WO2014191964A1 - New bis-indole alkaloids as anticancer drugs - Google Patents
New bis-indole alkaloids as anticancer drugs Download PDFInfo
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- WO2014191964A1 WO2014191964A1 PCT/IB2014/061836 IB2014061836W WO2014191964A1 WO 2014191964 A1 WO2014191964 A1 WO 2014191964A1 IB 2014061836 W IB2014061836 W IB 2014061836W WO 2014191964 A1 WO2014191964 A1 WO 2014191964A1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
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- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical class CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the field of this invention relates to novel cyclopropyl derivatives of the general formula (I) representing pharmaceutically applicable Vinca Rosea type alkaloid compounds, particularly having a cytostatic effect.
- the invention also is concerned processes for preparing these new alkaloids and their pharmacological compositions and the use of these compounds in treatment of cancer.
- R stands for a methyl or a formyl group
- Ri stands for a methoxy or an amino group
- R 2 represent a hydroxy or acetoxy group
- R 3 stands for a hydrogen atom or a hydroxy group
- R4 represents a hydrogen atom or R 3 and R 4 together represent a double bond
- R 5 and R6 represent hydrogen or fluorine atoms
- VLB vinblastine
- VCR vincristine
- vindesine (4-desacetyl VLB C-3 carboxamide - (III)) by the E. Lilly Laboratories in 1983, and two nor-derivatives, vinorelbine (IV) in 1989 and vinflunine (V) in 1995 by the Pierre Fabre Laboratories.
- Vinfunine proved or seems to be effective in chemotherapy of a sort of cancer types: nonsmall- and small-cell lung cancer, metastatic breast cancer, renal cell carcinoma, transitional cell carcinomas of the urothelium, malignant pleural mesothelioma and has neurological, hematological and some other adverse reactions (John S Ng. Vinflunine: review of a new vinca alkaloid and its potential role in oncology. J. Oncol. Pharm. Practice 17(3) 209-224.) Vinflunine
- Microtubule disruptive drugs like vinblastine and the novel vinca alkaloids have been reported to act by two mechanisms. At very low concentrations they suppress microtubule dynamics and at higher concentrations they reduce microtubule polymer mass. (Jordan, M. A.; Leslie, W. (2004). "Microtubules as a Target for Anticancer Drugs”. Nature Reviews Cancer 4 (4): 253-265.) They work by preventing mitosis in metaphase. These alkaloids bind to tubulin, thus preventing the cell from making the spindles it needs to be able to divide. However, recent clinical studies with vinflunine against many different malignant cell lines showed that the exact mechanisms of cytotoxic activities of vinca alkaloids are far not fully understood yet.
- the present invention relates to compounds represented by the general formula of (I)
- R stands for a methyl or a formyl group
- Ri stands for a methoxy or an amino group
- R 2 represent a hydroxy or acetoxy group
- R 3 stands for a hydrogen atom or a hydroxy group
- R4 represents a hydrogen atom or R 3 and R 4 together represent a double bond
- R 5 and 5 represent hydrogen or fluorine atoms
- n 1 or 2.
- the invention relates to pharmaceutically acceptable salts of the compounds of general formula (I) and/or hydrates and/or solvates thereof.
- the invention also relates to the pharmaceutical compositions containing one or more compounds of general formula (I) or hydrates or solvates thereof as active ingredient.
- the present invention relates to the synthesis of compounds of general formula (I), and the chemical and pharmaceutical manufacture of medicaments containing these compounds, as well as the methods of treatment with these compounds, which means administering to a mammal to be treated - including human - effective amount/amounts of compounds of general formula (I) of the present invention as such or as medicament.
- the present invention also relates to the pharmaceutical compositions comprising a therapeutically effective amount of one ore more compounds of general formula (I) or pharmaceutically acceptable salts thereof as active ingredient. Further, there is provided a pharmaceutical composition comprising a therapeutically effective amount of compound of general formula (I) or salt thereof and one or more pharmaceutically acceptable carrier and/or diluent.
- the present invention also relates to the process for manufacturing of the pharmaceutical compositions by mixing a therapeutically effective amount of one or more compounds of general formula (I) as active ingredient and a pharmaceutically acceptable carrier and/or diluent.
- methods for the treatment of cancer disease or condition comprising the step of administering to human, in need of such treatment and/or prophylaxis a pharmaceutical composition comprising a therapeutically effective amount of one ore more compounds of general formula (I) or pharmaceutically acceptable salts thereof alone or together with at least one and a pharmaceutically acceptable carrier and/or diluent.
- a pharmaceutical composition comprising a therapeutically effective amount of one ore more compounds of general formula (I) or pharmaceutically acceptable salts thereof alone or together with at least one and a pharmaceutically acceptable carrier and/or diluent.
- the said treatment and/or prophylaxis methods are used for the treatment of colorectal cancer and lung cancer.
- the present invention provides industrially applicable processes for the preparation of compounds of general formula (I).
- the field of this invention also relates to the use of the compounds of the general formula (I) in relieving, treating or preventing certain types of cancer diseases.
- the present invention relates to novel pharmaceutically applicable compounds of the general formula (I) or pharmaceutically acceptable salts thereof and/or hydrates and/or solvates thereof. Both organic and inorganic acids can be used for the formation of pharmaceutically acceptable acid addition salts of general formula (I).
- the salts of the present invention are pharmaceutically acceptable salts.
- Salts encompassed within the term “pharmaceutically acceptable salts” refer to salts of the compound of this invention formed with non-toxic acids. Salts of the compounds of the present invention may comprise acid addition salts. In general, the salts are formed from pharmaceutically acceptable inorganic and organic acids.
- suitable acid salts include maleic, hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, perchloric, fumic, acetic, propionic, succinic, glycolic, formic, lactic, aleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methansulfonic (mesylate), naphthalene-2-sulfonic, benzenesulfonic, hydroxynaphthoic, hydroiodic, malic, teroic, tannic and the like.
- the salts of the present invention are pharmaceutically acceptable salts.
- Salts encompassed within the term "pharmaceutically acceptable salts" refer to nontoxic salts of the compound of this invention.
- Salts of the compound of the present invention may comprise base addition salts, as well, because of the acidic character of the tetrazolyl group.
- Salts derived from appropriate bases include alkali metal (e.g. sodium, potassium, lithium), alkaline earth metal (e.g. magnesium) salts.
- Physiologically acceptable salts of a compound with a tetrazolyl group include the anion of said compound in combination with a suitable cation such as Na + , K + , Li + and Mg 2+ .
- Preferred salts include sodium, calcium, potassium, lithium, magnesium.
- salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl sulfate, monopotassium maleate, mucate, napsylate, nitrate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,
- salts which are not pharmaceutically acceptable, may be useful in the preparation of the compound of this invention and these should be considered to form a further aspect of the invention.
- These salts such as oxalic or trifluoroacetic, while not pharmaceutically acceptable by themselves, may be useful in the preparation of salts useful as intermediates in obtaining the compound of the invention and their pharmaceutically acceptable salts.
- the compounds of the present invention can be prepared in a number of ways well-known to one skilled in the art of organic synthesis using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.
- the novel compounds of general formula (I) may be prepared using the reactions and techniques described in this section.
- the invention further provides a pharmaceutical composition
- a pharmaceutical composition comprising the compounds of general formula (I) or pharmaceutically acceptable salt thereof and one or more carriers and/or diluents in the pharmaceutical arts (also referred to as excipients).
- the excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).
- a process for the preparation of a pharmaceutical composition comprising mixing (or admixing) the compounds of general formula (I) or salt thereof with at least one excipient.
- compositions can be in solid, liquid or semiliquid form and pharmaceutically adjuvant and auxiliary materials can be added, which are commonly used in practice, such as carriers, excipients, diluents, stabilizers, wetting or emulsifying agents, pH- and osmotic pressure-influencing, flavoring or aromatizing, as well as formulation-promoting or formulation-providing additives.
- Infusion therapy is a key component of many cancer treatment plans. Typically, it means that a drug is administered intravenously, but the term also may refer to situations where drugs are provided through other non-oral routes, such as intramuscular injections. Sometimes the bolus injections are used, in other cases long-acting forms, e.g. depot injections are more effective. Pharmaceutical solutions can be prepared both for inpatient and outpatient techniques. Patients receiving home infusion therapy enjoy the satisfaction of returning to their home surroundings and the care of their families.
- compositions may be in unit dose form containing a predetermined amount of active ingredient per unit dose.
- a unit may contain a therapeutically effective dose of one or more compounds of general formula (I) or salt thereof or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose.
- Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
- such pharmaceutical compositions may be prepared by any of the methods well-known in the pharmacy art.
- compositions may be adapted for administration by any appropriate route, for example, by oral or parenteral (including subcutaneous, intramuscular, intravenous) routes.
- Such compositions may be prepared by any method known in the art of pharmacy, for example, by bringing into association the active ingredient with the excipient(s).
- compositions When adapted for oral administration, pharmaceutical compositions may be in discrete units such as tablets or capsules; powders or granules; solutions or suspensions in aqueous or nonaqueous liquids.
- the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
- Powders or granules are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol.
