CN1159183A - BIS-(2-haloethyl) aminophenyl substituted distamycin derivatives as antitumor and antiviral agents - Google Patents
BIS-(2-haloethyl) aminophenyl substituted distamycin derivatives as antitumor and antiviral agents Download PDFInfo
- Publication number
- CN1159183A CN1159183A CN96190784A CN96190784A CN1159183A CN 1159183 A CN1159183 A CN 1159183A CN 96190784 A CN96190784 A CN 96190784A CN 96190784 A CN96190784 A CN 96190784A CN 1159183 A CN1159183 A CN 1159183A
- Authority
- CN
- China
- Prior art keywords
- methyl
- formamido group
- pyrroles
- group
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
Novel antitumor and antiviral agents of formula (I) wherein n is 2, 3 or 4; one of R and R1 is hydrogen, C1-C4 alkyl, CF3 or C1-C4 alkoxy and the other is independently CF3, C1-C4 alkyl or C1-C4 alkoxy; and X is halogen; and the salts thereof are disclosed.
Description
The present invention relates to new anti-tumor alkylating agent and antiviral agent, they and known microbiotic Distacin
(Distacin) is relevant, belongs to pyrroles amidine antibiotics; Reversibility and the selectivity [nature 203,1064 (1964) that interacts has between the DNA-AT sequence that it is reported they and interference replica and transcribe; FEBS communication 7 (1970) 90; The nucleic acids research Recent advances in molecular biology, 15,285 (1975)].
DE-A-1795539 has described the preparation method of distamycin derivatives, and wherein the formyl radical of distamycin is by hydrogen or organic C
1-C
4The sour residue of lipid acid or cyclopentanepropanoiacid acid replaces.
EP-B-246868 has described distamycin A analogues, and wherein the formyl radical of distamycin is had that the aromatics, aliphatic series of alkanisation group or heterocycle structure replace.
Find that now a selected compounds has fallen into the general formula of EB-B-246868, but they has more valuable biological characteristics than relevant prior art compound.
Therefore, the invention provides new site-specific nitrogen and be situated between, their preparation method contains their pharmaceutical composition and their purposes in treatment.
The invention provides the new formula of a class (I) compound
Wherein n is 2,3 or 4R and R
1One of be hydrogen, C
1-C
4Alkyl, CF
3Or C
1-C
4Alkoxyl group, another is CF independently
3, C
1-C
4Alkyl or C
1-C
4Alkoxyl group; And X is a halogen.
The present invention also comprises the pharmacologically acceptable salt of formula (I) compound and all by the possible isomer that formula (I) transforms, and comprises monomer and form of mixtures.
The present invention also comprises the metabolite and the pharmaceutically acceptable bioprecursor (being also referred to as prodrug in addition) of formula (I) compound.
Alkyl and alkoxyl group can be the ramose normal carbon chains.
C
1-C
4Alkyl preferable methyl or ethyl.
C
1-C
4The preferred methoxy or ethoxy of alkoxyl group.
Position or contraposition between the formamyl of phenyl ring and two halo ethylamino preferably are each other.
R and R
1Can be on any free carbon atom of phenyl ring, but not on same carbon atom.Preferred R and R
1One of be hydrogen or C
1-C
4Alkyl, another is C
1-C
4Alkyl, CF
3Or C
1-C
4Alkoxyl group; Perhaps R and R
1Identical, be C
1-C
4Alkoxyl group.
The pharmacologically acceptable salt of formula (I) compound is they and pharmaceutically acceptable mineral acid or organic acid salt.
The example of mineral acid is hydrochloric acid, Hydrogen bromide, sulfuric acid and nitric acid; The organic acid example is acetate, propionic acid, succsinic acid, propanedioic acid, citric acid, tartrate, methylsulfonic acid and tosic acid.
Preferred n value is 3.
X is chlorine or bromine preferably, especially chlorine.
The preferred The compounds of this invention of one class is formula (I) compound and pharmacologically acceptable salt thereof, and wherein: n is 3; X is a chlorine; R and R
1One of be hydrogen or C
1-C
4Alkyl, another is C
1-C
4Alkyl, CF
3Or C
1-C
4Alkoxyl group.
