WO2014059740A1 - 四环蒽醌衍生物 - Google Patents
四环蒽醌衍生物 Download PDFInfo
- Publication number
- WO2014059740A1 WO2014059740A1 PCT/CN2013/000233 CN2013000233W WO2014059740A1 WO 2014059740 A1 WO2014059740 A1 WO 2014059740A1 CN 2013000233 W CN2013000233 W CN 2013000233W WO 2014059740 A1 WO2014059740 A1 WO 2014059740A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ethoxy
- ethyl
- propyl
- oxo
- pyridin
- Prior art date
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- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 title 1
- 150000004056 anthraquinones Chemical class 0.000 title 1
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- -1 (tetrahydropyran-2-yl)oxy Chemical group 0.000 claims description 296
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- 125000000217 alkyl group Chemical group 0.000 claims description 117
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 83
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- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 45
- 125000000623 heterocyclic group Chemical group 0.000 claims description 43
- 229910052760 oxygen Inorganic materials 0.000 claims description 43
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 42
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 23
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
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- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 4
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- IWZKICVEHNUQTL-UHFFFAOYSA-M potassium hydrogen phthalate Chemical compound [K+].OC(=O)C1=CC=CC=C1C([O-])=O IWZKICVEHNUQTL-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- CBFZWGRQXZYRRR-UHFFFAOYSA-N pyridin-4-amine;hydrochloride Chemical compound Cl.NC1=CC=NC=C1 CBFZWGRQXZYRRR-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229940116353 sebacic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- JDVPQXZIJDEHAN-UHFFFAOYSA-N succinamic acid Chemical compound NC(=O)CCC(O)=O JDVPQXZIJDEHAN-UHFFFAOYSA-N 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- XKKDQIAPTPFIGW-UHFFFAOYSA-N tert-butyl n-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCOCCOCCOCCO XKKDQIAPTPFIGW-UHFFFAOYSA-N 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005031 thiocyano group Chemical group S(C#N)* 0.000 description 1
- 125000003396 thiol group Chemical class [H]S* 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000005152 trihalomethanesulfonyl group Chemical group 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/044—Pyrrole radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Definitions
- This application relates to the field of organic compounds and medicinal chemistry.
- the present application relates to tetracyclic indole derivatives and methods for their preparation and use.
- Tetracyclic antibiotics are widely used anticancer drugs, especially doxorubicin and daunorubicin.
- Doxorubicin has significant effects on many solid tumors, including liver cancer, stomach cancer, breast cancer, lung cancer, ovarian cancer, and various blood cancers.
- Daunorubicin is one of the most effective drugs for the treatment of leukemia.
- their clinical use is limited due to side effects such as severe bone marrow suppression, cardiotoxicity, and adverse effects of the digestive tract.
- many of their derivatives have been isolated or artificially synthesized from nature. Overview
- One aspect of the present application relates to a compound of formula (I), and a pharmaceutically acceptable salt thereof,
- R 1 is selected from H, an optionally substituted alkyl group or an optionally substituted alkoxy group
- R 2 is selected from H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (alkyleneoxy) m alkyl, optionally substituted heterocyclyl, optionally substituted alkyl or optionally substituted acyl bunk ;
- R 3 is selected from H, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted (alkyleneoxy) malkyl group, an optionally substituted heterocyclic group, an optionally substituted alkyl group or an optionally substituted sulfonyl group. ;
- NR 2 R 3 represents an optionally substituted heterocyclic group
- n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 1 1 ;
- W is selected from O or NH
- R 4 is selected from H, F or an optionally substituted alkyl group
- R 5 is selected from H, F, optionally substituted alkyl or OR 6 , wherein R 6 is selected from H or an optionally substituted tetrahydropyran-2-yl;
- n is selected from 1, 2 or 3.
- Another aspect of the present application relates to a compound of the formula (I) and a pharmaceutically acceptable salt thereof,
- R 1 is selected from H, C M alkyl or d. 4 alkoxy
- R 2 is selected from H, aryl, heteroaryl, (C M alkyloxy) m C M alkyl, heterocyclic, d. 4 alkyl or acyl;
- R 3 is selected from the group consisting of H, aryl, heteroaryl, (CM alkyleneoxy) M C M alkyl, heterocyclic, C, -4 alkyl or sulfonyl;
- NR 2 R 3 represents a heterocyclic group
- n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or U;
- W is selected from O or NH
- R 4 is selected from H, F or CM alkyl
- R 5 is selected from H, F, C M alkyl or OR 6 wherein R 6 is selected from H or tetrahydropyran-2-yl; n is selected from 1, 2 or 3.
- a further aspect of the application relates to a compound selected from the group consisting of
- Another aspect of the present application relates to a process for the preparation of a compound of formula (I), which comprises:
- R 1 is selected from H, C M alkyl or d. 4 alkoxy
- R 2 is selected from H, aryl, heteroaryl, (d. 4 alkyleneoxy) md .4 alkyl, heterocyclyl, C M alkyl or sulfonyl
- R 3 is selected from H, aryl, heteroaryl, (C M alkyloxy) m CM alkyl, heterocyclyl, (alkyl Or a hydrazide; or NR 2 R 3 represents a heterocyclic group
- m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11
- W is selected from 0 or NH
- R 5 is selected from H, F, C M alkyl or OR 6 , wherein R 6 is selected from H or tetrahydropyran-2-yl
- n is selected from 1, 2 or 3;
- the group represented by RW, R 4 and R 5 in the compound represented by the formula ( ⁇ ) is the same as the group represented by R 1 W, R 4 and R 5 in the compound represented by the formula (I);
- n in the compound represented by the formula (III) has the same meaning as n in the compound represented by the formula (I); and the group represented by R 7 and R 8 in the compound represented by the formula (III) and In the compound represented by the formula (I), the groups represented by R 2 and R 3 are the same, provided that the substituent represented by R 7 and R 8 does not contain NH or NH 2 ; when R 7 and R 8 represent When the substituent contains NH or NH 2 , the compound represented by the formula (III) has an amino-protecting group at the N-terminus and is subjected to a deprotection reaction to obtain a compound represented by the formula (I).
- a further aspect of the present application relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- a further aspect of the present application relates to a formulation comprising a compound of the formula (I) or a medicament thereof Acceptable salts, as well as pharmaceutically acceptable carriers.
- Another aspect of the present application relates to a method of treating and/or preventing a tumor and/or cancer comprising administering to a subject in need of the method a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, Or administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, or a therapeutically effective amount of a compound comprising formula (I) Or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier preparation.
