CN117715907A - 10-substituted-1-azaphenothiazine derivative and application thereof - Google Patents

10-substituted-1-azaphenothiazine derivative and application thereof Download PDF

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CN117715907A
CN117715907A CN202180098067.1A CN202180098067A CN117715907A CN 117715907 A CN117715907 A CN 117715907A CN 202180098067 A CN202180098067 A CN 202180098067A CN 117715907 A CN117715907 A CN 117715907A
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compound
alkyl
pharmaceutical composition
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endometrial cancer
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毛斐
王玉东
伍慧雯
孙笑
刘小虎
李丽娟
宋鸰沂
李剑
李晓康
朱进
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China Welfare Institute International Peace Maternal And Child Health Institute China Welfare Institute International Peace Medical Development Center
East China University of Science and Technology
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China Welfare Institute International Peace Maternal And Child Health Institute China Welfare Institute International Peace Medical Development Center
East China University of Science and Technology
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
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Abstract

A10-substituted-1-azaphenothiazine derivative and application thereof are disclosed, wherein the structure of the derivative is shown in a formula (I), and each substituent group is defined in the specification and the claims. The 10-substituted-1-azaphenothiazine derivative has remarkable proliferation inhibition effect on endometrial cancer cells, can inhibit clone formation and migration of endometrial cancer cells, induce apoptosis of endometrial cancer cells, and inhibit growth of subcutaneous transplantation tumor of nude mice in vivo. Therefore, the 10-substituted-1-azaphenothiazine derivative provided by the invention is expected to be used for preparing medicines for treating and/or preventing endometrial cancer.

Description

10-substituted-1-azaphenothiazine derivative and application thereof Technical Field
The invention relates to the fields of pharmaceutical chemistry and pharmacotherapeutics, in particular to a 10-substituted-1-azaphenothiazine derivative, a preparation method and application thereof.
Background
Endometrial cancer (Endometrial Cancer, EC) is a group of epithelial malignancies occurring in the endometrium, one of the most common gynaecological malignancies in the world, with both increased morbidity and mortality. Although EC is more common in postmenopausal women, in the last decade, the incidence of EC in young women has increased dramatically, with younger and younger women diagnosed with endometrial cancer, the root cause of the increased incidence being the prevalence of obesity and the resulting hyperinsulinemia, with the incidence of endometrial cancer rising as well. In 2015, the China newly increased about 63400 EC cases and about 21,800 EC death cases.
EC is generally classified into type I and type II, with the main difference being that type I EC progestogen receptor is positive for expression and type II EC progestogen receptor is negative for expression. Surgical treatment is currently the usual method of treating EC, but for patients who need to retain fertility, conservative treatment methods are needed, the main method of conservative treatment being hormonal therapy with progestogens. However, hormone therapy has limitations in that it is effective only for patients positive for the expression of the progestogen receptor and has a high recurrence rate, and is liable to develop drug resistance. With the full opening of policies for both the second and third-case, there is an increasing need for conservative treatments for younger EC patients that preserve fertility. Therefore, development of new EC therapeutic drugs is urgent.
Disclosure of Invention
The object of the present invention is to provide a class of EC therapeutic agents.
It is another object of the present invention to provide the use of the above-mentioned compounds for the preparation of a medicament for the treatment and/or amelioration of endometrial cancer.
In a first aspect of the invention, there is provided a compound of formula I, or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein n is 2, 3, 4, 5 or 6;
R 1 is H, hydroxy, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, nitroso, amino, formyl, acetyl or cyano;
R 2 A 6-14 membered heterocyclic group which is substituted or unsubstituted, said heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of: n, O, S; the substitution means having one or more substituents selected from the group consisting of: -COOC 1 -C 6 Alkyl, -C 1 -C 6 Alkylene C 6 -C 10 Aryl, oxo (=o), C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -COC 1 -C 6 Alkyl, -C 1 -C 6 Alkylene 5-7 membered heteroaryl, C 6 -C 10 Aryl, 5-7 membered heteroaryl, -C 1 -C 6 Alkylene halogeno C 6 -C 10 Aryl, C 3 -C 8 Cycloalkyl groups.
In another preferred embodiment, R 1 Is H, hydroxy, F, cl, br, methyl, ethyl, n-propyl, isopropyl, C 1 -C 4 Fluoroalkyl, methoxy, ethoxy.
In another preferred embodiment, R 2 A 7-12 membered spiroheterocyclyl or bridged heterocyclyl, substituted or unsubstituted, said spiroheterocyclyl or bridged heterocyclyl containing 1, 2 or 3 heteroatoms selected from the group consisting of: n, O; the substitution means having 1, 2, 3 or 4 substituents selected from the group consisting of: -COOC 1 -C 4 Alkyl, -C 1 -C 2 Alkylene phenyl, oxo (=o), C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, -COC 1 -C 4 Alkyl, -C 1 -C 2 Alkylene 5-7 membered heteroaryl, C 6 -C 10 Aryl, 5-7 membered heteroaryl, -C 1 -C 2 Alkylene halogeno C 6 -C 10 Aryl, C 3 -C 6 Cycloalkyl groups.
In another preferred embodiment, the spiroheterocyclyl is s 1 、s 2 、s 3 、s 4 Each independently 1, 2 or 3; z is CH 2 Or NH.
In another preferred embodiment, the bridged heterocyclic group isn 1 、n 2 、n 3 、n 4 Each independently is 0, 1, 2 or 3.
In another preferred embodiment, R 2 Is of the formula I-2 or I-3,
A 1 、A 2 、A 3 、A 4 each independently selected from: n, O, S, -CO (CH) 2 ) p -、-(CH 2 ) m -、-(CH 2 ) m O-、-(CH 2 ) m S-; m, p are each independently 0, 1, 2 or 3;
x is CH, N or O;
n 1 、n 2 、n 3 、n 4 each independently 0, 1, 2 or 3;
R 3 is H, -COOC 1 -C 6 Alkyl, -C 1 -C 6 Alkylene C 6 -C 10 Aryl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -COC 1 -C 6 Alkyl, -C 1- C 6 Alkylene 5-7 membered heteroaryl, C 6 -C 10 Aryl, 5-7 membered heteroaryl, -C 1 -C 6 Alkylene halogeno C 6 -C 10 Aryl, C 3 -C 8 Cycloalkyl groups.
In another preferred embodiment, R 3 Is H, t-butyloxycarbonyl, C 1 -C 4 Alkyl, chlorobenzyl, benzyl, -CH 2 -6-membered nitrogen containing heteroaryl, -COC 1 -C 4 Alkyl or C 2 -C 4 Alkynyl groups.
In another preferred embodiment, the compound is selected from the group consisting of:
in a second aspect of the present invention, there is provided a pharmaceutical composition comprising:
(1) A compound of the first aspect, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and (2) a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition further comprises an additional pharmaceutically acceptable ingredient that is an anti-endometrial cancer drug. In another preferred embodiment, the anti-endometrial cancer drug is a progestin. In another preferred embodiment, the progestogen is one or a combination of two or more of megestrol acetate, medroxyprogesterone acetate, or progesterone caproate.
In another preferred embodiment, the pharmaceutical composition is an injection, a tablet, a capsule, a pill, a suspension or an emulsion.
In another preferred embodiment, the pharmaceutical composition is in the form of an oral dosage form, a transdermal dosage form, an intravenous or intramuscular injection.
In a third aspect of the present invention there is provided the use of a compound according to the first aspect or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second aspect, for the manufacture of a medicament for the treatment and/or prophylaxis of endometrial cancer.
In a fourth aspect, the present invention provides a method for preparing a compound according to the first aspect, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to the following synthetic strategy:
the method comprises the following specific steps:
1) Dissolving different 4-substituted or unsubstituted 2-amino thiophenols in acetonitrile, slowly adding potassium tert-butoxide under ice bath, stirring for 30min, slowly adding 2-chloro-3-nitropyridine, reacting at room temperature for 2 hr, filtering, retaining filter cake, evaporating solvent under reduced pressure, dissolving the residue with ethanol, filtering, mixing filter cakes, and drying in infrared drying oven overnight to obtain intermediate II A (II B Or II C )。
2) Adding the intermediate II into a round bottom flask A (II B Or II C ) Filtering the reaction solution of acetic anhydride and pyridine at room temperature, retaining a filter cake, adding water into the filtrate to precipitate a product, filtering, combining the filter cakes, placing the filter cake into an infrared drying oven, and drying at about 90 ℃ overnight to obtain an intermediate III A (III B Or III C )。
3) Adding intermediate III to a round bottom flask A (III B Or III C ) Acetone, KOH and ethanol, at about 60 ℃ for 2h, column chromatography purification (petroleum ether: ethyl acetate=10:1) to intermediate iv A (Ⅳ B Or IV C )。
4) Adding the intermediate IV into a round bottom flask A (Ⅳ B Or IV C ) Reacting with concentrated hydrochloric acid and ethanol overnight at about 80deg.C, evaporating solvent under reduced pressure, adding ammonia water, and filtering to obtain pale yellow solid intermediate V A (Ⅴ B Or V (V) C )。
5) Intermediate V A (Ⅴ B Or V (V) C Or 10H-pyrido (3, 2-b) (1, 4) benzothiazine are respectively reacted with dibromoalkane with different chain lengths to obtain an intermediate VI A (ⅤI B Or VI C Or VI D Or VI E Or VI F )。
6) Key intermediate VI A (ⅤI B Or VI C Or VI D Or VI E Or VI F ) Respectively reacts with different amines to obtain different derivatives X01-19 and X27-35.
7) Adding trifluoroacetic acid and dichloromethane into X02, reacting for 2 hours at room temperature to obtain X19, and then respectively reacting X19 with different R 3 Cl reaction, addition of K 2 CO 3 And acetonitrile, reflux overnight at 60℃to give the different derivatives X20-26.
