CN1204321A - Phenanthridine derivatives, method of producing them and medicaments containing phenanthridine derivatives - Google Patents

Abstract

Disclosed are phenanthridine derivatives of general formulae (I) and (II) and the salts thereof. In the formulae, R1 is a hydrogen atom or aromatic carbocyclic or heterocyclic group, and R2 and R3 can be either identical or different and stand for a hydrogen atom, an alkyloxy group, an alkylene-oxy group, a halogen atom or a nitro group. The derivatives in question have anti-tumoral, anti-microbial, fungicidal, anti-viral and anti-inflammatory properties.

Description

Phenanthridine derivatives and its preparation method and contain the medicine of phenanthridine derivatives

The present invention relates to the preparation method that 6 new bit strips have amino phenanthridine derivatives, its preparation method and contain the medicine of phenanthridine derivatives.

Present known benzo (c) phenanthridines, its 11,12-dihydro derivative and analogue synthetic very complicated.This paper mentions that method that the use ring of light such as the method, Ninomiya of employing Bischler-Napieralski cyclizations such as Robinson closes and Enamiden or Shamma etc. and Cushman etc. adopt the method for Dickman-Thorpe cyclization, described these methods include considerable reactions steps (referring to Ninomya and T.Naito: benzo (c) piperidine alkaloid synthetic, Recent.Dev.Nat.Carbon compd.10,11-90 (1984) and the document of wherein mentioning).

In addition, benzo (c) phenanthridine derivatives and antitumor action thereof can be from pharmacy, the 44th volume, and 593-597 page or leaf (1989) is known.Other phenanthridine derivatives is recorded and narrated in tetrahedron, the 49th volume, 10305-10316 (1993), J.Chem.Soc.Perkin Trans.I, 1137-1140 page or leaf (1983) and J.Me.Chem.36, pp.3686-3692 (1993).In J.Med.Chem. and tetrahedral document, also having described 6 bit strips really has amino derivative, yet in each case, described amino all is substituted.Other derivative is also on the knees of the gods so far.This mainly is because present known derivative all is based on expensive and numerous and diverse synthetic method synthetic.Therefore, can't synthesize other phenanthridine derivatives so far.

Can imagine thus, the purpose of this invention is to provide new phenanthridine derivatives and its preparation method and application thereof.

The purpose of relevant phenanthridine derivatives is that the feature by claim 1 realizes, relevant preparation method's purpose is that the feature by claim 5 realizes.The application of these phenanthridine derivatives of the present invention is recorded and narrated in claim 10.The supplementary features that the dependent claims explanation is useful.

According to claim 1, new phenanthridine derivatives is defined by general formula I and II,

R wherein ₁Expression hydrogen atom, aromatics or heterocyclic group, R ₂And R ₃Can be identical or different, expression hydrogen atom, alkoxyl group, alkenyl oxygen, halogen atom or nitro.

Aromatic carbocyclyl groups R ₁Can understand particularly for by benzene, naphthalene, anthracene, phenanthrene and these groups of pyrene deutero-.Aromatic heterocyclic radical R ₁Can specifically be interpreted as by furans, thiophene, pyridine, 1,2,4-oxadiazole, 1,2,3-triazole, cumarone, benzoxazole, benzoglyoxaline, benzothiazole deutero-group also have by corresponding to be called as the naphtho-analogue of benzo five-membered heterocycle alkene (heterocyclenes) type and by indoles, quinolene and isoquinolene deutero-group.Aromatic carbocyclic or heterocyclic radical can be substituted once or several.

For this reason, be for example mono amino, alkylamino, dialkyl amido, alkyl, alkoxyl group, alkenyl oxygen and halogen as the substituting group under reaction conditions, inertia group and/or atom.

According to the pharmacological property of being found, the derivative of particularly important is those wherein R ₂And R ₃Hydrogen and R ₁Hydrogen or unsubstituted phenyl, have the phenyl or the N of one or several methoxyl groups, the derivative of N-dimethylamino functional group.That for this reason, be worth emphasizing is R wherein ₁Be to replace or unsubstituted phenyl, especially 2,4-Dimethoxyphenyl or 3, those derivatives of 4-Dimethoxyphenyl.This paper is especially preferred 2,4-dimethoxy benzene radical derivative.Phenanthridine derivatives of the present invention is easy to form physiologically acceptable salt.This class salt be for example with mineral acid or organic acid salt, as dihydrochloride, hydrobromate and vitriol.Good especially organic salt is the salt that forms with aliphatic monobasic or di-carboxylic acid.The example of this class salt is acetate, maleate or fumarate.

