Combinations containing antidiarrheal agent and epothylon or epothylon derivatives

FIELD: medicine; pharmacology.

SUBSTANCE: invention concerns a combination for proliferative disease treatment which contains antidiarrheal agent and epothylon derivative of formula (1) or epothylon derivative, method of diarrhoeia management, associated with epothylon introduction of formula (1), pharmaceutical composition, trade packing and medical product, including antidiarrheal agent and epothylon derivative.

EFFECT: compositions have improved efficiency.

9 cl, 6 ex

 

The invention relates to a pharmaceutical combination which comprises (a) antidiarrheal agent, in particular an inhibitor of dipeptidylpeptidase-IV (DPP-IV), (b) derived epothilone formula I and optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use, in particular for the treatment of a proliferative disease, especially a solid tumor; to pharmaceutical compositions comprising such a combination; the use of such a combination when getting medicines for the treatment of proliferative diseases; to trade package or tool comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treating a warm-blooded mammal, especially man.

The effect of stabilization of microtubules epothilone first described by Bollag and others, Cancer Research 55, 1995, 2325-33. The corresponding scheme of treatment of various types of tumors, especially tumors that are resistant to other chemotherapeutic agents, in particular Taxol™described in WO 99/43320.

The present invention relates to a combination, such as a combined preparation or pharmaceutical composition, which comprises (a) antidiarrheal agent and (b) derived epothilone Faure the uly I

where

A represents oxygen or NRN,

RNmeans hydrogen or (ness.)alkyl,

R means hydrogen or (ness.)alkyl, and

Z denotes oxygen or a bond,

where the active ingredients (a) and (b) are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate or sequential use.

The compound of formula I in which a represents oxygen, R is hydrogen and Z means oxygen, known as epothilone And; a compound of formula I in which a represents oxygen, R is methyl and Z means oxygen, known as epothilone In; a compound of formula I in which a represents oxygen, R is hydrogen and Z represents a relationship, known as epothilone With; a compound of formula I in which a represents oxygen, R is methyl and Z represents a relationship, known as epothilone D.

The term "a combined preparation", as used in the context, means, primarily, "a set of components" in the sense that included a combination of substances (a) and (b)as defined above can be dosed independently from each other or by applying various specific combinations with distinguished amounts of the combinations of substances (a) and (b), i.e. the simultaneous or at different time points. Then part of the set of components may, for example, be administered simultaneously or chronologically differentiation, i.e. at different time points and with equal or different time intervals for any part of the component set. The ratio of total amounts included in the combination of substances (a) to a member of a combination of substance (b), which must be entered in the combined preparation can vary, for example, in order to cover the needs of the needy in the treatment groups or the needs of one patient based on the severity they experienced diarrhea.

The present invention mainly relates to combination products that include (a) one or more standard dosage forms antidiarrheal agent and (b) one or more standard dosage forms derivative of the formula I, in particular, epothilone Century

The antidiarrheal agent is introduced in order to prevent, control or eliminate diarrhea, which is sometimes associated with the introduction of epothilones, especially epothilone Century, Therefore, the present invention relates also to a method of prevention or regulation of diarrhea associated with the introduction of derived epothilone formula I, which includes the introduction of an effective amount of antidiarrheal agent to the patient receiving treatment is proizvodnym epothilone.

The term "solid tumor" refers, mainly, breast cancer, ovarian cancer, cancer of the colon and generally the gastrointestinal tract, cervical cancer, lung cancer, in particular small cell lung cancer and non-small cell lung cancer, head and neck cancer, bladder cancer, prostate cancer or sarcoma Galoshes. This combination inhibits the growth of solid and solid tumors. Moreover, depending on the type of tumor and concrete used, the combination may be achieved by reducing tumor volume. Combinations disclosed in the context of the applicable also to prevent metastasis of tumors and the growth or development of metastases.

The structure of the active agents identified by code numbers, generic or trade names may be taken from the current edition of the standard pointer "The Merck Index" or from databases Patents International (e.g. IMS World Publications). Corresponding to the content is enabled thereby by reference.

It will be understood that references to included in the combination of compounds (a) and (b) imply the inclusion of pharmaceutically acceptable salts. If these are included in the combination of compounds (a) and (b) are, for example, at least one basic center, they can form acid additive salt. Appropriate acid-and detune salt can also be formed, having optionally present basically the center. Included in the combination of compounds (a) and (b)having an acid group (for example COOH)can also form salts with bases. Included in the combination of compounds (a) or (b) or its pharmaceutically acceptable salt can also be applied in the form of hydrates or include other solvents used for crystallization.

Derivatives epothilone formula I, where a represents oxygen or NRNwhere RNmeans hydrogen or (ness.)alkyl, R is hydrogen or (ness.)alkyl and Z means oxygen or a bond, and methods of obtaining such epothilone derivatives, in the generic designation or specifically disclosed in the patents and applications WO 93/10121, US 6194181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO 00/31247, in each case, in particular, in the claims, related compounds and final products of the working examples, the object of the final products, the pharmaceutical preparations and the claims are included, therefore, in the present application by reference to this publication. In this way covered by the corresponding stereoisomers as well as the corresponding crystalline modifications, such as a solvate and polymorph disclosed in the context.

Turning epothilone B into the corresponding lactam is disclosed in the application WO 99/02514 figure 21 (page 31, 32) is in example 3 (page 48-50). The transformation of compounds of formula I, which differs from epothilone In the corresponding lactam can be performed similarly. Appropriate derivative epothilone formula I, where RNmeans (ness.)alkyl, can be obtained by methods known in this field, such as the reaction of reductive alkylation, based on epothilone derivative, where RNmeans hydrogen.

Derivatives epothilone formula I, especially epothilone, can be entered as part of the pharmaceutical compositions disclosed in the application WO 99/39694.

In a specific embodiment, embodiments of the invention derived epothilone is a compound of formula I in which a represents oxygen or NRNwhere RNmeans hydrogen or (ness.)alkyl, R is hydrogen or (ness.)alkyl and Z means oxygen or link.

In a derived epothilone formula I is preferably a represents oxygen, R means (ness.)alkyl, e.g. ethyl, most preferably methyl, and Z means preferably oxygen.

