZ1701 were used to prepare XHZ 1702. The compounds 3-oxo-androst-4-ene-17 α - (1-oxopropoxy) -17 β -carboxylic acid (3) (0.25g,0.6mmol), HATU (0.36g,0.96mmol), TEA (0.35ml,2.57mmol), dichloromethane (3ml), 3-fluorobenzylamine (0.13ml,1.11mmol) were dosed. Column chromatography gave an off-white solid (0.09g, 30% molar yield). Mobile phase system (CH)2Cl2:CH3OH=100:1)。m.p.158.2-160.4℃,1H NMR(300MHz,DMSO-d6)δ8.12(t,J=6.2Hz,1H),7.42-7.29(m,1H),7.08(t,J=9.4Hz,3H),5.93(s,1H),4.29(q,J=6.6Hz,2H),2.89(t,J=13.5Hz,1H),1.14(s,3H),1.07-0.98(m,4H),0.63(s,3H).13C NMR(101MHz,CDCl3)δ199.46,173.06,170.85,169.49,164.17,161.71,140.98,130.22,123.95,123.45,114.83,92.58,53.27,50.83,47.20,43.19,38.58,35.70,33.94,32.74,31.93,30.44,30.17,28.13,23.80,20.61,17.39,14.40,9.86,8.95.19F NMR(282MHz,DMSO-d6)δ-113.85.HRMS(ESI)m/z calcd for[M+Na]+518.2677,found 518.2670.
Example 5: preparation of N- (3, 5-difluorobenzyl) -3-oxo-androst-4-ene-17 alpha- (1-oxopropoxy) -17 beta-carboxamide (XHZ1703)
Synthetic methods for compound XHZ1701 were used to prepare XHZ 1703. The compounds 3-oxo-androst-4-ene-17 α - (1-oxopropoxy) -17 β -carboxylic acid (3) (0.24g,0.61mmol), HATU (0.35g,0.92mmol), TEA (0.34mL,2.47mmol), dichloromethane (3mL), 3, 5-difluorobenzylamine (0.15mL,1.24mmol) were dosed. Column chromatography gave an off-white solid (30mg, molar yield 10%). Mobile phase system (CH)2Cl2:CH3OH=100:1)。m.p.87.1-89.3℃.1H NMR(400MHz,DMSO-d6)δ8.06(t,J=6.0Hz,1H),7.06(tt,J=9.4,2.4Hz,1H),7.00-6.88(m,2H),5.64(d,J=1.4Hz,1H),4.36(dd,J=15.9,6.5Hz,1H),4.19(dd,J=15.9,5.5Hz,1H),3.00-2.77(m,1H),1.16(s,3H),1.00(t,J=15.0Hz,3H),0.63(s,3H).13C NMR(101MHz,CDCl3)δ199.48,173.18,170.91,169.72,164.31(d,J=12.6Hz),161.84(d,J=12.7Hz),142.56,123.91,110.57,102.75,92.52,53.28,50.80,47.22,42.85,38.57,35.70,35.68,33.93,32.72,31.92,30.46,30.22,28.09,23.78,20.60,17.37,14.40,8.88.19F NMR(282MHZ,CDCl3)δ-114.87.HRMS(ESI)m/z calcd for[M+Na]+536.2582,found 536.2577.
Example 6: preparation of N- (4-trifluoromethylsulfanyl-benzyl) -3-oxo-androst-4-ene-17 alpha- (1-oxopropoxy) -17 beta-carboxamide (XHZ1704)
Synthetic methods for compound XHZ1701 were used to prepare XHZ 1704. The compounds 3-oxo-androst-4-ene-17 α - (1-oxopropoxy) -17 β -carboxylic acid (3) (0.25g,0.6mmol), HATU (0.36g,0.96mmol), TEA (0.35ml,2.57mmol), dichloromethane (3ml), 4-trifluoromethylsulfanylbenzylamine (0.18ml,1.16mmol) were dosed. Column chromatography gave an off-white solid (54mg, molar yield 15%). Mobile phase system (CH)2Cl2:CH3OH=100:1)。m.p.107.2-108.9℃.1H NMR(400MHz,DMSO-d6)δ8.05(t,J=6.0Hz,1H),7.65(d,J=8.0Hz,2H),7.43-7.36(m,2H),5.67-5.62(m,1H),4.31(d,J=6.0Hz,2H),2.85(dd,J=15.9,10.9Hz,1H),1.15(s,3H),1.00(t,J=7.5Hz,4H),0.60(s,3H).13C NMR(101MHz,DMSO-d6)δ198.53,173.26,171.27,169.35,144.39,136.47,131.65,129.17,123.67,121.13,92.12,53.34,50.80,47.33,42.60,38.66,35.51,34.08,32.43,32.18,30.61,30.41,27.81,23.96,20.57,17.36,14.64,9.14.19F NMR(282MHz,DMSO-d6)δ-42.39.HRMS(ESI)m/z calcd for[M+Na]+600.2365,found 600.2363.