Compound can be analyzed by IR or HNMR and obtain confirming.

The invention still further relates to the method for preparing phenanthridine derivatives.The applicant shockingly sees by replacing the aldehyde that suitably replaces with N-methyl (metho) benzonitrile that suitably replaces people just can obtain phenanthridine derivatives of the present invention.Specifically be in this step, to use the 2-methyl benzonitrile of 2 moles of formula IV to carry out the conversion of formula III aldehyde

R ₁-CHO III is R wherein ₁Have aforementioned implication,

R wherein ₂And R ₃Have aforementioned implication, in the presence of alkali, in non-proton dipole solvent, carry out; In following step, adopt conventional effective means to separate after, be with or without in the presence of the solvent, dewater with suitable dehydration medium.This reaction process can be expressed as follows:

The preferred acid amides that uses, as dimethyl formamide, N,N-DIMETHYLACETAMIDE, diethyl acetamide, hexamethyl phosphoric triamide and urea, as tetramethyl-urea, 1,3-dimethyl tetrahydro-2-pyrimidone (pyrimidinon) and 1,3-methylimidazole alkane ketone or methyl-sulphoxide are as the non-proton dipole solvent of the present invention's reaction.

For example, alkalimetal hydride or alkaline earth metal hydride are as sodium hydride; Alkali metal amino compound is as sodium amide, methyl kharophen sodium; Alkali metal alcoholate, alkaline-earth metal alcoholate or aluminum alcoholate, for example potassium tert.-butoxide, sodium methylate, sodium ethylate or aluminum ethylate can be used as alkali.

This reaction can followingly be carried out: under inert atmosphere, drip compound III and the solution of IV in this same solvent lentamente in a kind of suitable dipolar aprotic solvent solution of alkali.Under inert atmosphere after 35 ℃ of-50 ℃ of stirred for several hour, with in the product impouring icy water and with suitable organic solvent jolting.Organic solvent is reduced and by add haloid acid or from resistates, after neutralization and removing lixiviating, by using aqueous acid from aqueous phase precipitation or separate 6-amino-11,12-dihydrobenzo (c) phenanthridines II by it being told with suitable inorganic or organic acid jolting.Then, according to ordinary method, use suitable dehydration medium be with or without inert solvent in the presence of, can make 6-amino-11,12-dihydrobenzo (c) phenanthridines II dehydration forms amino benzo (c) phenanthridines of 6-I.

Answering ben is to have synthesized the phenanthridine derivatives that replacement or unsubstituted phenyl are arranged at 11 bit strips by method of the present invention.Beat all is this synthetic can being undertaken by simple reaction described herein, can have wide variation based on the initial substance relevant with the acquisition end product in this reaction.

Then find that previous described phenanthridine derivatives has remarkable antitumor, antimicrobial, antimycotic, antiviral and anti-inflammatory property.For detecting pharmacological property, with " extracorporeal anti-tumor screening " method detection general formula I and the II compound of the National Cancer Institute (NCI) that is positioned at Maryland, USA Bethesdal.Comprising about 58 kinds of different people's pathogeny tumor cell lines, they come from nine kinds of cancers (leukemia, nonsmall-cell lung cancer, large bowel cancer, central nervous system cancer, melanoma, ovarian cancer, kidney, prostate cancer and mammary cancer).For measuring level of significance, tumour cell is contacted two days with compound, then by calculating the protein biology amount and the indirect measurement growth-inhibiting with fanasil (sulphorhodomineB).Untreated culture as a reference.

In these experiments, for example 6-amino-11-(2, the 4-Dimethoxyphenyl) benzo (c) phenanthridines perchlorate demonstrates the growth-inhibiting effect.Beat allly be, the activity of this compound exhibits exceeds the activity with the antineoplastic compound of similarity method research, and the result obtains complete novel and effective resistance spectrum.