In a fifth aspect of the invention, there is provided a method of treating endometrial cancer comprising administering to a subject in need thereof a compound of the first aspect, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. Each feature disclosed in the description may be replaced by alternative features serving the same, equivalent or similar purpose. And are limited to a space, and are not described in detail herein.
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FIG. 1 is a schematic representation of the effect of compound X32 on ISK and KLE cell clone formation. (a) ISK cell crystal violet staining; (B) KLE cell crystal violet staining; (C) quantification of ISK cell crystal violet staining; (D) quantification of crystal violet staining of KLE cells; data are mean ± SD, p <0.05, p <0.01, p <0.001, p <0.0001vs Ctrl,One-way ANOVA.
FIG. 2 is a schematic of the effect of compound X32 on the migration capacity of ISK and KLE cells. (a) ISK cell crystal violet staining; (B) quantification of ISK cell crystal violet staining; (C) KLE cell crystal violet staining; (D) quantification of crystal violet staining of KLE cells; data are mean ± SD, p <0.05, p <0.01, p <0.001, p <0.0001vs Ctrl,One-way ANOVA.
FIG. 3 is a schematic of the effect of compound X32 on apoptosis of ISK and KLE cells. (a) effect on ISK apoptosis; (B) effect on KLE apoptosis; (C) quantitative proportion of ISK apoptosis; (D) quantification of the proportion of KLE apoptosis; data are mean ± SD, p <0.05, p <0.01, p <0.001, p <0.0001vs Ctrl,One-way ANOVA.
FIG. 4 is a graph showing the effect of compound X32 on the central nervous system of mice. Data are mean ± SEM, p <0.05, p <0.01, p <0.001, p <0.0001vs Vehicle,one-way ANOVA.
FIG. 5 is a graph showing the growth inhibition effect of compound X01 on mouse subcutaneous KLE cell transplantation tumor. (a) a profile of body weight of mice as a function of time of administration; (B) tumor volume 14 days after administration; (C) tumor pictures of mice 14 days after administration; (D) tumor weight 14 days after administration; data are mean ± SEM, p <0.05, p <0.01, p <0.001, p <0.0001vs Vehicle,one-way ANOVA.
Detailed Description
Through extensive and intensive studies, the inventors of the present application have found that a class of 10-substituted-1-azaphenothiazine derivatives having anti-endometrial cancer activity has a remarkable proliferation inhibition effect on EC cells, and can inhibit clone formation and migration of EC cells, induce apoptosis of EC cells, and inhibit growth of subcutaneous transplantation tumor of nude mice in vivo. On this basis, the present invention has been completed.
Terminology
The terms used in the present invention have the following meanings.
In the present invention, the term "C 1 -C 6 "means having 1, 2, 3, 4, 5 or 6 carbon atoms," C 1 -C 8 "means having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and so on. "5-7 membered" means having 5, 6 or 7 ring atoms, and so on.
"alkyl" refers to straight or branched chain alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
"alkylene" refers to a straight or branched chain saturated aliphatic group having the indicated number of carbon atoms and linking at least two other groups, i.e., a divalent hydrocarbon group. The two groups attached to the alkylene group may be attached to the same or different atoms on the alkylene group. For example, the linear alkylene group may be- (CH) 2 )q-Wherein q is 1, 2, 3, 4, 5 or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene.
The term "alkoxy" means-O- (C) 1 - 6 Alkyl) groups. For example, the term "C 1 -C 6 Alkoxy "refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms and includes, without limitation, methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, and the like.
The term "alkenyl" means a straight or branched hydrocarbon moiety containing at least one double bond, e.g., the term "C 2 -C 6 Alkenyl "refers to a straight or branched alkenyl group having 2 to 6 carbon atoms containing one double bond and includes, without limitation, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.
The term "alkynyl" refers to a straight or branched chain alkynyl group containing one triple bond and includes, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.
"cycloalkyl" means a saturated cyclic hydrocarbyl moiety such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
The term "aryl" means a hydrocarbyl moiety comprising one or more aromatic rings. For example, the term "C 6 -C 10 Aryl "refers to an aromatic cyclic group having 6 to 10 carbon atoms, such as phenyl, naphthyl, and the like, which does not contain a heteroatom in the ring.
In the present invention, the term "heteroaryl" means an aromatic cyclic group containing at least one (e.g., 1, 2, 3, or 4) ring heteroatom (e.g., N, O, or S), such as pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, pyridyl, pyrimidinyl, and the like.
The term "heterocyclyl" means a saturated or unsaturated, non-aromatic cyclic group containing at least one (e.g., 1, 2, 3 or 4) ring heteroatom (e.g., N, O or S), such as tetrahydropyridinyl, pyrrolinyl, dihydropyridinyl, dihydrofuranyl, dihydrothiophenyl, morpholinyl. The heterocyclic group may be a monocyclic heterocyclic ring, a polycyclic heterocyclic ring, and the polycyclic heterocyclic group includes spiro ring, condensed ring, and bridged ring.
"halogen" is F, cl, br or I.
The invention also includes pharmaceutically acceptable salts of the above compounds. The pharmaceutically acceptable salts of the 10-substituted-1-azaphenothiazine derivatives of the present invention are salts with inorganic or organic acids that retain the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, and the like; organic acid salts include, but are not limited to, formate, acetate, 2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalenedisulfonate, and the like. These salts can be prepared from the compounds of formula I by known salt formation methods.
The invention will be further illustrated in the following examples. These examples are only intended to illustrate the invention and do not limit the scope of the invention in any way. The experimental materials and reagents used in the following examples were obtained from commercial sources unless otherwise specified.
Example 1 intermediate II A 、Ⅱ B 、Ⅱ C Is prepared from
To a clean 500mL reaction flask was added acetonitrile 200mL,2 sequentially0.0g of 2-amino-4-chlorophenylthiol, slowly adding 14.1g of potassium tert-butoxide under ice bath, stirring for 30min, slowly adding 19.8g of 2-chloro-3-nitropyridine, after the addition, shifting to room temperature, reacting for 2h, monitoring the reaction to be complete by a TLC plate, filtering, retaining a filter cake, evaporating the filtrate under reduced pressure to remove the solvent, pulping the residual residue by ethanol, filtering, merging the filter cake, putting the filter cake into an infrared drying box, and drying at about 50 ℃ overnight to obtain a brown yellow solid which is II A Crude product.
1 H NMR(400MHz,Chloroform-d)δ8.55(dd,J＝3.9,1.9Hz,1H),8.51(dd,J＝8.2,1.8Hz,1H),7.38(d,J＝8.1Hz,1H),7.21(dd,J＝8.2,4.0Hz,1H),7.02(dd,J＝8.2,1.9 Hz,1H),6.96(d,J＝2.0Hz,1H).
Specific implementation procedure same as II A The difference is that the raw material 2-amino-4-chlorophenylthiol is changed into 2-amino-4-methoxy thiophenol to obtain a earthy yellow floccule II B Crude product.
1 H NMR(400MHz,DMSO-d 6 )δ8.63–8.55(m,2H),7.37(dd,J＝8.2,4.6Hz,1H),7.14(d,J＝8.4Hz,1H),6.31(d,J＝2.7Hz,1H),6.19(dd,J＝8.5,2.7Hz,1H),5.35(s,2H),3.72(s,3H).
Specific implementation procedure same as II A The difference is that the raw material 2-amino-4-chlorophenylthiol is changed into 2-amino-4-trifluoromethyl thiophenol, and the obtained earthy yellow solid is II C Crude product.
1H NMR(400MHz,DMSO-d6)δ8.66–8.54(m,2H),7.48(d,J＝7.9Hz,1H),7.42(dd,J＝8.2,4.7Hz,1H),7.02(d,J＝2.0Hz,1H),6.82(dd,J＝7.9,2.0Hz,1H),5.86(s,2H).
Example 2 intermediate III A 、Ⅲ B 、Ⅲ C Is prepared from
To a clean 250mL reaction flask was added 100mL acetic anhydride, 10.0g II in sequence A 2.0mL of pyridine, passing through the reaction solution at room temperature, monitoring the reaction completion by a TLC plate, filtering, reserving a filter cake, adding 500mL of water into the filtrate to precipitate a product, filtering, combining the filter cake, putting the filter cake into an infrared drying oven, and drying at about 90 ℃ overnight to obtain yellow solid III A Crude product.
1 H NMR(400MHz,CDCl3)δ8.01(dd,J＝4.8,1.6Hz,1H),7.26(dd,J＝7.6,2.0Hz,1H),6.95(d,J＝8.0Hz,1H),6.90(dd,J＝8.4,2.0Hz,1H),6.83(d,J＝2.0Hz,1H),6.79–6.76(m,1H),4.11(t,J＝6.4Hz,2H),3.61(t,J＝6.4Hz,2H),1.97–1.91(m,4H).
Specific implementation procedure is the same as III A Is different from the preparation of the raw material II A Change to II B Obtaining yellow solid as III B Crude product.
1 H NMR(400MHz,DMSO-d 6 )δ9.03(s,1H),8.62(dd,J＝8.3,1.6Hz,1H),8.55(dd,J＝4.7,1.6Hz,1H),7.64–7.57(m,1H),7.48–7.37(m,2H),6.80(dd,J＝8.6,2.8Hz,1H),3.80(s,3H),1.90(s,3H).
Specific implementation procedure is the same as III A Is different from the preparation of the raw material II A Change to II C Obtaining yellowThe solid is III C 。
1 H NMR(400MHz,DMSO-d 6 )δ9.40(s,1H),8.66(dd,J＝8.2,1.6Hz,1H),8.55(dd,J＝4.7,1.6Hz,1H),8.30(d,J＝2.0Hz,1H),7.81(d,J＝8.1Hz,1H),7.55(dd,J＝8.0,2.0Hz,1H),7.47(dd,J＝8.3,4.6Hz,1H),1.90(s,3H).