Particular compound example of the present invention, especially with the salt form of hydrochloric acid, be following compounds: β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimethyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-ethyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-diethyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methoxyl group-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-oxyethyl group-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methoxyl group-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; And β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-5-methyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine.
Compound of the present invention and salt thereof can obtain by the following method, and described method comprises that with n wherein be formula (II) compound as defined above
With formula (III) compound
R in the reaction, formula (III), R
1With X be hydroxyl or leavings group as above-mentioned definition and Y; And if desired, make formula (I) compound salify or obtain free cpds by its salt, and/or, if desired formula (I) compound isomers mixture separation is become individual isomer.
The reaction of formula (II) compound and formula (III) compound can be carried out in accordance with known methods, for example the method described in the EP-B-246868.
Specifically, leavings group Y can be selected from halogen, especially chlorine, and 2,4,5-Trichlorophenoxy, 2,4-2,4-dinitrophenoxy base, succinimido-N-oxygen base and imidazolyl.
Formula (II) compound with Y wherein is-and the reaction of formula (III) compound of OH is preferably with 1: and 1-1: 2 mol ratio is carried out in organic solvent in the presence of organic or inorganic alkali and condensing agent, described solvent is, for example dimethyl sulfoxide (DMSO), hexamethyl phosphoric triamide, N,N-DIMETHYLACETAMIDE, dimethyl formamide, ethanol, benzene or pyridine; Described organic or inorganic alkali is, for example triethylamine, diisopropyl ethyl amine or yellow soda ash or sodium bicarbonate; Described condensing agent is, N-ethyl-N '-(3-dimethylamino-propyl) carbodiimide or N for example, N '-dicyclohexyl carbodiimide.This temperature of reaction can change between-10 ℃-Yue 50 ℃ approximately, and the reaction times is about 24 hours of about 1-.
Y in the formula (III) is other leavings group, as halogen, 2,4, when 5-Trichlorophenoxy or succinimido-N-oxygen base or imidazolyl, the reaction between formula (II) compound and formula (III) compound can be carried out under the conditions of similarity that does not have condensing agent to exist.
Formula (II) compound is a known compound, perhaps can adopt the currently known methods preparation of preparation known compound, for example referring to Arcamone etc., and Italian chemical communique, 97,1097 (1967).Formula (III) compound also is a known compound, currently known methods preparation that perhaps can be by describing in detail in the organic chemistry: as referring to the pharmaceutical chemistry magazine, and 9,882 (1966) and 25,178 (1982).
Making formula (I) compound salify and preparing free cpds by salt to adopt known usual way to carry out.
Then, can adopt the method for knowing, the isomer mixture of formula (I) is separated into individual isomer as fractionation crystallization or chromatography.
The new compound of Zhi Bei formula (I) can adopt the ordinary method purifying according to the method described above, as silica gel or alumina column chromatography, and/or in organic solvent recrystallization, described organic solvent is, lower aliphatic alcohols for example is as methyl alcohol, ethanol or Virahol, perhaps dimethyl formamide.Pharmacology
The compounds of this invention can be used as antitumor and antiviral agent.Specifically, they show the cell rejection characteristic to tumour cell, so they can be used for suppressing various Mammalss, comprise people's growth of tumor, and cancer for example is as mammary cancer, lung cancer, bladder cancer, colorectal carcinoma, ovary and carcinoma of endometrium.Other tumour that the The compounds of this invention of being found is suitable for is that for example sarcoma as soft tissue and osteoma, reaches leukemia, as leukemia.
Estimate anti tumor activity in vitro with the Study of cytotoxicity that mouse L1210 leukemia cell carries out.Obtain cell and it is seeded in the cell culture medium by in-vivo tumour.Use until the tenth passage cell always.Record cytotoxicity by the survivaling cell of counting processing after 48 hours.