- the compounds of the present application and their salts have good anticancer and/or antitumor activity at the cellular level, have good water solubility and stability, are well tolerated in animals, and are thus easily developed into clinical drugs.
- Figure 1 shows the effect of 3,-pyrrolidinomycin on the body weight of experimental animals.
- Figure 2 shows the effect of the compound of Example 96 of the present application on the body weight of experimental animals.
- Figure 3 shows the effect of 3,-pyrrolidinomycin-14-oxo-succinic acid monoester on the body weight of experimental animals.
- C 7 -C 12 alkyl describes an alkyl group as defined below having a total of from 7 to 12 carbon atoms
- a C 4 -C 12 cycloalkylalkyl group is as defined below having a total of from 4 to 12 carbon atoms.
- Cycloalkylalkyl The total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.
- alkyl denotes a straight or branched hydrocarbon chain radical consisting solely of carbon and a hydrogen atom, containing no unsaturated bonds, having from one to twelve carbon atoms, preferably from one to eight carbons. An atom or one to six carbon atoms, and which is attached to the remainder of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl Base, 1,1 -didecylethyl (tert-butyl), 3-methylhexyl, 2-decylhexyl, and the like.
- the alkyl group may have from 1 to 12 carbon atoms (in each occurrence of the present application, a numerical range such as “1 to 12” refers to each integer in a given range; as “1 to 12” means The alkyl group may be up to and including 12 carbon atoms from 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., although this definition also encompasses the occurrence of the term "alkyl” in the unspecified range of values.
- the alkyl group may also be a medium size alkyl group having from 1 to 10 carbon atoms.
- the alkyl group may also be a lower alkyl group having 1 to 5 carbon atoms.
- the alkyl group of the compound of the present application can be designated as "C M alkyl” or the like.
- C M alkyl indicates the presence of from 1 to 4 carbon atoms in the alkyl chain, ie, the alkyl chain is selected from the group consisting of decyl, ethyl, propyl, isopropyl, n-butyl, isobutyl Base, sec-butyl or tert-butyl.
- the alkyl group can be optionally substituted, that is, substituted or unsubstituted.
- the substituent group is one or more groups selected individually and independently from the group consisting of: cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, Mercapto, alkylthio, arylthio, ⁇ , 13 ⁇ 4, carbonyl, carbonyl, 0-carbamoyl, N-carbamoyl, 0-thiocarbamoyl, N-thiocarbamoyl, C-acylamino, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, 0-carboxy, isocyanato, cyanide fluorenyl, isocalcocyanine 4 ⁇ Isothiocyanato, nitro, silyl, trihalodecanesulfonyl, -NR, R, or an amino group including a mono- and di-substituted amino group, and a protected derivative
- Typical hydrocarbyl groups include, but are not limited to, mercapto, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, propenyl, butenyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl and the like.
- substituent may be substituted by one of the above substituents.
- C M alkyl means an alkyl group as defined above containing one to four carbon atoms.
- the CM alkyl group can be optionally substituted as defined for the alkyl group.
- CM alkyl means an alkyl group as defined above containing one to six carbon atoms. d. The 6 alkyl group can be optionally substituted as defined for the alkyl group.
- Alkyl means an alkyl group as defined above containing one to twelve carbon atoms.
- the alkyl group may be optionally substituted as defined for an alkyl group.
- C 2 . 6 alkyl means a fluorenyl group as defined above containing two to six carbon atoms.
- the C 2 . 6 alkyl group can be optionally substituted as defined for the alkyl group.
- C 3-6 alkyl means an alkyl group as defined above containing three to six carbon atoms.
- the C 3 . 6 alkyl group can be optionally substituted as defined for the alkyl group.
- C 3 . 12 alkyl means an alkyl group as defined above containing three to twelve carbon atoms.
- the C 3 .12 alkyl group can be optionally substituted as defined for the alkyl group.
- C 6 . 12 alkyl means an alkyl group as defined above containing six to twelve carbon atoms.
- the C 6 .12 alkyl group can be optionally substituted as defined for the alkyl group.
- Cm alkyl means an alkyl group as defined above containing seven to twelve carbon atoms. C 7. 12 alkyl radical may be optionally substituted as defined embankment group.
- the alkyl group is C 12 alkyl.
- the alkyl group is C, .8 alkyl. In certain embodiments, the alkyl group is a C1-6 alkyl group.
- the alkyl group is an alkyl group.
- alkoxy refers to the formula -OR, wherein R is alkyl as defined above, such as decyloxy, ethoxy, n-propoxy, 1-methylethoxy (iso) Propyloxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, tert-pentyloxy and the like.
- the alkoxy group is C, -12 alkoxy.
- the alkoxy group is an alkoxy group.
- the alkoxy group is. ⁇ alkoxy.
- the alkoxy group is a CM alkoxy group.
- alkylene refers to a straight or branched divalent hydrocarbon chain consisting of only carbon and hydrogen and having from one to eight carbon atoms, linking the remainder of the molecule to the residue group, such as Aa Base, ethylene, propylene, n-butylene.
- the alkylene chain can be attached to the remainder of the molecule and to the residue group via one carbon in the chain or through any two carbons in the chain.
- the alkylene group is d. 12 alkylene.
- the alkylene group is a C 8 alkylene group.
- the alkylene group is ( ⁇ . 6 alkylene).
- the alkylene group is an alkylene group.
- alkoxy refers to the formula -OR, wherein R is alkylene as defined above, such as anthraceneoxy, ethyleneoxy, n-propoxy, isopropoxy Base, n-n-butoxy, iso-isobutoxy, sec-butyloxy, tert-butoxy, pentyleneoxy, tert-pentyloxy and the like.
- the alkyleneoxy group is a 0 ( ⁇ - 12 ) alkylene group.
- the alkyleneoxy group is a 0 (d. 8 ) alkylene group.
- the alkyleneoxy group is a 0 ( ⁇ .6) alkylene group.
- the alkyleneoxy group is 0 (( ⁇ . 4 ) alkylene.
- aryl refers to a carbocyclic ring (all carbon) having a fully delocalized pi-electron system or two or more fused rings (a ring sharing two adjacent carbon atoms).
- aryl groups include, but are not limited to, anthracenyl, phenyl, and naphthyl.
- the aryl group may have, for example, five to twelve carbon atoms.
- the aryl group of the present application may be substituted or unsubstituted.