Antidiarrheal agents and protocols for the introduction of well-known experts in this field. Antidiarrheal agents suitable for use in the methods and compositions of the invention include, but without limitation, natural opioids, such as tincture of opium, camphor tincture of opium and codeine synthetic opioids, such as Diphenoxylate, Difenoxin and loperamide, bismuth subsalicylate, lanreotide, vapreotide and octreotide, antagonists motilin, inhibitors of cyclooxygenase-2 (MOR-2), as celecoxib, glutamine, thalidomide and traditional antidiarrheal drugs, such as kaolin, pectin, berberine and muscarinic agents. In one variant embodiment of the invention the antidiarrheal agent is selected from codeine, tincture of opium, camphor tincture of opium, Diphenoxylate, Difenoxin and loperamide. In another variant embodiment of the invention antidiarrheal agent selected from lanreotide, vapreotide and octreotide. Of these three compounds are especially preferred is octreotide. The last connection or acetate can be obtained and applied as described in patent US 4395403, or, for example, in the form of its acetate or pamoate, as described in patent US 5538739. In particular, the patient can be entered octreotide, sold under the trade names SANDOSTATIN™ and SANDOSTATIN LAR™.

Antidiarrheal agent used in the present invention, can also be an inhibitor of DPP-IV. Inhibitors of DPP-IV is known in this area for the treatment of diabetes. Protocols to introduce them to treat diabetes. However, according to the present invention, the inhibitor of DPP-IV is effective to prevent and/or kontrolirovat diarrhea, which is sometimes associated the Ana with the introduction of derivatives epothilone.

The dipeptidyl peptidase responsible for the inactivation of GLP-1(glycosilated-1). More specifically, DPP-IV generates receptor antagonist GLP-1 and thereby shortens the physiological response to GLP-1. GLP-1 is the main stimulator of insulin secretion by the pancreas and has a direct beneficial effect on the removal of glucose.

Inhibitor of DPP-IV can be a peptide or ones nature. Preferably the inhibitor of DPP-IV has ones nature.

According to the present invention are preferably used inhibitors of DPP-IV, which in the generic designation or specifically disclosed in the application WO 98/19998, DE 19616486 A1, WO 00/34241 and WO 95/15309, 31247, in each case, in particular, in the claims, related compounds and final products of the working examples, the object of the final products, the pharmaceutical preparations and the claims are included, therefore, in the present application by reference to these publications. Inhibitors DPP728 and LAF237 specifically disclosed in example 3 of the application WO 98/19998 in example 1 application WO 00/34241, respectively. Other suitable inhibitor of DPP-IV formula VI (see below) specifically disclosed in Diabetes 1998, 47, 1253-1258. Inhibitor DPP728 can be obtained as described on page 20 of the application WO 98/19998.

N-Peptidyl-O-aroylhydrazines, for example, of formula VII or VIIa (see below), described H.U. Demuth, etc., J. Enzyme Inhibition 1988, volume 2, str-142, in which lastnosti, on str-132.

Unless otherwise stated, in the present disclosure, an organic radical, denoted by the term "lower", contains not more than 7, preferably not more than 4 carbon atoms, and the following terms have the meanings given below.

Halogen means preferably fluorine, chlorine or bromine.

Unless otherwise specified, (ness.)alkyl means preferably ethyl or most preferably methyl. (C1-C8)alkyl means a branched or preferably unbranched alkyl, preferably (ness.)alkyl, for example methyl or ethyl.

The term "(ness.)alkylene" means preferably methylene, ethylene or propylene. He may be unsubstituted or substituted, for example, hydroxy-group.

The term "(ness.)alkoxy" means preferably methoxy or ethoxy. (C2-C4)Alkoxy means, for example, ethoxy or propoxy.

Cycloalkyl means, for example, (C3-C12)cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclodecyl; or bicycloalkyl, such as bicycloheptene. Cycloalkenyl means preferably 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cyclopentenyl or 2-cyclopentenyl.

(C1-C3)Hydroxyalkyl means, for example, 3-hydroxypropyl, 1-hydroxyethyl or hydroxymethyl.

(C4-C6)Al is janimine, which is unsubstituted or substituted by one or two (ness.)alkyl groups, means, for example, pyrrolidinyl, methylpyrrolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 2-methyl-1-piperidinyl or hexamethyleneimino. Preferably (C4-C6)alkylamino means 1-piperidinyl.

Optionally substituted [3.1.1]bicyclic carbocyclic portion, as defined above, preferably means bicyclo[3.1.1]hept-2-yl, optionally disubstituted in position 6 stands, or bicyclo[3.1.1]hept-3-yl, optionally tizamidine one stands in position 2 and two metal groups in position 6. Preferably [2.2.1]bicyclic carbocyclic part, optionally substituted, as defined above, is bicyclo[2.1.1 ]hept-2-yl.

Aryl includes preferably 6-12 carbon atoms means, for example, phenyl, tolyl or naphthyl, each of which may be substituted, for example, (ness.)by alkyl or halogen.

The term "heteroaryl" refers to an aromatic heterocyclic radicals chosen, for example, from the group consisting of pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazoline, imidazoline, imidazolidine, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidine, isothiazole, isothiazoline, furil, t is traditionala, tanila, oxadiazolyl, piperidinyl, piperazinil, azepine, 4-piperidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl, thiomorpholine, teamoriented, tumorgenicity, 1,3-dioxolane, indolyl, benzothiazolyl, benzoxazolyl, benzothiazyl, hinokitiol, chinoline, tetrahydroisoquinoline, izochinolina, benzimidazolyl, benzopyranyl, indolizinyl, benzofuran, chromonema, coumarinyl, cinnoline, khinoksalinona, indazole, pyrrolopyridine, torpedine, dihydroisoquinolyl, dihydroisoquinolyl, dihydroquinazolines and tetrahydroquinazoline.