Cell in the substratum of handling growth percentage ratio and contrast are compared.Calculate IC according to dose-response curve
50Value (comparing the concentration of cell growth inhibiting 50% with control group).
Use following method, with The compounds of this invention in vivo to mouse L
1210Leukemia and mouse M5076 reticulum cell sarcoma test, show good antineoplastic activity.
Transplant L in the maintenance body continuously by vein
1210Murine leukemia.For experimentizing, with 10
5The cell peritoneal injection is to the CD2F1 female mice that obtains from Italian Charles River.During the experiment beginning, animal is 8-10 age in week.Behind tumor cell injection+vein was bestowed compound in 1 day.
Transplant maintenance M5076 reticulum cell sarcoma continuously by intramuscular.For experimentizing, with 5 * 10
5The cell intramuscularly is to the C57816 female mice that obtains from Italian Charles River.During the experiment beginning, animal is 8-10 age in week.3,7 and 11 days veins are bestowed compound behind tumor injection.
Calculate survival time and the tumor growth of mouse, represent activity with T/C%h and T.I%.
The %Tox of the inhibition tumor growth that T.I.=compares with control group: because toxicity and dead number of mice.
When mouse at control group and/or observe obvious body weight and reduce and/or observe spleen and/or liver and carry out Tox when dead before diminishing and measure.
In these tumor models, compound very close among compound of the present invention and the EP-B-0246868 is compared, and has higher anti-tumor activity.
For example, representational compound β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine (internal code FCE 29325) and β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimethyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] known compound β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group among third amidine (internal code FCE 29721) and the EP-B-0246868] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine (internal code FCE 24517) antagonism dissemination L
1210The activity data of mouse leukemia shows below.Table 1
| Compound (internal code) FCE 29325 FCE 29721 FCE 24517 | ?mg/kg 3.13 3.13 3.13 | T/C％ 191 183 133 | Tox 0/10 0/10 0/10 |
The activity data of last table shows that having described substituent compound of the present invention on the phenyl ring of benzoyl mustard compares with very close unsubstituted known compound FCE 24517, has higher activity.
The compounds of this invention can also disturb the replication activity of pathogenic virus effectively, thereby makes histocyte avoid virus infection.
They all have activity resistent following virus, and dna virus for example is as simplexvirus, as herpes simplex virus and varicella zoster virus; RNA viruses is as rhinovirus and adenovirus; And retrovirus, as sarcoma virus, as murine sarcoma virus and leukosis virus, as hemophilia virus (Friendleukemia).Followingly in circulatory mediator, test simplexvirus, cock plug base virus and breathing and close inclusion virus.Will be to 96 hole titer plate from the diluent of the twice in turn double allocation of 200-1.5mcg/ml, the 0.1ml/ hole is used for tissue culture.
Add with about 5 * 10 immediately
-3Individual TCID
50The cell suspending liquid (2 * 10 of virus infection
5Cell/ml), the 0.1ml/ hole.
At 5%CO
2, 37 ℃ cultivate after 33-5 days down, estimate cell culture with microscopic examination, and measure minimum inhibition concentration (MIC), MIC measures with the control group that infects to compare the Cmin of eliminating the cytopathy effect.
Compound of the present invention can pass through conventional route, for example through parenteral route, and as by intravenous injection or infusion, intramuscular, subcutaneous, part or oral route are bestowed and are comprised human Mammals.
Dosage depends on patient's age, body weight and physical appearance and route of administration.
For example, for compound F 17-hydroxy-corticosterone CE 20325, the optimal dose of bestowing adult patient is every dose of about 0.1～about 150-200mg, every day 1-4 time.
As noted earlier, pharmaceutical composition of the present invention contains formula (I) compound and one or more the pharmaceutically acceptable vehicle as activeconstituents.
Pharmaceutical composition of the present invention can be prepared according to following ordinary method usually, and the medicine type that they can suit is used.
For example, the solution that is used for intravenous injection or infusion can contain carrier, as sterilized water or preferred aseptic normal isotonic saline solution.