- the hydrogen atom is replaced by one or more groups independently selected from the group consisting of: alkyl, cyclic hydrocarbon Base, aryl, heteroaryl, heteroalicyclic, hydroxy, protected hydroxy, alkoxy, aryloxy, decyl, alkylthio, arylthio, cyano, carbonyl, thiocarbonyl, O-carbamoyl, N-carbamoyl, 0-thiocarbamoyl, N-thioaminodecanoyl, C-amido, N-acylamino, S-sulfinylamino, N-sulfin Amido, C-carboxy, protected C-carboxyl, 0-carboxyl, isodecanoate, sulfothio, isothioantate, nitro, silyl, tri! 3 ⁇ 4 generation methanesulfonyl, -NR, R" (R, and R" are alkyl groups
- aryl is C 6. 18 aryl group.
- the aryl group is a C 6 .12 aryl group.
- the aryl group is a C 6.1 ( aryl ) group.
- Heteroaryl aromatic heterocyclic
- a heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system which can comprise a fused or bridged ring system; and a nitrogen, carbon or sulfur atom in the heteroaryl group Optionally oxidized; the nitrogen atom can optionally be quaternized.
- Examples include, but are not limited to, aza, acridinyl, benzimidazolyl, benzothiazolyl, benzindenyl, benzodioxolanyl, benzofuranyl, benzoxazolyl, benzo Thiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxanyl, 1,4-benzodioxanyl, benzonaphthylfuranyl, benzodioxolan Cyclic, benzodioxyl, benzopyranyl, benzopyranone, benzofuranyl, benzofuranone, harmlessylthiophene, benzotriazolyl, benzo[4, 6]Imidazo[1,2-a]pyridyl, oxazolyl, porphyrinyl, dibenzofuranyl, dibenzothiophenyl, furyl, furanone, isothiazolyl, imidazolyl, carbazole Base
- heteroaryl is intended to include a heteroaryl group which may be optionally substituted by one or more substituents independently selected from the group consisting of alkyl, cycloalkyl, aryl.
- the alkyl group defined in the formula or the protected amino group.
- the heteroaryl is ⁇ 5 -18 heteroaryl.
- the heteroaryl is (: 5 12 heteroaryl.
- the heteroaryl is ( 5.1 () heteroaryl.
- heterocyclyl refers to a stable three to twelve membered non-aromatic cyclic group consisting of a carbon atom and one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
- heterocyclyl groups include, but are not limited to, dioxocyclopentyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, VIII Hydroquinone, octahydroisodecyl, 2-oxopiperrazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4 -piperidone, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, trithiaalky
- heterocyclyl is intended to include a heterocyclyl radical as defined above which is optionally substituted by one or more groups selected from the group consisting of cycloalkyl, aryl, heteroaryl.
- Base heteroalicyclic, hydroxy, alkoxy, aryloxy, decyl, alkylthio, arylthio, decyl, carbonyl, thiodecyl, 0-carbamoyl, N-aminodecanoyl , O-thioaminodecanoyl, N-thioaminodecanoyl, C-amido, N-acylamino, S-sulfonamido, N-sulfonamido, C-carboxy, 0-carboxy, iso Cyanate, thiocyano, isothiodecanoate, nitro, silane group, trihalomethanesulfonyl, -NR, R" (R, and R" are alkyl groups as defined in the present application) or include Amino groups including mono- and di-substituted amino groups, and protected derivatives thereof.
- the heterocyclic group is (: 3 -18 heterocyclyl.
- the heterocyclic group is (: 312 heterocyclyl.
- the heterocyclic group is C 3. 1Q heterocyclyl.
- “Arbitrary” or “arbitrarily” means that the condition of the subsequent description may or may not occur, and that the statement includes the occurrence or non-occurrence of the event or condition.
- “optionally substituted aryl” means that the aryl group may or may not be substituted, and the description includes substituted aryl groups and unsubstituted aryl groups.
- “Pharmaceutically acceptable carrier” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, which has been approved by the U.S. Food and Drug Administration for use in humans or animals. Preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers, etc., which have no side effects on the composition of the pharmaceutical composition.
- the form of the carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, which has been approved by the U.S. Food and Drug Administration for use in humans or animals. Preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers, etc.
- “Pharmaceutically acceptable salts” include “pharmaceutically acceptable acid addition salts” and “pharmaceutically acceptable base addition salts”.
- “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free base, which are biologically or otherwise suitable and which are formed using inorganic or organic acids.
- the inorganic acid is, for example but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.
- the organic acid is, for example but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, Aspartic acid, harmless sulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, citric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclohexyl Alkyl sulfamic acid, dodecyl sulphate, ethane-1
- “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acid, which are biologically or otherwise suitable. These salts are prepared by adding an inorganic or organic base to the free acid, including but not limited to salts derived from inorganic bases. Sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Preferred inorganic salts are the ammonium, sodium, potassium, calcium and magnesium salts.
- Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, salts of cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, Tridecylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimercaptoethanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, refined ammonia Acid, histidine, caffeine, procaine, seabamin, choline, betaine, benzylamine, phenethylenediamine, ethylenediamine, glucosamine, decyl glucosamine, theobromine, triethanolamine , tromethamine, hydrazine, piperazine, piperidine, N-ethylpiperidine, polyamine resin,
- “Pharmaceutical composition” refers to a formulation of a compound of the present invention and a medium which is generally accepted in the art for delivery of a biologically activating compound to a mammal such as a human.
- Such media include all pharmaceutically acceptable carriers, diluents or excipients.
- “Therapeutically effective amount” means that when administered to a mammal, preferably to a human, the compounds of the present invention are sufficient to effectively treat (as defined below) the amount of tumor and/or cancer in a mammal, preferably a human.
- the amount of the compound of the present application which constitutes a “therapeutically effective amount” will vary depending on the compound, the state of the disease and its severity, and the age of the mammal to be treated, but those skilled in the art will be able to rely on their own knowledge and the present disclosure.
- the formula determines the amount of the compound of the present application.
- treating encompasses a mammal having a related disease or condition, preferably a treatment-related disease or condition in a human, and includes:
- In vivo administration can be carried out in a single administration, continuous or intermittent administration (e.g., administration at appropriate intervals in divided doses) throughout the course of treatment.
- Methods for determining the most effective mode of administration and dosage are well known to those skilled in the art and will vary with the formulation used for the treatment, the purpose of the treatment, the target cells being treated, and the individual being treated. Single or multiple administrations can be performed, and the dosage level and mode are selected by the attending physician. detailed description
- the present application relates to a compound of formula (I) and a pharmaceutically acceptable salt thereof
- R 1 is selected from H, an optionally substituted alkyl group or an optionally substituted alkoxy group
- R 2 is selected from H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (alkyleneoxy) m alkyl, optionally substituted heterocyclyl, optionally substituted alkyl or optionally substituted Yi
- R 3 is selected from H, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted (alkyleneoxy) malkyl group, an optionally substituted heterocyclic group, an optionally substituted alkyl group or an optionally substituted sulfonyl group. ;
- NR 2 R 3 represents an optionally substituted heterocyclic group
- n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 1 1 ;
- W is selected from 0 or NH
- R 4 is selected from H, F or an optionally substituted alkyl group
- R 5 is selected from H, F, optionally substituted alkyl or OR 6 , wherein R 6 is selected from H or an optionally substituted tetrahydropyran-2-yl;
- n is selected from 1, 2 or 3.
