阅读说明：本技术 含异羟肟酸结构片段的18β-甘草次酸类化合物及其应用 (18 β-enoxolone class the compound of the segment containing hydroxamic acid structure and its application ) 是由 赵临襄 刘丹 黄敏 唐煜 谢晓瑞 景永奎 于 2019-09-10 设计创作，主要内容包括：本发明属于医药技术领域,具体涉及含异羟肟酸结构片段的18β-甘草次酸类化合物及其制备和应用,还涉及含异羟肟酸结构片段的18β-甘草次酸类化合物及其旋光异构体和药学上可接受的盐的药物组合物,及其它们在制备治疗和/或预防各种癌症的药物中的用途。所述的化合物的结构通式如下,其中X、R如权利要求和说明书所述。<Image he="217" wi="700" file="DDA0002197463790000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention belongs to pharmaceutical technology fields, more particularly to the 18 β-enoxolone class compound of the segment containing hydroxamic acid structure and its preparation and application, further relate to the 18 β-enoxolone class compound of the segment containing hydroxamic acid structure and its pharmaceutical composition of optical isomer and pharmaceutically acceptable salt and its their purposes in preparation treatment and/or the drug for preventing various cancers.The general structure of the compound is as follows, and wherein X, R are as described in claim and specification.)

1. general formula I or II compound represented, optical isomer or pharmaceutically acceptable salt:

X is

The left side X connects enoxolone skeleton, and the right connects hydroxamic acid segment；

R is halogen, trifluoromethyl, mesyl, cyano；

M is the integer of 1-6；

The integer that n is 1~8.

2. compound as described in claim 1, optical isomer or pharmaceutically acceptable salt:

X is

The left side X connects enoxolone skeleton, and the right connects hydroxamic acid segment；

R is iodine, trifluoromethyl, cyano；

M is the integer of 1-6；

The integer that n is 1~8.

3. compound as claimed in claim 1 or 2, optical isomer or pharmaceutically acceptable salt:

X is

The left side X connects enoxolone skeleton, and the right connects hydroxamic acid segment；

R is iodine, trifluoromethyl, cyano；

M is the integer of 2-3；

The integer that n is 3~6.

4. compound as described in claim 1, optical isomer or pharmaceutically acceptable salt,

4- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formamido group)-N- hydroxybutyrate amide

5- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formamido group)-N- hydroxyvaleramide

6- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formamido group)-N- hydroxyl hexanamide

7- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formamido group)-N- hydroxyl heptamide

N¹Hydroxy-n⁵(4- (2- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) ethyoxyl) Phenyl) glutaramide

N¹Hydroxy-n⁶(4- (2- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) ethyoxyl) Phenyl) adipamide

N¹Hydroxy-n⁷(4- (2- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) ethyoxyl) Phenyl) heptanedioyl amine

N¹Hydroxy-n⁸(4- (2- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) ethyoxyl) Phenyl) suberamide

N¹Hydroxy-n⁵(4- (3- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) propoxyl group) Phenyl) glutaramide

N¹Hydroxy-n⁶(4- (3- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) propoxyl group) Phenyl) adipamide

N¹Hydroxy-n⁷(4- (3- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) propoxyl group) Phenyl) heptanedioyl amine

N¹Hydroxy-n⁸(4- (3- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) propoxyl group) Phenyl) suberamide

4- (4- (2- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) ethyoxyl) benzene carbon amide Base)-N- hydroxybutyrate amide

5- (4- (2- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) ethyoxyl) benzene carbon amide Base)-N- hydroxyvaleramide

6- (4- (2- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) ethyoxyl) benzene carbon amide Base)-N- hydroxyl hexanamide

7- (4- (2- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) ethyoxyl) benzene carbon amide Base)-N- hydroxyl heptamide

4- (4- (3- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) propoxyl group) benzene carbon amide Base)-N- hydroxybutyrate amide

5- (4- (3- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) propoxyl group) benzene carbon amide Base)-N- hydroxyvaleramide

6- (4- (3- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) propoxyl group) benzene carbon amide Base)-N- hydroxyl hexanamide

7- (4- (3- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) propoxyl group) benzene carbon amide Base)-N- hydroxyl heptamide

N¹Hydroxy-n⁵(4- (4- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- acyl group) piperazine-1- base) Phenyl) glutaramide

N¹Hydroxy-n⁶(4- (4- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- acyl group) piperazine-1- base) Phenyl) adipamide

N¹Hydroxy-n⁷(4- (4- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- acyl group) piperazine-1- base) Phenyl) heptanedioyl amine

N¹Hydroxy-n⁸(4- (4- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- acyl group) piperazine-1- base) Phenyl) suberamide