Preferred inhibitors of DPP-IV are N(N′-substituted glycyl)-2-cyanopyrrolidine represented by the formula (I),

where R means:

(a) R1R1aN(CH2)mwhere

R1means pyridyloxy or pyramidalnou part, optionally mono - or independently disubstituted (ness.)the alkyl, (ness.)alkoxy, halogen, trifluoromethyl, cyano or nitro; or phenyl, optionally mono - or independently disubstituted (ness.)the alkyl, (ness.)alkoxy or halogen;

R1ameans hydrogen or (C1-C8)alkyl; and

m represents 2 or 3;

(b) (C3-C12)cycloalkyl, optionally substituted in position 1 (C1-C3 )hydroxyalkyl;

(C) R2(CH2)nwhere or

R2means phenyl, optionally mono - or independently tizamidine (ness.)the alkyl, (ness.)alkoxy, halogen or phenylthio, optionally monosubstituted in the phenyl ring with hydroxymethyl; or means (C1-C8)alkyl; or means [3.1.1]bicyclic carbocyclic part, optionally mono - or polyamidine (C1-C8)alkyl; pyridinyl or naftalina part, optionally mono - or independently disubstituted (ness.)the alkyl, (ness.)alkoxy or halogen; cyclohexene; or substituted; and

n means 1-3; or

R2means phenoxy, optionally mono - or independently disubstituted (ness.)the alkyl, (ness.)alkoxy or halogen; and

n represents 2 or 3;

(g) (R3)2CH(CH2)2where each R3means independently phenyl, optionally mono - or disubstituted by (ness.)the alkyl, (ness.)alkoxy or halogen;

(d) R4(CH2)pwhere R4mean 2-oxopyrrolidin or (C2-C4)alkoxy and R means 2-4;

(e) isopropyl, optionally monosubstituted in position 1 (C1-C3)hydroxyalkyl;

(W) R5where R5means of indanyl; pyrrolidinyloxy or piperidinyloxy part, optionally substituted benzyl; [2.2.1]or [3.1.1]bicyclic, carbocyclic the massive part, optionally mono - or polyamidine (C1-C8)alkyl; substituted; or (C1-C8)alkyl, optionally mono - or independently politeley hydroxy-group, hydroxymethyl or phenyl, optionally mono - or independently disubstituted (ness.)the alkyl, (ness.)alkoxy or halogen;

(C) substituted substituted;

in free form or in the form of an acid additive salt.

In a preferred variant embodiment of the invention N-(N′-substituted glycyl)-2-cyanopyrrolidine represented by formula (I), where

R means R1R1aN(CH2)mwhere

R1means pyridinoline or pyrimidinyl part, optionally mono - or independently disubstituted (ness.)the alkyl, (ness.)alkoxy, halogen, trifluoromethyl, cyano or nitro; or phenyl, optionally mono - or independently disubstituted (ness.)the alkyl, (ness.)alkoxy or halogen;

R1ameans hydrogen or (C1-C8)alkyl; and

m represents 2 or 3;

in free form or in the form of an acid additive salt.

More preferably N-(N′-substituted glycyl)-2-cyanopyrrolidine represented by formula (I), where

R means R1R1aN(CH2)mwhere

R1means pyridinoline part, optionally mono - or independently disubstituted (ness.)the alkyl, (ness.)alkoxy, halogen, trifluoromethyl, tzia is about or nitro;

R1Ameans hydrogen or (C1-C8)alkyl; and

m represents 2 or 3;

in free form or in the form of an acid additive salt.

Most preferably N-(N′-substituted glycyl)-2-cyanopyrrolidine formula I is (S)-1-{2-[5-cyano-2-yl)amino]acylaminoacyl}-2-cyano-pyrrolidin (DPP728) or (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyano-pyrrolidine (LAF237).

In another preferred variant of embodiment of the invention the inhibitor of DPP-IV are selected from compounds of formulas II, III, IV and V:

where In the means

f denotes 1 or 2;

g is 0, 1 or 2;

X is CH2, oxygen, sulfur, SO, SO2, NH or NRα1,

where

1means (ness.)alkyl (C1-C6);

- Y represents N, CH or C=(when a group WITH a substituted-CH - or-CF=);

Rα means hydrogen, CN, Cho, (OH)2, RHO3N or their ester, CC-Rα7or CH=N-Rα8where

7means hydrogen, fluorine, (ness.)alkyl (C1-C6), CN, NO2, ORα9, CO29or CORα9;

9means (ness.)alkyl (C1-C6);

8means phenyl, HE ORα 9, OCORα9or OBn;

But is connected to Y;

and where for compounds of group G1

(a) when Rα means hydrogen, And means α-aminoacyl group, formed from α-amino acids bearing cycloaliphatic side chain, the General formula

where h stands for 1-6, in any case, the ring optionally unsaturated and/or substitution of a heteroatom;

(b) when Rα means CN, CC-Rα7or CH=NRα8And matter under item(a) and, in addition, may be derived from any L-α-amino acids containing lipophilic side chain;

(in) and when Rα means Cho or B(OH)2And means β-aminoacyl group, as described under item(a);

for compounds of group G2

Rα means hydrogen, CN, C=C-Rα7or-CH=NRα8and

And means

or

where

and means 1-5;

D1means-G-(CH2)b-Rα4)q-Rα3;

G denotes Oh, NH or NMe;

b means 0-12;

q means s is 0-5;

D mean s D G≠O;

4mean Z-NH-(CH2)c- or NH-Z-(CH2)c-where means 1-12 and

Z means CO, CH2or SO2;

3means CO2N or its ester, CONH2, CONHNH2, CONRα5 , CONHNRα56, RHO3N or its ester, SO3N, SO2NH2, SO2NRα56HE ORα5substituted or unsubstituted aryl or heteroaryl, NH2, NRα56, NHCO25, NHSO2NRα56, NHCORα5, NH-SO25, NH-CH(:NRα5NRα56, NHCONHRα56sugar, amino sugar, NHCO-amino sugar or NHCS-amino sugar; and

5and Rα6independently selected from H and (ness.)of alkyl, foralkyl and cycloalkyl group containing up to 8 atoms, and the aryl, heteroaryl and alkylchlorosilanes groups containing up to 11 atoms, or

5and Rα6can work together to deliver (3-C8)chain; or means

or

where

10means hydrogen or methyl, and the ring may contain one or more heteroatoms,

E. means J-(CH2)b-Rα4)q-Rα3,

J means CO, CH2or SO2and a, b, q, Rα3and Rα4have the meanings given under item(i); or means

or

where

2means hydrogen or methyl, and the ring can containing the one or more heteroatoms, and

L means (CH2)d-(CO)r-(CH2)b-Rα4)q-Rα3or (CH2)e-NRα10-(CH2)b-Rα4)q-Rα3where

r is 0 or 1,

d is 0-4,

E. means 2-4, and

b, q, Rα3and Rα4have the meanings given under item(i);

and for compounds of group G3 each Deputy can have the meaning given above, each Deputy And may be selected from a group G2 of any structure (i), (ii) or (iii)above, with the terminal group Rα3the Deputy And replaced by a paired group -ε-ω-ε- or -ε-ε- or -ω-and ε and ω chosen independently of CH2, O, NH, CO, S, SO2, And Ph NHMe; and where in the groups G2 and G3, at least one group of CH2in the chain can be replaced by its bioisostere or any amide group, which connects a and B in the connection group G1, G2 or G3 or in the side chain substituent And connection group G2 or G3 may be substituted amide by bioisosteres, in free form or in the form of an acid additive salt.