- the present application relates to a compound of formula (I), and pharmaceutically acceptable salts thereof,
- R 1 is selected from H, alkyl or d. 4 alkoxy
- R 2 is selected from H, aryl, heteroaryl, (C M alkyleneoxy) m C M alkyl, heterocyclic, C M alkyl or acyl;
- R 3 is selected from H, aryl, heteroaryl, (C M alkyleneoxy) m C M alkyl, heterocyclic, alkyl or sulfonyl;
- NR 2 R 3 represents a heterocyclic group
- n is selected from 0, 1, 2, 3, 4, 5, 6> 7, 8, 9, 10 or 11;
- W is selected from O or NH
- R 4 is selected from H, F or C M alkyl
- R 5 is selected from H, F, C M alkyl or OR 6 wherein R 6 is selected from H or tetrahydropyran-2-yl; n is selected from 1, 2 or 3.
- R 1 is selected from H or OCH 3 .
- W is selected from o.
- the compound of formula (I), in R 4 is selected from CH 3.
- R 5 is selected from OH or (tetrahydropyran-2-yl)oxy.
- R 2 is selected from the group consisting of H, decyl, ethyl, (morpholinylmethyl)phenyl, 4-((morphinolin-1-yl)methyl)phenyl, (dimethylaminomethyl)phenyl, 4-((dimethylamino)indenyl)phenyl , 2-(2-(didecylamino)ethoxy)ethyl, morpholine-1-yl, piperidin-1-yl, tetrahydropyrrole-1-yl, 4-(2-hydroxyethyl) Piperazin-1-yl, (4-methylpiperazine)-1-yl, (4-ethylpiperazine)-1-yl, 2-(tetrahydropyrrol-1-yl)ethyl, 3- ( Tetrahydropyrrol-1-yl)propyl, (2-(morpholine-1-yl)pyridine)-4-yl, (2-(morpholine-1-yl)propyl, (2-(morph
- 2-(Diethylamino)ethyl 2 2-(dipropylamino)ethyl, 2-(piperidin-1-yl)ethyl, 2-(morpholine-1-yl)ethyl, 2- ( Tetrahydropyrrol-1-yl)ethyl, 3-(diamino)propyl, 3-(diethylamino)propyl, 3-(dipropylamino)propyl, 3-(piperidin-1-yl )propyl, 3-(morpholine-1-yl)propyl,
- R 3 is selected from the group consisting of H, methyl, ethyl,
- 2-(Diethylamino)ethyl 2 2-(dipropylamino)ethyl, 2-(piperidin-1-yl)ethyl, 2-(morpholine-1-yl)ethyl, 2- ( Tetrahydropyrrol-1-yl)ethyl, 3-(diamino)propyl, 3-(diethylamino)propyl, 3-(dipropylamino)propyl, 3-(piperidin-1-yl )propyl, 3-(morpholine-1-yl)propyl,
- the compound of formula (I) wherein NR 2 R 3 is selected from the group consisting of piperidin-1-yl, morpholine-1-yl, tetrahydropyrrolidin-1-yl, (4-(2- Hydroxyethyl)) piperazin-1-yl, (4-indolyl)piperazin-1-yl, ( 4 -ethyl)piperazine-1-yl, ( 4 -propyl)piperazin-1-yl , 4 _(3-hydroxypropyl)piperazin-1-yl, 3-(morpholine-1-yl)propyl, adenine-1-yl, (4-(3-(dimethylamino)propyl) Piperazine)-1-yl, (4-(2-(dimethylamino)ethyl)piperazine) small group, (4-(3-(diethylamino)propyl)piperazine)-1-yl , (4-(2-(diethylamino
- the present application is directed to a compound selected from the group consisting of
- the present application relates to a process for the preparation of a compound of formula (I), which comprises:
- R 1 is selected from H, C M alkyl or d. 4 alkoxy; R 2 is selected from
- R 3 is selected from H, aryl, heteroaryl, (C M alkyloxy)alkyl, heterocyclyl, ( ⁇ . 4 alkyl or decanoyl;
- R 3 is selected from H, aryl, heteroaryl, (C M Alkyleneoxy) m C 4 alkyl, heterocyclyl, 1-4 alkyl or acyl; or NR 2 R 3 represents heterocyclyl;
- m is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 1 1 ;
- W is selected from O or NH;
- R 4 is selected from H, F or C M pit base;
- R 5 is selected from H, F, d. 4 alkyl or OR 6 , Wherein R 6 is selected from H or tetrahydropyran-2-yl; n is selected from 1, 2 or 3;
- the method of preparing a compound of formula (I) further comprises adding an activator.
- activators that can be used in the process of the present invention for preparing compounds of formula (I) include, but are not limited to, N-hydroxysuccinimide (HOSu), hydroxy-7-azobenzotriazine Oxazole (HOAt), 1-hydroxybenzotriazole (HOBt), N-hydroxyphthalimide (NHPI), N-hydroxy-1,8-naphthalimide (NHNI), pentafluoro Phenol (PFPOH), 2-(7-azobenzotriazole)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylurea hexafluorophosphate (HATU), harmless triazole-N,N ,N,,N,-tetradecylurea hexafluorophosphate (HBTU), 6-chlorobenzotriazole-1,1,3,3-tetradecylurea hexafluorophosphate (HCTU), 0- (7-Azabenzotriazol-1-yl)-bis(t
- PyAOP diphenylphosphinyl chloride
- DPP A diphenyl azide
- DECP diethyl decyl phosphate
- BOP-C1 bis(2-oxo-3-oxazolidinyl)phosphoryl chloride
- the method of preparing a compound of formula (I) further comprises adding a catalyst.
- Illustrative examples of the catalyst which can be used in the process for producing the compound of the formula (I) of the present application include, but are not limited to, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, and a mixture thereof.