N¹Hydroxy-n⁸(4- (3- (2- iodo -3,11- dioxygen generation -18 β-oleanane -1,12- diene -30- formyloxy) third Oxygroup) phenyl) suberamide

N¹Hydroxy-n⁸(4- (3- (2- trifluoromethyl -3,11- dioxygen generation -18 β-oleanane -1,12- diene -30- methanoyl Base) propoxyl group) phenyl) suberamide

N¹Hydroxy-n⁸(4- (3- (2- cyano -3,11- dioxygen generation -18 β-oleanane -1,12- diene -30- formyloxy) third Oxygroup) phenyl) suberamide

N¹Hydroxy-n⁸(4- (4- (2- iodo -3,11- dioxygen generation -18 β-oleanane -1,12- diene -30- acyl group) piperazine - 1- yl) phenyl) suberamide

N¹Hydroxy-n⁸(4- (4- (2- trifluoromethyl -3,11- dioxygen generation -18 β-oleanane -1,12- diene -30- acyl group) piperazine Piperazine -1- base) phenyl) suberamide

N¹Hydroxy-n⁸(4- (4- (2- cyano -3,11- dioxygen generation -18 β-oleanane -1,12- diene -30- acyl group) piperazine - 1- yl) phenyl) suberamide.

5. a kind of pharmaceutical composition, it is characterised in that: compound, optical isomer comprising any one of claim 1-4 Or pharmaceutically acceptable salt and pharmaceutically acceptable excipient.

6. the preparation method of compound as described in claim 1, optical isomer or pharmaceutically acceptable salt, feature exist In,

7. compound, optical isomer or pharmaceutically acceptable salt described in any one of claim 1-4 are controlled in preparation Treat and/or prevent the application in anti-tumor drug.

8. application of the pharmaceutical composition described in claim 5 in preparation treatment and/or prevention anti-tumor drug.

9. application as claimed in claim 7 or 8, which is characterized in that the tumour is breast cancer, lung cancer, colon cancer, rectum Cancer, gastric cancer, prostate cancer, liver cancer, bladder cancer, uterine cancer, cancer of pancreas, oophoroma, lymph cancer, oophoroma, cutaneum carcinoma or blood Cancer.

Technical field:

The invention belongs to pharmaceutical technology fields, and in particular to the 18 β-enoxolone class chemical combination of the segment containing hydroxamic acid structure Object and its preparation and application further relate to the 18 β-enoxolone class compound and its optical isomerism of the segment containing hydroxamic acid structure The pharmaceutical composition of body and pharmaceutically acceptable salt and its they in preparation treatment and/or the drug for preventing various cancers Purposes.

Background technique:

18 β-enoxolone is a kind of pentacyclic triterpene natural products, from a wealth of sources, has a variety of pharmacological activity.It resists Function of tumor is also paid close attention to by people, but its activity is not strong, it is difficult to reach the requirement of clinical use.To improve 18 β-Radix Glycyrrhizae The antitumous effect of hypo acid, researcher by heterozygosis strategy by 18 β-enoxolone and other active fragments (such as: ferulic acid, The structures such as cinnamic acid, rhodamine B) split is carried out, a variety of hybrid molecules are obtained, activity has certain compared with parent compound It improves.

Hydroxamic acid structure can chelate a variety of transition metal, and this sequestering power makes it in a variety of drugs and quasi-medicated property point It is widely present in son.Wherein, inhibitory activity quilt of the hydroxamic acid compound to metalloproteinases and histon deacetylase (HDAC) Further investigation, and there are several compounds to enter the treatment for being clinically used for cancer.By principle of hybridization in different anti-target ligand molecules Or hydroxamic acid is introduced in Structures of Natural Products, it is expected to obtain the collaboration inhibitory effect of multiple action targets and stronger tumor suppression Effect.

The present inventor has designed and synthesized a series of 18 β-enoxolone analog of segments containing hydroxamic acid structure, through thin Cytoactive screening, synthesized compound have preferable growth of tumour cell inhibitory activity.

Summary of the invention:

Technical problem solved by the invention is to provide a series of 18 β-enoxolone class of segments containing hydroxamic acid structure Like object, preventing and/or treat in preparation for the 18 β-enoxolone analog of the segment containing hydroxamic acid structure is additionally provided Application in tumour medicine.

The present invention relates to derivative shown in general formula I or II and its optical isomers and pharmaceutically acceptable salt:

X is

The left side X connects enoxolone skeleton, and the right connects hydroxamic acid segment；

R is halogen, halogenated C1-C4 alkyl, mesyl, cyano；

M is the integer of 1-6；

The integer that n is 1~8.

The compound and its optically active form and pharmaceutically acceptable salt that the present invention preferably has the following structure,

Wherein,

X is

The left side X connects enoxolone skeleton, and the right connects hydroxamic acid segment；

R is iodine, trifluoromethyl, cyano；

M is the integer of 1-6；

The integer that n is 1~8.