EXAMPLE 3 intermediate IV A 、Ⅳ B 、Ⅳ C Is prepared from
To a clean 250mL reaction flask was added acetone 100mL,10.0g III in sequence A 5.2g KOH and 1mL ethanol, heating to about 60 ℃, reacting for 2h, monitoring the reaction by TLC plate, cooling the reaction system to room temperature, decompressing, evaporating the solvent, purifying the residual residue by column chromatography (petroleum ether: ethyl acetate=10:1), obtaining yellow solid crude product IV A 。
Specific implementation procedure same as IV A Is different from the preparation of the raw material III A Change to III B Obtaining yellow solid IV B 。
1 H NMR(400MHz,DMSO-d 6 )δ8.50(dd,J＝4.8,1.7Hz,1H),8.12(dd,J＝7.8,1.7Hz,1H),7.97(d,J＝2.0Hz,1H),7.82(d,J＝8.2Hz,1H),7.68(dd,J＝8.4,2.0Hz,1H),7.45(dd,J＝7.9,4.8Hz,1H),3.75(s,3H),2.26(s,3H).
Specific implementation procedure same as IV A Is different from the preparation of the raw material III A Change to III C Obtaining yellow solid IV C 。
1 H NMR(400MHz,Chloroform-d)δ7.81(dd,J＝5.1,1.6Hz,1H),7.19(dd,J＝7.6,1.6Hz,1H),7.07(ddd,J＝8.1,1.8,0.8Hz,1H),7.00(d,J＝8.0Hz,1H),6.78–6.73(m,2H).
Example 4 intermediate V A 、Ⅴ B 、Ⅴ C Is prepared from
To a clean 250mL reaction flask was added 2g IV in sequence A 60ml of ethanol, 2ml of concentrated hydrochloric acid, heating to about 80 ℃, reacting overnight, monitoring the reaction by TLC plate, cooling the reaction system to room temperature, evaporating the solvent under reduced pressure, adding ammonia water, filtering to obtain pale yellow solid V A 。
1 H NMR(400MHz,DMSO-d6)δ9.34(s,1H),7.83(dd,J＝4.9,1.6Hz,1H),7.30(dd,J＝7.6,1.6Hz,1H),6.94(d,J＝8.2Hz,1H),6.86(d,J＝2.2Hz,1H),6.82(dd,J＝8.2,2.2Hz,1H),6.76(dd,J＝7.5,4.9Hz,1H).
The specific implementation steps are as follows A Is different from the preparation of the raw material IV A Change to IV B The yellow solid obtained was V B 。
1 H NMR(400MHz,Chloroform-d)δ7.72(d,J＝5.3Hz,1H),7.66(s,1H),7.24–7.19(m,1H),6.82(d,J＝8.5Hz,1H),6.72(t,J＝6.4Hz,1H),6.46(d,J＝8.6Hz,1H),6.24(d,J＝2.5Hz,1H),3.75(s,3H).
The specific implementation steps are as follows A Is different from the preparation of the raw material IV A Change to IV C The yellow solid obtained was V C 。
1H NMR(400MHz,Chloroform-d)δ7.81(dd,J＝5.1,1.6Hz,1H),7.19(dd,J＝7.6,1.6Hz,1H),7.07(ddd,J＝8.1,1.8,0.8Hz,1H),7.00(d,J＝8.0Hz,1H),6.79–6.70(m,2H).
Example 5 intermediate vi A 、ⅤI B 、ⅤI C 、ⅤI D 、ⅤI E 、ⅤI F Is prepared from
To a clean 100mL reaction flask was added sequentially 50mL of DMF, 10.0g of intermediate V A 20.1g of 1, 5-dibromopentane, 5.1g of potassium hydroxide, 1h of reaction at room temperature, TLC plate monitoring of reaction completion, addition of 150mL of water quenching reaction, extraction of ethyl acetate multiple times until no product point is reached in the aqueous phase, combination of the organic phases, one time with saturated brine, drying over anhydrous sodium sulfate, evaporation of the solvent under reduced pressure, and column chromatography purification of the remaining residue (petroleum ether: ethyl acetate=100:1, v/v) to give a pale yellow solid VI A 。
1 H NMR(400MHz,CDCl3)δ8.01(dd,J＝4.8,1.6Hz,1H),7.24(dd,J＝7.2,1.6Hz,1H),6.93–6.85(m,3H),6.77(dd,J＝7.6,4.8Hz,1H),4.08(t,J＝7.6Hz,2H),2.34(t,J＝7.2Hz,2H),1.86–1.78(m,2H),1.65–1.58(m,4H).
Specific implementation procedure same as VI A Is different from the preparation of the raw material V A Change to V B The yellow solid obtained is VI B 。
1 H NMR(600MHz,Chloroform-d)δ8.01(s,1H),7.35–7.27(m,1H),6.96(d,J＝8.4Hz,1H),6.78(s,1H),6.47(d,J＝2.3Hz,2H),4.12(p,J＝6.5,5.9Hz,2H),3.79(s,3H),3.42(t,J＝6.8Hz,2H),1.92(dt,J＝15.0,6.9Hz,2H),1.84(q,J＝7.6Hz,2H),1.63–1.56(m,2H).
Specific implementation procedure same as VI A Is different from the preparation of the raw material V A Change to V C The yellow solid obtained is VI C 。
1H NMR(400MHz,Chloroform-d)δ8.06(d,J＝4.9Hz,1H),7.34(d,J＝7.4Hz,1H),7.19(d,J＝8.0Hz,1H),7.14(d,J＝8.0Hz,1H),7.04(s,1H),6.86(dd,J＝7.4,4.9Hz,1H),4.19(t,J＝7.2Hz,2H),3.42(t,J＝6.7Hz,2H),1.96–1.87(m,2H),1.83(q,J＝7.5Hz,2H),1.61(dd,J＝10.4,5.0Hz,2H).
Specific implementation procedure same as VI A Is different from the preparation of the raw material V A Changing to 10H-pyrido (3, 2-b) (1, 4) benzothiazine gives a yellow solid as VI D 。
1 H NMR(400MHz,Chloroform-d)δ7.99(d,J＝4.9Hz,1H),7.24(dd,J＝7.5,1.8Hz, 1H),7.14(t,J＝7.8Hz,1H),7.05(dd,J＝7.6,1.6Hz,1H),6.91(t,J＝7.5Hz,1H),6.84(d,J＝8.2Hz,1H),6.78–6.68(m,1H),4.10(q,J＝8.3Hz,2H),3.42(t,J＝6.7Hz,2H),1.88(dp,J＝35.3,7.3Hz,4H),1.60(q,J＝8.0Hz,2H).
Specific implementation procedure same as VI A Except that 1, 5-dibromopentane was changed to 1, 4-dibromobutane to give a yellow oil VI E 。
1H NMR(400MHz,Chloroform-d)δ7.28(d,J＝3.5Hz,1H),6.98(d,J＝8.4Hz,2H),6.92(dd,J＝8.3,2.2Hz,1H),6.88–6.76(m,2H),4.13(t,J＝7.3Hz,2H),3.55–3.40(m,4H),2.04–1.95(m,2H).
Specific implementation procedure same as VI A Except that the starting material 1, 5-dibromopentane was changed to 1, 6-dibromohexane to give a yellow oil VI F 。
1 H NMR(400MHz,Chloroform-d)δ8.01(dd,J＝5.0,1.7Hz,1H),7.26–7.22(m,1H),6.94(d,J＝8.1Hz,1H),6.88(dd,J＝8.2,2.0Hz,1H),6.82–6.74(m,2H),4.11–4.01(m,2H),3.56–3.37(m,2H),1.91–1.75(m,4H),1.49(dt,J＝8.9,5.3Hz,4H).
Example 6 preparation of 10- (5- (3-azaspiro [5.5] undec-3-yl) pentyl) -8-chloro-10H-benzo [ b ] pyridine [2,3-e ] [1,4] thiazine (X01)
To a clean 50mL single neck round bottom flask was added 15mL acetonitrile, 200mg of intermediate VI in sequence A 、87mg K 2 CO 3 95mg of 3-azaspiro [5, 5]]Undecane was reacted at 60℃under reflux overnight, distilled under reduced pressure and purified by column chromatography (dichloromethanol: methanol=20:1, v/v) to give X01 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ7.93(dd,J＝4.9,1.6Hz,1H),7.16(dd,J＝7.5,1.7Hz,1H),6.86(d,J＝8.1Hz,1H),6.80(dd,J＝8.2,1.9Hz,1H),6.74–6.67(m,2H),3.97(t,J＝7.3Hz,2H),2.36(t,6H),1.74(p,J＝7.4Hz,3H),1.46(m,6H),1.40–1.31(m,8H),1.25(m,J＝7.0Hz,4H).HRMS(ESI)m/z calcd for C 26 H 34 ClN 3 S(M+H) + 456.2162,found 456.2242.
Example 7 9 preparation of tert-butyl 5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -3, 9-diazaspiro [5.5] undec-3-carboxylate (X02)
The procedure was followed as in example 6, except that the starting 3-azaspiro [5,5] undecane was changed to tert-butyl 3-methyl-3, 9-diazaspiro [5,5] undecane-3-carboxylate to give X02 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝5.0,1.7Hz,1H),7.24(d,J＝1.7Hz,1H),6.95(d,J＝8.2Hz,1H),6.88(dd,J＝8.2,1.9Hz,1H),6.80–6.75(m,2H),4.05(t,J＝7.1Hz,2H),3.37(t,J＝5.9Hz,4H),2.75(m,4H),1.83(m,J＝7.6Hz,8H),1.45(m,17H).HRMS(EI)m/z calcd for C 30 H 41 ClN 4 O 2 S(M + )556.2639,found 556.2630.