- Capsules are made by preparing a powder mixture, as described above and filling formed gelatin or non-gelatinous sheaths.
- Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol can be added to the powder mixture before the filling operation.
- a disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicine when the capsule is ingested.
- suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
- Suitable binders include starch, gelatin, natural sugars, such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
- Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
- Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like.
- Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
- a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above and optionally, with a binder such as carboxymethylcellulose and aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin, or dicalcium phosphate.
- a binder such as carboxymethylcellulose and aliginate, gelatin, or polyvinyl pyrrolidone
- a solution retardant such as paraffin
- a resorption accelerator such as a quaternary salt
- an absorption agent such as bentonite, kaolin, or dicalcium phosphate.
- the powder mixture can be granulated by wetting a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
- a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials
- the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
- the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets.
- the compound or salt of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
- Suspensions can be formulated by dispersing the compound or salt of the invention in a nontoxic vehicle.
- Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners and the like, can also be added.
- dosage unit formulations for oral administration can be microencapsulated.
- the formulation can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.
- tablets and capsules are preferred for delivery of the pharmaceutical composition.
- treatment includes slowing or eliminating the progression of the condition and preventing or delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject.
- the present invention provides methods for treatment or prevention of cancer, especially in cases of cancer types of leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, renal cancer, prostate cancer and breast cancer.
- therapeutically effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, or a decrease in the rate of advancement of a disease.
- therapeutically effective amounts of the compounds of general formula (I), as well as salts thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.
- the precise therapeutically effective amount of the compound or salt thereof of the invention will depend on a number of factors, including, but not limited to, the age and weight of the subject (patient) being treated, the precise disorder requiring treatment and its severity, the nature of the pharmaceutical formulation/composition and route of administration and will ultimately be at the discretion of the attending physician or veterinarian.
- reaction mixture was stirred for 30 min at 0°C and then for 6 h at room temperature. After allowing to stand overnight, further diethylzinc (6.99 ml) and diiodomethane (0.44 ml) were added. After stirring for 4 h at room temperature the reaction mixture was filtered, dichloromethane (100 ml) was added to the filtrate and was washed with water (100 ml). The aqueous phase was washed with dichloromethane (2x50 ml). The combined organic phase was dried with magnesium sulfate and the solvent was evaporated in vacuum.
- Catharanthine sulfate (238 mg) was added to a mixture of dichloromethane (30 ml) and distilled water (30 ml) and the mixture was basified to pH 8 with aqueous ammonium hydroxide. After extraction the water phase was washed with dichloromethane (20 ml) and the combined organic phase was dried with magnesium sulfate and the solvent was evaporated.
- 14,15-cyclopropanovinblastine sulfate 64 mg; 0.069 mmol was solved in a mixture of acetone (14 ml) and acetic acid (3.2 ml), and at -60°C Cr0 3 (31 mg; 0.31 mmol) in acetic acid anhydride (11.7 ml) was dropped to the mixture. After stirring for 8 min, 25% aqueous ammonium hydroxide at -50°C was added to pH 9 keeping the temperature of the reaction mixture below 50°C, and distilled water (50 ml) was added.
- the mixture was extracted with dichlorom ethane (5x20 ml), the combined organic phase was washed with water (2x30 ml), dried with magnesium sulfate and evaporated to dryness.
- Formic acid (0.95 ml) and acetic acid anhydride (0.16 ml) was added to the residue and after standing at room temperature for 5 min distilled water (20 ml) was added and basified with 25% aqueous ammonium hydroxide to pH 9.
- the solution was extracted with dichloromethane (5x10 ml), the combined organic phase was dried with magnesium sulfate and the solvent was evaporated.
- 14,15-Cyclopropanoanhydrovinblastine (244 mg; 0.302 mmol) was solved in dry dichloromethane (9 ml) and at -70°C in the dark, under Ar N-bromosuccinimide (64 mg; 0.362 mmol) was added in a mixture of dichloromethane (7.2 ml) and trifluoroacetic acid (0.13 ml; 1.66 mmol), then diethyl amine (0.21 ml; 2.07 mmol) in dichloromethane (1.8 ml) was dropped to the reaction mixture.
- the compounds of the invention were sent to the US National Institute of Health (NIH) where they were subjected to pharmacological trials. These experiments on 56 different tumor cell lines embracing 9 frequently occurring tumor types demonstrated the therapeutic activity of these substances in comparison with other known effective catharanthus alkaloids.
- cyclopropylvinblastine has significant tumor cell inhibiting effect in leukemia, non-small-cell lung cancer, colon cancer, melanoma and breast cancer
- cyclopropylvincristine has significant tumor cell inhibiting effect in colon cancer, melanoma ovarian cancer and prostate cancer
- cyclopropylvinorelbine has significant tumor cell inhibiting effect in non-small-cell lung cancer, colon cancer, CNS cancer, melanoma, renal cancer and breast cancer.
Abstract
The field of this invention relates to novel cyclopropyl derivatives of the general formula (I) representing pharmaceutically applicable Vinca Rosea type alkaloid compounds, particularly having a cytostatic effect. The invention also is concerned processes for preparing these new alkaloids and their pharmacological compositions and the use of these compounds in treatment of cancer. R stands for a methyl or a formyl group, R1 stands for a methoxy or an amino group, R2 represents a hydroxy or acetoxy group, R3 stands for a hydrogen atom or a hydroxy group, R4 represents a hydrogen atom or R3 and R4 together represent a double bond, R5 and R6 represent hydrogen or fluorine atoms n = 1 or 2.
Description
New bis-indole alkaloids as anticancer drugs
FIELD OF THE INVENTION
The field of this invention relates to novel cyclopropyl derivatives of the general formula (I) representing pharmaceutically applicable Vinca Rosea type alkaloid compounds, particularly having a cytostatic effect. The invention also is concerned processes for preparing these new alkaloids and their pharmacological compositions and the use of these compounds in treatment of cancer.
(I) wherein the cyclopropyl ring is in the 14α, 15a or the 14β, 15β position,
R stands for a methyl or a formyl group,
Ri stands for a methoxy or an amino group,
R2 represent a hydroxy or acetoxy group,
R3 stands for a hydrogen atom or a hydroxy group,
R4 represents a hydrogen atom or R3 and R4 together represent a double bond,
R5 and R6 represent hydrogen or fluorine atoms
n = 1 or 2.
BACKGROUND OF THE INVENTION
The first agents in the vinca alkaloid class, the vinblastine (VLB) and vincristine (VCR) of general formula (II) were isolated from the Madagascar periwinkle Catharanthus roseus (1958). The concentration of VCR in the plant material is by an order of magnitude less than that of VLB, so the main source of VCR is the oxidation of VLB (Hungarian Patent No. 165 599, U.S. Patent No. 3,889,493). As antimitotic drugs both materials have been used in anticancer chemotherapy for more than forty years.
Chemically and pharmacologically, a great number of semi-synthetic derivatives have been studied and a few of them reached the stage of clinical studies [O. Van Tellingen, J. H. M. Sips, J. H. Beijnen, A. Bult and W. J. Nooijen, Anticancer Research, 12, 1699-1716 (1992)].
Several additional products, obtained by semi-synthesis, have been marketed worldwide: vindesine (4-desacetyl VLB C-3 carboxamide - (III)) by the E. Lilly Laboratories in 1983, and two nor-derivatives, vinorelbine (IV) in 1989 and vinflunine (V) in 1995 by the Pierre Fabre Laboratories.
(III)
Vinorelbine
(IV)
In WO95/03312 PCT application of Pierre Fabre Laboratories discovery of new antimitotic agents were reported, with utilization that the binary alkaloids of the vinblastine and vinorelbine family react selectively in "superacid", type media, in order to lead to novel products, fluorinated on sites which are inaccessible by the standard chemical routes. This group is represented by Vinflunine. Vinflunine is a unique agent within the vinca alkaloid family with unique antiangiogenesis, vascular disrupting and antimetastatic properties. Vinfunine proved or seems to be effective in chemotherapy of a sort of cancer types: nonsmall- and small-cell lung cancer, metastatic breast cancer, renal cell carcinoma, transitional cell carcinomas of the urothelium, malignant pleural mesothelioma and has neurological, hematological and some other adverse reactions (John S Ng. Vinflunine: review of a new vinca alkaloid and its potential role in oncology. J. Oncol. Pharm. Practice 17(3) 209-224.)
Vinflunine
(V)
Microtubule disruptive drugs like vinblastine and the novel vinca alkaloids have been reported to act by two mechanisms. At very low concentrations they suppress microtubule dynamics and at higher concentrations they reduce microtubule polymer mass. (Jordan, M. A.; Leslie, W. (2004). "Microtubules as a Target for Anticancer Drugs". Nature Reviews Cancer 4 (4): 253-265.) They work by preventing mitosis in metaphase. These alkaloids bind to tubulin, thus preventing the cell from making the spindles it needs to be able to divide. However, recent clinical studies with vinflunine against many different malignant cell lines showed that the exact mechanisms of cytotoxic activities of vinca alkaloids are far not fully understood yet.