- nitrogen protecting groups that can be used in the process of the present invention for preparing compounds of formula (I) include, but are not limited to, Fmoc ( ⁇ oxycarbonyl), Boc (tert-butoxycarbonyl), CBZ (benzyloxy) Carbonyl), Tr (triphenylsulfonyl) or Alloc (allyloxycarbonyl), Teoc (trimethylsilyloxycarbonyl), oxime oxycarbonyl, ethoxycarbonyl, Pht (o-phthaloyl), Tos (pair Methanesulfonyl), Ns (o/p-nitrophenylsulfonyl), Tfa (trifluoroacetyl), pivaloyl, benzoyl, Trt (triphenyl), Dmb (2,4-dimethyl Oxybenzyl), PMB (p-methoxybenzyl), Bn (benzyl).
- deprotecting reactants that can be used in the process of the present invention for preparing a compound of formula (I) include, but are not limited to, hydrogen, NH 3 , aminoethanol, dimethylamine, diethylamine, piperidine, Piperazine, DBU, hydrochloric acid, phosphoric acid, acetic acid, citric acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and mixtures thereof.
- the compound of formula (III) is prepared from a compound of formula (IV) and is reacted with HNR 7 R 8 in a process for preparing a compound of formula (I).
- n in the compound represented by the formula (IV) has the same meaning as n in the compound represented by the formula (I);
- R 2 and R 3 in HNR 7 R 8 is the same as the group represented by R 2 and R 3 in the compound represented by the formula (I).
- the method of preparing a compound of formula (III) further comprises adding an alkaline compound.
- Illustrative examples of the basic compound which can be used in the method for producing a compound represented by the formula (III) of the present application include, but are not limited to, triethylamine, pyridine, diisopropylethylamine, tridecylamine,
- N-methylpyrrolidine N-methylpiperidine, N-decylmorpholine, N-ethylpyrrolidine, N-ethylpiperidine, N-ethylmorpholine and mixtures thereof.
- the present application relates to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
- R 1 is selected from H, C M alkyl or C M alkoxy
- R 2 is selected from the group consisting of H, aryl, heteroaryl, (d. 4 alkyleneoxy) m C M alkyl, heterocyclic,
- Ci 4 alkyl or sulfonyl
- R 3 is selected from H, aryl, heteroaryl, (d. 4 alkyleneoxy) m C M alkyl, heterocyclic, C M alkyl or sulfonyl;
- NR 2 R 3 represents a heterocyclic group
- n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 1 1 ;
- W is selected from O or NH
- R 4 is selected from H, F or C M alkyl
- R 5 is selected from H, F, C M alkyl or OR 6 wherein R 6 is selected from H or tetrahydropyran-2-yl; n is selected from 1, 2 or 3.
- the present application relates to a formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
- R 1 is selected from H, C 1-4 alkyl or C 1-4 alkoxy
- R 2 is selected from H, aryl, heteroaryl, (C 4 alkyleneoxy) M C M alkyl, heterocyclic, CM alkyl or sulfonyl;
- R 3 is selected from the group consisting of H, aryl, heteroaryl, (C M alkyleneoxy) m C M alkyl, heterocyclic group, C, .4 alkyl or sulfonyl;
- NR 2 R 3 represents a heterocyclic group
- n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 1 1 ;
- W is selected from O or NH
- R 4 is selected from H, F or C M alkyl
- R 5 is selected from H, F, C M alkyl or OR 6 wherein R 6 is selected from H or tetrahydropyran-2-yl; n is selected from 1, 2 or 3.
- the formulation comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier is an injectable formulation.
- formulations that can be used in the present application include, but are not limited to, conventional powder needles, frozen powder needles, water needles, emulsions, solutions, and suspensions.
- the present application relates to a method of treating and/or preventing a tumor and/or cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, Or administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, or a therapeutically effective amount of a compound comprising formula (I) Or a pharmaceutically acceptable salt thereof, and a formulation of a pharmaceutically acceptable carrier,
- R 1 is selected from H, C M alkyl or C M alkoxy
- R 2 is selected from H, aryl, heteroaryl, (C M alkyleneoxy) m C M alkyl, heterocyclic, C M alkyl or acyl;
- R 3 is selected from H, aryl, heteroaryl, (d. 4 alkyleneoxy) m C M alkyl, heterocyclic, C M alkyl or sulfonyl;
- NR 2 R 3 represents a heterocyclic group
- n is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 1 1 ;
- W is selected from 0 or NH
- R 4 is selected from H, F or C M alkyl
- R 5 is selected from H, F, CM alkyl or OR 6 wherein R 6 is selected from H or tetrahydropyran-2-yl; n is selected from 1, 2 or 3.
- tumors and/or cancers that can be treated and/or prevented using the methods described herein include, but are not limited to, liver cancer, gastric cancer, breast cancer, lung cancer, colon cancer, ovarian cancer, pancreatic cancer, head and neck cancer, cervix Cancer, kidney cancer, melanoma, prostate cancer, glioma, various blood cancers, lymphoma, and multiple osteoarthritis.
- the compounds of the present application and their salts have good anticancer and/or antitumor activity at the cellular level, have good water solubility and stability, are well tolerated in animals, and are thus easily developed into clinical drugs.
- succinimide Bt: benzotriazin-1-yl; At: 7-azobenzotriazol-1-yl; Fmoc: oxime oxycarbonyl; Boc: tert-butoxycarbonyl; CBZ: benzyloxycarbonyl; Tr: tridecylphenyl; Alloc: allyloxycarbonyl; DBU: 1,8-diazacyclo[5,4,0]undecene-7; DIEA: diisopropyl Dethyl 4-aminopyridinium chloride; Nitrobenzotriazole; DCC: dicyclohexylcarbinimine; DIC: hydrazine, hydrazine-diisopropylcarbodiimide.
- NCI-H446 human small cell lung cancer cell line; BxPC-3: human pancreatic cancer cell line; SK-OV-3: human ovarian cancer cell line; MDA-MB-453: human breast cancer cell line; 22Rvl: human prostate cancer Cell line; A375: human skin melanoma cell line; A431: human epidermal cancer cell line; MCF-7: human breast cancer cell line; NCI-446: human small cell lung cancer cell line; NCI-H460: human large cell lung cancer cell line B16: mouse melanoma cell line; 786-0: human 1 clear cell adenocarcinoma cell line; DU-145: prostate cancer cell line; Hep3B: liver cancer cell line; SK-Br-3: human breast cancer cell line; MTT: tetrazolium blue; McCoy's 5A: McCoy's 5A Medium; FBS: fetal bovine serum; PBS: phosphate buffer, pH 7.4; EDTA: ethylenediaminetetraacetic
- reaction solution was suction filtered, and the filtrate was concentrated, and then ethyl acetate (400 mL) and distilled water (400 mL) was dissolved, and the mixture was allowed to stand for separation, the organic layer was discarded, and the aqueous phase was washed with dichloromethane. After (100 mL X 3), adjust the pH to 9 with NaOH solids. A large amount of brown solid precipitated in the solution, suction filtration, and the filter cake was rinsed with distilled water (20 mL x 2), and the filtrate was treated with sodium hydroxide (NaOH).
- NaOH sodium hydroxide
- N,N-Dimercapto(4-nitrophenyl)methanamine (4.553 g) was added to a reaction flask, dissolved in absolute ethanol (50 mL), and acetic acid (5.2 mL) was added, and mechanical stirring was started.
- Iron powder (11.339g) was added to IN in HC1 (40 mL) for 10 min. After suction filtration, the filter cake was rinsed with absolute ethanol and added to the reaction flask. The oil bath was heated to reflux and maintained at reflux until the end of the reaction. About 35 minutes). After the reaction, the reaction solution was suction filtered, and the filter cake was washed with anhydrous ethanol.
- the filtrate was concentrated, and then distilled water (100 mL) was added thereto, and the pH was adjusted to 14 with NaOH, and a large amount of precipitation was observed, and the filtrate was filtered with dichloromethane (100).
- mL X 1) the aqueous phase is discarded, distilled water (60 mL) is added to the organic phase, and the pH is adjusted to 2 with 2N HCl. After mixing, the mixture is allowed to stand for separation, the organic phase is discarded, and the aqueous phase is adjusted to pH with NaOH.
- Dimethylamine hydrochloride (U6.1 g) was added to the reaction flask, and distilled water (60 mL) was added to dissolve it; after cooling in an ice bath, a 20% aqueous sodium hydroxide solution (284, 8 g) was added dropwise to the reaction flask. Medium (takes 70 min); after completion of the dropwise addition and stirring for 20 min, tert-butyl-bis(2-p-toluenesulfonylethyl)carbamate (73.2 g) was used in tetrahydrofuran (200 mL) Dissolve and add to the reaction flask and at 40. Stir under C oil bath until the end of the reaction.
- the reaction mixture was concentrated and ethyl acetate (250 mL) and distilled water (200 mL), allowed to stand after mixing liquid separation, and the organic phase was washed with saturated aqueous NaCl (150 mL) washed once after 30 min was dried over anhydrous MgS0 4
- the crude product was concentrated by filtration.
- the crude product was recrystallized from absolute ethanol to give the title compound.
- Preparation 18 2-(2-(2-(2-tert-butoxyethoxy)ethoxy)ethoxy)ethylamine 2-(2-(2-(2-(2-)-tert-butyl) Oxyethoxy)ethoxy)ethyl)isoindole-1,3-dione (193.515 g) was added to the reaction flask, and tetrahydrofuran (350 mL) was added to dissolve it, and 25% was added. An aqueous solution of guanamine (127.410 g) was dissolved by mechanical stirring at room temperature and allowed to react overnight. The reaction will be carried out in an oil bath 40.
- Diammine hydrochloride (40.766 g) was added to the reaction flask, and distilled water (60 mL) was added to dissolve it, and the mixture was cooled in an ice bath.
- a 20% aqueous sodium hydroxide solution (101.464 g) was added dropwise to the reaction flask, and then The solution obtained in Preparation Example 22 was placed in a reaction flask, and stirred at 40 ° C in an oil bath until the end of the reaction. After the reaction mixture was concentrated to remove tetrahydrofuran, dichloromethane (200 mL) was added, and the mixture was separated, and the mixture was partitioned. The aqueous phase was discarded, and the organic phase was added to distilled water (100 mL).
- Example 76 10-((3,-(pyrrole-1-yl)-2,3,6,3-trideoxy-alphal-L-lais-hexanyl) Oxygen)-7,8 ,9,10-tetrahydro-6,8,1 1-trihydroxy-13-oxo-14-(4-(2-(2-(dimethylamino)ethoxy)ethylamino)-4- Oxo-butyrate-based 1-methoxy-5,12-naphthalenedione acetate 10 mg of the target compound obtained in Example 6 was dissolved in 10 ml of chloroform, dissolved by stirring, and 1 mg of aqueous acetic acid was dissolved. 10 ml of chloroform was dropped into the reaction flask, stirring was continued for 10 minutes, and the solvent was removed by rotary evaporation to obtain the target compound.
- Example 77 10 - ((3 - (pyrrol-1-yl) -2, 3,, 6, - trideoxy -alphal-L- lyxo - hexyl pyranyl) oxy) 7,8 ,9,10-tetrahydro-6,8,1 1-trihydroxy-13-oxo- 14-(4-((4-(2-hydroxy)ethyl)piperazine)
- Example 78 10-((3,-(pyrrol-1-yl)-2,3,6,3-trioxo-alphal-L-laisu -hexylpyranyl)oxy)-7,8,9,10-tetrahydro-6,8,1 1-trihydroxy-13-oxo-14-(4-((3-(morpholine-1-) () propyl) amino) -4-oxo-butyrate) - 1-methoxy-5, 12-naphthalenedione acetate
- Example 79 10-((3,-(pyrrol-1-yl)-2,3,6,-trideoxy-alphal-L-laisu- Hexylpyranyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-((4-methyl)piperazin-1- (amino)-4-oxo-butyrate)-1-methoxy-5,12-naphthalenedione acetate
- Example 80 10-((3, -(pyrrole-1-yl)-2,3,6,-trideoxy-alphal-L-lais-hexanyl) Oxygen)-7,8 ,9,10-tetrahydro-6,8,11-trihydroxy- 13-oxo-14-(4-(4-ethylpiperazin-1-yl)-4-oxo-butyrate) 1-methoxy-5,12-caiedione acetate
- the solubility of this compound in water is greater than 11 mg/mL.
- Example 81 10-((3,-(pyrrole-yl)-2,,3,,6,-trideoxy-alphal-L-lasu-hexidine ⁇ )oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-((3-(4-mercaptopiperazine)) Propyl)amino)-4-oxo-butyrate)-1-decyloxy-5,12-naphthalenedione acetate
- the solubility of this compound in water is greater than 7 mg/ml.
- Example 82 10-((3, -(pyrrole-1-yl)-2,3,6,3-trideoxy-alphal-L-lysyl-hexanyl) Oxygen)-7,8 , 9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-((pyridin-4-yl)indolyl)amino)-4-oxo-butyrate 1-methoxy-5,12-naphthalenedione acetate The solubility of this compound in water is greater than 6 mg/mL
- Example 83 10-((3,-(pyrrol-1-yl)-2, ,3,6,-trideoxy-alphal-L-lais-hexanyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo -14-(4-((pyridin-3-yl)methyl)amino)-4-oxo-butanoate)-1-methoxy-5,12-naphthalened
- Example 84 10-((3, -(pyrrole-1-yl)-2,3,6,3-trideoxy-alphal-L-lais-hexanyl) Oxygen)-7,8 ,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-(2-(pyridin-2-yl)ethyl)amino)-4-oxo-butyric acid Esteryl)-1-nonyloxy-5,12-naphthalenedione acetate The solubility of this compound in water is greater than 12 mg/ml.
- Example 85 10-((3,-(pyrrol-1-yl)-2,3,6,3-trideoxy-alphal-L-lysyl-hexanyl) Oxygen)-7,8 ,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-(2-(pyridin-3-yl)ethyl)amino)-4-oxo-butyric acid Esteryl)-1-methoxy-5,12-naphthalenedione acetate The solubility of this compound in water is greater than 11 mg/ml.
- Example 86 10-((3, -(pyrrole-1-yl)-2,3,6,3-trideoxy-alphal-L-lysyl-hexanyl) Oxygen)-7,8 ,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-(2-(pyridin-4-yl)ethyl)amino)-4-deutero-butyric acid Ethyl)-1-methoxy-5,12-naphthalenedione acetate
- the solubility of the compound in water is greater than 3 mg/mh.
- Example 87 10-((3, -(pyrrole-1-yl)-2,3,6,-trideoxy-alphal-L-laisu- Hexylpyranyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-(4-(3-(diamino)propyl) Base) piperazin-1-yl)-4-oxo-butyrate)-1-decyloxy-5,12-naphthalenedione acetate
- the solubility of this compound in water is greater than 16 mg/mL.
- Example 99 10-((3,-(pyrrole-yl)-2,3,6,-trideoxy-alphal-L-lysyl-hexanyl)oxy)-7,8,9 ,10-tetrahydro-6,8,11-trihydroxy-13-oxo-14-(4-((2-(morpholine-1-yl)ethyl)amino)-4-oxo-butyric acid
- Example 1 SK-OV-3 cell growth inhibition test (MTT test) 1. Experimental materials:
- Cell line SK-OV-3 (human ovarian cancer cell line); MTT; antitumor compound; DMSO.
- PC OD value after normal growth of control well cells without compound
- n OD value after growth of the experimental well cells after the addition of the compound
- NC Background OD value of blank wells without compound and cells. Table 2.
- Example 35 57.8 Example 38 67.6 Example 40 47.9 Example 44 52.3
- Example 60 58.9 Example 62 63.6
- Example 64 65.9
- Example 66 66.5
- Example 76 46.4
- Example 77 60.4
- Example 81 56.4
- Example 94 71.4 Example 95 66.3
- Example 2 BxPc-3 cell growth inhibition test (MTT assay)
- BxPC-3 human pancreatic cancer cell line
- MTT antitumor compound
- DMSO DMSO
- PC OD value after normal growth of control well cells without compound
- n OD value after growth of the experimental well cells after the addition of the compound
- NC Background OD value of blank wells without compound and cells. Table 3. Inhibition activity of some compounds in the examples on BxPc-3 cells at 2000 nM
- NCI-H446 human small cell lung cancer cell line
- MTT antitumor compound
- DMSO DMSO
- PC OD value after normal growth of control well cells without compound
- n OD value after growth of the experimental well cells after the addition of the compound
- NC Background OD value of blank wells without compound and cells. Table 4. Growth inhibition activity of some compounds in NCI-H446 cells at 222 nM
- Example 4 MDA-MB-453 cell growth inhibition test (SRB test) First, the experimental materials:
- Cell line MDA-MB- 453 (human breast cancer cell line); SRB: 0.4% (w/v) working solution formulated with 1% aqueous acetic acid, stored at 4 ° C; antitumor compound; DMSO.
- PC OD value after normal growth of control well cells without compound
- n OD value after growth of the experimental well cells after the addition of the compound; NC: Background OD value of blank wells without compound and cells. Table 5. Growth inhibitory activity of some compounds in the examples on MDA-MB-453 cells at 2000 nM
- Cell line 22Rvl (human prostate cancer cell line); SRB: 0.4% (w/v) working solution was prepared with 1% aqueous acetic acid, 4. Preservation under C; antitumor compound; DMSO.
- PC OD value after normal growth of control well cells without compound
- n OD value after growth of the experimental well cells after the addition of the compound
- NC Background OD value of blank wells without compound and cells. Table 6. Growth inhibition activity of 22Rvl cells in 222 nM in some examples
- Example 6 A375 cell growth inhibition test (MTT assay)
- Cell line A375 (human skin melanoma cell line); MTT: tetrazolium blue; antitumor compound; Compound A: 3,-pyrrolidinomycin-14-oxo-succinic acid monoester; DMSO.
- MTT tetrazolium blue
- antitumor compound Compound A: 3,-pyrrolidinomycin-14-oxo-succinic acid monoester
- DMSO 3,-pyrrolidinomycin-14-oxo-succinic acid monoester
- PC OD value after normal growth of control well cells without compound
- n OD value after growth of the experimental well cells after the addition of the compound
- NC Background OD value of blank wells without compound and cells. Table 7. Growth inhibitory activity of some compounds on A375 cells in the examples Inhibitory activity inhibiting activity inhibiting active compound compound
- Cell line A431 (human epidermal cancer cell line); MTT: tetrazolium blue; antitumor compound; Compound A: 3,-pyrrolidinomycin-14-oxo-succinic acid monoester; DMSO.
- PC OD value after normal growth of control well cells without compound
- n OD value after growth of the experimental well cells after the addition of the compound
- NC Background OD value of blank wells without compound and cells.
- Table 8 Growth inhibitory activity of some compounds on A431 cells in the examples
- Example 8 MCF-7 cell growth inhibition test (SRB test) 1. Experimental materials:
- Cell line MCF-7 (human breast cancer cell line); SRB: formulated with 1% glacial acetic acid
- PC OD value after normal growth of control well cells without compound
- n OD value after growth of the experimental well cells after the addition of the compound
- NC Background OD value of blank wells without compound and cells. Table 9. Growth inhibitory activity of some compounds on MCF-7 cells in the examples
- Example 9 NCI-446 cell growth inhibition test (MTT assay) 1. Experimental materials:
- NCI-446 human small cell lung cancer cell line
- MTT tetrazolium blue
- antitumor compound Compound A: 3,-pyrrolidinomycin-14-oxo-succinic acid monoester
- DMSO 3,-pyrrolidinomycin-14-oxo-succinic acid monoester
- PC OD value after normal growth of control well cells without compound
- n OD value after growth of the experimental well cells after the addition of the compound
- NC Background OD value of blank wells without compound and cells. Table 10. Growth inhibition activity of some compounds in the examples on NCI-446 cells
- Example 10 NCI-H460 cell growth inhibition test (MTT test) 1. Experimental materials:
- Cell line NCI-H460 (human large cell lung cancer cell line); MTT: tetrazolium blue; antitumor compound; Compound A: 3,-pyrrolidinomycin- 14-oxo-succinic acid monoester; DMSO.
- MTT tetrazolium blue
- antitumor compound Compound A: 3,-pyrrolidinomycin- 14-oxo-succinic acid monoester
- DMSO 3,-pyrrolidinomycin- 14-oxo-succinic acid monoester
- PC OD value after normal growth of control well cells without compound
- n OD value after growth of the experimental well cells after the addition of the compound
- NC Background OD value of blank wells without compound and cells. Table 11. Growth inhibition activity of some compounds in the examples on NCI-460 cells
- Example 1 1 B16 cell growth inhibition test (MTT test) First, the experimental materials:
- Cell line B16 (mouse melanoma cell line); MTT: tetrazolium blue; antitumor compound; Compound A: 3,-pyrrolidinomycin-14-oxo-succinic acid monoester; DMSO.
- MTT tetrazolium blue
- antitumor compound Compound A: 3,-pyrrolidinomycin-14-oxo-succinic acid monoester
- DMSO 3,-pyrrolidinomycin-14-oxo-succinic acid monoester
- PC OD value after normal growth of control well cells without compound
- n OD value after growth of experimental well cells after compound addition
- NC Background OD value of blank wells without compound and cells. Table 12. Growth inhibition activity of some compounds on B16 cells in the examples Inhibitory activity inhibiting activity inhibiting active compound compound
- Cell line 786-0 (human kidney clear cell adenocarcinoma cell line); MTT: tetrazolium blue; antitumor compound; compound A: 3,-pyrrolidinomycin-14-oxy-succinic acid monoester; DMSO.
- MTT tetrazolium blue
- antitumor compound compound A
- compound A 3,-pyrrolidinomycin-14-oxy-succinic acid monoester
- DMSO 3,-pyrrolidinomycin-14-oxy-succinic acid monoester
- PC OD value after normal growth of control well cells without compound
- n OD value after growth of the experimental well cells after the addition of the compound
- NC Background OD value of blank wells without compound and cells. Table 13. Growth inhibition activity of some compounds on 786-0 cells in the examples
- Example 13 DU-145 cell growth inhibition test (MTT test) 1. Experimental materials:
- Cell line DU-145 (prostate cancer cell line); MTT: tetrazolium blue; antitumor compound; Compound A: 3,-pyrrolidinomycin-14-oxo-succinic acid monoester; DMSO.
- MTT tetrazolium blue
- antitumor compound Compound A: 3,-pyrrolidinomycin-14-oxo-succinic acid monoester
- DMSO 3,-pyrrolidinomycin-14-oxo-succinic acid monoester
- PC OD value after normal growth of control well cells without compound
- n OD value after growth of the experimental well cells after the addition of the compound
- NC Background OD value of blank wells without compound and cells. Table 14. Growth inhibitory activity of some compounds on DU-145 cells in the examples
- Example 14 Hep3B cell growth inhibition test (SRB test) 1. Experimental materials:
- Cell line Hep3B (hepatoma cell line); SRB: 0.4% (w/v) working solution was prepared with 1% aqueous acetic acid, 4. Preservation under C; antitumor compound; Compound A: 3,-pyrrolidinomycin - 14-oxo-succinic acid monoester; DMSO.
- the OD value was measured at 13.570 nM.
- PC OD value after normal growth of control well cells without compound
- n OD value after growth of the experimental well cells after the addition of the compound
- NC Background OD value of blank wells without compound and cells. Table 15. Inhibition activity of some compounds in the examples on Hep3B cell growth
- Cell line SK-Br-3 (human breast cancer cell line); SRB: 0.4% (w/v) working solution was prepared with 1% glacial acetic acid, 4. Preservation under C; antitumor compound; Compound A: 3'-pyrrolidinomycin-14-oxo-succinic acid monoester; DMSO.
- PC OD value after normal growth of control well cells without compound
- n OD value after growth of experimental well cells after compound addition
- NC Background OD value of blank wells without compound and cells. Table 16. Growth inhibitory activity of some compounds on SK-Br-3 cells in the examples Compound A 93 Example 98 15 MTD (maximum tolerated dose) experiment in mice
- mice ICR mice, weighing 18-22 g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., license number: SCXK (Beijing) 2007-0001.
- Dosing regimen Each experimental animal is given a corresponding dose of the test substance every three days, once every dose is scheduled to be administered 5 times. The specific number of administrations depends on the animal condition, and the animals are observed in detail within 2 hours after administration. Performance, the performance of the animals was observed every 4 hours on the day after administration, and the survival of the animals was recorded daily, weighed, and observed for abnormalities on the surface. The experimental animals were sacrificed on the 14th day after withdrawal and dissected.
- Test compound 1 3,-pyrrolidinomycin:
- Group I (20mg/kg) group
- Group II (25mg/kg) group
- Group III (30mg/kg) group
- Group IV solvent control group
- Test compound 1 had an MTD of less than 20 mg/kg (0.0338 mmol/kg) under the q4d X 5 regimen.
- Test compound 2 Compound of Example 96
- Group I (40mg/kg) group
- Group II (45 mg/kg) group
- Group III (50mg/kg) group
- Group IV (55 mg/kg) group
- Group V (60 mg/kg) group
- Test compound 2 had an MTD of 50-55 mg/kg (0.0525-0.0578 mmol/kg) under the q4d X 5 dosing regimen.
- Test compound 3 3,-pyrrolidinomycin -14-oxo-succinic acid monoester
- Group I (30mg/kg) group
- Group II (40mg/kg) group
- Group III (50mg/kg) group
- Group IV (60 mg/kg) group
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CN104628602B (zh) * | 2015-02-05 | 2016-08-17 | 宋和璇 | 四甲基二乙烯三胺基甲酸盐类化合物及其制备方法和应用 |
WO2019140417A1 (en) * | 2018-01-15 | 2019-07-18 | Daly Thomas P | Aminopyridine based buffers with wide buffering ranges antibiotics and myelin disease therapy |
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US20120308646A1 (en) * | 2007-01-18 | 2012-12-06 | Hesheng Zhang | Tetracyclic anthraquinones possessing anti-cancer properties |
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