Example 8 7 preparation of tert-butyl 5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -2, 7-diazaspiro [4.4] nonane-2-carboxylate (X03)
The procedure was followed as in example 6, except that the starting 3-azaspiro [5,5] undecane was changed to tert-butyl 2, 7-diazaspiro [4.4] nonane-2-carboxylate to give yellow oil X03.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.88(dd,J＝8.2,1.9Hz,1H),6.80–6.75(m,2H),4.05(t,J＝7.2Hz,2H),3.44–3.22(m,5H),2.58(m,4H),1.94–1.77(m,6H),1.68(m,4H),1.46(m,11H).HRMS(EI)m/z calcd forC 28 H 37 ClN 4 O 2 S(M + )528.2326,found 528.2322.
Example 9 8 preparation of tert-butyl 5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -2, 8-diazaspiro [4.5] decane-2-carboxylate (X04)
The procedure was followed as in example 6, except that the starting 3-azaspiro [5,5] undecane was changed to tert-butyl 2, 8-diazaspiro [4.5] decan-2-carboxylate to give X04 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.88(dd,J＝8.1,2.0Hz,1H),6.81–6.74(m,2H),4.05(t,J＝7.2Hz,2H),3.38(dt,J＝21.4,7.1Hz,2H),3.17(d,J＝33.0Hz,2H),1.90–1.55(m,13H),1.46(s,14H).HRMS(EI)m/z calcd for C 29 H 39 ClN 4 O 2 S(M + )542.2842,found 542.2478.
Example 10 preparation of tert-butyl 4- (5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -1-oxo-4, 9-diazaspiro [5.5] undec-9-carboxylate (X05)
The procedure was followed as in example 6, except that the starting 3-azaspiro [5,5] undecane was changed to tert-butyl 1-oxa-4, 9-diazaspiro [5.5] undecane-9-carboxylate to give X05 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.25–7.21(m,1H),6.94(d,J＝8.1Hz,1H),6.88(dd,J＝8.2,1.9Hz,1H),6.81–6.74(m,2H),4.05(t,J＝7.2Hz,2H),3.70(m,4H),3.12(m,2H),2.43–2.07(m,6H),1.80(d,J＝7.5Hz,3H),1.62(m,3H),1.46(m,16H).HRMS(EI)m/z calcd for C 29 H 39 ClN 4 O 3 S(M + )558.2431,found 558.2429.
Example 11 preparation of tert-butyl 6- (5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -2, 6-diazaspiro [3.4] octane-2-carboxylate (X06)
The procedure was followed as in example 6, except that the starting 3-azaspiro [5,5] undecane was changed to tert-butyl 2, 6-diaza-spiro [3.4] octane-2-carbonate to give X06 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.1Hz,1H),6.88(dd,J＝8.2,1.9Hz,1H),6.81–6.74(m,2H),4.04(t,J＝7.3Hz,2H),3.85(q,J＝8.6Hz,4H),2.70(d,J＝49.7Hz,4H),2.48(d,J＝7.8Hz,2H),2.07(t,J＝7.1Hz,2H),1.81(p,J＝7.4Hz,3H),1.60(t,J＝7.8Hz,3H),1.44(m,11H).HRMS(EI)m/z calcd for C 27 H 35 ClN 4 O 2 S(M + )514.2169,found 514.2171.
Example 12 preparation of tert-butyl 2- (5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -2, 8-diazaspiro [4.5] decane-8-carboxylate (X07)
The procedure was followed as in example 6, except that the starting 3-azaspiro [5,5] undecane was changed to tert-butyl 2, 8-diazaspiro [4.5] decane-8-carboxylate to give X07 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.88(dd,J＝8.2,2.0Hz,1H),6.81–6.74(m,2H),4.04(t,J＝7.2Hz,2H),3.41(dt,J＝11.3,5.4Hz,2H),3.35–3.26(m,2H),2.55(m,4H),1.81(p,J＝7.4Hz,12H),1.45(m,12H).HRMS(EI)m/z calcd for C 29 H 39 ClN 4 O 2 S(M + )542.2482,found 542.2483.
Example 13 preparation of tert-butyl 7- (5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -2, 7-diazaspiro [3.5] nonane-2-carboxylate (X08)
The procedure was carried out as in example 6, except that the starting 3-azaspiro [5,5] undecane was changed to 2-t-butoxycarbonyl-2, 7-diazaspiro [3.5] nonane, to give yellow oil X08.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.23(dd,J＝7.5,1.7Hz,1H),6.93(d,J＝8.1Hz,1H),6.87(dd,J＝8.2,1.9Hz,1H),6.80–6.74(m,2H),4.03(t,J＝7.3Hz,2H),3.60(m,4H),2.35(m,4H),1.80(p,J＝7.4Hz,7H),1.44(m,14H).HRMS(EI)m/z calcd for C 28 H 37 ClN 4 O 2 S(M + )528.2326,found 528.2323.
EXAMPLE 14 preparation of tert-butyl 2- (5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -2, 7-diazaspiro [3.5] nonane-7-carboxylate (X09)
The procedure was followed as in example 6, except that the starting 3-azaspiro [5,5] undecane was changed to tert-butyl 2, 7-diazaspiro [3.5] nonane-7-carboxylate to give a yellow oil X09.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.88(dd,J＝8.2,2.0Hz,1H),6.81–6.74(m,2H),4.04(t,J＝7.2Hz,2H),3.38–3.27(m,6H),2.77(t,J＝7.8Hz,2H),1.80(d,J＝7.1Hz,6H),1.60(q,J＝7.8Hz,2H),1.45(s,13H).HRMS(EI)m/z calcd for C 28 H 37 ClN 4 O 2 S(M + )528.2326,found 528.2324.
EXAMPLE 15 preparation of tert-butyl 2- (5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -2, 9-diazaspiro [5.5] undec-9-carboxylate (X10)
The procedure was followed as in example 6, except that the starting 3-azaspiro [5,5] undecane was changed to tert-butyl 2, 9-diazaspiro [5,5] undecane-2-carboxylate to give X10 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.23(dd,J＝7.4,1.7Hz,1H),6.93(d,J＝8.2Hz,1H),6.87(dd,J＝8.2,2.0Hz,1H),6.81–6.73(m,2H),4.04(t,J＝7.3Hz,2H),3.34(m,4H),2.25(m,4H),1.80(p,J＝7.4Hz,2H),1.45(m,21H),1.28(m,J＝18.4Hz,2H).HRMS(EI)m/z calcd for C 30 H 41 ClN 4 O 2 S(M + )556.2639,found 556.2635.
EXAMPLE 16 preparation of tert-butyl 6- (5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -2, 6-diazaspiro [3.4] octane-2-carboxylate (X11)
The procedure was followed as in example 6, except that the starting 3-azaspiro [5,5] undecane was changed to tert-butyl 2, 6-diaza-spiro [3.4] octane-2-carboxylate to give X11 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.88(dd,J＝8.1,1.9Hz,1H),6.80–6.74(m,2H),4.05(t,J＝7.3Hz,2H),3.93–3.79(m,5H),2.85–2.38(m,6H),2.15–2.02(m,2H),1.81(p,J＝7.4Hz,3H),1.44(d,J＝4.2Hz,13H).HRMS(EI)m/z calcd for C 27 H 35 ClN 4 O 2 S(M + )514.2169,found 514.2163.
EXAMPLE 17 preparation of tert-butyl 8- (5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -1, 8-diazaspiro [4.5] decane-1-carboxylate (X12)
The procedure was followed as in example 6, except that the starting 3-azaspiro [5,5] undecane was changed to tert-butyl 1, 8-diaza-spiro [4.5] decane-1-carboxylate to give X12 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ8.01(dd,J＝4.9,1.7Hz,1H),7.23(dd,J＝7.4,1.7Hz,1H),6.93(d,J＝8.2Hz,1H),6.87(dd,J＝8.2,2.0Hz,1H),6.82–6.72(m,2H),4.03(t,J＝7.3Hz,2H),3.42(m,2H),2.88(m,4H),1.92–1.67(m,8H),1.55–1.18(m,15H).HRMS(EI)m/z calcd for C 29 H 39 ClN 4 O 2 S(M + )542.2482,found 542.2457.
EXAMPLE 18 preparation of tert-butyl 1- (5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -1, 8-diazaspiro [4.5] decane-8-carboxylate (X13)
The procedure was followed as in example 6, except that the starting 3-azaspiro [5,5] undecane was changed to tert-butyl 1, 8-diazaspiro [4.5] decane-8-carboxylate to give X13 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝5.0,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.88(dd,J＝8.1,1.9Hz,1H),6.81–6.74(m,2H),4.23–3.98(m,5H),2.74(s,4H),1.59(m,7H),1.46(m,13H),1.27(d,J＝12.4Hz,3H).HRMS(EI)m/z calcd for C 29 H 39 ClN 4 O 2 S(M + )542.2482,found 542.2488.
Example 19 preparation of tert-butyl 1- (5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -1, 7-diazaspiro [3.5] nonane-7-carboxylate (X14)
The procedure was followed as in example 6, except that the starting 3-azaspiro [5,5] undecane was changed to tert-butyl 1, 7-diazaspiro [3.5] nonane-7-carboxylate to give yellow oil X14.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝5.0,1.7Hz,1H),7.23(dd,J＝7.4,1.7Hz,1H),6.93(d,J＝8.2Hz,1H),6.87(dd,J＝8.2,2.0Hz,1H),6.81–6.73(m,2H),4.03(t,J＝7.3Hz,3H),2.67(d,J＝13.7Hz,3H),2.48(m,2H),1.97(m,3H),1.88–1.72(m,4H),1.59 (d,J＝17.8Hz,4H),1.45(m,15H).HRMS(EI)m/z calcd for C 28 H 37 ClN 4 O 2 S(M + )528.2326,found 528.2328.