In another preferred embodiment of the invention the inhibitor of DPP-IV is a compound of formula VI

in free form or in the form of an acid additive salt.

Additional preference is sustained fashion the embodiment of the invention the inhibitor of DPP-IV is N-peptidyl-O-aroylhydrazines or its pharmaceutically acceptable salt. Aroyl means, for example, afterburner; or benzoyl which is unsubstituted or mono - or disubstituted, for example, (ness.)alkoxy, (ness.)by alkyl, halogen or preferably nitrogroup. Piptadenia part preferably includes two α-amino acids, e.g. glycine, alanine, leucine, phenylalanine, lysine, or Proline, one of which is attached directly to the nitrogen atom of the hydroxylamine is preferably a Proline.

Preferably N-peptidyl-O-aroylhydrazines is a compound of formula VII

where

j means 0,1 or 2;

1means the side chain of natural amino acids; and

2means (ness.)alkoxy, (ness.)alkyl, halogen or nitro; or its pharmaceutically acceptable salt.

In a very preferred variant of embodiment of the invention N-peptidyl-O-aroylhydrazines is a compound of formula VIIa

or its pharmaceutically acceptable salt.

In a highly preferred variant of embodiment of the invention component (a) is an inhibitor of DPP-IV is (S)-1-{2-[5-cyano-2-yl)amino]acylaminoacyl)-2-cyanopyrrolidine (DPP728)and component (b) is derived epothilone is epothilone Century

In another highly preferred variant embodiment of the invention to mponent (a) an inhibitor of DPP-IV is (S)-1-[(3-hydroxy-1-substituted)amino]acetyl-2-cyanopyrrolidine (LAF237), and the component (b) is derived epothilone is epothilone Century

The present invention mainly relates to combination products that include one or more standard dosage forms of an inhibitor of DPP-IV and (b) one or more standard dosage forms derived epothilone formula I, in particular, epothilone Century

A combination which comprises (a) entityarray agent and (b) derived epothilone formula I, the compound in which a represents oxygen or NRNwhere RNmeans hydrogen or (ness.)alkyl, R is hydrogen or (ness.)alkyl and Z means oxygen or connection, the combination in which the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier, will be referred to hereinafter as a combination according to the invention.

When included in the combination of the compounds used in the combinations according to the invention, applied in the form sold as single drugs, their dosage and method of administration can be carried out in accordance with the information provided on the packing insert the appropriate selling the drug to get the beneficial effects described in the context of, if not mentioned otherwise.

Antidiarrheal AG the NT is administered as a preventative measure throughout the treatment cycle, or as needed when there is diarrhea.

In a preferred variant embodiment of the present invention, the subject receives the derived epothilone formula I, once a week for several weeks, for example, three weeks, with a break in one or more weeks, and antidiarrheal agent is administered as a preventative measure, previously giving the subject antidiarrheal agent prior to the introduction derived epothilone and continuing the introduction of antidiarrheal agent throughout the cycles, or by entering the antidiarrheal agent throughout cycles without prior treatment, or by entering the antidiarrheal agent is necessary when diarrhea occurs during cycles, with a pre-treatment or without it. As an example, when derived epothilone injected once a week for three weeks with a break of one week, each four-week interval will be considered as one cycle.

An effective amount of antidiarrheal agent is the amount sufficient to prevent, control or eliminate diarrhea, associated with the introduction of derived epothilone, in particular, this quantity, which increases the amount derived epothilone, which can be entered when diarrhea is a manifestation doselimiting toxicity derived epothilone, especially epothilone Century

The combination according to the invention can be combined preparation or pharmaceutical composition.

One objective of this invention is to provide pharmaceutical compositions containing a quantity that is therapeutically effective against a proliferative disease, comprising the combination according to the invention, i.e. in such pharmaceutical compositions included in the combination of compounds (a) and (b) are introduced together in a given combination.

The pharmaceutical compositions according to the invention can be obtained by known fact way and is suitable for enteral administration, such as oral or rectal, and parenteral administration mammals (warm-blooded animals), including humans.

A new pharmaceutical composition contains, for example, from about 10% to about 100%, preferably from about 20% to about 60% of the active ingredients. Pharmaceutical drugs for combination therapy with enteral or parenteral administration are, for example, drugs in standard dosage forms, such as tablets, sugar coated tablets, capsules or suppositories, and also ampoules. If not stated otherwise, get them known fact way, for example by conventional mixing, granulation, coating sugar coating, dissolution and and lyophilization. It will be recognized that it is not required that a standard Raman content connections in individual dose of each dosage form in itself constituted an effective amount since the necessary effective amount can be achieved by introducing a variety of standard doses.

Upon receipt of the compositions for oral dosage forms may be used any of the usual pharmaceutical media, such as, for example, water, glycols, oils, flavorings, preservatives, dyes; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrators and the like in the case of oral solid preparations such as powders, capsules and tablets, with the solid oral preparations are preferable to liquid preparations. Due to the ease of their administration tablets and capsules represent the most favorable standard oral dosage form, a case in which, of course, use solid pharmaceutical carriers.

In particular, a therapeutically effective amount of each Raman compound combinations according to the invention can be introduced separately, i.e. components can be administered simultaneously or sequentially and in any order. For example, the pic is b treatment of proliferative diseases according to the invention may include (i) the introduction of the first connection combinations in free form or in the form of a pharmaceutically acceptable salt and (s) introduction the second connection combinations in free form or in the form of a pharmaceutically acceptable salt, simultaneously or sequentially in any order, in jointly therapeutically effective amounts, preferably in synergistically effective amounts, e.g. in daily dosages corresponding to the amounts described in the context. Individual Raman components of the combination according to the invention can be introduced separately at different times during the course of therapy or competition in the form of a fraction or a single combination. One component may be, for example, enteral composition, and the other may be introduced parenterally. Moreover, the term "introduction" also covers the use of depo-shaped Raman connection, which in vivo is transformed into a compound combination as such. Therefore, the invention should be understood as embracing all such regimes of simultaneous or alternative treatment and the term "introducing" shall be construed accordingly.