But the suspension or the solution that are used for intramuscularly can contain active compound and pharmaceutically acceptable carrier, as sterilized water, and sweet oil, ethyl oleate, glycols is as propylene glycol; And many cacaines of the power hydrochloride that also contains if desired, sufficient quantity.
Be used for the topical application formulation such as the creme of epidermis treatment, in lotion or the paste, activeconstituents can with oiliness or emulsification mixed with excipients commonly used.
Solid oral dosage form as tablet and capsule, can contain activeconstituents and thinner, as lactose, glucose, sucrose, Mierocrystalline cellulose, W-Gum and yam starch; Lubricant is as silicon-dioxide, talcum, stearic acid, calcium stearate or magnesium and/or polyoxyethylene glycol; Tackiness agent is as starch, gum arabic, gelatin, methylcellulose gum, carboxymethyl cellulose, polyvinylpyrrolidone; Disintegrating agent is as starch, alginic acid, alginate, sodium starch glycol; Foaming mixtures; Pigment; Sweeting agent; Wetting agent is as Yelkin TTS, soil temperature, lauryl sulfate; And in general, the nontoxic pharmacology inert substance of using always in the pharmaceutical preparation.Described pharmaceutical preparation can known method be prepared, as preparing by mixing, granulation, compressing tablet, sugar coating or dressing process.
In addition, the present invention also provides a kind of tumour of treatment and the method for virus infection to the patient of this treatment of need, comprises to described patient and uses composition of the present invention.
Another object of the present invention provides the method that a kind of combination therapy comprises human mammalian cancer patient's cancer or alleviates its symptom, this method comprises and giving: 1) compound or pharmaceutically acceptable salt thereof of the present invention, with 2) another kind of antineoplastic agent, their combined amount should be enough to produce curative effect on time.
The present invention also provides the product that contains The compounds of this invention or its pharmacologically acceptable salt and another kind of antineoplastic agent, and as combined preparation, they can use simultaneously, separately or in order in anticancer therapy.
Term " antineoplastic agent " is meant and comprises independent a kind of antitumour drug and " mixture ", the i.e. mixture of this class medicine in the clinical practice.
Can comprise Zorubicin, daunorubicin, epirubicin, darubicin, etoposide, Fluracil, melphalan, endoxan, 4-idarubicin, bleomycin, vinealeucoblastine(VLB) and mitomycin and two or three above-mentioned mixture with the example of The compounds of this invention preparation or the antineoplastic agent of can combinational therapeutic methods using.
Therefore, compound of the present invention can be used for treatment alleviation cancer.They can be bestowed medicable cancer patients with a kind of antineoplastic agent, described antineoplastic agent is that for example above-mentioned anthracycline glucoside is as Zorubicin, daunorubicin, epirubicin, 4-idarubicin or darubicin.
Compound of the present invention and antineoplastic agent, can improve patient's symptom as the anthracycline glucoside, described patient is lymphoma leukemia and sarcoma, for example myeloblastic leukemia, neuroblastoma, this tumour of Weir nurse or bladder, mammary gland, lung or thyroid malignancy.
Following embodiment is intended to explanation and does not have restricted.
Abbreviation DMF, DMSO and P.M.R. represent dimethyl formamide, dimethyl sulfoxide (DMSO) and proton magnetic resonance (PMR) respectively.Embodiment 1
Compound β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N, N-two-(2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine hydrochloride the first step intermediate 3-methyl-4-N, N-two (2-chloroethyl) benzaminic acid
In the 100ml25% acetic acid suspension of the commercially available 3-methyl-4-subcutin of 2g, add 20ml oxyethane.With this mixture stirring at room 2 days, with the sodium bicarbonate neutralization and with ethyl acetate extraction (2 * 100ml).With the organic phase drying (Na that merges
2SO
4) and vacuum concentration, obtaining white precipitate 3-methyl-4-N, N-two (2-chloroethyl) benzaminic acid is filtered, and it is suspended in the 10ml23% hydrochloric acid soln, cools off in ice, adds the 1.8ml phosphoryl chloride.This mixture was refluxed 2 hours, cooling and dilute with water, ethyl acetate extraction (2 * 50ml) again.