Example 7: preparation of N- (4-trifluoromethylbenzyl) -3-oxo-androst-4-ene-17 alpha- (1-oxopropoxy) -17 beta-carboxamide (XHZ1705)
Synthetic methods for compound XHZ1701 were used to prepare XHZ 1705. The compounds 3-oxo-androst-4-ene-17 α - (1-oxopropoxy) -17 β -carboxylic acid (3) (0.13g,0.38mmol), HATU (0.19g,0.58mmol), TEA (0.18ml,1.54mmol), dichloromethane (3ml), 4-trifluoromethylbenzylamine (0.072ml,0.58mmol) were dosed. Column chromatography gave an off-white solid (31mg, molar yield 17%). Flow ofDynamic phase system (CH)2Cl2:CH3OH=100:1)。m.p.102.1-104.2℃.1H NMR(300MHz,DMSO-d6)δ8.12(t,J=6.0Hz,1H),7.70(d,J=8.1Hz,2H),7.49(d,J=8.0Hz,2H),5.68(s,1H),4.36(d,J=5.8Hz,2H),2.88(dd,J=15.8,11.0Hz,1H),1.19(s,3H),1.03(t,J=7.5Hz,4H),0.65(s,3H).13C NMR(101MHz,CDCl3)δ199.46,173.11,170.88,169.66,142.59,129.78,129.45,128.04,125.53,123.91,92.55,53.27,50.80,47.23,43.15,38.56,35.69,33.92,32.72,31.92,30.43,30.20,28.11,23.78,20.61,17.36,14.42,8.96.19F NMR(282MHz,DMSO-d6)δ-60.69.HRMS(ESI)m/z calcd for[M+Na]+568.2645,found 568.2639.
Example 8: preparation of N- (3-trifluoromethylbenzyl) -3-oxo-androst-4-ene-17 alpha- (1-oxopropoxy) -17 beta-carboxamide (XHZ1706)
XHZ1706 is prepared using the synthetic approach of compound XHZ 1701. The compounds 3-oxo-androst-4-ene-17 α - (1-oxopropoxy) -17 β -carboxylic acid (3) (0.25g,0.6mmol), HATU (0.36g,0.96mmol), TEA (0.35ml,2.57mmol), dichloromethane (3ml), 3-trifluoromethylbenzylamine (0.16ml,1.16mmol) were dosed. Column chromatography gave an off-white solid (56mg, 16% molar yield). Mobile phase system (CH)2Cl2:CH3OH=100:1)。m.p.59.3-61.4℃.1H NMR(300MHz,DMSO-d6)δ8.15(t,J=6.0Hz,1H),7.65-7.51(m,4H),5.66(s,1H),4.46-4.25(m,2H),2.94-2.79(m,1H),1.17(s,3H),1.01(t,J=7.5Hz,4H),0.61(s,3H).13C NMR(101MHz,CDCl3)δ199.43,173.03,170.77,169.58,139.52,131.34,129.14,124.42,124.28,123.98,92.56,53.28,50.84,47.23,43.14,38.58,35.71,33.94,32.73,31.94,31.52,30.49,30.20,28.13,23.81,20.56,17.39,14.37,8.92.19F NMR(282MHz,DMSO-d6)δ-61.05.HRMS(ESI)m/z calcd for[M+Na]+568.2645,found 568.2642.
Table 1 shows the assignment of substituents to Clascoterone derivatives or pharmaceutically acceptable salts thereof in some of the examples above.
TABLE 1 assignment of substituents to Clascoterone derivatives or pharmaceutically acceptable salts thereof
Example 9: performance testing
Table 2 is a source of reagents used in the following performance tests.