EXAMPLE 20 preparation of tert-butyl 2- (5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -2, 6-diazaspiro [3.4] octane-6-carboxylate (X15)
The procedure was followed as in example 6, except that the starting 3-azaspiro [5,5] undecane was changed to tert-butyl 2, 6-diazaspiro [3.4] octane-6-carboxylate to give X15 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.1Hz,1H),6.88(dd,J＝8.2,2.0Hz,1H),6.80–6.75(m,2H),4.04(t,J＝7.2Hz,2H),3.45(s,4H),3.33(d,J＝14.6Hz,5H),1.80(p,J＝7.3Hz,3H),1.45(s,17H).HRMS(EI)m/z calcd for C 27 H 35 ClN 4 O 2 S(M + )514.2169,found 514.2164.
EXAMPLE 21 preparation of tert-butyl 6- (5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -2, 6-diazaspiro [3.3] heptane-2-carboxylate (X16)
The procedure was followed as in example 6, except that the starting 3-azaspiro [5,5] undecane was changed to tert-butyl 2, 6-diazaspiro [3.3] heptane-2-carboxylate to give X16 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ8.00(d,J＝4.9Hz,1H),7.24(d,J＝7.4Hz,1H),6.94(d,J＝8.1Hz,1H),6.90–6.85(m,1H),6.80–6.73(m,2H),4.00(d,J＝18.7Hz,6H),3.30(s,4H),2.40(t,J＝6.7Hz,2H),1.79(q,J＝7.2Hz,2H),1.43(s,14H).HRMS(EI)m/z calcd for C 26 H 33 ClN 4 O 2 S(M + )500.2013,found 500.2018.
EXAMPLE 22 preparation of 9-benzyl-3- (5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -3, 9-diazaspiro [5.5] undecane-2, 4-dione (X17)
The procedure was followed as in example 6, except that the starting 3-azaspiro [5,5] undecane was changed to 9-benzyl-3, 9-diaza [5.5] undecane-2, 4-dione to give X17 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ7.98(dd,J＝4.9,1.7Hz,1H),7.33(s,4H),7.21(dd,J＝7.5,1.7Hz,1H),6.91(d,J＝8.2Hz,1H),6.85(dd,J＝8.1,2.0Hz,1H),6.81–6.70(m,2H),4.01(t,J＝7.3Hz,2H),3.75(t,J＝7.5Hz,2H),3.57(m,2H),2.57(s,7H),1.79(p,J＝7.5Hz,2H),1.71–1.47(m,7H),1.45–1.21(m,4H).HRMS(EI)m/z calcd for C 32 H 35 ClN 4 O 2 S(M + )574.2169,found 574.2159.
EXAMPLE 23 preparation of 8- (5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -2, 8-diazaspiro [4.5] decane-1, 3-dione (X18)
The procedure was followed as in example 6, except that the starting 3-azaspiro [5,5] undecane was changed to 2, 8-diazaspiro [4.5] decane-1, 3-dione hydrochloride to give X18 as a yellow oil.
1 H NMR(400MHz,DMSO-d 6 )δ11.10(s,1H),8.05(dd,J＝4.9,1.7Hz,1H),7.46(dd,J＝7.5,1.7Hz,1H),7.12(d,J＝7.9Hz,1H),7.01(d,J＝7.9Hz,2H),6.91(dd,J＝7.5,4.8Hz,1H),4.06(t,J＝7.1Hz,2H),2.71(m,2H),2.23(m,2H),1.90–1.62(m,6H),1.56–1.15(m,8H).HRMS(EI)m/z calcd for C 24 H 27 ClN 4 O 2 S(M + )470.1543,found 470.1541.
EXAMPLE 24 preparation of 10- (5- (3, 9-diazaspiro [5.5] undec-3-yl) pentyl) -8-chloro-10H-benzo [ b ] pyridine [2,3-e ] [1,4] thiazine (X19)
200mg of X02, 10mL of trifluoroacetic acid and 10mL of dichloromethane were added to a clean round-bottom flask and reacted at room temperature for 2 hours to give X19 as a yellow oil.
1 H NMR(400MHz,DMSO-d 6 )δ10.52(s,1H),9.04(s,2H),8.07(dd,J＝4.9,1.5Hz,1H),7.49(dd,J＝7.6,1.6Hz,1H),7.14(d,J＝8.1Hz,1H),7.08–6.99(m,2H),6.93(dd,J＝7.5,4.9Hz,1H),4.06(d,J＝7.1Hz,3H),3.25(d,J＝12.5Hz,2H),3.00(dt,J＝12.0,5.7Hz,8H),1.86–1.61(m,10H),1.53(t,J＝5.8Hz,2H),1.40(p,J＝7.6Hz,2H).HRMS(ESI)m/z calcd for C 25 H 33 ClN 4 S(M+H) + 457.2114,found 457.2170.
EXAMPLE 25 preparation of 8-chloro-10- (5- (9- (prop-2-yn-1-yl) -3, 9-diazaspiro [5.5] undec-3-yl) pentyl) -10H-benzo [ b ] pyridine [2,3-e ] [1,4] thiazine (X20)
200mg of X19, 90mg of 3-chloropropionine and 120mg of K are added to a clean round bottom flask 2 CO 3 And 10mL of acetonitrile, reflux overnight at 60 ℃ to give yellow oil X20.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.4,1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.87(dd,J＝8.2,1.9Hz,1H),6.81–6.73(m,2H),4.04(t,J＝7.3Hz,2H),3.31(d,J＝2.4Hz,2H),2.50(q,J＝12.4,9.0Hz,9H),2.24(t,J＝2.4Hz,1H),1.81(p,J＝7.5Hz,3H),1.55(d,J＝11.1Hz,10H),1.49–1.39(m,3H),1.34–1.18(m,3H).HRMS(EI)m/z calcd for C 28 H 35 ClN 4 S(M + )494.2271,found 494.2275.
EXAMPLE 26 preparation of 1- (9- (5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -3, 9-diazaspiro [5.5] undec-3-yl) ethan-1-one (X21)
The procedure was carried out as in example 25, except that the starting 3-chloropropionine was changed to acetyl chloride, to give X21 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(d,J＝1.6Hz,1H),6.95(d,J＝8.2Hz,1H),6.89(dd,J＝8.2,1.9Hz,1H),6.81–6.76(m,2H),4.06(t,J＝7.0Hz,2H),3.56(t,J＝5.7Hz,2H),3.42(d,J＝7.7Hz,4H),2.95(s,2H),2.74(s,2H),2.09(s,4H),1.83(ddd,J＝24.2,16.8,12.2Hz,7H),1.27(d,J＝12.3Hz,2H).HRMS(EI)m/z calcd for C 27 H 35 ClN 4 OS(M+H) + 499.2220,found 499.2270.
EXAMPLE 27 preparation of 8-chloro-10- (5- (9-propyl-3, 9-diazaspiro [5.5] undec-3-yl) pentyl) -10H-benzo [ b ] pyridine [2,3-e ] [1,4] thiazine (X22)
The procedure was carried out as in example 25, except that the starting material 3-chloropropionine was changed to 1-chloropropane to give X22 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.23(d,J＝1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.88(dd,J＝8.2,1.9Hz,1H),6.80–6.73(m,2H),4.04(t,J＝7.3Hz,2H),2.48(s,6H),1.81(p,J＝7.5Hz,4H),1.63(s,18H),1.46(q,J＝7.8Hz,3H),1.27(d,J＝12.3Hz,2H),0.92(t,J＝7.4Hz,3H).HRMS(EI)m/z calcd for C 28 H 39 ClN 4 S(M + )498.2584,found 498.2578.
EXAMPLE 28 preparation of 8-chloro-10- (5- (9- (pyridin-2-ylmethyl) -3, 9-diazaspiro [5.5] undec-3-yl) pentyl) -10H-benzo [ b ] pyridine [2,3-e ] [1,4] thiazine (X23)
The procedure was carried out as in example 25, except that the starting 3-chloropropionine was changed to 2-chloromethylpyridine to give X23 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ8.57(d,J＝4.4Hz,1H),8.00(d,J＝4.3Hz,1H),7.67(t,J＝7.5Hz,1H),7.44(s,1H),7.21(dd,J＝12.8,7.1Hz,3H),6.94(d,J＝8.2Hz,1H),6.88(d,J＝8.2Hz,1H),6.79(d,J＝9.2Hz,2H),4.05(t,J＝6.8Hz,2H),3.74(m,2H),2.89(m,4H),2.56(m,4H),1.85(dt,J＝14.7,6.9Hz,9H),1.65(s,4H),1.54–1.41(m,3H).HRMS(EI)m/z calcd for C 32 H 39 ClN 4 S(M-H) - 546.2536,found 546.2465.
EXAMPLE 29 preparation of 8-chloro-10- (5- (9-methyl-3, 9-diazaspiro [5.5] undec-3-yl) pentyl) -10H-benzo [ b ] pyridine [2,3-e ] [1,4] thiazine (X24)
To a clean round bottom flask was added 800mg of X19, 1g of paraformaldehyde, 300mg of sodium borohydride and 10mL of trifluoroethanol and reacted at room temperature for 3 hours to give X24 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.88(dd,J＝8.2,1.9Hz,1H),6.81–6.72(m,2H),4.04(t,J＝7.3Hz,2H),2.50(d,J＝18.2Hz,8H),2.39(s,3H),1.81(p,J＝7.4Hz,2H),1.64(t,J＝5.8Hz,10H),1.46(h,J＝7.5,6.4Hz,2H),1.33(t,J＝7.3Hz,2H).HRMS(EI)m/z calcd for C 26 H 35 ClN 4 S(M + )470.2271,found 470.2263.