The compound and its optically active form and pharmaceutically acceptable salt that the present invention preferably has the following structure,

Wherein,

X is

The left side X connects enoxolone skeleton, and the right connects hydroxamic acid segment；

R is iodine, trifluoromethyl, cyano；

M is the integer of 2-3；

The integer that n is 3~6.

Particularly preferred compound includes:

4- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formamido group)-N- hydroxybutyrate amide is (real Apply example 1)

5- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formamido group)-N- hydroxyvaleramide is (real Apply example 2)

6- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formamido group)-N- hydroxyl hexanamide is (real Apply example 3)

7- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formamido group)-N- hydroxyl heptamide is (real Apply example 4)

N¹Hydroxy-n⁵(4- (2- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) second Oxygroup) phenyl) glutaramide (embodiment 5)

N¹Hydroxy-n⁶(4- (2- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) second Oxygroup) phenyl) adipamide (embodiment 6)

N¹Hydroxy-n⁷(4- (2- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) second Oxygroup) phenyl) heptanedioyl amine (embodiment 7)

N¹Hydroxy-n⁸(4- (2- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) second Oxygroup) phenyl) suberamide (embodiment 8)

N¹Hydroxy-n⁵(4- (3- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) third Oxygroup) phenyl) glutaramide (embodiment 9)

N¹Hydroxy-n⁶(4- (3- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) third Oxygroup) phenyl) adipamide (embodiment 10)

N¹Hydroxy-n⁷(4- (3- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) third Oxygroup) phenyl) heptanedioyl amine (embodiment 11)

N¹Hydroxy-n⁸(4- (3- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) third Oxygroup) phenyl) suberamide (embodiment 12)

4- (4- (2- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) ethyoxyl) benzene first Acylamino-)-N- hydroxybutyrate amide (embodiment 13)

5- (4- (2- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) ethyoxyl) benzene first Acylamino-)-N- hydroxyvaleramide (embodiment 14)

6- (4- (2- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) ethyoxyl) benzene first Acylamino-)-N- hydroxyl hexanamide (embodiment 15)

7- (4- (2- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) ethyoxyl) benzene first Acylamino-)-N- hydroxyl heptamide (embodiment 16)

4- (4- (3- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) propoxyl group) benzene first Acylamino-)-N- hydroxybutyrate amide (embodiment 17)

5- (4- (3- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) propoxyl group) benzene first Acylamino-)-N- hydroxyvaleramide (embodiment 18)

6- (4- (3- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) propoxyl group) benzene first Acylamino-)-N- hydroxyl hexanamide (embodiment 19)

7- (4- (3- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- formyloxy) propoxyl group) benzene first Acylamino-)-N- hydroxyl heptamide (embodiment 20)

N¹Hydroxy-n⁵(4- (4- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- acyl group) piperazine-1- Base) phenyl) glutaramide (embodiment 21)

N¹Hydroxy-n⁶(4- (4- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- acyl group) piperazine-1- Base) phenyl) adipamide (embodiment 22)

N¹Hydroxy-n⁷(4- (4- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- acyl group) piperazine-1- Base) phenyl) heptanedioyl amine (embodiment 23)

N¹Hydroxy-n⁸(4- (4- (3-18 β of beta-hydroxy-11- oxo-oleanane-12- diene-30- acyl group) piperazine-1- Base) phenyl) suberamide (embodiment 24)

N¹Hydroxy-n⁸(4- (3- (2- iodo -3,11- dioxygen generation -18 β-oleanane -1,12- diene -30- methanoyl Base) propoxyl group) phenyl) suberamide (embodiment 25)

N¹Hydroxy-n⁸(4- (3- (2- trifluoromethyl -3,11- dioxygen generation -18 β-oleanane -1,12- diene -30- first Acyloxy) propoxyl group) phenyl) suberamide (embodiment 26)

N¹Hydroxy-n⁸(4- (3- (2- cyano -3,11- dioxygen generation -18 β-oleanane -1,12- diene -30- methanoyl Base) propoxyl group) phenyl) suberamide (embodiment 27)

N¹Hydroxy-n⁸(4- (4- (2- iodo -3,11- dioxygen generation -18 β-oleanane -1,12- diene -30- acyl group) piperazine Piperazine -1- base) phenyl) suberamide (embodiment 28)

N¹Hydroxy-n⁸(4- (4- (2- trifluoromethyl -3,11- dioxygen generation -18 β-oleanane -1,12- diene -30- acyl Base) piperazine -1- base) phenyl) suberamide (embodiment 29)

N¹Hydroxy-n⁸(4- (4- (2- cyano -3,11- dioxygen generation -18 β-oleanane -1,12- diene -30- acyl group) piperazine Piperazine -1- base) phenyl) suberamide (embodiment 30)

The invention also includes the prodrugs of the compounds of this invention.According to the present invention, prodrug is the derivative of general formula I or II, it Itself may have weaker activity or even without activity, but upon administration, (such as pass through generation in physiological conditions Thank, solvolysis and other mode) it is converted to corresponding biologically active form.