TABLE 2 sources of reagents
Name of reagent | Manufacturer of the product |
DMEM/HIGH GLUCOSE(1×) | Hyclone |
German Fetal Bovine Serum (FBS) | GIBCO |
MTT | Amresco |
Trypsin | Biosharp |
PBS | Self-made |
Serum-free frozen stock solution | Bambanker |
DMSO | NANJING CHEMICAL REAGENT Co.,Ltd. |
Estradiol | MERYER |
Chloroform | Aladdin |
Isopropanol (I-propanol) | Aladdin |
Ethanol | Aladdin |
RNAiso Plus | takara |
PrimeScrip RT reagent Kit with gDNA Eraser | takara |
SYBR Premix Ex Taq | takara |
Table 3 is the source of the instruments used for the following performance tests.
TABLE 3 Instrument sources
Pharmacological (proliferation promoting) experiment of compound
Since the HHDPC cell proliferation-promoting assay can be used to preliminarily evaluate the inhibitory effect of the compound on androgenic alopecia in vitro, an in vitro HHDPC antiproliferative assay was performed on some of the synthesized compounds herein.
1. Experimental materials and cell culture
1.1 rejuvenation of HHDPC cells
The vial was removed from the liquid nitrogen and immediately placed in a 37 ℃ water bath with gentle shaking. After the liquid is melted. The cell suspension was pipetted into a centrifuge tube and centrifuged for 5min at 1000 rpm. The supernatant was decanted and 2ml of medium was added to blow the cells. The cell suspension was then pipetted into a T25 flask, 3ml of medium was added, and the medium was incubated in a 5% CO2 incubator and changed once a day.
1.2 passage of HHDPC cells
When the cell coverage rate in the culture dish reaches 80% -90%, the original culture medium is poured. Adding appropriate trypsin in 5% CO2Digesting in an incubator for 1-2 min. After digestion was complete, 2ml of medium was added to stop digestion. Cells were blown up with a pipette. The cell suspension was transferred to a centrifuge tube and centrifuged for 5min at 1000 rpm. And pouring off the supernatant, and adding 1-2 ml of culture medium. The cell suspension was divided into 2T 25 flasks and the culture was continued.
2. MTT method for measuring cell proliferation rate
2.1 cell plating: digesting HHDPC cells in logarithmic growth phase with trypsin to prepare cell suspension with concentration of 1-10 × 104/ml, inoculating 3000-5000 cells per well into 96-well plate, adding 100 μ l per well, and placing in 5% CO2The cells were incubated in an incubator at 37 ℃ overnight for attachment and the marginal wells were filled with sterile PBS.
2.2, adding medicine: and (3) observing the adherence of the cells under a mirror, adding each medicament, incubating for 48h, and marking each group with the final concentration of 10 mu M of the sample. Each sample concentration was set to 3 replicates.
2.3 MTT reaction: mu.l MTT solution (5mg/ml, i.e.0.5% MTT) was added to all wells and incubated for 4h in the incubator.
2.4 DMSO dissolution: carefully remove the supernatant, add 150. mu.l DMSO to each well, and shake the well at a low speed (120-140 rpm/min) in a shaker to dissolve the crystals sufficiently.
2.5 absorbance measurement: the 490nm light absorption was determined using a microplate reader.
Table 4 shows the results of the proliferative activity of HHDPC cell lines.
TABLE 4 results of the proproliferative Activity of HHDPC cell lines
Compound | Proliferation Rate (%) |
XHA1701 | 11.275 |
XHA1702 | 13.865 |
XHA1703 | 27.374 |
XHA1704 | 14.728 |
XHA1705 | 12.951 |
XHA1706 | 14.119 |
Clacoterone | 30.168 |
The HHDPC cell line was obtained from Kyoki Biotechnology, Inc. of Jiangsu, and Clacoterone example was used as a control group.
Research results show that the compound of the invention has better proliferation promoting activity on HHDPC cells.
(II) RT-PCR method for testing AR receptor expression
By combining HHDPC cell proliferation promotion experiments, we select a compound XHZ1703 with better activity from the HHDPC cell proliferation promotion experiments, and test the inhibition effect of the compound on the transcription level of the AR target gene by using an RT-PCR technology and Clascoterone as a positive control.