With the organic phase drying (Na that merges
2O
4), vacuum is steamed and is desolventized, and obtains the 2g intermediate.m.p.108-110℃FAB-MS：m/z：276(20，[M+H]
+)P.M.R.(CDCl
3)δ：7.9(m，2H)；7.15(m，1H)；3.5(m，8H)；
2.35 (s, 3H) the second step title compound
In the 10ml benzole soln of 630mg intermediate, add the 1.8ml thionyl chloride.This mixture was refluxed 2 hours, and vacuum is steamed and is desolventized, and thick solid residue is dissolved in the 15ml dioxan, and a small amount of this solution is added in the 10ml aqueous solution of 400mg N-Distacin and 255mg sodium bicarbonate.This mixture was stirred 1 hour, add the 2N hydrochloric acid soln then until pH=1.Vacuum is steamed and is desolventized, and solid residue with methylene dichloride, carbinol mixture purifying, obtains 500mg title mixture through the silica gel flash column chromatography.FAB-MS：m/z：711(45[M+H]
+)，258(75)P.M.R.(DMSO)δ：10.19(s，1H)；9.97(s，1H)；9.91(s，1H)；8.7(bs，4H)；8.21(t，J＝5.7Hz，1H)7.74(m，2H)；7.29(d，J＝1.8Hz，1H)；7.28(d，J＝7.5Hz，1H)；7.22(d，J＝1.8Hz1H)；7.17(d，J＝1.8Hz，1H)；7.08(d，J＝1.8Hz，1H)；7.05(d，J＝1.8Hz，1H)；6.94(d，J＝1.8Hz，1H)；3.85(s，3H)；3.83(s3H)；3.80(s，3H)；3.3-3.7(m，10H)；2.6(t，J＝6.6Hz，2H)；2.33(s，3H).
Pass through similar approach, use suitable intermediate can obtain following compounds: β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimethyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] the third amidine hydrochloride FAB-MS:m/z:725 (90[M+H]
+) U.V. (EtOH95%) λ 310. ε=42985P.M.R. (DMSO) δ: 10.22 (s, 1H); 10.01 (s, 1H); 9.94 (s, 1H); 8.99 (s, 2H); 8.64 (s, 2H); 8.21 (t, J=5.7Hz, 1H); 7.61 (s, 2H); 7.29 (d, J=1.7Hz, 1H); 7.21 (d, J=1.7Hz, 1H); 7.18 (d, J=1.7Hz, 1H); 7.08 (d, J=1.7Hz, 1H); 7.05 (d, J=1.7Hz, 1H); 6.91 (d, J=1.7Hz, 1H); 3.86 (s, 3H); 3.84 (s, 3H); 3.81 (s, 3H); 3.62 (m, 2H); 3.60-3.30 (m, 8H); 2.62 (m, 2H); 2.35 (s, 6H). β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-ethyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] the third amidine hydrochloride; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-diethyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methoxyl group-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-oxyethyl group-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methoxyl group-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; And β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-5-methyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine.Embodiment 2
Tablet (the heavy 0.250mg of sheet contains the 50mg active substance) can followingly be prepared: per 10,000 composition
| β-[1-methyl-4-[1-methyl 4-[1-methyl-4-[3-methyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] the third amidine hydrochloride; Lactose W-Gum talcum powder Magnesium Stearate | 500g 1,400g 500g 80g 20g |
With β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] the third amidine hydrochloride, the W-Gum of lactose and half amount mixes; 0.5mm mesh sieve then pressurizeed this mixture.
W-Gum (10g) is suspended in the warm water (90ml), sticks with paste with gained powdered mixture is granulated.Part makes it in small, broken bits with particle drying and on the 1.4mm mesh sieve, adds starch, talcum and the Magnesium Stearate of residual content then, carefully mixes and tablet forming.