Example 30 preparation of 10- (5- (9-benzyl-3, 9-diazaspiro [5.5] undec-3-yl) pentyl) -8-chloro-10H-benzo [ b ] pyridine [2,3-e ] [1,4] thiazine (X25)
The procedure was carried out as in example 25, except that the starting 3-chloropropionine was changed to benzyl chloride to give X25 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ7.99(dd,J＝4.9,1.7Hz,1H),7.31(d,J＝4.3Hz,4H),7.26–7.20(m,2H),6.93(d,J＝8.1Hz,1H),6.87(dd,J＝8.2,1.9Hz,1H),6.80–6.73(m,2H),4.03(t,J＝7.2Hz,2H),3.52(s,2H),2.66–2.46(m,6H),2.40(d,J＝5.7Hz,4H),1.82(q,J＝7.4Hz,2H),1.63(q,J＝7.7,5.6Hz,6H),1.52(t,J＝5.6Hz,4H),1.45(p,J＝7.8Hz,3H).HRMS(EI)m/z calcd for C 32 H 39 ClN 4 S(M + )546.2584,found 546.2574.
Example 31 preparation of 8-chloro-10- (5- (9- (4-chlorobenzyl) -3, 9-diazaspiro [5.5] undec-3-yl) pentyl) -10H-benzo [ b ] pyridine [2,3-e ] [1,4] thiazine (X26)
The procedure was carried out as in example 25, except that the starting material 3-chloropropionine was changed to 4-chlorobenzyl chloride to give X26 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝5.1,1.7Hz,1H),7.28(d,J＝2.4Hz,2H),7.26–7.19(m,3H),6.93(d,J＝8.1Hz,1H),6.87(dd,J＝8.3,1.9Hz,1H),6.81–6.72(m,2H),4.03(t,J＝7.3Hz,2H),3.45(s,2H),2.76(s,2H),2.46–2.31(m,8H),1.80(p,J＝7.5Hz,2H),1.47(td,J＝21.4,20.1,10.5Hz,14H).
Example 32 preparation of tert-butyl 9- (5- (8- (trifluoromethyl) -10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -3, 9-diazaspiro [5.5] undecane-3-carboxylate (X27)
The procedure is as in example 7, except that the starting material VI A Change to VI C Yellow oil X27 was obtained.
1 H NMR(400MHz,Chloroform-d)δ8.01(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),7.16–7.08(m,2H),6.96(d,J＝1.5Hz,1H),6.79(dd,J＝7.5,4.9Hz,1H),4.10(q,J ＝7.5Hz,2H),3.37(t,J＝5.8Hz,4H),2.70(s,4H),1.83(p,J＝7.4Hz,5H),1.45(s,15H),1.31–1.21(m,2H).HRMS(EI)m/z calcd for C 31 H 41 F 3 N 4 O 2 S(M + )590.2902,found 590.2897.
Example 33 preparation of tert-butyl 9- (5- (8-methoxy-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -3, 9-diazaspiro [5.5] undecane-3-carboxylate (X28)
The procedure is as in example 7, except that the starting material VI A Change to VI B Yellow oil X28 was obtained.
1 H NMR(400MHz,Chloroform-d)δ7.99(dd,J＝5.0,1.7Hz,1H),7.25(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.3Hz,1H),6.74(dd,J＝7.5,4.9Hz,1H),6.51–6.43(m,2H),4.07(q,J＝7.1Hz,2H),3.78(s,3H),3.36(t,J＝5.8Hz,4H),1.83(p,J＝7.4Hz,2H),1.63(m,6H),1.45(m,15H).HRMS(EI)m/z calcd for C 31 H 44 N 4 O 3 S(M + )552.3134,found 552.3132.
EXAMPLE 34 preparation of tert-butyl 9- (5- (10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -3, 9-diazaspiro [5.5] undec-3-carboxylate (X29)
The procedure is as in example 7, except that the starting material VI A Change to VI D Yellow oil X29 was obtained.
1 H NMR(400MHz,Chloroform-d)δ7.98(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),7.13(ddd,J＝8.4,7.4,1.6Hz,1H),7.04(dd,J＝7.6,1.6Hz,1H),6.90(td,J＝7.5,1.1Hz,1H),6.84(dd,J＝8.2,1.1Hz,1H),6.74(dd,J＝7.4,4.9Hz,1H),4.12–4.03(m,2H),3.41–3.32(m,4H),3.02(q,J＝7.3Hz,2H),1.83(p,J＝7.4Hz,2H),1.66(m,6H),1.45(m,15H),1.36(t,J＝7.3Hz,2H).HRMS(ESI)m/z calcd for C 30 H 42 N 4 O 2 S(M+H) + 523.3028,found 523.3075.
Example 35 preparation of tert-butyl 9- (4- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) butyl) -3, 9-diazaspiro [5.5] undecane-3-carboxylate (X30)
The procedure is as in example 7, except that the starting material VI A Change to VI E Yellow oil X30 was obtained.
1 H NMR(600MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.26–7.23(m,1H),6.95(d,J＝8.2Hz,1H),6.89(dd,J＝8.3,1.9Hz,1H),6.82–6.75(m,2H),4.10(dq,J＝23.5,6.2,5.3Hz,4H),3.36(t,J＝5.8Hz,4H),2.05(m,2H),1.84(m,2H),1.56(m,6H),1.45(m,13H),1.26(t,J＝7.1Hz,2H).HRMS(ESI)m/z calcd for C 29 H 39 ClN 4 O 2 S(M+H) + 543.2482,found 543.2520.
Example 36 preparation of tert-butyl 9- (6- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) hexyl) -3, 9-diazaspiro [5.5] undecane-3-carboxylate (X31)
The procedure is as in example 7, except that the starting material VI A Change to VI F Yellow oil X31 was obtained.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.24(dd,J＝7.5,1.7Hz,1H),6.94(d,J＝8.2Hz,1H),6.88(dd,J＝8.2,2.0Hz,1H),6.80–6.74(m,2H),4.03(t,J＝7.3Hz,2H),3.37(dd,J＝7.0,4.5Hz,4H),2.60(m,4H),1.84–1.59(m,8H),1.45(m,19H).HRMS(ESI)m/z calcd for C 31 H 43 ClN 4 O 2 S(M+H) + 571.2795,found 571.2843.
Example 37 preparation of 8-methoxy-10- (5- (9-methyl-3, 9-diazaspiro [5.5] undec-3-yl) pentyl) -10H-benzo [ b ] pyridine [2,3-e ] [1,4] thiazine (X32)
200mg of X28, 10mL of trifluoroacetic acid and 10mL of dichloromethane were added to a clean round-bottom flask, reacted at room temperature for 2 hours, then spin-dried, 1g of paraformaldehyde, 300mg of sodium borohydride and 10mL of trifluoroethanol were added, and reacted at room temperature for 3 hours to obtain a yellow oily substance X32.
1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.9,1.7Hz,1H),7.27(dd,J＝7.4,1.8Hz,1H),6.96(d,J＝8.4Hz,1H),6.76(dd,J＝7.4,4.9Hz,1H),6.53–6.42(m,2H),4.08(t,J＝7.1Hz,2H),3.80(s,3H),3.13(q,J＝7.3Hz,4H),2.72(d,J＝29.9Hz,8H),2.55(s,3H),1.85(p,J＝7.4Hz,2H),1.47(p,J＝7.4Hz,2H),1.34(t,J＝7.3Hz,6H).HRMS(ESI)m/z calcd for C 27 H 38 N 4 OS(M+H) + 467.2766,found 467.2810.
EXAMPLE 38 preparation of tert-butyl (1R, 4R) -5- (5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (X33)
The procedure is followed as in example 6 except that the starting 3-azaspiro [5,5] undecane is changed to tert-butyl (1R, 4R) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate to give X33 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ7.92(dd,J＝4.9,1.7Hz,1H),7.14(dd,J＝7.5,1.7Hz,1H),6.84(d,J＝8.2Hz,1H),6.78(dd,J＝8.2,2.0Hz,1H),6.72–6.65(m,2H),4.18(d,J＝50.3Hz,1H),3.96(t,J＝7.3Hz,2H),3.48–3.34(m,2H),3.04(ddd,J＝10.2,7.8,2.2Hz,1H),2.84(ddd,J＝34.1,9.6,2.2Hz,1H),2.58–2.38(m,3H),1.73(q,J＝6.8Hz,3H),1.59(dd,J＝19.4,9.7Hz,1H),1.49–1.39(m,4H),1.38(d,J＝2.0Hz,9H).HRMS(ESI)m/z calcd for C 26 H 33 ClN 4 O 2 S(M+H) + 501.2013,found 501.2105.
Example 39 preparation of tert-butyl 3- (5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylate (X34)
The procedure was followed as in example 6 except that the starting 3-azaspiro [5,5] undecane was changed to 6- (t-butoxycarbonyl) -3, 6-diazabicyclo [3.1.1] heptane to give X34 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ7.93(dd,J＝4.9,1.7Hz,1H),7.16(dd,J＝7.5,1.7Hz,1H),6.86(d,J＝8.1Hz,1H),6.80(dd,J＝8.2,2.0Hz,1H),6.74–6.67(m,2H),3.96(t,J ＝7.4Hz,4H),3.01(s,1H),2.87(s,1H),2.73(s,2H),2.44(t,J＝7.3Hz,2H),2.28(q,J＝6.6Hz,1H),1.72(q,J＝7.4Hz,2H),1.67–1.61(m,1H),1.48(p,J＝7.1Hz,2H),1.39(s,2H),1.37(s,9H).HRMS(ESI)m/z calcd for C 26 H 33 ClN 4 O 2 S(M+H) + 501.2013,found 501.2147.
EXAMPLE 40 preparation of tert-butyl (1S, 4S) -5- (5- (8-chloro-10H-benzo [ b ] pyridin [2,3-e ] [1,4] thiazin-10-yl) pentyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate (X35)
The procedure was followed as in example 6, except that the starting 3-azaspiro [5,5] undecane was changed to tert-butyl (1S, 4S) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate to give X35 as a yellow oil.