By these data, accompanying drawing 1 to 9 has been described the dosage-effect curve of embodiment compound.Nine groups of different data have comprised various forms of cancers.Percentage growth rate is drawn with compound concentration respectively (with the log10 of volumetric molar concentration).Each curve of all kinds of cancers derives from the different cell strains of such cancer, and they are represented with abbreviation commonly used.Sea line in the accompanying drawing represent percentage growth rate+100 ,+50,0 ,-50 and-100.100% growth table example does not change as comparing two days later with the culture growth that does not add material.By in each curve as can be seen, with the increase of material concentration, percentage growth rate reduces.

The invention still further relates to the medicine that contains phenanthridine derivatives described herein.For this reason, described medicine contains at least a phenanthridine derivatives as herein described and at least a inertia pharmaceutically acceptable carrier or diluent media.The general formula I derivative is preferably wherein R ₁Be 2,4-p-methoxy-phenyl and R ₂And R ₃It is the phenanthridine derivatives of hydrogen.Compound of the present invention can per os, part or non-stomach and intestine or with the suppository form administration.Preferred administering mode is oral.Compound can alkali form or as the physiological acceptable salt administration.Usually compound and pharmaceutically acceptable carrier or diluent media are mixed with medicine.For ease of oral, medicine can be made into modal capsule, tablet or slow releasing tablet form.They also can be made into dragee or syrup form.Suitable topical preparation is for example salt, lotion, creme, powder and sprays.

Further specify the present invention by embodiment below.Specific embodiments: 6-amino-11, the preparation of 12-dihydrobenzo (c) phenanthridines II: embodiment 1:6-amino-11,12-dihydrobenzo (c) phenanthridines hydrochloride

Under nitrogen atmosphere, prepare the 20ml DMPU solution of 2.47g (22mmol) potassium tert.-butoxide and in the nitrogen of convection current, solution in 12ml DMPU is added drop-wise in this preparation liquid lentamente with each 2ml with 300mg (10mmol) paraformaldehyde and 2.34g (20mmol) 2-methyl benzonitrile, and adding is 15 minutes at interval.Under nitrogen atmosphere in 35 ℃ stir 6 hours after, with in the 100ml frozen water of product impouring 2.2g (40mmol) ammonium chloride and with 100ml methylene dichloride jolting three times.The organic phase that merges is filtered wadding filter, and rotary evaporation is to about 100ml, with the violent jolting of 3N hydrochloric acid.The organic phase that decantation is crossed rotary evaporation again places it in refrigerator overnight then until there being a large amount of precipitations to produce.Capture precipitation, use a small amount of washed with dichloromethane, drying and recrystallization in ethanol/methylene.Obtain 6-amino-11,12-dihydrobenzo (c) phenanthridines hydrochloride.Light yellow plate crystal, yield: 16% of theoretical amount, fusing point: 350 ℃.

IR(KBr)：ν=3244cm ^-1，3102，2946，1654，1630，1616．- ¹H?NMR(360MHz，[D ₆]DMSO)：δ=3．0(mc，2H，-CH ₂-)，3．08(mc，2H，-CH ₂，-)，7．43(mc，3H，Ar-H)，7．77(t，1H，Ar-H)，8．02(t，1H，Ar-H)，8．16(d，1H，Ar-H)，8．27(mc，1H，Ar-H)，8．60(d，1H，Ar-H)，9．49(br，2H，-NH ₂)，13．78(br，1H，≡N ⁺-H)．

C ₁₇H ₁₅N ₂Cl (292.77) theoretical value .C 72.21 H 5.35 N 9.91

Measured value .C 72.13 H 5.35 N 9.99 embodiment 2:6-amino-11,12-dihydro-11-phenyl benzo (c) phenanthridines hydrochloride

Under nitrogen atmosphere, the 5ml DMPU solution of 1.06g (10mmol) phenyl aldehyde and 2.34g (20mmol) 2-methyl benzonitrile is added drop-wise in the 20mlDMPU solution of 2.47g (22mmol) potassium tert.-butoxide lentamente.Under nitrogen atmosphere in 35 ℃ stir 5 hours after, in the 100ml frozen water solution with product impouring 2.2g (40mmol) ammonium chloride, and with 100ml methylene dichloride jolting three times.Organic phase is filtered wadding filter, and rotary evaporation is to 100ml, with the violent jolting of 3N hydrochloric acid.Suction strainer gained precipitation is with a small amount of washed with dichloromethane and dry.In ethanol/methylene, behind the recrystallization, obtain 6-amino-11,12-dihydro-11-phenyl benzo (c) phenanthridines hydrochloride.The glassy yellow plate crystal, yield: 52% of theoretical amount, fusing point: 355 ℃.

-IR(KBr)：ν=3446cm ^-1，3076，1662，1620，1570．- ¹H?NMR(400MHz，[D ₆]?DMSO)：δ=3．18(mc，1H，12-H)，3．56(mc，1H，12-H)，4．95(mc，1H，11-H)，7．09(mc，5H，C6H5-)，7．24(d，1H，Ar-H)，7．35(t，1H，Ar-H)，7．44(t，1H，Ar-H)，7．74(mc，1H，Ar-H)，7．91(mc，2H，Ar-H)，8．3(d，1H，Ar-H)，8．61(d，1H，Ar-H)，9．3(br，2H，-NH ₂，)，13．7(br，1H，≡N ⁺-H)．

C ₂₃H ₁₉N ₂Cl (358.87) theoretical value .C 76.98 H 5.34 N 7.81

Measured value .C 76.52 H 5.37 N 7.75 embodiment 36-amino-11,12-dihydro-11-(3, the 4-Dimethoxyphenyl) benzo [c] phenanthridines hydrochloride

Be similar to embodiment 1.Light yellow needle crystal.Yield: 53% of theoretical amount, fusing point: 205 ℃ (methanol).

-IR (KBr): ν=3438cm-, 3268,3106,2938,1648,1616,1584.- ¹H NMR (400MHz, [D6] DMSO): δ=3.08 (mc, 1H, 12-H), 3.42 (mc, 1H, 12-H), 3.61 (s, 3H ,-OCH ₃), 3.99 (s, 3H ,-OCH ₃), 5.02 (mc, 1H, 11-H), 6.04 (mc, 1H, Ar-H), 6.21 (mc, 1H, Ar-H), 6.61 (mc, 1H, Ar-H), 7.20 (d, 1H, Ar-H), 7.34 (t, 1H, Ar-H), 7.43 (t, 1H, Ar-H), 7.63 (d, 1H, Ar-H), 7.73 (t, 1H, Ar-H), 7.91 (t, 1H, Ar-H), 8.36 (d, 1H, Ar-H), 8.61 (d, 1H, Ar-H), 9.56 (br, 2H ,-NH ₂), 13.85 (br, 1H, ≡ N ⁺-H) .C ₂₅H ₂₃N ₂O ₂Cl (418.92) theoretical value .C 71.68 H 5.53 N 6.69

The preparation of amino benzo (c) phenanthridines of measured value .C 70.95 H 5.37 N 6.806-I: amino benzo (c) phenanthridines of embodiment 16-perchlorate

The 35ml dioxane solution of 404mg (1.7mmol) DDQ is added to 250mg (1.02mmol) 6-amino-11, heated 4 hours in the 15ml dioxane solution of 12-dihydrobenzo (c) phenanthridines and under the convection current situation.Subsequently with in the refrigerative solution impouring sodium hydrogen carbonate solution and with the ether jolting.This ether with rare sodium bicarbonate washing once, washes with water three times mutually.After adding 70% perchloric acid, obtain precipitation.Drying also behind the recrystallization, obtains brown needle crystal, yield in methyl alcohol: 44% of theoretical amount, fusing point: 325 ℃.

-IR (Kbr): ν=3404cm ^-1, 3348,3298,3276,3234,1666,1616.- ¹H NMR (300MHz, [D ₆] DMSO): δ=7.82 (mc, 3H, Ar-H, 8.0 (d, 1H, Ar-H), 8.13 (mc, 2H, Ar-H), 8.56 (mc, 2H, Ar-H), 8.69 (d, 1H, Ar-H), 8.83 (d, 1H, Ar-H), 9.73 (br, 2H ,-NH ₂), 12.84 (br, 1H, ≡ N ⁺-H) .C ₁₇H ₁₃N ₂O ₄Cl (344.06) theoretical value .C 59.29 H 3.81 N 8.14

Measured value .C 59.23 H 3.83 N 8.24 embodiment 26-amino-11-phenyl benzo [c] phenanthridines perchlorate

Be similar to embodiment 1.Obtain taupe brown needle crystal, yield: theoretical amount 50%, fusing point: 345 ℃.

-IR (KBr) ν=3412cm ^-1, 3358,3310,3226,1668,1642,1612.- ¹H NMR (300MHz, [D6] DMSO): δ=7.51 (mc, 7H, Ar-H), 7.80 (mc, 4H, Ar-H), 8.15 (d, 1H, Ar-H), 8.66 (mc, 2H, Ar-H), 9.88 (br, 2H ,-NH ₂), 12.8 (br, 1H, ≡ N ⁺-H) .C ₂₃H ₁₇N ₂O ₄Cl (420.09) theoretical value .C 65.70 H 4.08 N 6.67

Measured value .C 65.67 H 4.03 N, 6.67 embodiment 36-amino-11-(2, the 4-Dimethoxyphenyl) benzo [c] phenanthridines perchlorate

Be similar to embodiment 1.Obtain dark brown needle crystal, yield: 45% of theoretical amount, fusing point: 336 ℃.

-IR (KBr): ν=3418cm ^-1, 3352,3302,3270,1660,1608.- ¹H NMR (300MHz, [D6] DMSO): δ=3.38 (s, 3H ,-OCH ₃), 3.87 (s, 3H ,-OCH ₃), 6.69 (mc, 1H, Ar-H), 6.77 (mc, 1H, Ar-H), 7.34 (mc, 1H, Ar-H), 7.77 (mc, 6H, Ar-H), 8.11 (mc, 1H, Ar-H), 8.77 (mc, 2H, Ar-H), 9.72 (br, 2H ,-NH ₂); 12.58 (br, 1H, ≡ N ⁺-H) .C ₂₅H ₂₁N ₂O ₆Cl (480.19) theoretical value .C 62.49 H 4.41 N 5.83

Measured value .C 62.56 H 4.3O N 5.87

Claims (11)

1. the phenanthridine derivatives of general formula I and II

And salt, wherein R ₁Expression hydrogen atom, aromatic carbocyclic or heterocyclic radical and R ₂And R ₃Can be identical or different, expression hydrogen atom, alkoxyl group, alkenyl oxygen, halogen atom or nitro.

2. according to the phenanthridine derivatives of claim 1, be characterised in that

R ₁Be hydrogen or unsubstituted phenyl or the phenyl that has or several methoxyl groups or have N, the group of N dimethylamine functional group, R ₂And R ₃All be hydrogen.

3. according to the phenanthridine derivatives of claim 2, be characterised in that

R ₁Be phenyl, 2,4-p-methoxy-phenyl or 3,4-p-methoxy-phenyl.

4. according to the phenanthridine derivatives of claim 3, be characterised in that

In general formula I, R ₁Be 2, the 4-p-methoxy-phenyl.

5. the method for the general formula I I phenanthridine derivatives of one of preparation claim 1-4 is characterised in that

Aldehyde with formula III

R ₁-CHO

2-methyl benzonitrile with formula IV

Reaction in the presence of alkali in non-proton dipole solvent, radicals R ₁, R ₂And R ₃Has implication described in the claim 1-4.

6. the method for the general formula I phenanthridine derivatives of one of preparation claim 1-4 is characterised in that

Aldehyde with formula III

R ₁-CHO

2-methyl benzonitrile with formula IV

Reaction in the presence of alkali in non-proton dipole solvent, radicals R ₁, R ₂And R ₃Have implication described in the claim 1-4, and in further reaction, be with or without in the presence of the solvent and dewater with the suitable medium that dewaters.

7. according to the method for preparing phenanthridine derivatives of claim 5 or 6, be characterised in that

R in the aldehyde of the general formula III that is added ₁Be phenyl, 2,4-p-methoxy-phenyl or 3,4-p-methoxy-phenyl or hydrogen.

8. according to the method for claim 7, be characterised in that

R ₁Be 2,4-or 3,4-p-methoxy-phenyl.

9. according to claim 5-8 each method at least, be characterised in that

In the 2-methyl benzonitrile of the general formula I V that is added, R ₂And R ₃All be hydrogen.

10. medicine is characterised in that

It contains phenanthridine derivatives and at least a inert pharmaceutically acceptable carrier or the diluent media of at least a claim 1-4.

11. the medicine according to claim 10 is characterised in that

It contains the phenanthridine derivatives of general formula I, wherein R ₁Be 2,4-p-methoxy-phenyl and R ₂And R ₃All be hydrogen.

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