Embodiment 3
Capsule (the heavy 0.200g of every capsule contains the 20mg active substance) can followingly be prepared: the composition of per 500 capsules
| β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] the third amidine hydrochloride; Lactose W-Gum Magnesium Stearate | ?10g ?80g ?5g ?5g |
Said preparation is encapsulated in two sections the hard gelatin capsule every capsules 0.200g.Embodiment 4
Intramuscular injection 25mg/ml
With 25g β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] the third amidine hydrochloride is dissolved in the injectable pharmaceutical composition of preparation in the propylene glycol (1000ml), and it enclosed in the ampoule of 1-5ml.
Claims (10)
1. formula (I) compound and pharmacologically acceptable salt thereof,
Wherein n is 2,3 or 4R and R
1One of be hydrogen, C
1-C
4Alkyl, CF
3Or C
1-C
4Alkoxyl group, another is CF independently
3, C
1-C
4Alkyl or C
1-C
4Alkoxyl group; And X is a halogen.
2. the formula of claim 1 (I) compound and pharmacologically acceptable salt thereof, wherein: n is 3; X is a chlorine; R and R
1One of be hydrogen or C
1-C
4Alkyl, another is C
1-C
4Alkyl, CF
3Or C
1-C
4Alkoxyl group.
Be selected from following compound: β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group 3.-plant] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-dimethyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-ethyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3,5-diethyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-methoxyl group-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-oxyethyl group-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methoxyl group-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[2-methyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine; And β-[1-methyl-4-[1-methyl-4-[1-methyl-4-[3-trifluoromethyl-5-methyl-4-N, N-two (2-chloroethyl) amino-benzene-1-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] pyrroles-2-formamido group] third amidine, perhaps their pharmacologically acceptable salt.
4. the salt of the compound of claim 3, wherein said salt is hydrochloride.
5. the method for a preparation formula (I) compound or its salt, described method comprise that with n wherein be as defined in claim 1 formula (II) compound
With formula (III) compound
R in the reaction, formula (III), R
1With X such as claim 1 definition and Y be hydroxyl or leavings group; And if desired, make formula (I) compound salify or obtain free cpds by its salt, and/or, if desired formula (I) compound isomers mixture separation is become individual isomer.
6. pharmaceutical composition contains appropriate carrier and/or thinner and as formula (I) compound or pharmaceutically acceptable salt thereof of the claim 1 of activeconstituents.
7. the formula of claim 1 (I) compound or pharmaceutically acceptable salt thereof is used as antitumor and antiviral agent.
8. the combined preparation product that contains the defined formula of claim 1 (I) compound or pharmaceutically acceptable salt thereof and another kind of antineoplastic agent, they can use simultaneously, separately or in order in anticancer therapy.
9. the defined formula of claim 1 (I) compound or pharmaceutically acceptable salt thereof is preparing as the purposes in the pharmaceutical composition of antitumor and antiviral agent.
10. the mammiferous method of tumour is suffered from a treatment, and this method comprises the defined formula of claim 1 (I) compound or pharmaceutically acceptable salt thereof from the treatment significant quantity to described Mammals that bestow.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9514993.6A GB9514993D0 (en) | 1995-07-21 | 1995-07-21 | Site specific phenyl nitrogen mustards |