1 H NMR(400MHz,Chloroform-d)δ7.93(dd,J＝4.9,1.6Hz,1H),7.17(dd,J＝7.5,1.7Hz,1H),6.87(d,J＝8.1Hz,1H),6.80(dd,J＝8.2,1.9Hz,1H),6.74–6.67(m,2H),4.21(d,J＝50.8Hz,1H),3.97(t,J＝7.3Hz,2H),3.45(t,J＝12.4Hz,2H),3.06(t,J＝8.8Hz,1H),2.89(d,J＝37.7Hz,1H),2.56–2.35(m,3H),1.74(dd,J＝14.9,7.6Hz,3H),1.66–1.59(m,1H),1.51–1.39(m,4H),1.38(d,J＝2.0Hz,9H).HRMS(ESI)m/z calcd for C 26 H 33 ClN 4 O 2 S(M+H) + 501.2013,found 501.2129.
EXAMPLE 41 proliferation inhibition of endometrial cancer cells by Compounds of the invention
The proliferation inhibition activity of the 10-substituted-1-azaphenothiazine derivative on endometrial cancer cells is evaluated through a CCK-8 experiment.
1. Experimental materials and methods
Endometrial cancer cells ISK and KLE were purchased from American Type Culture Collection (ATCC); phosphate Buffered Saline (PBS) was purchased from Bio-channel company; DMEM/F12 medium is available from Biosharp; fetal Bovine Serum (FBS) and trypsin were purchased from Gibco company; CCK-8 was purchased from Biyun Biotechnology Inc.
ISK and KLE cells were incubated with DMEM/F12 (10% fetal calf serum, 1% penicillin/streptomycin) and placed at 37℃in 5% CO 2 Is cultured in an incubator of (a). After endometrial cancer cells have substantially grown in cell culture dishes (10 cm), the cells are digested with trypsin and seeded into 96-well plates at a cell density of 5000 cells/well, 100 μl per well. After overnight incubation, DMEM/F12 medium containing different concentrations of the derivatives was added, 200. Mu.L per well, with 3 multiplex wells per group, respectively, after cell attachment. Incubate in cell culture incubator for 48h. The medium was then removed, 100. Mu.L of serum-free medium containing 10% CCK-8 was added to each well, incubated at 37℃for 1 hour in an incubator, absorbance A at 450nm was measured using a Bio-Tek multifunctional microplate reader, and inhibition and IC were calculated 50 Values. The inhibition rate calculation formula: cell inhibition ratio% = [1- (dosing group a value-blank group a value)/(control group a value-blank group a value)]×100％，IC 50 The values were fitted by Graphpad Prism 8.0 software.
2. Experimental results
The proliferation inhibition activity of the 10-substituted-1-azaphenothiazine derivative on endometrial cancer cells is shown in table 1 and table 2, and the results show that the derivative has a remarkable inhibition effect on proliferation of endometrial cancer cells ISK and KLE.
TABLE 1 proliferation inhibition Activity results of 10-substituted-1-azaphenothiazine derivatives on ISK cells
TABLE 2 proliferation inhibition Activity results of 10-substituted-1-azaphenothiazine derivatives on KLE cells
EXAMPLE 42 inhibition of endometrial cancer cell clonogenic action by the Compounds of the invention
The effect of compound X32 on the clonogenic capacity of endometrial cancer cells ISK and KLE was tested at the cellular level by plate clone formation experiments. The study results show that the compound X32 can inhibit the clone formation of endometrial cancer cells ISK and KLE in a concentration-dependent manner.
1. Experimental materials and methods
0.5% crystal violet dye liquor was purchased from Biyun biotechnology Co., ltd; methanol is a common reagent in the laboratory, purchased commercially, and not subjected to any treatment. The rest of the experimental materials were from the same sources as in example 41. EC cells in the logarithmic growth phase were prepared as single cell suspensions by trypsinization, seeded into 6-well plates at a density of about 1000 cells per well, and cultured overnight. After the cells are attached, the cells are divided into 4 groups, namely a control group and different administration groups, and each group is provided with 3 compound holes. The administration group uses 2mL of DMEM/F12 culture medium containing different concentrations of drugs, the control group is added with culture medium without drugs, and the culture is continued for about 8 days after the culture is carried out for 48 hours. After the cells grew to a macroscopic population, they were placed on ice and washed twice with pre-chilled PBS for 3min each. The cells were then fixed with pre-chilled methanol at-20℃for 10min. Methanol was removed by suction, 1mL of crystal violet dye was added, and the mixture was dyed for 30 minutes. And removing the crystal violet dye liquor, and cleaning with clear water until the dye liquor is eluted. And (3) taking a picture by using a gel imager after the back-off 6-hole plate is dried, manually counting by using Image J software, and counting the clone formation number of each hole.
2. Experimental results
The experimental results are shown in FIG. 1, wherein Ctrl is a control group, and each black dot in the photograph represents a cell population. The results show that for ISK cells, the number of cell populations in the dosing group was reduced compared to Ctrl and significantly reduced with increasing concentration of compound X32, especially in the 2 μm group of compound X32, indicating that compound X32 has an inhibitory effect on the colony formation of ISK cells and is able to inhibit the colony formation of endometrial cancer cells ISK in a concentration-dependent manner. For KLE cells, the number of cell populations in the dosing group was also reduced compared to the control group, and significantly decreased with increasing concentration of compound X32, indicating that compound X32 has an inhibitory effect on the clonal formation of KLE cells and is capable of concentration-dependently inhibiting the clonal formation of endometrial cancer cells KLE. The histogram ordinate represents the number of cell populations in each group, and the significant differences in data were analyzed by One-way ANOVA (Graphpad Prism 8.0 software).
EXAMPLE 43 inhibition of the ability of the Compounds of the invention to migrate endometrial cancer cells
The effect of compound X32 on the migration ability of endometrial cancer cells ISK and KLE was tested by a Transwell experiment at the cellular level. The research result shows that X32 can inhibit the migration of endometrial cancer cells ISK and KLE.
1. Experimental materials and methods
Transwell cells were purchased from Costar; paraformaldehyde is a common laboratory reagent, commercially available, and without any treatment, the remainder of the experimental materials were from the same sources as in example 41. EC cells in the logarithmic growth phase were trypsinized down and prepared as single cell suspensions using serum-free DMEM/F12 medium and inoculated above the Transwell chamber at a density of about 10 ten thousand cells per well. 600. Mu.L of DMEM/F12 medium containing 20% FBS was added below the chamber, taking care to avoid air bubbles. The cells were divided into 4 groups, a control group and a different administration group, each group having 3 duplicate wells. The upper chamber of the administration group was charged with 150. Mu.L of serum-free DMEM/F12 medium containing different drugs, and the upper chamber of the control group was charged with 150. Mu.L of serum-free DMEM/F12 medium containing different drugs. Placed at 37 ℃ and 5% CO 2 Is cultured for 24 hours. The chamber was then carefully removed with forceps, the upper chamber liquid was blotted and transferred to a 24-well plate pre-filled with approximately 800. Mu.L of pre-chilled PBS, and washed 2 times for 5 min each. The cells were removed and transferred to 24-well plates into which about 800. Mu.L of paraformaldehyde solution had been previously added, and fixed at room temperature for 30 minutes. The cells were removed, the upper chamber fixative was blotted and transferred to a 24 well plate with about 800. Mu.L of crystal violet dye pre-added and stained at room temperature for 30min. Gently washing with clear water for several times, and wetting with wet cotton The rod carefully wipes off cells on the surface of the upper chamber membrane. 5 fields were randomly photographed under a 200-fold microscope, and Image J software was manually counted to count the number of cells in each field.
2. Experimental results
The results are shown in FIG. 2, where Ctrl is the control group and each point in the photograph represents a cell passing through the chamber. The results show that in ISK and KLE cells, the number of cells passing through the chamber was reduced in the dosing group compared to Ctrl group and significantly reduced with increasing concentration of compound X32, especially in the high dose group, with only a small number of cells passing through, demonstrating that compound X32 has the ability to inhibit ISK and KLE cell migration and is able to inhibit endometrial cancer cell migration in a concentration-dependent manner. The histogram ordinate represents the number of cells across the cell for each group, and the significant differences in data were analyzed using One-way ANOVA (Graphpad prism8.0 software).
EXAMPLE 44 Effect of the Compounds of the invention on endometrial cancer apoptosis
The invention adopts an Annexin V-FITC/PI apoptosis detection kit to test the influence of compound X32 on endometrial cancer cells ISK and KLE apoptosis at the cellular level. The research result shows that the compound X32 can induce the apoptosis of endometrial cancer cells ISK and KLE.
1. Experimental materials and methods
Annexin V-FITC/PI apoptosis detection kit is purchased from Biyun biotechnology Co., ltd, wherein Annexin V-FITC binding solution, annexin V-FITC and Propidium Iodide (PI) are all reagents in the kit. The rest of the experimental materials were from the same sources as in example 41. EC cells in the logarithmic growth phase were prepared as single cell suspensions by trypsinization, inoculated into 6-well plates at a density of about 12 ten thousand cells per well, and cultured overnight. After the cells are attached, the cells are divided into 4 groups, namely a control group and different administration groups, and each group is provided with 3 compound holes. The drug-administration group was added with 2mL of DMEM/F12 medium containing the derivative at different concentrations, and the control group was added with 2mL of drug-free DMEM/F12 medium. At 37 ℃,5% CO 2 Is incubated for 48h. The cell culture broth was then aspirated into a 10ml centrifuge tube, the adherent cells were washed once with PBS and digested with 300. Mu.L of pancreatinCells were gently blown off for 2min, transferred to corresponding centrifuge tubes, centrifuged at 1000rpm for 5min, the supernatant discarded, the cells collected, gently resuspended in PBS and counted. Taking 5-10 ten thousand resuspended cells, centrifuging at 1000rpm for 5min, discarding the supernatant, adding 195 mu L of Annexin V-FITC binding solution to lightly resuspend the cells, adding 5 mu L of Annexin V-FITC and 10 mu L of Propidium Iodide (PI) staining solution, and lightly mixing. Incubate at room temperature for 20min in the dark and immediately detect with Beckman Coulter (cytoFLEX LX) flow cytometer.