The effective dose of each combinational component used in combination according to the invention may vary depending on the particular compound or pharmaceutical composition, the method of administration, the condition treated, and its severity. So, dose combination mode according to the invention are chosen according to a number of factors, including route of administration and the status of renal and hepatic function of the patient. A physician, Clinician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the ingredients one activity required to prevent, counter or arrest the progression of the condition. Optimal precision in achieving concentrations derived epothilone in the range that provides efficacy without toxicity requires a regimen based around kinetics availability of the active ingredients in the planned locations. This includes consideration of the distribution, equilibrium, and elimination of the active ingredients.

If a warm-blooded mammal is a human, the dose of a compound of formula I is preferably in the range of about 0.25 to 75 mg/m2, preferably 0.5 to 50 mg/m2for example, 2.5 mg/m2once a week for 2-4 weeks, for example, 3 weeks with an interval of 6-8 days in the case of an adult patient.

The antidiarrheal agent is preferably administered one to four times per day in accordance with established protocols for antidiarrheal agent.

Inhibitor of DPP-IV, if used, is preferably introduced in accordance with known protocols for the treatment of diabetes. Preferably the dose is in the range from 25 mg to 1000 m the day.

In addition, the present invention relates to a method of treatment of a warm-blooded animal suffering from a proliferative disease, comprising an introduction to the animal a combination according to the invention in a quantity which is therapeutically effective against a proliferative disease which weakens any diarrhea that is associated with the introduction of derived epothilone.

In addition, the present invention relates to the use of the combinations according to the invention to treat proliferative diseases and receiving drugs for the treatment of proliferative diseases.

Moreover, the present invention provides trading package comprising as active ingredients combination of the invention together with instructions for simultaneous, separate or sequential their application in the treatment of proliferative diseases.

The following examples illustrate the invention described above; however, they do not purport to limit the scope of the invention. The beneficial effects of the combination according to the invention can also be demonstrated using other test models, known as such to a specialist in its respective field.

Example 1. A patient suffering from a proliferative disease, were subjected to treatment with 6 cycles epothilone is In, where each cycle consisted of a drip for 5 minutes once a week 2.5 mg epothilone or drip for 15 min for three weeks with the subsequent 14 days. During treatment the patient received daily from 2 mg to 16 mg of loperamide in the form of cleaners containing hydrochloride salt to regulate diarrhea.

Example 2. A patient suffering from a proliferative disease, were subjected to treatment with 6 cycles epothilone, where each cycle consisted of a drip for 5 minutes once a week 2.5 mg epothilone In for three weeks with the subsequent 14 days. The patient received daily up to 16 mg of loperamide in the form of cleaners containing hydrochloride salt, when it happened diarrhea.

Example 3. A patient suffering from a proliferative disease, were subjected to treatment with 6 cycles epothilone, where each cycle consisted of a drip for 5 minutes once a week 2.5 mg epothilone In for three weeks with the subsequent 14 days. During treatment the patient received daily from one to six doses of 50 mg DPP728 to regulate diarrhea.

Example 4. A patient suffering from a proliferative disease, were subjected to treatment with 6 cycles epothilone, where each cycle consisted of a drip for 5 minutes once a week 2.5 mg epothilone In for three weeks followed the mi 14 days. The patient received daily to 300 mg DPP728, when it happened diarrhea.

Example 5. A patient suffering from a proliferative disease, were subjected to treatment with 6 cycles epothilone, where each cycle consisted of a drip for 5 minutes once a week 2.5 mg epothilone In for three weeks with the subsequent 14 days. During treatment the patient received daily from one to six doses of 50 mg LAP 237 to control diarrhea.

Example 6. A patient suffering from a proliferative disease, were subjected to treatment with 6 cycles epothilone, where each cycle consisted of a drip for 5 minutes once a week 2.5 mg epothilone In for three weeks with the subsequent 14 days. The patient received daily to 300 mg LAF 237, when it happened diarrhea.

1. Combination for the treatment of proliferative diseases, which includes (a) antidiarrheal agent and (b) derived epothilone formula I,

where a represents oxygen or NRNwhere RNmeans hydrogen or (ness.)alkyl,

R means hydrogen or (ness.)alkyl, and

Z denotes oxygen or a bond,

where the active ingredients (a) and (b) are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmacist who Cesky acceptable carrier; for simultaneous, separate or sequential use.

2. The combination according to claim 1, including derivative epothilone formula I,

where a represents oxygen, R means (ness.)alkyl or hydrogen, and Z means oxygen or link.

3. The combination according to claim 1 or 2, where the antidiarrheal agent is an inhibitor of DPP-IV.

4. The combination according to claim 1 or 2, where the antidiarrheal agent is a natural drug, synthetic drug, bismuth subsalicylate, lanreotide, vapreotide, octreotide, an inhibitor of cyclooxygenase-2, an antagonist of motilin, kaolin, glutamine, thalidomide, pectin or berberine or its pharmaceutically acceptable salt.

5. The way to prevent or control diarrhea in a patient associated with the introduction of derived epothilone formula I

where a represents oxygen or NRNwhere RNmeans hydrogen or (ness.)alkyl,

R means hydrogen or (ness.)alkyl, and

Z denotes oxygen or a bond,

in free form or in the form of a pharmaceutically acceptable salt, which comprises introducing an effective amount of antidiarrheal agent to the patient receiving treatment derived epothilone.

6. The method according to claim 5, where the derivative epothilone is epothilone Century

7. Pharmaceutical composition having a therapeutic effect in respect of proliferative diseases containing from 10 to 100% combination according to any one of claims 1 to 3, and at least one pharmaceutically acceptable carrier.

8. Trade pack containing (a) antidiarrheal agent and (b) derived epothilone formula I

where a represents oxygen or NRNwhere RNmeans hydrogen or (ness.)alkyl,

R means hydrogen or (ness.)alkyl, and

Z denotes oxygen or a bond,

along with instructions for simultaneous, separate or sequential use in the treatment of proliferative diseases.

9. Combined drug, which is aimed at reducing the undesirable side effect in the form of diarrhea when it is used in the treatment of proliferative diseases, containing (a) antidiarrheal agent and (b) derived epothilone formula I

in which

connection And means oxygen or NRNwhere RNmeans hydrogen or (ness.)alkyl,

R means hydrogen or (ness.)alkyl, and

Z denotes oxygen or a bond,

in free form or in the form of pharmaceutically acceptable salts.



 

Same patents:

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to new nucleoside analogues characterised as inhibitors of purinephosphoribosiletransferase, purinenucleosidephosphorylase, 5 '-methylthioadenosinephosphorylase, 5 '-methylthioadenosinenucleosidase and/or nucleosidehydrolase and can be applied for treatment of malignant neoplasm, bacterial infections, protozoal infections, T- cell mediated diseases. In formula V is selected of CH2 and NH, and W is selected of NR1 and NR2; X is selected of CH2 and CHOH in R or S - configurations; Y is selected of hydrogen and hydroxy; Z is selected of hydrogen, halogen and hydroxy, SQ and Q where Q is optionally substituted with halogen C1-C6alkyl or benzyl group; R1 is radical of formula ; R2 is radical of formula ; A is selected of N, CH; B is selected of OH, NH2 and halogen; D is selected of NH2 and hydrogen; E means N; G is selected of CH2 or G is absent. Invention also refers to based pharmaceutical composition, methods of disease or condition treatment requiring inhibition of purinephosphoribosiletransferase, purinenucleosidephosphorylase, 5 '-methylthioadenosinephosphorylase, 5 '-methylthioadenosinenucleosidase and/or nucleosidehydrolase, and to application of invention compounds for medical product preparation.

EFFECT: products are characterised with increased efficiency.

30 cl, 6 tbl, 19 dwg, 51 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new pyrimidine of the general formula (I), which possess properties of the inhibitor of CDK-kinase. In the general formula (I) R1 designates hydrogen, halogen, C1-C6alkyl, R2 designates C1-C10alkyl, C1-C10alkenyl, or C3-C10cycloalkyl which can be mono-, bi- or tricyclic or denotes one- or polysubstituted by identical or different substitutes from the number of hydroxy-group, halogen, C1-C6alkoxygroup, C1-C6kalkylthiogroup, -NH-(CH2)n-C3-C10cycloalkyl, C3-C10 cycloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy-C1-C6alkyl, C1-C6alkoxy-C1-C6alkoxy-C1-C6alkyl, -NHC1-C6alkyl, -N(C1-C6alkyl)2, C1-C6alkanoil, -CONR3R4, -COR5, C1-C6alkylOAc, where Ac indicates C1-C4alkylCO-group, carboxygroups, phenyl, 5-6-member heteroaryl, containing 1-2-heteroatom in the ring, selected from nitrogen, -(CH2)n- phenyl, -(CH2)n-5-6-member heteroaryl containing 1-2-heteroatom in a ring, selected from nitrogen, phenyl-(CH2)n-R5, -(CH2)nPO3(R5)2 and -R6 and -NR3R4C1-C10alkyl, or C3-C10cycloalkyl, in this case phenyl, C3-C10 cycloalkyl, heteroaryl, -(CH2)n-phenyl and -(CH2)n heteroaryl can be one or polysubstituted by identical or different substitutes from halogens, hydroxygroup, C1-C6alkyl, C1-C6alkoxygroup, benzoxy-group and -CF3 groups, and ring of C3-C10 cycloalkyl and C1-C10alkyl can be separated by one or several nitrogen atoms, oxygen and/or sulfur and/or the said ring can be interrupted by one or two groups of =C=O or R2 designates the group X designates oxygen or group-NH-, and one of A and B independently indicates hydrogen, and the other indicates hydrogen, hydroxygroup, C1-C3alkyl, C1-C6alkyoxy,group SR7, SO2R7, CO(OH)R7, CR7(OH)R7, C1-C6alkyl-P(O)OR3OR4, COR7 or A and B together form C3-6-cycloalkyl ring which does not necessarily have to be interrupted by 1-3 atoms of nitrogen, oxygen and/or sulfur and/or can be interrupted by =C=O or =SO2 groups, and/or does not necessarily have to contain one or several double bonds, X designates oxygen or group-NH-, either one from A and B independently indicates hydrogen, and the other indicates hydrogen, hydroxygroup, C1-C3alkyl, C1-C6alkyoxy,group SR7, SO2R7, CO(OH)R7, CR7(OH)R7, C1-C6alkyl-P(O)OR3OR4, COR7 or A and B together form C3-6-cycloalkyl ring which does not necessarily have to be interrupted by 1-3 atoms of nitrogen, oxygen and/or sulfur and/or can be interrupted by =C=O or =SO2 groups, and/or does not necessarily have to contain one or several double bonds, values of R3 -R10 are specified in the formula of the invention.

EFFECT: connections can be used for the treatment of cancer, autoimmune diseases caused by chemotherapeutic means of alopecia and inflammations of mucous membrane, cardiovascular diseases, infectious diseases, chronic neurodegenerative and viral infections.

13 cl, 1 tbl, 540 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new pyridine and new pyrimidine derivative, their pharmaceutically accepted salt or hydrate of the general formula (I): . The invention also relates to the pharmaceutical composition, which possesses the inhibiting activity with respect to the receptor of the growth factor of hepatocytes; to the inhibitor of the receptor of the growth factor of hepatocytes, the inhibitor of angiogenesis, the antitumor drug, the inhibitor of cancerous metastatic spreading, that contains the pharmacologically effective dose of the said compounds, its pharmaceutically acceptable salt or hydrate.

EFFECT: inhibitory activity.

27 cl, 45 tbl, 540 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new pyridine and new pyrimidine derivative, their pharmaceutically accepted salt or hydrate of the general formula (I): . The invention also relates to the pharmaceutical composition, which possesses the inhibiting activity with respect to the receptor of the growth factor of hepatocytes; to the inhibitor of the receptor of the growth factor of hepatocytes, the inhibitor of angiogenesis, the antitumor drug, the inhibitor of cancerous metastatic spreading, that contains the pharmacologically effective dose of the said compounds, its pharmaceutically acceptable salt or hydrate.

EFFECT: inhibitory activity.

27 cl, 45 tbl, 540 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and concerns angiogenesis-preventing immunotherapy. Invention substance includes immunogenic compositions for treatment of disorders associated with angiogenesis intensification, containing oligonucleotides, coding polypeptides VEGFR2, introduced as a part of plasmid or viral vectors, as well as polypeptides VEGFR2, oligonucleotides, coding autologous VEGF with damaged function of receptor activation, polypeptides VEGF and their combinations. Immunogenic compositions can be used for treatment of malignant neoplasms and metastasises, at benign neoplasm and chronic inflammatory and autoimmune diseases. Advantage of invention lies in humoral and cellular immunity induction by means of specified compositions.

EFFECT: development of effective method angiogenesis preventive immunotherapy.

19 cl, 11 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: tricyclic bonds are substituted with heterocyclic ones, which have the formula (I), or its pharmaceutically acceptable salt or solvate in which: n denotes 0-2; Q denotes , R1 denotes H, R2 represents H or alkyl with 1-6 carbon atoms, R3 represents H, hydroxy-group, -NR22R23, Het denotes mono- or bycyclic heteroaryl group from 5 - 10 atoms, containing from 1 to 9 carbon atoms and 1 heteroatom N, where Het bonds with B through the cyclic carbon atom, and the group Het has a substitute W. W consists of from 1 to 4 substitutes, independently selected from the group containing H, halogen, R21-aryl and P21-heteroaryl, R4 and R5 are independently selected from the group containing H and alkyl with 1 - 6 carbon atoms, R7, R8, R10 and R11 denote R1, R9 represent H, B represents -(CH2)n3-. cis- or trans -(CH2)n4CR12=CR12a(CH2)n5 or -(CH2)n4C=C(CH2)n5, where n3 denotes 0-5, n4 and n5 independently denote 0-2, and R12 and R12a denote H, X represents -O-, Y represents =O, each R13 is independently selected from the group containing H, alkyl with 1-6 carbon atoms, -(CH2)n6NHC(O)OR16b, -(CH2)n6NHC(O)R16b, -(CH2)n6NHC(O)NR4R5, -(CH2)n6NHSO2R16, and -(CH2)n6C(O)NR28R29, where n6 denotes 0, each R14 is independently selected from the group containing H, alkyl with 1-6 carbon atoms, -(CH2)n6NHC(O)OR16b, -(CH2)n6NHC(O)R16b, -(CH2)n6NHC(O)NR4R5, -(CH2)n6NHSO2R16 and -(CH2)n6C(O)NR28R29, where n6 denotes 0, where, at least one of R13 and R14 is chosen from the group containing -(CH2)n6NHC(O)OR16b, -(CH2)n6NHC(O)R16b, -(CH2)n6NHC(O)NR4R5, -(CH2)n6NHSO2R16 and -(CH2)n6C(O)NR28R29, where n6 denotes 0, R16 represents an alkyl with 1-6 carbon atoms, R16b represents H, an alkyl with 1-6 carbonatoms, (an alkoxy with 1-6 carbon atoms)-(an alkyl with 1 - 6 carbon atoms)-, R22-O-C(O)-(an alkyl with 1 - 6 carbon atoms)-, a cycloalkyl with 3-6 carbon atoms, R21 represents from 1 to 3 substitutes, which are independently selected from a group comprising of H, -CN, -CF3, halogen, alkyl with 1 - 6 carbon atoms, -OH, alkoxy- group with 1 - 6 carbon atoms, -C(O)NR25R26 and -SR13, R22 represents H or an alkyl with 1-6 carbon atoms, R23 represents H, R25 and R26 are independently selected from a group comprising of H and an alkyl with 1 - 6 carbon atoms, and R28 and R29 are independently selected from a group comprising of H, an alkyl with 1 - 6 carbon atoms, heteroaryl, heterocyclil and also a pharmaceutical composition, containing these bonds.

EFFECT: application for getting medication for the treatment of diseases related to thrombosis, atherosclerosis, restenosis, hypertension, sternocardia, arrythmia, cardiac insufficiency and cancer, the way of administering is specified in the bonds Also therapy in combination with other cardiovascular agents is allowed.

23 cl, 7 tbl, 92 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to non-peptide antagonists GnRH, with general formula 1 , where each of A1, A2 and A3 are independently chosen from A5 and A6; and A4 represents either a covalent bond, or A5; under the condition that, if A4 is a covalent bond, then one of A1-A3 represent A6, and the other two represent A5, and that, if A4 represents A5, then all of A1-A3 represent A5; A5 is chosen from C-R13 and N; A6 is chosen from N-R14, S and O; R1 is chosen from H, NHY1 and COY2, and R2 represents H; or and R1, and R2 represents methyl or together represent =O; each of R3, R4 and R5 independently represents H or low alkyl; each of R6, R7, R8, R9, R10, R11 and R12 are independently chosen from H, NH2, F, CI, Br, O-alkyl and CH2NMe2; R13 is chosen from H, F, CI, Br, NO2, NH2, OH, Me, Et, OMe and NMe2; R14 is chosen from H, methyl and ethyl; W is chosen from CH and N; X is chosen from CH2, O and NH; Y1 is chosen from CO-low alkyl, CO(CH2)bY3, CO(CH2)bCOY3 and CO(CH2)bNHCOY3; Y2 is chosen from OR15, NRI6R17 and NH(CH2)cCOY3; Y3 is chosen from alkyl, OR15 and NR16R17; R15 represents H; each of R16 and R17 is independently chosen from H, low alkyl and (CH2)aR18, or together represent -(CH2)2-Z-(CH2)2-; R18 is chosen from OH, pyridyl, pyrizinyl and oxadiazolyl; Z represents NH; a represents 0-4; and b and c represent 1-3. The invention also relates to use of formula 1 a compound as a therapeutic agent and pharmaceutical composition, with antagonistic effect to GnRH receptor. Description is also given of the method of obtaining compounds with the given formula.

EFFECT: obtaining new compounds, with useful biological properties.

27 cl, 70 ex

FIELD: medicine.

SUBSTANCE: invention can be used for photodynamic therapy method (PDT) of oncology diseases. As nanocomposite photosensitiser, powder consisting of porous silicon particles, including silicon crystals of sizes 2 to 4 nm with fullerene molecules adsorbed on crystal surface (e.g., C60 or C70) is offered, at relative fullerene in nanocomposite 0.3% to 4% by mass. The powder can be used in PTD, as, e.g. aqueous or saline suspension.

EFFECT: photosensitiser is high-effective to generate singlet oxygen, stable to water solutions aggregation, nontoxic for organism.

5 cl, 1 dwg

FIELD: bioengineering.

SUBSTANCE: novel polynucleotide is invented which is produced from the nucleotide sequence of the IFNα-17 gene, containing the single nucleotide polymorphism SNP g771c. Also, the novel polynucleotide is invented which is derived from the natural protein IFNα-17 of the wild type containing SNP G45R.

EFFECT: can be used for producing effective therapeutic agent with antiviral, antiproliferative and/or immunomodulating activity.

13 cl, 5 dwg, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel compounds with the common formula III: where, if X is selected from the group containing NH and S, R1, R2, R3, R4, R5, R6, R7, R8 and R9, each independently is selected from the group containing H, OH, OR', substituted or unsubstituted aryl, where substitutes independently correspond to H, OH, C1-C12alkoxy; where, if X means O, R1, R2, R3, R4, R5, R6, R7 and R8, each independently, selected from the group containing H, OH, OR', SH, SR', SOR', SO2R', OSO2R', NHR', N(R') CO2R', OC(=O)R'; and R9 independently selected from the group containing H, OR', unsubstituted or substituted with aminogroup or halogen C2-C12 alkenyl, unsubstituted C2- C12 alkenyl, unsubstituted thienyl and halogen; where each of the R' groups are independently selected from the group containing H, substituted or unsubstituted C1-C18 alkyl, substituted or unsubstituted aryl; where substitutes are independently selected from the group containing halogen, OH, CN, C1-C12 alkoxy, phenyl; and the dotted line represents the simple or double bind; or its pharmaceutically compatible salt or complex ether. Other novel lamellarin analogs are described.

EFFECT: compounds have antitumor activity.

24 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to antagonists of adenosine A2B receptors and their using in treatment of mammals in different pathological states, such as digestive, immunological, neurological disorders and cardiovascular diseases caused both hyper-proliferation of cells and their apoptosis and similar disorders. Also, invention relates to methods for synthesis of these compounds and pharmaceutical composition containing thereof. The aim of the present invention is use of compounds of the general formulae (I) and (II) for preparing pharmaceutical composition possessing antagonistic activity with respect to adenosine A2B receptors wherein radical values are given in the invention description.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

41 cl, 12 sch, 35 ex

FIELD: medicine.

SUBSTANCE: means has 0.001-0.05 mg of Ramozetron Hydrochloride as daily dose or equivalent molar quantity of Ramozetron or its other pharmaceutically permissible salt as active ingredient.

EFFECT: enhanced effectiveness of treatment.

12 cl

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutical compositions with anti-diarrheic effect. Pharmaceutical composition comprises the therapeutically effective amount of loperamide hydrochloride as an active component and special additives. Lactose, starch, aerosil, talk and stearate are used as special additives. Pharmaceutical composition is prepared in the form of solid gelatinous capsules. Loperamide capsules satisfy all requirement of the State Pharmacopoeia of XI Edition. Invention provides bioavailability of the pharmaceutical composition of loperamide capsules at the level 98.5%.

EFFECT: improved and valuable pharmaceutical properties of composition.

3 cl, 1 tbl, 3 ex

FIELD: veterinary science.

SUBSTANCE: the suggested preparation for treating diarrhea in farm animals youngsters contains bismuth salt in the form of bismuth-potassium ammonium citrate and, additionally, polyethylenoxide, moreover, preferably, it contains 1.5-2.5%-polyethylenoxide solution and 1.5-2.5%-bismuth-potassium ammonium citrate solution. The method for treating diarrhea deals with introducing the above-mentioned preparation once or twice daily for 1-2 d at the dosage of 1-75 ml/kg body weight. In young foxes it should be introduced at the dosage of 60-75 ml/kg body weight, in calves - at the dosage of 1-3 ml/kg body weight, in lambs - at the dosage of 2-3 ml/kg body weight. Application of the present complex preparation and therapeutic method enables to shorten terms of therapy by 1.5-2 times, decreases expenses for therapy by 3-5 times and provides decreased toxicological impact the preparation upon animal body.

EFFECT: higher efficiency of therapy.

6 cl, 3 ex, 2 tbl

The invention relates to pharmaceutical

The invention relates to new guanidinium heterocyclic compounds of the formula (I), where R1denotes H, alkyl or is absent when R1missing link (a) is a double bond, D represents CR2, R2selected from H, alkyl, halogen, or, when is a CR3D can be N, denotes NR9, CR3=CR8, CR3, S, where R9denotes H, alkyl, alkenyl or quinil and where R3and R8selected from H, alkyl, alkenyl, quinil or cyano, R4, R5, R6each independently selected from H, alkyl, alkenyl, quinil, cyano, halogen or NH-C(= NR10)OTHER11(guanidine), R10and R11selected from H, methyl and ethyl, and where only one of R1, R5and R6is guanidines, R7selected from H, alkyl, alkenyl, quinil and halogen
The invention relates to medicine, specifically to medicines antidiarrheal action

The invention relates to the field of organic chemistry and medicine and relates to new quinoline derivatives of General formula I, where R represents unsubstituted C1-C3-alkyl or C2-C3alkenyl; R1is cyano, which are agonists alpha-2-adrenergic receptors and can be used when obtaining drugs suitable for the treatment of nasal congestion, glaucoma, diarrhea, asthma

The invention relates to medicine, specifically to experimental physiology, pharmacology and pathophysiology related to the possibility of modeling violations of motor-evacuation function of the intestines - constipation

FIELD: medicine.

SUBSTANCE: invention refers to methods and compositions for treatment and/or prevention maintenance of infectious condition in liquid-containing organ or organ with natural external aperture. Composition includes antibacterial agent, and also, probably, other active agents, amphipathic oil which is soluble in water and insoluble in ethanol, microcrystalline wax and pharmaceutically acceptable nonaqueous carrier. The method of treatment is realised by introduction of a pharmaceutical composition in body through natural external aperture.

EFFECT: regarding composition, invention provides stability of the active agent against oxidising decomposition, low interfacial tension of composition, easy solubility in liquids, and short time of excretion; invention provides effective treatment and reduction of by-effects and toxicity.

61 cl, 12 ex

FIELD: medicine.

SUBSTANCE: invention concerns method of pain relief by introduction of pharmaceutical composition containing effective amount of α-adrenergic antagonist and pharmaceutical composition, containing effective amount of the selective α-2A-antagonist.

EFFECT: method provides prolonged relief of chronic pain.

104 cl, 12 dwg, 4 tbl, 7 ex

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