| GB9514993.6 | 1995-07-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1159183A true CN1159183A (en) | 1997-09-10 |
Family
ID=10778062
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96190784A Pending CN1159183A (en) | 1995-07-21 | 1996-06-19 | BIS-(2-haloethyl) aminophenyl substituted distamycin derivatives as antitumor and antiviral agents |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0787126A1 (en) |
| JP (1) | JPH10506410A (en) |
| KR (1) | KR970706251A (en) |
| CN (1) | CN1159183A (en) |
| AR (1) | AR003456A1 (en) |
| AU (1) | AU6357996A (en) |
| BR (1) | BR9606528A (en) |
| CA (1) | CA2199635A1 (en) |
| EA (1) | EA000033B1 (en) |
| GB (1) | GB9514993D0 (en) |
| HU (1) | HUP9702393A3 (en) |
| IL (1) | IL120342A0 (en) |
| MX (1) | MX9701949A (en) |
| NO (1) | NO971142D0 (en) |
| PL (1) | PL319352A1 (en) |
| TW (1) | TW367325B (en) |
| WO (1) | WO1997003957A1 (en) |
| ZA (1) | ZA965028B (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998037066A1 (en) | 1996-02-26 | 1998-08-27 | California Institute Of Technology | Improved polyamides for binding in the minor groove of double stranded dna |
| US6635417B1 (en) | 1996-07-31 | 2003-10-21 | California Institute Of Technology | Complex formation between DSDNA and oligomer of cyclic heterocycles |
| US5998140A (en) | 1996-07-31 | 1999-12-07 | The Scripps Research Institute | Complex formation between dsDNA and oligomer of cyclic heterocycles |
| GB9623522D0 (en) * | 1996-11-11 | 1997-01-08 | Pharmacia & Upjohn Spa | Benzoheterocycle distamycin derivatives process for preparing them and their use as antitumour and antiviral agents |
| GB9816652D0 (en) * | 1998-07-30 | 1998-09-30 | Pharmacia & Upjohn Spa | Sulfurated distamycin derivatives process for preparing them and their use as antitumor agents |
| GB9907414D0 (en) | 1999-03-31 | 1999-05-26 | Cancer Res Campaign Tech | Improvements relating to prodrugs |
| US6559125B1 (en) | 2000-01-28 | 2003-05-06 | California Institute Of Technology | Polyamide-alkylator conjugates and related products and method |
| WO2002101007A2 (en) | 2001-06-13 | 2002-12-19 | Genesoft Pharmaceuticals, Inc | Antipathogenic benzamide compounds |
| US7498349B2 (en) | 2002-08-02 | 2009-03-03 | Genesoft Pharmaceuticals, Inc. | Biaryl compounds having anti-infective activity |
| EP1562931A2 (en) | 2002-10-25 | 2005-08-17 | Genesoft Pharmaceuticals, Inc. | Anti-infective biaryl compounds |
| EP1587529A4 (en) | 2002-12-10 | 2009-08-12 | Oscient Pharmaceuticals Corp | Antibacterial compounds having a (pyrrole carboxamide)-(benzamide)-(imidazole carboxamide) motif |
| EP2792355A1 (en) | 2013-04-17 | 2014-10-22 | Albert-Ludwigs-Universität Freiburg | Compounds for use as bromodomain inhibitors |
| CN115414356A (en) * | 2022-09-27 | 2022-12-02 | 广西科技大学 | Application of indenopyrrole derivatives in preparation of antitumor pharmaceutical composition |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8612218D0 (en) * | 1986-05-20 | 1986-06-25 | Erba Farmitalia | Site specific alkylating agents |
-
1995
- 1995-07-21 GB GBGB9514993.6A patent/GB9514993D0/en active Pending
-
1996
- 1996-06-13 ZA ZA965028A patent/ZA965028B/en unknown
- 1996-06-18 TW TW085107334A patent/TW367325B/en active
- 1996-06-19 EP EP96922849A patent/EP0787126A1/en not_active Withdrawn
- 1996-06-19 WO PCT/EP1996/002659 patent/WO1997003957A1/en not_active Application Discontinuation
- 1996-06-19 EA EA199700046A patent/EA000033B1/en not_active IP Right Cessation
- 1996-06-19 IL IL12034296A patent/IL120342A0/en unknown
- 1996-06-19 MX MX9701949A patent/MX9701949A/en unknown
- 1996-06-19 PL PL96319352A patent/PL319352A1/en unknown
- 1996-06-19 CA CA002199635A patent/CA2199635A1/en not_active Abandoned