SUMMARY OF THE INVENTION
Traditional chemotherapy agents have been the backbone therapies for malignancy treatment. Although in the recent decades most of the researches have been focusing on molecular targeted therapy agents because of their target specificity and hence relatively more benign adverse effect profile, these agents frequently have narrow biological spectrum, and resistance may theoretically occur with mutation on the target antigen or pathway. Therefore, the search for new traditional chemotherapy agents with broad clinical spectrum and reduced adverse effects is still an active field within oncology. All known therapeutically effective natural and synthetic vinca alkaloids have limitations in their effectiveness and all over the world intensive research has been doing to find even more
effective synthetically modified molecules. Surprisingly has been attained that some new alkaloids having cyclopropyl ring in the vindoline skeleton at the 14α, 15a or the 14β,15β position of the bis-indole alkaloid shows outstanding cytostatic effect and can uniquely be effective in different oncology treatments, in non-small lung cancer, CNS cancer, colon cancer, melanoma and breast cancer therapy.
The present invention relates to compounds represented by the general formula of (I)
(I) wherein the cyclopropyl ring is in the 14α, 15a or the 14β, 15β position,
R stands for a methyl or a formyl group,
Ri stands for a methoxy or an amino group,
R2 represent a hydroxy or acetoxy group,
R3 stands for a hydrogen atom or a hydroxy group,
R4 represents a hydrogen atom or R3 and R4 together represent a double bond,
R5 and 5 represent hydrogen or fluorine atoms
n = 1 or 2.
In another aspect the invention relates to pharmaceutically acceptable salts of the compounds of general formula (I) and/or hydrates and/or solvates thereof.
In another aspect the invention also relates to the pharmaceutical compositions containing one or more compounds of general formula (I) or hydrates or solvates thereof as active ingredient.
In another aspect of the present invention relates to the synthesis of compounds of general formula (I), and the chemical and pharmaceutical manufacture of medicaments containing these compounds, as well as the methods of treatment with these compounds, which means administering to a mammal to be treated - including human - effective amount/amounts of compounds of general formula (I) of the present invention as such or as medicament.
In another aspect the present invention also relates to the pharmaceutical compositions comprising a therapeutically effective amount of one ore more compounds of general formula (I) or pharmaceutically acceptable salts thereof as active ingredient. Further, there is provided a pharmaceutical composition comprising a therapeutically effective amount of compound of general formula (I) or salt thereof and one or more pharmaceutically acceptable carrier and/or diluent.
In another aspect the present invention also relates to the process for manufacturing of the pharmaceutical compositions by mixing a therapeutically effective amount of one or more compounds of general formula (I) as active ingredient and a pharmaceutically acceptable carrier and/or diluent.
In another aspect there is still further provided methods for the treatment of cancer disease or condition as well as comprising the step of administering to human, in need of such treatment and/or prophylaxis a pharmaceutical composition comprising a therapeutically effective amount of one ore more compounds of general formula (I) or pharmaceutically acceptable salts thereof alone or together with at least one and a pharmaceutically acceptable carrier and/or diluent. Particularly, the said treatment and/or prophylaxis methods are used for the treatment of colorectal cancer and lung cancer.
Furthermore, in another embodiment the present invention provides industrially applicable processes for the preparation of compounds of general formula (I).
The field of this invention also relates to the use of the compounds of the general formula (I) in relieving, treating or preventing certain types of cancer diseases.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to novel pharmaceutically applicable compounds of the general formula (I) or pharmaceutically acceptable salts thereof and/or hydrates and/or solvates thereof. Both organic and inorganic acids can be used for the formation of pharmaceutically acceptable acid addition salts of general formula (I).
Typically, but not absolutely, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to salts of the compound of this invention formed with non-toxic acids. Salts of the compounds of the present invention may comprise acid addition salts. In general, the salts are formed from pharmaceutically acceptable inorganic and organic acids. More specific examples of suitable acid salts include maleic, hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, perchloric, fumic, acetic, propionic, succinic, glycolic, formic, lactic, aleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methansulfonic (mesylate), naphthalene-2-sulfonic, benzenesulfonic, hydroxynaphthoic, hydroiodic, malic, teroic, tannic and the like.
Typically, but not absolutely, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to nontoxic salts of the compound of this invention. Salts of the compound of the present invention may comprise base addition salts, as well, because of the acidic character of the tetrazolyl group. Salts derived from appropriate bases include alkali metal (e.g. sodium, potassium, lithium), alkaline earth metal (e.g. magnesium) salts. Physiologically acceptable salts of a compound with a tetrazolyl group include the anion of said compound in combination with a suitable cation such as Na+, K+, Li+ and Mg2+. Preferred salts include sodium, calcium, potassium, lithium, magnesium.
Other representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,
lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl sulfate, monopotassium maleate, mucate, napsylate, nitrate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate salts. Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of the compound of this invention and these should be considered to form a further aspect of the invention. These salts, such as oxalic or trifluoroacetic, while not pharmaceutically acceptable by themselves, may be useful in the preparation of salts useful as intermediates in obtaining the compound of the invention and their pharmaceutically acceptable salts. The compounds of the present invention can be prepared in a number of ways well-known to one skilled in the art of organic synthesis using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The novel compounds of general formula (I) may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being affected. Also in the description of the synthetic methods described below, it is understood that all proposed reaction conditions, including solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be conditions standard for that reaction, which should be readily recognized by one skilled in the art of organic synthesis. This expert understands that the functionality present on various portions of the edict molecule must be compatible with general formula (I) falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Compounds of general formula (I) of the invention can be prepared according to the following scheme shown below. This scheme comprises main synthesis routes without restricting only for these possibilities.
The invention further provides a pharmaceutical composition comprising the compounds of general formula (I) or pharmaceutically acceptable salt thereof and one or more carriers and/or diluents in the pharmaceutical arts (also referred to as excipients). The excipients are
acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).
In accordance with another aspect of the invention there is provided a process for the preparation of a pharmaceutical composition comprising mixing (or admixing) the compounds of general formula (I) or salt thereof with at least one excipient.
The compounds of the invention as well as their pharmaceutically acceptable salts can be used as such or suitably in the form of pharmaceutical compositions. These compositions (drugs) can be in solid, liquid or semiliquid form and pharmaceutically adjuvant and auxiliary materials can be added, which are commonly used in practice, such as carriers, excipients, diluents, stabilizers, wetting or emulsifying agents, pH- and osmotic pressure-influencing, flavoring or aromatizing, as well as formulation-promoting or formulation-providing additives.
Infusion therapy is a key component of many cancer treatment plans. Typically, it means that a drug is administered intravenously, but the term also may refer to situations where drugs are provided through other non-oral routes, such as intramuscular injections. Sometimes the bolus injections are used, in other cases long-acting forms, e.g. depot injections are more effective. Pharmaceutical solutions can be prepared both for inpatient and outpatient techniques. Patients receiving home infusion therapy enjoy the satisfaction of returning to their home surroundings and the care of their families.
It is advantageous that in application of these bisindol alkaloid compounds in many cases the effective dose is relatively low and instead of parenteral the much more pleasant oral forms can provide equally effective options. Moreover, this usually means a far lower cost to the patient and insurer.
Pharmaceutical compositions may be in unit dose form containing a predetermined amount of active ingredient per unit dose. Such a unit may contain a therapeutically effective dose of one or more compounds of general formula (I) or salt thereof or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction
thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well-known in the pharmacy art.
Pharmaceutical compositions may be adapted for administration by any appropriate route, for example, by oral or parenteral (including subcutaneous, intramuscular, intravenous) routes. Such compositions may be prepared by any method known in the art of pharmacy, for example, by bringing into association the active ingredient with the excipient(s).
When adapted for oral administration, pharmaceutical compositions may be in discrete units such as tablets or capsules; powders or granules; solutions or suspensions in aqueous or nonaqueous liquids. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders or granules are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Capsules are made by preparing a powder mixture, as described above and filling formed gelatin or non-gelatinous sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicine when the capsule is ingested. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum and the like.
Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by
mixing the compound, suitably comminuted, with a diluent or base as described above and optionally, with a binder such as carboxymethylcellulose and aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets. The compound or salt of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. Suspensions can be formulated by dispersing the compound or salt of the invention in a nontoxic vehicle. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners and the like, can also be added.
Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like. In the present invention, tablets and capsules are preferred for delivery of the pharmaceutical composition.
As used herein, the term "treatment" includes slowing or eliminating the progression of the condition and preventing or delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject. The present invention provides methods for treatment or prevention of cancer, especially in cases of cancer types of leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, renal cancer, prostate cancer and breast cancer.
The term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment,
healing, or a decrease in the rate of advancement of a disease. The term also includes within its scope amounts effective to enhance normal physiological function. For use in therapy, therapeutically effective amounts of the compounds of general formula (I), as well as salts thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.
The precise therapeutically effective amount of the compound or salt thereof of the invention will depend on a number of factors, including, but not limited to, the age and weight of the subject (patient) being treated, the precise disorder requiring treatment and its severity, the nature of the pharmaceutical formulation/composition and route of administration and will ultimately be at the discretion of the attending physician or veterinarian.