1. Extraction of RNA
After the HHDPC cells were treated, the medium was removed, the cells were washed once with PBS in a six-well plate, the PBS was removed, 1ml of trizol was added, and the trizol was left at room temperature for 2min and transferred to an RNase-free EP tube. Adding chloroform 200ul, shaking vigorously for 15s, standing at room temperature for 15min, centrifuging (4 deg.C, 12,000g,15min), separating the supernatant into three layers, and carefully sucking the colorless supernatant into a new EP tube. Adding equal volume of isopropanol, mixing by turning upside down, standing at room temperature for 5min, and centrifuging (4 deg.C, 12,000g,10 min). The supernatant was removed, and the precipitate was added to 1ml of 75% ethanol, shaken gently for 15s, and centrifuged (4 ℃,7,500g, 5min). Carefully removing supernatant, and blowing, standing and drying the precipitate in the tube for 3-5 min in an ultra-clean bench. Dissolving in 50 μ l DEPC water, and storing in refrigerator at-80 deg.C.
2. Synthesis of cDNA
Reverse transcription Experimental procedure following the reverse transcription kit protocol (takara, RR047), the extracted RNA was first prepared as the reaction solution required for reverse transcription on ice and left to react at room temperature for 10 min. Then according to the operation of the reverse transcription kit specification, reagents such as buffer, reverse transcriptase, reverse transcription random primer and the like are added into the reaction solution, and the reaction solution is placed into a PCR instrument for reverse transcription to synthesize cDNA, wherein the conditions are that the temperature is 37 ℃ for 15min and the temperature is 85 ℃ for 5 s.
3. Fluorescent quantitative PCR
The synthesized cDNA was used as a template, and PCR amplification was performed in a Stepone plus fluorescent quantitative PCR apparatus according to the SYBR qPCR mix protocol. GAPDH was used as an internal control and was quantitated using SYBR Green I dye. Wherein the forward sequence of the AR primer is: CCAGGGACCATGTTTTGCC, reverse sequence: CGAAGACGACAAGATGGACAA, respectively; the forward sequence of the internal reference primer is as follows: AGGTCGGTGTGAACGGATTTG, reverse sequence: GGGGTCGTTGATGGCAACA are provided.
The results show that the compound XHZ1703 in the patent has obvious down-regulation effect on the mRNA level of AR, and the effect is equivalent to that of a positive drug.
Claims (8)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein,
R1selected from alkoxy with 1-6 carbon atoms, alkyl with 1-3 carbon atoms, hydrogen, hydroxyl, amino and substituted or unsubstituted benzylamine group;
R2selected from acyl with 1-6 carbon atoms, alkyl with 1-3 carbon atoms, hydrogen and trifluoromethyl.
2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of:
n- (4-fluorophenylmethyl) -3-oxo-androst-4-ene-17 alpha- (1-oxopropoxy) -17 beta-carboxamide
N- (3-fluorophenylmethyl) -3-oxo-androst-4-ene-17 alpha- (oxopropoxy) -17 beta-carboxamide
N- (3, 5-difluorobenzyl) -3-oxo-androst-4-ene-17 alpha- (1-oxopropoxy) -17 beta-carboxamide
N- (4-trifluoromethylsulfanyl benzyl) -3-oxo-androst-4-ene-17 alpha- (1-oxopropoxy) -17 beta-carboxamide
N- (4-trifluoromethylbenzyl) -3-oxo-androst-4-ene-17 alpha- (1-oxopropoxy) -17 beta-carboxamide
N- (3-trifluoromethylbenzyl) -3-oxo-androst-4-ene-17 alpha- (1-oxopropoxy) -17 beta-carboxamide
3. A pharmaceutical composition comprising one or more compounds according to claim 1 or 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
5. the process for preparing a compound according to claim 4, or a pharmaceutically acceptable salt thereof, comprising the steps of:
taking a compound 1 as a raw material, firstly carrying out oxidation reaction with periodic acid to obtain a compound 2; then carrying out esterification reaction on the compound 2 and propionic anhydride to obtain a compound 3, and finally carrying out condensation reaction on the compound 3 and various benzylamines under the catalysis of a condensing agent HATU and triethylamine to obtain a compound of a general formula (I); or also by salt-forming reaction to obtain the medicinal salt of the compound.
6. A process for preparing a compound according to claim 4, wherein compound 1 is 17 α, 21-dihydroxy-pregn-4-ene-3, 20-dione, compound 2 is 3-oxo-androst-4-ene-17 α -hydroxy-17 β -carboxylic acid, and compound 3 is 3-oxo-androst-4-ene-17 α - (1-oxopropoxy) -17 β -carboxylic acid, or a pharmaceutically acceptable salt thereof.
7. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of acne.
8. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of androgenetic alopecia.
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