The present invention includes pharmaceutical composition, and the composition contains 18 β-of the segment containing hydroxamic acid structure of general formula I or II Enoxolone compound and its optically active form and pharmaceutically acceptable salt and pharmaceutically acceptable excipients.It is described pharmaceutically Acceptable excipients refer to any diluent that can be used for drug field, adjuvant and/or carrier.The compound of the present invention It can be applied in combination with other active components, as long as they do not generate other unfavorable effects, such as allergic reaction.

Pharmaceutical composition of the invention can be configured to several dosage form, wherein containing some excipients common in drug field Agent, for example, oral preparation (such as tablet, capsule, solution or suspension)；(solution of such as injectable is mixed for the preparation of injectable The dried powder of suspension or injectable, water for injection is added before the injection to be used immediately)；Topical formulations (such as it is soft Cream or solution).

Carrier for pharmaceutical composition of the present invention is available common type in drug field, comprising: oral preparation Adhesive, lubricant, disintegrating agent, cosolvent, diluent, stabilizer, suspending agent, pigment, corrigent etc.；Injectable system Preservative, solubilizer, stabilizer of agent etc.；Matrix, diluent, lubricant, preservative of topical formulations etc..Drug system Agent can by oral administration or parenteral (such as in intravenous, subcutaneous, peritonaeum or part) is administered, if some drugs are in stomach Be under the conditions of portion it is unstable, enteric coated tablets can be configured to.

It is screened by external activity, it has been found that the compounds of this invention has anti-tumor activity, therefore the compounds of this invention The drug that can be used for preparing treatment and/or the various cancers of prevention, such as breast cancer, lung cancer, colon and rectum carcinoma, gastric cancer, preceding Column gland cancer, liver cancer, bladder cancer, uterine cancer, cancer of pancreas, oophoroma, lymph cancer, oophoroma, cutaneum carcinoma and blood cancer.

Reactive compound of the present invention can be used as unique anticancer drug and use, or with one or more other antineoplastics Object is used in combination.Combination therapy by by each therapeutic component simultaneously, sequence or separate administration and realize.

Examples provided hereinafter and preparation example further elucidate and illustrate the present invention compound and its preparation side Method.It should be appreciated that the range of following embodiments and preparation example does not limit the scope of the invention in any way.

Synthetic route one:

Reagent and conditions:a)1,2-dibromoethane or 1,3-dibromopropane, K₂CO₃,dry-DMF,80℃,40min；b) 4-Nitrophenol or Methylparaben,K₂CO₃,dry-DMF,80℃, 1~3h；c)Fe,NH₄Cl,EtOH/H₂O,80℃,3h；D) HOBT, EDCI, DIEA, dry-DCM, r.t., 3~for 24 hours；e)1M NaOH(aq),NH₂OH (50%in water), MeOH, 0 DEG C~r.t., 2h；f)1M KOH(aq),EtOH,reflux,1.5h； g)substituted amine,EDCI,DMAP,dry-DCM,r.t.,6h.

Synthetic route two:

Reagent and conditions:a)IBX,DMSO,85℃,6h；b)I₂,pyridine,THF,reflux, overnight；c)CuCN,NMP,130 ℃,2h；d)BnBr,K₂CO₃,dry-DMF,r.t.,1h；e)FSO₂CF₂COOCH₃, HMPA,CuI,dry-DMF,70℃,3.5h；f)TiCl₄, dry-CH₂Cl₂,r.t.,2h.

Synthetic route three:

Reagent and conditions:a)HOBT,EDCI,DIEA,dry-DMF,60℃,1.5h；b)1M NaOH (aq),MeOH,reflux,0.5h；c)HOBT,EDCI,DIEA,dry-DMF,r.t.,6h；d)1,3-dibromopropane, K₂CO₃,dry-DMF,r.t.,1h；e)K₂CO₃, dry-DMF,80℃,2h；e)CF₃COOH,dry-DCM,r.t.,10min.

Synthetic route four:

Reagent and conditions:a)1-(4-nitrophenyl)piperazine,EDCI,DMAP,CH₂Cl₂, r.t.,2h；b)Fe,NH₄Cl, EtOH/H₂O,80℃,3h；c)HOBT,EDCI,DIEA,DMF,60℃,4h；d)CF₃COOH, dry-CH₂Cl₂,r.t.,10min.

Specific embodiment: