The drug with improved tolerability in vivo

 

(57) Abstract:

The preparation contains the compound of the formula (I) glycosyl - Y[-C(=Y)-X]p-W(R)n-X-C(=Y)- active substance (I) where the radicals R and n are given in the claims, sugar and/or sugar alcohol, a pharmaceutically acceptable carrier and, optionally, the divalent metal ions of CA, Mg, Fe, Cu or Ni. The preferred compound of formula (I) is doxorubicin. The drug used in the treatment of malignant tumors, inflammatory processes and autoimmune diseases. Modification of the drug provides improved tolerance in vivo and effectiveness of actions. 2 s and 5 C.p. f-crystals, 1 table.

Treatment of malignant tumors, inflammation or autoimmune diseases, along with the insufficient efficacy of therapeutic agents are associated with serious side effects. This disadvantage can be explained mainly too small tolerance in vivo to the active substances.

The subject of the invention is to improve the portability of active substances used in the treatment, and, if necessary, improving the efficiency by modification of the drug.

where glycosyl is enzymatically otdalennym poly-, oligo - or monosaccharide,

W is an aromatic or heteroaromatic hydrocarbon or alfacom with conjugated double bonds or a derivative of amino acids, tsiklitiria after removal of the remainder of glycosyl,

when the substituent R is a hydrogen atom, stands, methoxy, carboxy, CN, methylcarbamyl, hydroxy, nitro, fluorine, chlorine, bromine, sulfonyl, sulfonamide or sulfon-(C1-C4-alkylamino,

p is 0 or 1,

n is an integer

X is an oxygen atom, NH, metalinox, methylamino or methylene-(C1-C4)-alkylamino and

Y is an oxygen atom or NH, and

activetestsuite substance means connected across the group hydroxy, -, amino - or imino-compound with biological activity,

and/or a physiologically tolerable salt of the compounds of formula (I)

2) sugar and/or sugar alcohol and

3) pharmaceutically acceptable carrier. Under activedayton substance refers to compounds as, for example, anthracycline, preferably is committed to etoposide, N-bis(2-chloroethyl)-4-hydroxyanisol, 4-hydroxycyclophosphamide, vindesine, vinblastine, vincristine, terfenadine, terbutaline, fenoterol, salbutamol, muscarin, oxyphenbutazone, salicylic acid, p-aminosalicylic acid, 5-fluorouracil inside the body, methotrexate, diclofenac, flufenacet, 4-metilaminofenazon, theophylline, nifedipine, mitomycin C, mitoxantrone, camptothecin and derivatives camptothecin, m-AMSA, Taxol and other taxanes, nocodazole, colchicine, fexofenadin, cyclophosphamide, rahalison, cisplatin, melphalan, bleomycin, nitrogen mustard gas, phosphoramide mustard gas, verrucarin And, neocarzinostatin, calicheamicin, dynemicin, spiramycin And, quercetin, genistein, erbstein, tyrphostin derived rohitukine, retinology acid, butyric acid, complex phorbolester, dimethylsulfoxide, aclacinomycin, progesterone, buserelin, tamoxifen, mifepristone, onapristone, N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonate, pyridyloxy-2-it, quinolyl, isoquinolinyl-2-it, staurosporin, ethanolamine, verapamil, Forskolin, 1,9-dideoxyinosine, quinine, quinidine, reserpine, 18-O-(3,5-dimethoxy-4-hydroxybenzoyl)-Reservat, lonidamine, butanesulfonyl, diethyldithiocarbamate, cyclosporin a, rapamycin, azathioprine, chlorambucil, mesalazin, penicillamine, chloroquine, dexamethasone, prednisolone, mefenamico acid, paracetamol, 4-aminophenazone, moccasin, ortsiprenalin, isoprenaline, amiloride, p nitrophenylacetylene or their derivatives, optionally substituted by one or more hydroxy groups, amino or imino.

n is an integer from 1 to 8, preferably from 1 to 6.

The term "sugar" refers to an aldose having 3-7 carbon atoms, which may belong to the series D or R; this includes an amino sugar or uronic acid. As examples are glucose, mannose, fructose, galactose, ribose, erythrose, glyceraldehyde, sedoheptulose, glucosamine, galactosamine, glucuronic acid, galacturonic acid, gluconic acid, Galaktionova acid or mononofu acid.

Sugar alcohols occur, for example, by restoring the above sugars; this includes glucitol, mannitol (mannitol), sorbitol, glycerol or Inositol.

Suitable pharmaceutically tolerated salts of the compounds of formula (I) are, for example, alkali, alkaline earth and ammonium salts, including salts of organic ammonium bases, and salts of protonated amino acid residues. Before the briteney contain, in particular, addition of divalent ions. The term "divalent ions" refers, for example, divalent metal ions, e.g., Sa, SB, Fe, cu or Ni.

It is preferable to use compounds of the formula (I), where

W is a phenyl residue or multiply substituted phenyl residue, and the Deputy

R is a hydrogen atom, stands, methoxy, carboxy, methoxycarbonyl, CN, hydroxy, nitro, fluorine, chlorine, bromine, sulfonyl, sulfonamide or sulfon-(C1-C4-alkylamides and

p is 0 or 1,

n is 1-4,

X is an oxygen atom, NH, metalinox, methylamino or methylene-(C1-C4)-alkylamino and

Y is an oxygen atom or NH, and

active substance refers to the above connection.

Especially preferred is the use of compounds of formula (I), where

glycosyl is poly-, oligo - or monosaccharide, in particular, - or-O-glycoside associated residue D-glucuronyl, D-glucopyranosyl, D-galactopyranosyl, N-acetyl-D-glucosamine, N-acetyl-D-galactosamine, D-mannopyranosyl or L-fucopyranoside,

W is odecarbono, CN, hydroxy, nitro, fluorine, chlorine, bromine, sulfonyl or sulfonamide and the others are hydrogen atom,

X is O, NH, metalinox, methylamino or methylenediamine and

Y is O or NH and

activetestsuite substance indicates the specified connection described above.

Used, preferably, compounds which are characterized by the fact that the rest of glycosyl can be derived by enzymatic hydrolysis, the separator can be spontaneously derived chemical hydrolysis that activetestsuite substance is a pharmaceutical vehicle or its derivatives obtained by introducing additional groups hydroxy, amino or imino that they are more hydrophilic than activetestsuite substance that they are in vivo lead to less toxic reactions than activetestsuite substance as such that the active substance is a pharmacologically active substance that activetestsuite substance optionally substituted by one or more hydroxy groups, amino or imino, and slows the growth of tumors that the active substance is a standard cytotoxic agent that activetestsuite the substance of the two is aminosides or methotrexate, what activetestsuite substance is introduced into the DNA substance that activetestsuite agent is doxorubicin, daunomycin, idarubitsina, or mitoxantrone that activetestsuite substance inhibits topoisomerase I+II that activetestsuite substance is camptothecin and derivatives camptothecin, etoposide and M-AMSA that activetestsuite substance is an inhibitor of tubulin that activetestsuite agent is vincristine, vinblastine, Taxol and takanami, nocodazole, colchicine or atoroidal that activetestsuite substance is alkylator that activetestsuite agent is cyclophosphamide, mitomycin C, rachelbilson, cisplatin, phosphoramide mustard gas, melphalan, bleomycin, nitrogen mustard gas or N-bis(2-chloroethyl-4-hydroxyanisole) that activetestsuite substance is neocarzinostatin, calicheamicin, epothilones a-C, dynamicism or espiramicina And that activetestsuite substance is a compound, inactivating ribosomes that activetestsuite substance is Verrucaria And that activetestsuite substance is an inhibitor of tirosingidroksilazy that activetestsuite substance assetsto is a differential inductor, what activetestsuite substance is retinology acid, butyric acid, complex formulation, DMSO or aclacinomycin that activetestsuite substance is a hormone, hormone agonist or hormone antagonist that activetestsuite substance is progesterone, busereline, tamoxifen or onapristone that activetestsuite substance is a substance that changes the pleiotropic resistance towards cytotoxic means that activetestsuite substance is an inhibitor of calmoduline that activetestsuite substance is an inhibitor of protein kinase C, which activetestsuite substance is an inhibitor of P-glycoprotein, which active substance is a modulator of mitochondrial bound hexokinase, what activetestsuite substance is an inhibitor-glutamylcysteine synthetase or glutathione-S-transferase that activetestsuite substance is an inhibitor superoksidismutazy that the active substance is a specific inhibitor Mak Ki67 proliferation associate a particular protein in the cell nucleus of dividing cells that activetestsuite substance is a substance that obliteration, what activetestsuite substance is a macrolide that activetestsuite substance is cyclosporine a, rapamycin, FK 506 that activetestsuite substance is azathioprine, methotrexate, cyclophosphamide or hlorambuzila that activetestsuite substance is a substance that has anti-inflammatory action that activetestsuite substance is asteroidal anti-inflammatory agent, that activetestsuite substance is slow acting Antirheumatic remedy that activetestsuite substance is a steroid that activetestsuite substance is a substance that has anti-inflammatory, analgesic or antipyretic effect that activetestsuite substance is derived organic acids that activetestsuite substance is not acidic analgesic agent, anti-inflammatory agent that activetestsuite substance is oxyphenbutazone that active-active substance is locally analiziruem means that activetestsuite substance is an antiarrhythmic agent that activetestsuite substance is an antagonist Sa

sodium salt of N-[4-O-( -D-glucopyranosyloxy acid)-3-nitrobenzenesulfonyl]-doxorubicin (compound II)

sodium salt of N-[4-O-( -D-glucopyranosyloxy acid)-3-chloro-benzyloxycarbonyl]-doxorubicin,

sodium salt of N-[4-O-( -D-glucopyranosyloxy acid)-3-fluorescent-benzyloxy-carbonyl]-doxorubicin,

sodium salt of N-[4-O-( -D-glucopyranosyloxy acid)-3-nitro-benzyloxycarbonyl]-daunorubicin,

sodium salt of N-[4-O-( -D-glucopyranosyloxy acid)-3-chloro-benzyloxycarbonyl]-daunorubicin,

N-[4-O-( -D-Gal is biloxicasino] -daunorubicin,

N-[4-O-( -D-galactopyranosyl)-3-fluorescent-benzyloxy-carbonyl]-daunorubicin,

sodium salt of N-[4-O-( -D-glucopyranosyloxy acid)-3-nitro-benzyloxycarbonyl]-doxorubicin,

sodium salt of N-[2-O-( -D-glucopyranosyloxy acid)-5-chloro-benzyloxycarbonyl]-doxorubicin,

sodium salt of N-[2-O-( -D-glucopyranosyloxy acid)-5-fluorescent-benzyloxycarbonyl]-doxorubicin,

sodium salt of N-[2-O-( -D-glucopyranosyloxy acid)-5-nitro-benzyloxycarbonyl]-daunorubicin,

sodium salt of N-[2-O-(beta-D-glucopyranosyloxy acid)-5-chloro-benzyloxycarbonyl]-daunorubicin,

N-[2-O-(alpha-D-galactopyranosyl)-5-nitro-benzyloxycarbonyl]-daunorubicin,

N-[2-O-( -D-galactopyranosyl)-5-chloro-benzyloxycarbonyl]-daunorubicin,

N-[2-O-(alpha-D-galactopyranosyl)-5-fluorescent-benzyloxycarbonyl]-daunorubicin,

4'-O-[4-( -D-glucopyranosyloxy)-phenylenecarbonyl]-etoposide,

4'-O-[4-( -D-galactopyranosyl)-phenylenecarbonyl]-etoposide,

4'-O-[4-( -D-glucuronidase)-phenylenecarbonyl]-etoposide,

4'-O-[4-( -D-glucuronidase)-3-nitro-benzylaminocarbonyl]-etoposide,

4'-O-[4-( -D-glucuronidase)-3-chloro-D-glucuronidase)-3-nitrobenzeneboronic]-doxorubicin,

4-O-[4-( -D-glucuronidase)-benzylamino-carbonyl]-4-hydroxy-1-N-(bis-2-chloroethyl)-aniline,

4-O-[4-( -D-glucuronidase)-benzylaminocarbonyl]-terfenadine,

3'-O-[4-( -D-glucuronidase)-benzylaminocarbonyl]-terbutaline,

3'-O-[4-( -D-glucuronidase)-benzylaminocarbonyl]-fenoterol,

1"-O-[4-( -D-glucuronidase)-benzylaminocarbonyl] salbutamol,

3-O-[4-( -D-glucuronidase)-benzylaminocarbonyl]-muscarin,

4'-O-[4-( -D-glucuronidase)-benzylaminocarbonyl]-expensedate,

2-O-[4-( -D-glucuronidase)-benzylaminocarbonyl]-salicylic acid

N-[4-( -D-glucuronidase)-benzylaminocarbonyl]-diclofenac,

N-[4-( -D-glucuronidase)-benzylaminocarbonyl]-flufenamic acid

4-N-[4-( -D-glucuronidase)-benzylaminocarbonyl]-4-metilaminofenazon,

7-N-[4-( -D-glucuronidase)-benzylaminocarbonyl]-theophylline

1-N-[4-( -D-glucuronidase)-benzylaminocarbonyl]-nifedipine,

[4-( -D-glucuronidase)-3-nitrobenzyl]-2-[1-cyano-1-(N-4-triptoreline)-carbarnoyl]propen-1-yl-carbonate

3'-N-[4-N-( -D-galactosylceramide)-4-aminobenzyl-oxycarbonyl]-doxorubicin,

9-O-[4-( -D-glucuronidase)-3-chloromethyloxirane]-quinin ilistory, it is preferable to use as activitiesthese matter connection II

and mannitol as a sugar alcohol and CA2+as the divalent ion.

Obtaining the compounds of formula I is carried out, for example as described in European patent EP 0751144.

Compound II is used in an amount of from 1 to 1000 mg/kg body weight, preferably from 5 to 500 mg/kg

If the drug is soluble, the use of mannitol in an amount of from 1 mg/ml to 150 mg/ml, preferably from 10 to 100 mg/ml soluble drug use ions of CA2+for example, in the form of CaCl2in the amount of from 0.01 mg/ml to 10 mg/ml, preferably from 0.05 to 2 mg/ml, in particular, 0.4 mg/ml CaCl22H2O.

The solid preparation according to the invention are suitable, for example, for the treatment of:

acute immunologic manifestations, such as sepsis, Allergy, graft versus host and host versus graft",

- autoimmune diseases, in particular rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis,

- psoriasis, atopic dermatitis, asthma, urticaria, rhinitis,

The solid preparation according to the invention may include a package or compositions, in which the components are placed next to each other and therefore can be used simultaneously, separately or in stages over time on the same human or animal organism.

In accordance with the invention, parts 1, 2 and, if necessary, the divalent ions may be present in parallel, divided dosage forms, in particular, when the dosage form due to the spatial dimensions make it difficult to use. This especially applies to oral forms, because often older patients have an aversion to large tablets or capsules. Urgent is that divided, standing next to each other form should be prepared for the total time of admission. This can also be used in various forms, e.g. tablets and capsules), facing each other.

In addition, the invention relates to a method fragment ions and pharmaceutical carriers are processed in a single pharmaceutical form application.

The solid preparation according to the invention can be present as the dosage units in the form of dosage forms such as capsules (including microcapsules), tablets (including tablets and pills) or candle, while the use of capsules material of the capsules can perform the function of the media, and content can be in the form of a powder, gel, emulsion, dispersion or solution. However, the most preferred and easiest way is to manufacture oral (oral) forms with three components 1), 2) and, if necessary, divalent ions, which contain the estimated number of active substances together with each desired pharmaceutical carrier. It may also be relevant form (suppositories for rectal therapy. It is also possible transdermal application in the form of ointments, creams or oral administration of solutions containing preparation according to the invention. In addition, the compounds of formula I can also be in the form of a lyophilisate, which before application to reconstruct a solution containing 5% mannitol and 0.4 mg CaCl22H2O/ml (pH about 7).

Ointments, pastes, creams and powder along with activetestsuite substances may contain conventional carriers, likely, silicones, bentonites, talc, zinc oxide, lactose, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances.

Tablets, pills or granules can be obtained by conventional means, as, for example, by means of pressing, dipping or fluidization or boiler drazhirovanija, and they can contain media and other conventional excipients, such as, for example, gelatin, agarose, starch (e.g. potato, corn or wheat starch), cellulose, for example, ethylcellulose, silicon dioxide, various sugars, for example lactose, magnesium carbonate and/or calcium phosphate. The solution for drazhirovanija consists, usually, of sugar and/or starch syrup and contains, more often, gelatin, gum Arabica, polyvinylpyrrolidone, synthetic esters of cellulose, surfactants, softeners, pigments and similar additives according to the prior art. To obtain drugs can be used every ordinary means of regulation of fluidity, lubricating or sliding means, for example, magnesium stearate and separation means.

The applied dosage depends, naturally, on various factors, Napanee health, the severity of symptoms to be treated of the disease, possible concomitant diseases (if any), types of concurrent treatment with other therapeutic agents or frequency of treatment. Doses are given, for example, from one to three times per week (intravenous).

The number of active components depends, of course, from a number of separate dosages, as well as from the underlying disease. Individual dosage may consist of several simultaneously given dosing units.

Examples

Pharmacological test

As experimental animals are naked mouse breeding strain NMRI with body weight from 17 to 25 g, bearing the tumor. In each experimental group using 6-8 animals. Animals receive an intravenous connection II in solution with a physiological salt solution (dose of compound II as indicated in table 1 in 0.9% NaCl), mannitol (dose of compound II as indicated in table 1 in a 5% solution of mannitol in water with a pH 7), and the preparation according to the invention containing the compound II, CaCl2and mannitol (dose of compound II, as indicated in table 1 in a 5% solution of mannitol with 0.4 mg l22N-2O). The use of orienta. The survival rate was determined daily. The results are presented in the table.

(T-C) 200% indicates: the doubling time of the tumor (tumor volume) in the treatment of compound II in the corresponding drug in days minus the doubling time of the tumor during the treatment of the corresponding drug without compound (II) in the days.

(T-s) 400% means: time Echeverria tumor (tumor volume) in the treatment of compound II in the corresponding drug in days, minus the time Echeverria tumors in the treatment of the corresponding drug without compound (II) in the days.

The minimum ratio of T/C (%) means the lowest value of tumor growth therapeutic groups compared with the control group.

The minimum ratio of T/C (day) means the day on which the growth of the tumor therapeutic group has the lowest value in comparison with the control group.

With the help of intravenous application of compound II in physiological salt solution with a dose of 3 to 25 mg/kg is achieved only weak anti-tumor effect. (T-C) 200% 3.9 days. However, the reduction of weight (a measure side effects of compound (II) is already quite high (24% weight reduction and 33% of deaths LM is Troy the death of all animals tested.

The introduction of the compound (II) in the mannitol leads to obvious antitumor effect (T-C) 200% 17.3 days) and moderate endurance (28% weight reduction and 17% of the dead animals).

Introduction 3 400 mg/kg of compound (II) in Sa/mannitol leads to a strong antitumor effects (T-C) 200% 19.6 days) and well tolerated by the experimental animals (18% weight loss and no dead animals).

Similar positive results were observed in experiments on monkeys of Massa fascicularis after the introduction of 3 120 mg/kg of compound (II) in solution CA/mannitol. Animals survived this extremely high dose without apparent side effects. By dissolving the compound (II) in 0.1 M phosphate buffer, pH 7,35, is at most 1 to 40 mg/kg, These studies show that the compound II in solution CA/mannitol according to the invention not only tolerated, but is clearly more effective.

1. The drug with improved tolerability in vivo, containing 1) a compound of the formula I

glycosyl - Y[-C(=Y)-X]p-W(R)n-X-C(=Y)- active substance (I)

where glycosyl is enzymatic otdalennym poly-, oligo - or monosaccharide;

W is a phenyl residue or mnogokratnoi, methyloxycarbonyl, CN, hydroxy, nitro, fluorine, chlorine, bromine, sulfonyl, sulfonamide or sulfon-(C1-C4-alkylamino;

p is 0 or 1;

n is 1-4;

X is an oxygen atom, NH, metalinox, methylamino or methylene-(C1-C4)-alkylamino;

Y is an oxygen atom or NH,

active substance means connected through a hydroxy, amino or aminogroup connection with biological activity, and as the active substance contains anthracyclin, preferably doxorubicin, as well as active substances from the group comprising etoposide, epothilone a-C, N-bis(2-chloroethyl)-4-hydroxyanisol, 4-hydroxycyclophosphamide, vindesine, vinblastine, vincristine, 5-fluorouracil, methotrexate, mitomycin C, mitoxantrone, camptothecin and derivatives camptothecin, m-SA, Taxol and other taxanes, cyclophosphamide, rahalison, melphalan, bleomycin, neocarzinostatin, calicheamicin, dynemicin, spiramycin And derived rohitukine, Leflunomide, or optionally substituted by one or more hydroxy-, amino - or aminopropane derivatives

and/or a physiologically tolerable salt of the compounds of formula I, 2) sugar and/or sugar alcohol is present divalent metal ions of CA, Mg, Fe, Cu or Ni.

3. The drug under item 1 or 2, characterized in that as sugar and/or sugar alcohol contains glucose, mannose, fructose, galactose, ribose, erythrose, glyceraldehyde, sedoheptulose, glucosamine, galactosamine, glucuronic acid, galacturonic acid, gluconic acid, Galaktionova acid, mononofu acid, glucitol, mannitol, sorbitol, glycerol or Inositol.

4. The drug is one of the p. 1-3, characterized in that the compound of formula I is a compound of formula II

5. The drug under item 4, characterized in that it is made in the form of a solution and contains ions of CA2+and mannitol.

6. The drug under item 5, characterized in that it contains 50 mg/ml mannitol, 0.4 mg/ml l22H2O and 25 mg/ml of compound (II) under item 5.

7. The way to obtain the drug on one of the PP.1-6, characterized in that the compound of formula I, the sugar or sugar alcohol, if necessary, divalent ions and the pharmaceutical carrier is processed in the pharmaceutical form of application.

 

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