2. Experimental results
The results are shown in fig. 3, wherein Ctrl is a control group, the first quadrant in the apoptosis diagram is late apoptotic cells, the fourth quadrant is early apoptotic cells, and the apoptosis ratio is the sum of the first quadrant ratio and the fourth quadrant ratio. Compound X32 was able to significantly induce ISK and KLE apoptosis compared to the control group, and was concentration dependent. The ordinate of the bar graph shows the proportion of apoptosis in each group, and the significant difference in data was analyzed by One-way ANOVA (Graphpad prism8.0 software).
EXAMPLE 45 Effect of the Compounds of the invention on the mouse CNS
The invention tests the influence of compound X32 on the central nervous system of mice, namely extrapyramidal side effects, through a rotarod test. The research result shows that the side effect of the central nervous system of the compound X32 is lower, the administration doses of 100mg/kg and 50mg/kg basically do not influence the grasping movement ability of mice, and no extrapyramidal side effect exists.
1. Experimental materials and methods
The experimental animals were selected from 7-8 week old female C57BL/6 nude mice purchased from Shanghai Laike Co., ltd; cisplatin (DDP) is derived from the laboratory old drug library. The compound is prepared by weighing a certain amount of compound, dissolving in physiological saline, and administering corresponding solvent to control group. The compounds are formulated prior to administration.
Mice were randomly divided into 4 groups: control group, positive drug chlorpromazine 5mg/kg, X32 50mg/kg, X32 100mg/kg. Each group of 12. Mice were trained three days in advance to accommodate rotarod movements: mice were trained to exercise for 3min at 35rpm/min per day. On the fourth day, after administration of 0.1mL of the intraperitoneal injection for 1 hour (control group injected with physiological saline 0.1 mL), the duration of persistence on the rotating stick for 5min was recorded at a rotation speed of 35 rpm/min.
2. Experimental results
The experimental results are shown in fig. 4, in which Vehicle is a control group, the ordinate represents the mouse drop time, and each point represents one mouse drop time. It can be seen that the doses of the compound X32 mg/kg and 50mg/kg have no obvious effect on the grasping movement ability of the mice, the average time of the mice rotating along with the rod is 255s and 243s respectively, and the average time of the mice rotating along with the rod is not significantly different from that of the control group; the 5mg/kg dose of chlorpromazine has a great influence on the ability of the mice to grip and exercise, and the average time of the mice rotating with the stick is 142s (p < 0.001). Experimental results show that the administration doses of X32 to 100mg/kg and 50mg/kg do not substantially affect the grasping movement ability of mice. The data significance differences were analyzed using One-way ANOVA (Graphpad prism8.0 software).
EXAMPLE 46 inhibition of the growth of subcutaneous transplants in endometrial cancer tumor-bearing mice by the Compounds of the present invention
The invention tests the influence of compound X01 on the growth of endometrial cancer cell (KLE) transplanted tumor through a nude mouse in-vivo subcutaneous tumor experiment. The research result shows that the compound X01 can obviously inhibit the growth of the subcutaneous KLE cell transplantation tumor of the mice.
1. Experimental materials and methods
The experimental animals were selected from SPF-class female BALB/C nude mice of 5-6 weeks old, purchased from Shanghai Laike animal experiments Co., ltd; cisplatin (DDP) is derived from the laboratory old drug library. The compound is prepared through weighing a certain amount of compound, dissolving in physiological salt to dilute to required concentration, and adding corresponding solvent to control group. The compounds are formulated prior to administration.
KLE cells were first subcutaneously implanted in the right armpit of 5-6 week old nude mice, each of which was implanted with approximately 500 ten thousand cells. When the tumor grows to 800-1000mm 3 Mice were sacrificed and tumor tissue was cut into uniform sized tumor tissue pieces and surgically transplanted under the right underarm of new 5-6 week old nude mice. When the volume of the newly grown tumor reaches 300-400mm on average 3 At this time, mice were randomly grouped into 4 groups: control group, positive drug DDP 2mg/kg, X012mg/kg of the administration group, X01 mg/kg of the administration group, and 5mg/kg of chlorpromazine. The mice were weighed daily by intraperitoneal injection of 0.1mL of physiological saline at different drug concentrations, and the control group was administered daily. After 2 weeks of continuous administration, mice were sacrificed, tumors were peeled off, and photographs were taken. Tumor length L (mm) and width W (mm) were measured with vernier calipers on the day of dissection, and tumor volume calculation formula V (mm) 3 )＝0.5×L(mm)×W(mm) 2 。
2. Experimental results
The experimental results are shown in FIG. 5, in which Vehicle is the control group. Wherein in fig. 5, a is a curve of the change of the weight of the mice with the administration time, the abscissa is the administration days, and the ordinate is the weight of the mice, and it can be seen from the graph that the weight of the X01 administration group is stable, and the weight of the cisplatin DDP group is obviously reduced. In FIG. 5, B, C, D shows that after the administration is finished, compared with the control group, the tumor growth of the compound X01 administration group is inhibited, and X01 2mg/kg and X01 5mg/kg can obviously inhibit the tumor growth of mice, and the effect of the compound is equivalent to or even slightly better than that of cisplatin as a positive drug. The data significance differences were analyzed using One-way ANOVA (Graphpad prism8.0 software). The experiment proves that the compound X01 can inhibit the growth of the mouse subcutaneous KLE cell transplantation tumor and has no influence on the body weight, and the drug effect is equivalent to that of a positive drug cisplatin, and the toxicity is less than that of cisplatin.
The foregoing description is only illustrative of the preferred embodiment of the present invention, and is not to be construed as limiting the invention, but is to be construed as limiting the invention to any and all simple modifications, equivalent variations and adaptations of the embodiments described above, which are within the scope of the invention, may be made by those skilled in the art without departing from the scope of the invention.

Claims (13)

  1. A compound of formula I, or a stereoisomer or pharmaceutically acceptable salt thereof,
    wherein n is 2, 3, 4, 5 or 6;
    R 1 is H, hydroxy, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, nitro, nitroso, amino, formyl, acetyl or cyano;
    R 2 a 6-14 membered heterocyclic group which is substituted or unsubstituted, said heterocyclic group containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of: n, O, S; the substitution means having one or more substituents selected from the group consisting of: -COOC 1 -C 6 Alkyl, -C 1 -C 6 Alkylene C 6 -C 10 Aryl, oxo (=o), C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -COC 1 -C 6 Alkyl, -C 1 -C 6 Alkylene 5-7 membered heteroaryl, C 6 -C 10 Aryl, 5-7 membered heteroaryl, -C 1 -C 6 Alkylene halogeno C 6 -C 10 Aryl, C 3 -C 8 Cycloalkyl groups.
  2. The compound of claim 1, wherein R 1 Is H, hydroxy, F, cl, br, methyl, ethyl, n-propyl, isopropyl, C 1 -C 4 Fluoroalkyl, methoxy, ethoxy.
  3. The compound of claim 1, wherein R 2 Is of the formula I-2 or I-3,
    A 1 、A 2 、A 3 、A 4 each independently selected from: n, O, S, -CO (CH) 2 ) p -、-(CH 2 ) m -、-(CH 2 ) m O-、-(CH 2 ) m S-; m, p are each independently 0, 1, 2 or 3;
    x is CH, N or O;
    n 1 、n 2 、n 3 、n 4 each independently 0, 1, 2 or 3;
    R 3 Is H, -COOC 1 -C 6 Alkyl, -C 1 -C 6 Alkylene C 6 -C 10 Aryl, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, -COC 1 -C 6 Alkyl, -C 1- C 6 Alkylene 5-7 membered heteroaryl, C 6 -C 10 Aryl, 5-7 membered heteroaryl, -C 1 -C 6 Alkylene halogeno C 6 -C 10 Aryl, C 3 -C 8 Cycloalkyl groups.
  4. The compound of claim 1, wherein R 3 Is H, t-butyloxycarbonyl, C 1 -C 4 Alkyl, chlorobenzyl, benzyl, -CH 2 -6 membered nitrogen containing heteroaryl, -COC 1 -C 4 Alkyl or C 2 -C 4 Alkynyl groups.
  5. The compound of claim 1, wherein the compound is selected from the group consisting of:
  6. a pharmaceutical composition, the pharmaceutical composition comprising:
    (1) The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof; and (2) a pharmaceutically acceptable carrier.
  7. The pharmaceutical composition of claim 6, further comprising an additional pharmaceutically acceptable ingredient that is an anti-endometrial cancer drug.
  8. The pharmaceutical composition of claim 7, wherein the anti-endometrial cancer drug is a progestin.
  9. The pharmaceutical composition of claim 8, wherein the progestin is one or a combination of two or more of megestrol acetate, medroxyprogesterone acetate, or progesterone caproate.
  10. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is an injection, a tablet, a capsule, a pill, a suspension, or an emulsion.
  11. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is in an oral dosage form, a transdermal dosage form, an intravenous or intramuscular injection dosage form.
  12. Use of a compound according to claim 1 or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 6 for the preparation of a medicament for the treatment and/or prophylaxis of endometrial cancer.
  13. A process for the preparation of a compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:
CN202180098067.1A 2021-10-13 2021-10-13 10-substituted-1-azaphenothiazine derivative and application thereof Pending CN117715907A (en)

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US2974139A (en) * 1954-10-02 1961-03-07 Degussa Thiophenylpyridyl amines
US3106561A (en) * 1955-07-26 1963-10-08 Olin Mathieson Certain 2-(2'-lower alkanoyl-amidophenylthio)-3-nitropyridines
US2943086A (en) * 1955-07-26 1960-06-28 Olin Mathieson Pharmaceutical compounds
GB814065A (en) * 1957-02-13 1959-05-27 Smith Kline French Lab Substituted phenoselenazine compounds
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DE1160442B (en) * 1959-03-18 1964-01-02 Degussa Process for the preparation of 3-trifluoromethylphenthiazines
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