EXAMPLES
The invention is further defined in the following Examples. It should be understood that the Examples are given by way of illustration only. From the above discussion and the Examples, one skilled in the art can ascertain the essential characteristics of the invention, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the invention to various uses and conditions. As a result, the invention is not limited by the illustrative examples set forth herein below, but rather defined by the claims appended hereto. In general, the compounds of general formula (I) can be prepared in accordance with the general knowledge of one skilled in the art and/or using methods set forth in the Example and/or Intermediate sections that follow. Solvents, temperatures, pressures, and other reaction conditions can readily be selected by one of ordinary skill in the art. Starting materials are commercially available and/or readily prepared by one skilled in the art.
Example 1.: 10-Bromo-14,15-cyclopropanovindoline
10-Bromovindoline [Gorka-Kereskenyi, A., Szabo, L., Hazai, L., Lengyel, M., Szantay, Cs., Jr., Santa, Zs., Kalaus, Gy., and Szantay, Cs. Heterocycles, 71, 1553-1563 (2007)] (1.466 g, 2.74 mmol) was dissolved in dichloromethane (50 ml) under argon, and at 0°C diethylzinc (6.99 ml, 6.99 mmol) in l hexane solution, then diiodomethane (0.44 ml, 5.46 mmol) were injected into the solution. The reaction mixture was stirred for 30 min at 0°C and then for 6 h at room temperature. After allowing to stand overnight, further diethylzinc (6.99 ml) and diiodomethane (0.44 ml) were added. After stirring for 4 h at room temperature the reaction mixture was filtered, dichloromethane (100 ml) was added to the filtrate and was washed with water (100 ml). The aqueous phase was washed with dichloromethane (2x50 ml). The combined organic phase was dried with magnesium sulfate and the solvent was evaporated in vacuum. The crude product was purified by preparative TLC (dichloromethane-methanol 20: 1) and 910 mg (60%) of cyclopropano derivative was isolated as a yellow solid, mp 226- 228°C. Molecular weight 549.45 g/mol (C26H33N2O6).
TLC (CH2Cl2-methanol 20: 1), R/=0.50.
[a]22 D = -50.9 (c=l, chloroform)
IR (KBr): 3436, 2970, 1748, 1728, 1253, 1188, 960 cm"1.
1H- MR (500 MHz, OMSO-d6) δ 0.29 (m, 1H, Ha-15); 0.60 (m, 1H, Hx-22); 0.67 (t, J= 7.5, 3H, H3-I8); 0.78 (ABq, J= 14.1, J= 7.0, 1H, Hx-19); 0.81 (m, 1H, Hy-22); 1.14 (m, 1H, Ha- 14); 1.71 (ABq, J= 14.1, J= 7.0, 1H, Hy-19); 1.97 (s, 3H, H3-C(17)OCOCH3); 2.10 (m, 1H, Hp-6); 2.19 (ddd, J= 13.5, J= 10.0, J= 3.3, 1H, Ha-6); 2.36 (s, 1H, H-21); 2.40 (dd, J= 10.8, J= 3.6, 1H, Ha-3); 2.46 (td, J= 10.0, J= 9.1, 1H, Ha-5); 2.58 (s, 3H, H3-N(1)CH3); 3.11 (td , J= 9.1, J= 3.3, 1H, Hp-5); 3.19 (d br, J= 10.8, 1H, Hp-3); 3.46 (s, 1H, H-2); 3.67 (s, 3H, H3- C(16)COOCH3); 3.81 (s, 3H, H3-C(l l)OCH3); 5.21 (s, 1H, H-17); 6.42 (s, 1H, H-12); 7.36 (s, 1H, H-9); 7.86 (s, 1H, OH).
C- MR (125 MHz, OMSO-d6) δ 7.9 (C-18); 8.6 (C-22); 11.4 (C-14); 15.8 (C-15); 20.8 (C- C(17)OCOCH3); 32.8 (C-19); 38.4 (C-l); 40.4 (C-20); 44.4 (C-6); 51.7 (C-7); 51.8 (C- C(16)COOCH3); 52.3 (C-5); 52.5 (C-3); 56.2 (C-C(l l)OCH3); 69.0 (C-21); 76.4 (C-17); 77.9 (C-16); 83.1 (C-2); 94.9 (C-12); 99.0 (C-10); 126.4 (C-9); 127.4 (C-8); 152.9 (C-13); 155.9 (C- 11); 169.9 (C- C(17)OCOCH3); 171.6 (C-C(16)COOCH3).
HRMS: 549.15945 (C26H3406N2Br; calc. 549.15948). ESI-MS-MS (549.16@cid35) (rel. int. %): 489(100); 471(3); 429(7); 401(3); 266(23).
Example 2.: 14,15-Cyclopropanovindoline
10-Bromo-14, 15-cyclopropanovindoline (1.341 g; 2.441 mmol) was solved in methanol (67 ml), the mixture was cooled to 10 °C, then under Ar palladium on charcoal (2.012 g) and sodium borohydride (1.385 g; 36.615 mmol) was added in portions. After 30 min another 1.385 g (36.615 mmol) of sodium borohydride was added in portions and after 30 min some drops of acetic acid were added to the reaction mixture. After filtration of the catalyst the filtrate was evaporated, solved in dichloromethane (150 ml) and was washed with 10% of aqueous sodium carbonate (100 ml). The water phase was washed with dichloromethane (50 ml) and the combined organic phase was extracted with water (100 ml), dried with magnesium sulfate and the solvent was evaporated. The crude product was purified by preparative TLC (dichloromethane-methanol 20: 1) and 707 mg (62%) white crystals were obtained. Mp. 89-91°C. Molecular weight 470.56 g/mol (C26H34N206).
TLC (CH2Cl2-methanol 20: 1), R^=0.52.
[a]29 D = -34.4 (c=\, dichloromethane)
JR (KBr) 3440,2962, 1741, 1613, 1598, 1371, 1250, 1039 cm"1.
1H- MR (800 MHz, OMSO-d6) δ 0.29 (m, IH, Ha-15); 0.60 (m, IH, Hx-22); 0.65 (t, J= 7.3, 3H, H3-18); 0.81 (ABq, J= 14.0, J= 7.3, IH, Hx-19); 0.82 (m, IH, Hy-22); 1.13 (m, IH, Ha- 14); 1.69 (ABq, J= 14.0, J= 7.3, IH, Hy-19); 1.97 (s, 3H, H3-C(17)OCOCH3); 2.10 (dt, J= 13.5, J= 9.2, IH, Hp-6); 2.17 (ddd, J= 13.5, J= 10.0, J= 3.4, IH, Ha-6); 2.31 (s, IH, H-21); 2.34 (dd, J= 10.9, J= 3.7, IH, Ha-3); 2.39 (dt, J= 10.0, J= 9.2, IH, Ha-5); 2.54 (s, 3H, H3- N(1)CH3); 3.14 (td , J= 9.2, J= 3.4, IH, Hp-5); 3.19 (d br, J= 10.9, IH, Hp-3); 3.41 (s, IH, H- 2); 3.67 (s, 3H, H3- C(16)COOCH3); 3.71 (s, 3H, H3-C(l 1)0CH3); 5.23 (s, IH, H-17); 6.21 (d, J= 2.3, IH, H-12); 6.29 (dd, J= 8.3, J= 2.3, IH, H-10); 7.36 (d, J= 8.3, IH, H-9); 7.74 (s, IH, OH).
13C- MR (200 MHz, OMSO-d6) δ 8.0 (C-18); 8.5 (C-22); 11.3 (C-14); 15.8 (C-15); 20.8 (C- C(17)OCOCH3); 34.1 (C-19); 38.5 (C-1); 40.3 (C-20); 44.5 (C-6); 51.6 (C-7); 51.8 (C- C(16)COOCH3); 52.69 (C-5); 52.74 (C-3); 55.1 (C-C(l 1)0CH3); 69.4 (C-21); 76.5 (C-17); 78.1 (C-16); 83.2 (C-2); 95.6 (C-12); 104.9 (C-10); 123.0 (C-9); 126.3 (C-8); 153.4 (C-13); 160.4 (C-l l); 169.9 (C- C(17)OCOCH3); 171.7 (C-C(16)COOCH3).
MS: 471 (C26H3506N2 M+W). ESI-MS-MS (471.3@cid35) (rel. int. %): 411(100); 188(28).
Example 3.: 14,15-Cyclopropanoanhydrovinblastine
Catharanthine sulfate (238 mg) was added to a mixture of dichloromethane (30 ml) and distilled water (30 ml) and the mixture was basified to pH 8 with aqueous ammonium hydroxide. After extraction the water phase was washed with dichloromethane (20 ml) and the combined organic phase was dried with magnesium sulfate and the solvent was evaporated. 200 mg (0.594 mmol) of catharanthine base was obtained and it was solved together with 14,15-cyclopropanovindoline (280 mg; 0.594 mmol) in a mixture of 0.1 MHO (11.2 ml), distilled water (11.2 ml) and 2,2,2-trifluoroethanol (2.2 ml), then under Ar FeCl3x6H20 (802 mg; 2.97 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and at 0°C a solution of sodium borohydride (24 mg; 0.594 mmol) in distilled water (1.9 ml) was dropped. After 30 min stirring at 0°C 25% aqueous ammonium hydroxide (12 ml) was added to the reaction mixture and filtrated. The filtrate was extracted with dichloromethane (3x60 ml) then the combined organic phase was washed with distilled water (100 ml), dried with magnesium sulfate and the solvent was evaporated. The crude product was purified by preparative TLC (ethyl acetate-m ethanol 9: 1) and 244 mg (51%) pale yellow crystals were obtained.
From the base the sulfate salt was prepared. 41 mg (0.050 mmol) of 14,15- cyclopropanoanhydrovinblastine was solved in a mixture of dichloromethane (0.4 ml) and ethanol (0.25 ml) then 0.28 ml of sulfuric acid-ethanol (from a mixture of 1 ml of cc. sulfuric acid and 100 ml of ethanol) was added and the mixture was evaporated to dryness. The solid product was treated with diethyl ether and after filtration 34 mg of 14,15- cyclopropanoanhydrovinblastine sulfate was obtained. Mp. (sulfate) 242-244°C. Molecular weight (base) 806.99 g/mol (C47H58N408). Molecular weight (sulfate) 905.06 g/mol
TLC (base) (CH2Cl2-methanol 10: 1), R^O.45.
TLC (sulfate) (CH2Cl2-methanol 10: 1), R/=0.45.
IR (sulfate) (KBr) 3416, 3088, 2963, 1736, 1614, 1503, 1434, 1373 cm"1.
1H- MR (800 MHz, DMSO-i¾+TFA) δ 0.56 (br, 1H, Ha-15); 0.73 (br, 1H, Hx-22); 0.86 (br, 1H, Hy-22); 0.97 (t br, 3H, H3-18); 1.00 (t br, 3H, H3-18'); 1.37 (br, 1H, Hx-19); 1.38 (m, 1H, Ha-14); 1.87 (br, 1H, Hy-19); 1.95 (br, 1H, Ha-6); 2.05 (s, 3H, H3-C(17)OCOCH3); 2.05 (br, 1H, H2-19'); 2.10 (br, 1H, Ha-17'); 2.25 (br, 1H, Hp-6); 2.67 (s, 3H, H3-N(1)CH3); 2.75 (br, 1H, Ha-3'); 2.99 (br, 1H, Hp-17'); 3.21 (br, 2H, Ha-3, Ha-5); 3.36 (br, 1H, Ha-6'); 3.45 (br, 1H, H-21); 3.46 (br, 1H, Hx-5'); 3.52 (br, 1H, Hy-5'); 3.53 (br, 1H, Hp-5); 3.59 (s, 3H, H3-
C(16')COOCH3); 3.61 (s, 1H, H-2); 3.67 (br, 1H, Hp-3); 3.69 (br, 1H, Hp-6'); 3.70 (br, 1H, Ha-21 '); 3.79 (s, 3H, H3- C(16)COOCH3); 3.80 (s, 3H, H3-C(l 1)0CH3); 4.00 (br, 1H, Hy- 21 '); 4.10 (d, J= 12.7, 1H, Hp-3 '); 5.23 (s, 1H, H-17); 5.75 (br, 1H, H-15'); 6.50 (s br, 1H, H- 12); 7.04 (s br, 1H, H-9); 7.03 (br, 1H, H-10'); 7.1 1 (br, 1H, H-l l '); 7.32 (br, 1H, H-12'); 7.57 (br, 1H, H-9'); 8.23 (br, 1H, H-4); 1 1.22 (br, 1H, H-4').
13C- MR (200 MHz, D20+CD3CN 1 : 1) δ 6.9 (C-22); 7.8 (C-18); 10.2 (C-14); 1 1.5 (C-18'); 15.4 (C-15); 19.0 (C-6'); 20.7 (C-C(17)OCOCH3); 27.4 (C-19'); 29.7 (C-14'); 34.3 br (C- 17'); 35.9 (C-19); 38.2 (C-1); 40.0 (C-20); 44.4 (C-6); 45.3 (C-3 '); 47.9 (C-21 '); 50.4 (C-3); 50.6 (C-5); 51.5 (C-7); 52.4 (C-C(16')COOCH3); 52.8 (C-C(16)COOCH3); 55.0 br (C-16'); 56.3 (C-C(1 1)0CH3); 53.6 (C-5'); 66.5 (C-21); 74.7 (C-17); 78.1 (C-16); 80.4 (C-2); 94.7 (C- 12); 11 1.9 (C-7'); 112.1 (C-12'); 1 17.9 (C-9'); 118.8 (C-10'); 120.8 br (C-10); 121.9 (C-1 1 '); 122.2 (C-8); 124.5 (C-15'); 124.9 (C-9); 128.6 (C-8'); 131.9 (C-2'); 135.8 (C-20'); 135.9 (C- 13 '); 152.5 (C-13); 157.9 (C-1 1); 169.9 (C- C(17)OCOCH3); 171.6 (C-C(16)COOCH3); 173.5 (C-C(16')COOCH3).
HRMS: 807.43268
/Mbase+H/; calc. 807.43274). ESI-MS-MS (807.43@cid55) (rel. int. %): 747(100); 577(49); 559(16); 522(45); 490(19); 379(8); 352(29); 337(10); 238(9).
14,15-C clopropanovinblastine
1) Fe2(ox)3*6H20 2) NaBH4 / H20
air,
CF3CH2OH
HC1 /H20
3.0 g (6.21 mmol) of Fe2(oxalate)3x6H20 was solved in distillated water (725 ml), then the solution cooled at 0°C and air was bubbled through the mixture for 10 min. Then 167 mg (0.207 mmol) of 14,15-cyclopropanoanhydrovinblastine was added at 0°C in a mixture of 0.1 HO (5.0 ml), distillated water (5.0 ml) and 2,2,2-trifluoroethanol (1.0 ml), and a solution of sodium borohydride (157 mg; 4.14 mmol) in distillated water (10 ml) was dropped to the reaction mixture. After stirring for 30 min, 25% aqueous ammonium hydroxide (23 ml) was added, and was extracted with a mixture of dichloromethane-methanol 9: 1 (3x100 ml), the combined organic phase was washed with distillated water (100 ml), dried with magnesium sulfate and the solvent was evaporated. The crude product was purified by preparative TLC (dichloromethane-methanol 10: 1) and 25 mg of product was obtained which was immediately transformed to the sulfate salt. The base was solved in a mixture of dichloromethane (0.24 ml) and ethanol (0.16 ml) then 0.16 ml of a mixture of sulfuric acid (0.030 mmol)-ethanol was
added and the mixture was evaporated to dryness. The solid product obtained was treated with diethyl ether and after filtration 24 mg (13%) of 14, 15-cyclopropanovinblastine sulfate was obtained as pale yellow crystals. Mp. (sulfate)>280°C. Molecular weight (base) 825.00 g/mol (C47H60N4O9). Molecular weight (sulfate) 923.08 g/mol (C47H62N4O13S).
TLC (base) (CH2Cl2-methanol 10: 1), R^O.39.
TLC (sulfate) (CH2Cl2-methanol 10: 1), R/=0.39.
IR (sulfate) (KBr) 3672, 3432, 2951, 1736, 1649, 1614, 1460, 1337 cm"1.
1H- MR (800 MHz, D20+CD3CN 1 : 1) δ 0.67 (m, 1H, Ha-15); 0.90 (m, 1H, H2-22); 0.91 (t,
J= 7.5, 3H, H3-I8'); 1.03 (t, J= 7.0, 3H, H3-I8); 1.21 (ABq, J= 14.3, J= 7.0, 1H, Hx-19); 1.39 (m, 1H, H-14'); 1.41 (m, 1H, Ha-14); 1.50 (m, 1H, H2-19'); 1.60 (dd, J= 14.6, J= 7.0, 1H, Ha-15'); 1.65 (d, J= 14.6, 1H, Hp-15'); 1.95 (ABq, J= 14.0, J= 7.3, 1H, Hy-19); 2.08 (s, 3H, H3-C(17)OCOCH3); 2.04 (ddd, J= 14.4, J= 10.6, J= 4.3, 1H, Ha-6); 2.26 (dt, J= 14.4, J= 8.7, 1H, Hp-6); 2.32 (dd, J= 15.7, J= 4.4, 1H, Ha-17'); 2.65 (s, 3H, H3-N(1)CH3); 2.85 (dd, J= 14.5, J= 6.0, 1H, Ha-3'); 2.98 (dd, J= 11.9, J= 3.3, 1H, Ha-3); 3.12 (td, J= 11.2, J= 9.6, 1H, Ha-5); 3.16 (s, 1H, H-21); 3.18 (AB, 2H, H2-21 '); 3.35 (dd, J= 16.9, J= 6.3, 1H, Ha- 6'); 3.55 (s, 1H, H-2); 3.60 (m, 1H, Ηβ-5'); 3.62 (m, 1H, Ha-5'); 3.64 (s, 3H, H3- C(16')COOCH3); 3.64 (m, 1H, Hp-5); 3.67 (d br, J= 11.9, 1H, Hp-3); 3.80 (dd, J= 15.7, J= 14.2, 1H, Ηβ-17'); 3.82 (s, 3H, H3-C(l l)OCH3); 3.83 (s, 3H, H3- C(16)COOCH3); 3.92 (d, J= 14.5, 1H, Ηβ-3'); 4.42 (dd, J= 16.9, J= 11.3, 1H, Ηβ-6'); 5.27 (s, 1H, H-17); 6.40 (s, 1H, H- 12); 6.76 (s, 1H, H-9); 7.16 (m, 1H, H-10'); 7.23 (m, 1H, H-l l '); 7.31 (d, J= 8.0, 1H, H-12'); 7.61 (d, J= 8.0, 1H, H-9'); 8.75 (s, 1H, H-l ').
13C- MR (200 MHz, D20+CD3CN 1 : 1) δ 6.1 (C-18'); 7.0 (C-22); 7.8 (C-18); 10.4 (C-14);
15.3 (C-15); 20.2 (C-C(17)OCOCH3); 20.5 (C-6'); 26.3 (C-14'); 34.0 (C-19'); 35.3 (C-17');
35.4 (C-19); 36.1 (C-15'); 38.5 (C-1); 40.3 (C-20); 44.0 (C-6); 44.8 (C-3'); 51.1(C-3); 51.5 (C-5); 51.7 (C-7); 52.8 (C-C(16')COOCH3); 53.4 (C-C(16)COOCH3); 55.2 br (C-16'); 56.1
(C-C(l l)OCH3); 56.6 (C-5'); 60.6 (C-21 '); 67.8 (C-20'); 68.5 (C-21); 75.2 (C-17); 78.5 (C-16); 80.9 (C-2); 94.8 (C-12); 111.3 (C-12'); 113.8 (C-7'); 118.2 (C-9'); 119.8 (C-10'); 121.1 br (C- 10); 122.3 (C-8); 123.2 (C-l l '); 123.5 (C-9); 128.7 (C-8'); 131.0 (C-2'); 135.7 (C-13'); 153.0 (C-13); 158.7 (C-l l); 171.9 (C- C(17)OCOCH3); 172.3 (C-C(16)COOCH3); 175.5 (C- C(16')COOCH3).
HRMS: 825.43996
/Mbase+H/; calc. 825.44331). ESI-MS-MS (825.40@cid25) (rel. int. %): 807(6); 765(100); 747(30); 715(5); 540(7); 522(9).
14,15-Cyclopropanovincristine
14,15-cyclopropanovinblastine sulfate (64 mg; 0.069 mmol) was solved in a mixture of acetone (14 ml) and acetic acid (3.2 ml), and at -60°C Cr03 (31 mg; 0.31 mmol) in acetic acid anhydride (11.7 ml) was dropped to the mixture. After stirring for 8 min, 25% aqueous ammonium hydroxide at -50°C was added to pH 9 keeping the temperature of the reaction mixture below 50°C, and distilled water (50 ml) was added. The mixture was extracted with dichlorom ethane (5x20 ml), the combined organic phase was washed with water (2x30 ml), dried with magnesium sulfate and evaporated to dryness. Formic acid (0.95 ml) and acetic acid anhydride (0.16 ml) was added to the residue and after standing at room temperature for 5 min distilled water (20 ml) was added and basified with 25% aqueous ammonium hydroxide to pH 9. The solution was extracted with dichloromethane (5x10 ml), the combined organic phase was dried with magnesium sulfate and the solvent was evaporated. The crude product
was purified by preparative TLC (dichloromethane-methanol 10: 1) and 35 mg (0.042 mmol) of product was obtained, which was transformed immediately to the sulfate salt. The product was solved in a mixture of dichloromethane (0.33 ml) and ethanol (0.21) then 0.23 ml of a mixture of sulfuric acid (0.042 mmol)-ethanol was added. The solution was evaporated to dryness and after treating the residue with diethyl ether 34 mg (52%) 14,15- cyclopropanovincristine sulfate was obtained as pale yellow crystals, which contained 10% of starting material, mp. (sulfate) > 280°C. Molecular weight (base) 838.98 g/mol (C47H58N4O10). Molecular weight (sulfate) 937.06 g/mol (C47H60N4O14S).
TLC (base) (CH2Cl2-methanol 10: 1), R^O.36.
TLC (sulfate) (CH2Cl2-methanol 10: 1), R/=0.36.
IR (sulfate) (KBr) 3425, 3059, 2954, 1750, 1689, 1617, 1493, 1434, 1373 cm"1.
1H- MR (800 MHz, D20+CD3CN 1 : 1) δ 0.67 (m, 1H, Ha-15); 0.84 (m, 1H, Hx-22); 0.90 (t, J= 7.5, 3H, H3-I8'); 1.08 (t, J= 7.0, 3H, H3-I8); 1.14 (m, 1H, Hy-22); 1.17 (ABq, J= 14.3, J= 7.0, 1H, Hx-19); 1.43 (m, 1H, H-14'); 1.41 (m, 1H, Ha-14); 1.49 (m, 1H, H2-19'); 1 54 (dd, J= 14.6, J= 7.3, 1H, Ha-15'); 1.66 (d, J= 14.6, 1H, Hp-15'); 1.82 (ABq, J= 14.4, J= 7.3, 1H, Hy-19); 1.92 (m, 1H, Hp-6); 2.04 (s, 3H, H3-C(17)OCOCH3); 2.31 (ddd, J= 14.1, J= 9.0, J= 5.3, 1H, Ha-6); 2.38 (d br, J= 14.5, 1H, Ha-17'); 2.76 (dd, J= 14.5, J= 6.3, 1H, Ha- 3'); 3.03 (d br, J= 11.9, 1H, Ha-3); 3.16 (m, 1H, Ha-5); 3.17 (AB, 2H, H2-21 '); 3.37 (dd, J= 17.4, J= 6.7, 1H, Ha-6'); 3.44 (s, 1H, H-21); 4.50 (s, 1H, H-2); 3.55 (dd, J= 14.2, J= 10.5, 1H, Ha-5'); 3.62 (dd, J= 14.2, J= 6.6, 1H, Hp-5'); 3.67 (s, 3H, H3- C(16)COOCH3); 3.68 (s, 3H, H3- C(16')COOCH3); 3.71 (m, 1H, Hp-3); 3.72 (m, 1H, Hp-5); 3.80 (m, 1H, Hp-17'); 3.83 (m, Hp-3'); 3.90 (s, 3H, H3-C(l l)OCH3); 4.48 (dd, J= 17.4, J= 11.8, 1H, Hp-6'); 5.02 (s, 1H, H-17); 7.08 (s, 1H, H-9); 7.16 (m, 1H, H-10'); 7.17 (s, 1H, H-12); 7.24 (m, 1H, H-l l '); 7.36 (d, J= 8.2, 1H, H-12'); 7.62 (d, J= 8.1, 1H, H-9'); 8.88 (s, 3H, H-N(l)CHO); 8.94 (s, ΙΗ, Η-Ι ').
13C- MR (200 MHz, D20+CD3CN 1 : 1) δ 6.8 (C-18'); 7.8 (C-22); 8.4 (C-18); 11.3 (C-14); 16.1 (C-15); 20.7 (C-C(17)OCOCH3); 21.0 (C-6'); 26.7 (C-14'); 34.7 (C-19'); 35.5 (C-17'); 36.4 (C-19); 36.4 (C-15'); 41.0 (C-20); 41.5 (C-6); 45.3 (C-3'); 51.4 (C-5); 51.9 (C-7); 52.5 (C-3); 53.6 (C-C(16')COOCH3); 54.4 (C-C(16)COOCH3); 56.1 (C-16'); 57.1 (C-C(l l)OCH3); 57.4 (C-5'); 61.4 (C-21'); 67.6 (C-21); 68.2 (C-20'); 71.0 (C-2); 75.8 (C-17); 78.3 (C-16); 96.8 (C-12); 112.3 (C-12'); 114.9 (C-7'); 119.0 (C-9'); 120.5 (C-10'); 123.5 (C-8); 124.0 (C-l l '); 125.4 (C-9); 128.2 (C-10); 129.5 (C-8'); 130.6 (C-2'); 136.6 (C-13'); 141.8 (C-13); 159.1 (C-
11); 163.9 (C-l); 172.0 (C- C(17)OCOCH3); 171.3 (C-C(16)COOCH3); 175.3 (C- C(16')COOCH3).
HRMS: 839.42334 (C47H59O10N4 /M ase+H/; calc. 839.42257). ESI-MS-MS (839.42@cid65) (rel. int. %): 821(49); 779(100); 761(22); 737(12); 719(25); 701(6); 618(4); 353(7).
Example 6. 14,15-Cyclopropanovinorelbine
1) NBS, CF3COOH
dichloromethane
2) HNEt2
3) AgBF4
THF/H20
14,15-Cyclopropanoanhydrovinblastine (244 mg; 0.302 mmol) was solved in dry dichloromethane (9 ml) and at -70°C in the dark, under Ar N-bromosuccinimide (64 mg; 0.362 mmol) was added in a mixture of dichloromethane (7.2 ml) and trifluoroacetic acid (0.13 ml; 1.66 mmol), then diethyl amine (0.21 ml; 2.07 mmol) in dichloromethane (1.8 ml) was dropped to the reaction mixture. After stirring at -70°C for 1.5 h 235 mg (1.21 mmol) of AgBF4 solved in THF-distilled water mixture (72 ml) was added, stirred the reaction mixture
further in dark under Ar for 3 h at 50°C. The reaction mixture was filtrated, to the filtrate 10% aqueous sodium carbonate was added to pH 9 then THF was evaporated. The residue was extracted with dichloromethane (3x20 ml), the combined organic phase was washed with saturated aqueous sodium chloride, dried with magnesium sulfate, and evaporated to dryness. The crude product was purified with preparative TLC (ethyl acetate-methanol-triethyl amine 97:3 :3) and 64 mg (0.081 mmol) base was obtained. The base was solved in a mixture of dichloromethane (0.58 ml) and ethanol (0.42 ml) then 0.43 ml of sulfuric acid (0.081 mmol)- ethanol mixture was added and the solution was evaporated to dryness. After treating the residue with diethyl ether, 71 mg (26%) of 14, 15-cyclopropanovinorelbine sulfate was obtained, as pale yellow crystals. Mp 221-223°C. Molecular weight (base) 792.96 g/mol (C46H56N408), molecular weight (sulfate) 891.04 g/mol (C46H58N4Oi2S).
TLC (base) (CH2Cl2-methanol 10: 1), R^O.32.
TLC (sulfate) (CH2Cl2-methanol 10: 1), R^=0.32.
IR (sulfate) (KBr) 3432, 2927, 1741, 1613, 1617, 1501, 1433, 1374, 1229, 1038 cm"1.
1H- MR (500 MHz, DMSO-i¾) δ 0.35 (m, 1H, Ha-15); 0.55 (m, 1H, Hx-22); 0.90 (m, 1H, Hy-22); 0.85 (t, J= 7.5, 3H, H3-18); 1.05 (t, J= 7.0, 3H, H3-18'); 1.08 (m, 1H, Ha-14); 1.08 (ABq, J= 14.1, J= 7.4, 1H, Hx-19); 1.62 (br, 1H, Ha-6); 1.74 (ABq, J= 14.1, J= 7.4, 1H, Hy- 19); 1.82 (br, 1H, H-14'); 1.86 (br, 1H, Ha-5); 1.96 (s, 3H, H3-C(17)OCOCH3); 1.99 (m, 1H, Ha-3); 2.00 (br, 1H, Hp-6); 2.06 (m, 1H, H2-19'); 2.08 (s, 1H, H-21); 2.52 (br, 1H, Ha-17'); 2.61 (s, 3H, H3-N(1)CH3); 2.85 (dd, J= 13.2, J= 4.0, 1H, Ha-3 '); 2.98 (br, 1H, Hp-17'); 3.03 (br, 1H, Hp-5); 3.10 (br, 1H, Hp-3); 3.38 (br, 1H, Ηβ-3 '); 3.43 (s, 1H, H-2); 3.66 (s, 3H, H3- C(16)COOCH3); 3.67 (s, 3H, H3- C(16')COOCH3); 3.72 (d, J= 16.7, 1H, Hx-21 '); 3.81 (s, 3H, H3-C(l l)OCH3); 3.96 (d, J= 16.7, 1H, Hy-21 '); 4.52 (d, J= 14.2, 1H, Ha-5'); 4.93 (d, J= 14.2, 1H, Hp-5'); 5.17 (s, 1H, H-17); 5.80 (br, 1H, H-15'); 6.02 (s br, 1H, H-9); 6.43 (s, 1H, H-12); 7.19 (m, 1H, H-10'); 7.22 (m, 1H, H-l 1 '); 7.48 (d, J= 8.1, 1H, H-12'); 7.79 (d, J= 8.1, 1H, H-9').
13C- MR (200 MHz, DMSO-i¾) δ 8.1 (C-22); 8.6 (C-18); 1 1.3 (C-14); 1 1.6 (C-18'); 15.7 (C- 15); 20.9 (C-C(17)OCOCH3); 26.6 (C-19'); 26.8 (C-14'); 34.2 (C-17'); 34.5 (C-19); 37.9 (C- 1); 40.3 (C-20); 44.6 (C-6); 43.2 (C-3 '); 46.2 (C-5'); 51.6 (C-21 '); 51.8 (C-5); 51.9 (C- C(16)COOCH3); 52.8 (C-3); 52.9 (C-C(16')COOCH3); 56.2 (C-C(l l)OCH3); 67.7 (C-21); 76.1 (C-17); 78.0 (C-16); 82.5 (C-2); 94.3 (C-12); 104.2 (C-7'); 1 12.0 (C-12'); 118.3 (C-9'); 118.6 (C-10); 1 19.8 (C-10'); 122.2 (C-l l '); 122.2 (C-15'); 123.4 (C-8'); 123.5 (C-9); 127.8 (C-
8); 135.9 (C-2'); 131.1 (C-20'); 134.8 (C-13'); 152.7 (C-13); 158.0 (C-l l); 169.9 (C- C(17)OCOCH3); 171.3 (C-C(16)COOCH3); 173.2 (C-C(16')COOCH3).
HRMS: 793.41693 (T^HsvO^ /M ase+H/; calc. 793.41709). ESI-MS-MS (793.42@cid35) (rel. int. %): 733(100); 683(30); 672(41); 612(29); 580(16); 562(15); 552(17); 510(20); 471(48); 389(19); 357(8); 323(8).
The compounds of the invention were sent to the US National Institute of Health (NIH) where they were subjected to pharmacological trials. These experiments on 56 different tumor cell lines embracing 9 frequently occurring tumor types demonstrated the therapeutic activity of these substances in comparison with other known effective catharanthus alkaloids.
The NCI screening procedures were described (Monks, A. et al. JNCI, J. Natl. Cancer Inst. 1991, 83, 757-766.) as were the origins and processing of the cell lines ( Monks, A. et al. JNCI, J. Natl. Cancer Inst. 1991, 83, 757-766; Alley, M. C. et al. Cancer Res. 1988, 48, 589- 601.; Shoemaker, R. H. et al. Prog. Clin. Biol. Res. 1988, 276, 265-286.; Stinson, S. F. et al. Proc. Am. Assoc. Cancer Res. 1989, 30, 613.)
In Tables 1-9 percentages of growths are listed for the reference alkaloids and the appropriate cyclopropyl derivatives at the concentration of 10"5M. The inhibition effect is expressed by the difference of growth. The bigger negative numbers show more significant decrease of cell number or stronger inhibition effects. In cases of VNR in the last three columns there are rounded were available.
Table 1.: Leukemia
In case of leukemia cancer cell line HL-60(TB) treated with cVLB a significant cell number decrease was observed. In three of four cases of the leukemia cell lines cyclopropanation enhanced the inhibiting effect: cVLB showed better results than VLB.
Table 2.: Non-Small Cell Lun Cancer
In case of non-small cell lung cancer line NCI-H226 treated with cVLB and in case of NCI-H522 line treated with cVNR significant cell number decrease was observed, and in case of NCI-H23 treated with cVCR the intensive cell number increase were stopped practically. In cases of all three alkaloid molecule types there were such cell lines where very significant increase of the inhibiting effect was measured for the cyclopropanised molecule against the appropriate reference molecule.
Table 3.: Colon Cancer
In case of colon cancer cell line COLO-205 at all three molecule types gave great cell number decrease and at both molecule types the cyclopropanation resulted significant extra decreasing effect against the non-cyclopropanated forms. In case of HCT-116 line treated with cVLB significant cell number decrease was observed as a result of cyclopropanation. In case of HT29
line treated with cVCR also significant cell number decrease was observed as the result of cyclopropanation, and this effect is even stronger at use of cVNR. In case of KM12 line treated with cVCR cyclopropanation also resulted significant decrease of cell numbers. Table 4.: CNS Cancer
In all five CNS cancer cell lines treated with VLB type molecules the cyclopropanation resulted extra inhibiting effects. At treatments with VCR and VNR type molecules at four of six cell lines cyclopropanation also resulted such effect. In cases of SF-295 and U251 lines treated with cVNR significant cell number decreasing effect was measured.
Table 5. : Melanoma
In two Melanoma lines (M14 and SK-MEL-5) significant and in case of MDA-MB-435 moderate inhibiting effects were detected with cVLB. In five of seven cases the cVLB showed bigger inhibition than VLB. In cases of MDA-MB-435 and SK-MEL-5 significant inhibiting effects were detected with cVCR. In case of SK-MEL-2 the inhibiting effect is significantly and in other three cases (LOX IMVI, MALME-3M and MDA-MB-435) this effect is moderately bigger with cVCR than that of VCR. In three cases (M14, MDA-MB-435, SK-MEL-5)
significant and in other two cases moderate cell number decreases were detected at treatment with cV R. cV R showed greater effects than "simple" V R in five of seven cases.
Table 6.: Ovarian cancer
In two ovarian cancer lines (NCI/ADR-RES, SK-OV-3) small inhibiting effects were detected with cVLB. In three of six cases the cVLB showed extra inhibition against VLB. In case of OVCAR-3 cVCR caused significant, in two other cases (NCI/ADR-RES and SK-OV-3) moderate inhibiting effects. In three of six cases cVCR caused bigger effects than VCR. In four of six cases cVNR caused bigger effects than VNR.
Table 7. : Renal cancer
In two cases of renal cancer lines (786-0 and CAKI-1) cVLB showed moderate cell-number decreasing effects. In six of eight cases this effect was stronger for cVLB than VLB. In case of treatment with cVCR and cVNR instead of VCR and VNR, respectively, significant extra decreasing effects were not detected.
Table 8.: Prostate cancer
In case of the prostate cancer line DU-145 cVCR caused significant cell number decrease, but extra inhibiting effects were not detected.
Table 9. : Breast cancer
In case of the breast cancer line BT-549 a significant, in case of MD A-MB-23 l/ATCC a moderate decrease of cell numbers were measured. In three of five cases cVLB caused bigger effect than VLB and similarly cVNR caused bigger effect than VNR. In two of four cases cVCR and in one case of cVNR cell number decrease were measured, but extra effects against VCR were not observed.
Table 10. : Cell lines on which significant (not less than 20%) cell number decreases and cyclopropanation effects were measured:
According to Table 10 cyclopropylvinblastine has significant tumor cell inhibiting effect in leukemia, non-small-cell lung cancer, colon cancer, melanoma and breast cancer, cyclopropylvincristine has significant tumor cell inhibiting effect in colon cancer, melanoma ovarian cancer and prostate cancer, cyclopropylvinorelbine has significant tumor cell inhibiting effect in non-small-cell lung cancer, colon cancer, CNS cancer, melanoma, renal cancer and breast cancer.
Claims
CLAIMS:
1. New bis-indole alkaloid derivatives of the general formula (I) having anticancer activity
(I)
- wherein
R stands for a methyl or a formyl group,
Ri stands for a methoxy or an amino group,
R2 represents a hydroxy or acetoxy group,
R3 stands for a hydrogen atom or a hydroxy group,
R4 represents a hydrogen atom or R3 and R4 together represent a double bond, R5 and 5 represent differently or both identically hydrogen and fluorine atoms n = 1 or 2
2. Cyclopropyl derivatives of formula (la), which is a limited group of bis-indole alkaloid derivatives of claim 1,
- wherein
R stands for a methyl or a formyl group,
Ri stands for a methoxy or an amino group,
R2 represents a hydroxy or acetoxy group,
R3 stands for a hydrogen atom or a hydroxy group,
R4 represents a hydrogen atom or R3 and R4 together represent a double bond, n = 1 or 2
in the 14β,15β position with a methylene bridge a cyclopropane ring is formed.
R stands for a methyl or a formyl group,
Ri stands for a methoxy or an amino group,
R2 represents a hydroxy or acetoxy group,
4. Cyclopropyl derivatives of formula (Ic), which is a limited group of bis-indole alkaloid derivatives of claim 2
(Ic)
- wherein
R stands for a methyl or a formyl group,
Ri stands for a methoxy or an amino group,
R2 represents a hydroxy or acetoxy group,
5. Cyclopropan -anhydro-vinblastine of formula (VIII).
(VIII)
6. Cyclopropanovinblastine of formula (IX).
(X)
8. Cyclopropanovinorelbine of formula (XI).
9. Cyclopropanovindoline derivatives of the formula (VI)
(VI)
- wherein
Ri stands for a methoxy or an amino group,
R2 represents a hydroxy or acetoxy group.
10. Cyclopropanovindoline of formula (Via) as claimed in claim 9,
(Via)
- wherein
Ri stands for a methoxy group,
R2 represents an acetoxy group.
11. A cyclopropanovindoline derivative (VIb) of the formula (VI) as claimed in claim 9
(VIb)
- wherein
Ri stands for an amino group,
R2 represents a hydroxy group.
12. A process for preparing a dimeric alkaloid of Vinca, which comprises using a derivative of cyclopropano-vindoline (VI) as claimed in claim 9.
13. A process for preparing a dimeric alkaloid of Vinca, which comprises using cyclopropano-vindoline (Via) or the cyclopropano-vindoline derivative (VIb) as claimed in claims 10 and 11.
14. The process as claimed in claims 12 and 13, wherein the preparation of a dimeric alkaloid comprises a coupling reaction with a catharanthine derivative of the general formula of (VII).
(VII)
- wherein
R3 stands for a hydrogen atom or a hydroxy group,
the dotted line expresses the presence of a double bond when the substitution R3 is absent, or else of a single bond when R3 designates a hydroxy group,
R5 and P6 represent differently or both identically hydrogen and fluorine atoms n = 1 or 2.
15. The process as claimed in claims 12-13, wherein the preparation of a dimeric alkaloid comprises a coupling reaction with a catharanthine derivative of the general formula of (Vila).
(Vila)
- wherein
R3 stands for a hydrogen atom or a hydroxy group,
the dotted line expresses the presence of a double bond when the substitution R3 is absent, or else of a single bond when R3 designates a hydroxy group,
n = 1 or 2.
16. Process for the preparation of 10-bromo-14, 15-cyclopropanovindoline comprising reacting 10-bromo-vindoline with diiodomethane in neutral organic solvent under inert atmosphere in the presence of diethylzinc.
17. Process for the preparation of 14, 15-cyclopropanovindoline comprising reacting 10- bromo-14, 15-cyclopropanovindoline with sodium borohydride in neutral organic solvent under inert atmosphere in the presence of palladium on charcoal.
18. Process for the preparation of cyclopropano-anhydro-vinblastine of formula (VIII) comprising reacting catharanhine base with 14,15-cyclopropanovindoline with 2,2,2- trifluoroethanol and FeCl3x6H20 in an acidic aqueous media under inert atmosphere.
19. Process for the preparation of cyclopropano-vinblastine of formula (IX) comprising reacting cyclopropano-anhydro-vinblastine of formula (VIII) with aqueous solution of Fe2(oxalate)3 saturated with air, then trifluoroethanol and sodium borohydride.
20. Process for the preparation of 14, 15-cyclopropano-vincristine of formula (X)
comprising reacting 14,15-cyclopropano-vinblastine of formula (IX) in acetic acid anhydride under at least -40°C temperature with Cr03 .
21. Process for the preparation of 14, 15-cyclopropano-vinorelbine of formula (XI) comprising reacting cyclopropano-anhydro-vinblastine (VIII) with N- bromosuccinimide in dichloromethane and then with diethylamine followed by AgBF4 in THF/water mixture.
22. Pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in any of the claims of 1-11, stereo isomeric and/or diastereomeric compounds thereof, or pharmaceutically acceptable salts hydrates or solvates thereof, as active ingredients and also comprising pharmaceutically acceptable auxiliary materials.
23. The use of a compound as claimed in claims 1-11 in the manufacture of a medicament for the treatment and/or prevention of cancer.
24. The use of a compound as claimed in claims 1-11 in the manufacture of a medicament for the treatment and/or prevention of any of cancer types of leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, renal cancer, prostate cancer and breast cancer.
25. The use of cyclopropanovinblastine of formula (IX) as claimed in claim 6 in the manufacture of a medicament for the treatment and/or prevention of leukemia or non- small cell lung cancer or colon cancer or melanoma or prostate cancer or breast cancer.
26. The use of cyclopropanovincristine of formula (X) as claimed in claim 7 in the manufacture of a medicament for the treatment and/or prevention of colon cancer or melanoma or ovarian cancer or prostate cancer.
27. The use of cyclopropanovinorelbine of formula (XI) as claimed in claim 8 in the manufacture of a medicament for the treatment and/or prevention of non-small cell lung cancer or colon cancer or CNS cancer or melanoma or renal cancer or breast cancer.
28. A method for treatment of cancer disease comprising the step of administering a human in need of such treatment a therapeutically effective amount of a compound in accordance with claims 1-11.
29. A method for treatment of any of cancer types of leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, renal cancer, prostate cancer and breast cancer comprising the step of administering a human in need of such treatment a therapeutically effective amount of a compound in accordance with claims 1-11.
30. A method for treatment of any of cancer types of leukemia, non-small cell lung cancer, colon cancer, melanoma and breast cancer comprising the step of administering a human in need of such treatment a therapeutically effective amount of a cyclopropanovinblastine of formula (IX) as claimed in claim 6.
31. A method for treatment of any of cancer types of colon cancer, melanoma, ovarian cancer, prostate cancer comprising the step of administering a human in need of such treatment a therapeutically effective amount of a cyclopropanovincristine of formula (X) as claimed in claim 7.
32. A method for treatment of any of cancer types of non-small cell lung cancer, colon cancer, CNS cancer, melanoma, renal cancer and breast cancer comprising the step of administering a human in need of such treatment a therapeutically effective amount of a cyclopropanovinorelbine of formula (XI) as claimed in claim 8.
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WO2017210206A1 (en) * | 2016-05-31 | 2017-12-07 | The Scripps Research Institute | Ultra-potent vina alkaloids: added molecular complexity further disrupts the tublin dimer-dimer interface |
CN108117566A (en) * | 2017-12-28 | 2018-06-05 | 广州白云山汉方现代药业有限公司 | A kind of preparation method of desacetyl vinblastine hydrazides |
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