- 1996-06-19 BR BR9606528A patent/BR9606528A/en not_active Application Discontinuation
- 1996-06-19 AU AU63579/96A patent/AU6357996A/en not_active Abandoned
- 1996-06-19 CN CN96190784A patent/CN1159183A/en active Pending
- 1996-06-19 JP JP9506209A patent/JPH10506410A/en active Pending
- 1996-06-19 HU HU9702393A patent/HUP9702393A3/en unknown
- 1996-07-15 AR ARP960103583A patent/AR003456A1/en unknown
- 1996-09-19 KR KR1019970701796A patent/KR970706251A/en not_active Application Discontinuation
-
1997
- 1997-03-12 NO NO971142A patent/NO971142D0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO971142L (en) | 1997-03-12 |
| EP0787126A1 (en) | 1997-08-06 |
| EA000033B1 (en) | 1998-02-26 |
| HUP9702393A2 (en) | 1998-04-28 |
| EA199700046A1 (en) | 1997-12-30 |
| GB9514993D0 (en) | 1995-09-20 |
| BR9606528A (en) | 1997-12-23 |
| ZA965028B (en) | 1997-01-23 |
| CA2199635A1 (en) | 1997-02-06 |
| WO1997003957A1 (en) | 1997-02-06 |
| AR003456A1 (en) | 1998-08-05 |
| MX9701949A (en) | 1997-06-28 |
| JPH10506410A (en) | 1998-06-23 |
| AU6357996A (en) | 1997-02-18 |
| IL120342A0 (en) | 1997-06-10 |
| TW367325B (en) | 1999-08-21 |
| HUP9702393A3 (en) | 1998-05-28 |
| PL319352A1 (en) | 1997-08-04 |
| KR970706251A (en) | 1997-11-03 |
| NO971142D0 (en) | 1997-03-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9351970B2 (en) | Anti-viral pyrimidine nucleoside analogues | |
| JP4049477B2 (en) | Side effect reducing agent | |
| JPH10507772A (en) | L-ribofuranosyl nucleoside | |
| CN1159183A (en) | BIS-(2-haloethyl) aminophenyl substituted distamycin derivatives as antitumor and antiviral agents | |
| CN101977923A (en) | Novel cytostatic 7-deazapurine nucleosides | |
| CN1116281C (en) | Acryloyl substituted distamycin derivative, process for preparing them, and use as antitumor and antiviral agents | |
| CN1960734A (en) | Treatment of t-cell lymphoma using 10-propargyl-10-deazaaminopterin | |
| JP2003532735A (en) | Antiviral pyrimidine nucleosides | |
| CN1089755C (en) | Distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents | |
| CN112479974B (en) | Preparation and application of 3-carbonyl-2, 3' -bisindole nitrogen oxide derivative | |
| CN114394965B (en) | Triazolopyridine compound and preparation method and application thereof | |
| WO2019007003A1 (en) | Alkanosulfide-terminated oligomer-peg modified amino-pyrazolo[3,4-d]pyrimidine derivative and application to non-small cell lung cancer resistance | |
| TW553945B (en) | Triazolopurine derivatives, medicinal composition containing the derivatives, adenosine A3 receptor compatibilizing agent, and asthmatic remedy | |
| DE69533856T2 (en) | L-pyranosyl NUCLEOSIDES | |
| CN111484541A (en) | Dinucleotide precursor medicine and its preparing method | |
| US4861873A (en) | 8-Chloroadenosine 3', 5'-cyclic monophosphate preparations | |
| JPS62919B2 (en) | ||
| CN112300235B (en) | Benzimidazole derivative BI321 and preparation method and application thereof | |
| EP0499291A1 (en) | Treatment of malignant tumours with 8-chloroadenosine 3'-5'-cyclic phosphate, 8-aminoadenosine 3',5'-cyclic phosphate and preparation thereof | |
| CN116217621B (en) | Nucleoside double-prodrug, synthesis method and application | |
| CN112375112B (en) | Benzimidazole derivative BI361 and preparation method and application thereof | |
| JP2781073B2 (en) | Novel quinoline derivative and anticancer drug effect enhancer containing the same as active ingredient | |
| CN114656449A (en) | Silibinin derivative containing carbamic acid structure and application thereof | |
| WO2024051795A1 (en) | Substituted purinone derivative used as ubiquitin-specific protease inhibitor | |
| CN117247319A (en) | 5, 6-dihydroxynaphthoate compound and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |