RU2431484C2 - Diarylcarbamide for treating pulmonary hypertension - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to pharmaceutics and medicine, and concerns application of a compound of diarylcarbamide of formula

for treating, preventing and managing pulmonary hypertension.

EFFECT: development of the preparation for treating, preventing and managing pulmonary hypertension.

4 cl, 1 tbl, 1 ex

Description

The invention relates to pharmaceutical compositions for the treatment, prevention or management of pulmonary hypertension, comprising at least a diarylurea compound, optionally combined with at least one additional therapeutic agent. Suitable combinations include diarylureas, for example, BAY 43-9006.

BAY 43-9006 relates to 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) ureido] -3-fluorophenoxy} pyridine-2-carboxylic acid methylamide and is a type of diarylurea compounds that are potent anti-cancer and antiangiogenic agents, which are characterized by various types of activity, including inhibitory activity on signal molecules of VEGFR-, PDGFR-, raf-, p38- and / or flt-3 kinase. See, for example, WO 2004/113274 and WO 2005/000284.

The term "pulmonary hypertension" is used to refer to a disease characterized by a prolonged increase in pressure in the pulmonary artery (L. J. Rubin, The New England Journal of Medicine, 1997, 336 (2), 111). Modern treatment of pulmonary hypertension depends on the stage and mechanism of the disease. Typical treatments for pulmonary hypertension include anticoagulant therapy, oxygen support, traditional vasodilator therapy, transplantation, and surgical treatment. The therapeutic agents currently used to treat pulmonary hypertension include, for example, calcium channel blockers and pulmonary vasodilators (vasodilators).

The present invention provides pharmaceutical compositions for treating, preventing or controlling pulmonary hypertension, comprising a compound of formula I and, if necessary, at least one additional therapeutic agent.

The present invention can be applied, for example, by administering a diarylurea compound of formula I and, if necessary, an additional therapeutic agent, its pharmaceutically acceptable salts and derivatives, etc.

Compounds with a structure of formula I, their pharmaceutically acceptable salts, polymorphic modifications, solvates, hydrates, metabolites and prodrugs, including diastereoisomeric forms (both isolated stereoisomers and mixtures of stereoisomers), are collectively referred to herein by the term “compounds of formula I”.

Formula I has the following form:

Where

Q means —C (O) R _x ,

R _x is hydroxy, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or NR _a R _b,

R _a and R _b independently:

a) hydrogen;

b) C ₁ -C ₄ alkyl optionally substituted

- hydroxy,

- C ₁ -C ₄ alkoxy,

- a heteroaryl group selected from pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, imidazine, benzinazole azinazoleazole

- a heterocyclic group selected from tetrahydropyran, tetrahydrofuran, 1,3-dioxolane, 1,4-dioxane, morpholine, thiomorpholine, piperazine, piperidine, piperidinone, tetrahydropyrimidone, pentamethylene sulfide, dihydrofen, dihydrofen

amino, —NH ₂ optionally substituted with one or two C ₁ -C ₄ alkyl groups, or

- phenyl,

c) phenyl optionally substituted

- halogen or

amino, —NH ₂ optionally substituted with one or two C ₁ -C ₄ alkyl groups, or

d) a heteroaryl group selected from pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, imazinazinazoleazole ;

And means an optionally substituted phenyl group of the formula 1xx:

optionally substituted pyridinyl group of formula 1x:

or an optionally substituted naphthyl portion of formula 1y:

B means optionally substituted phenyl or naphthyl of formulas 2a and 2b:

и

and

L is a bridging group which means —S— or —O—,

p has a value of 0, 1, 2, 3 or 4,

n is 0, 1, 2, 3, 4, 5, or 6,

m is 0, 1, 2 or 3;

each R ² means independently: C ₁ -C ₅ alkyl, C ₁ -C ₅ haloalkyl, C ₁ -C ₃ alkoxy, N-oxo or N-hydroxy.

Structures of the optionally substituted phenyl moieties of formula I that are of particular interest include those of formula 1xx:

Structures of optionally substituted pyridinyl moieties of formula I that are of particular interest include those of formula 1x:

Structures of optionally substituted naphthyl moieties of formula I that are of particular interest include those of formula 1y:

Structure 1y shows that the substituents R ³ can be on any carbon atom in any ring that has a valency, which in other cases is filled with a hydrogen atom as a substituent. The bond with the urea group can also be through any carbon atom on any ring that has a valency, which in other cases is filled with a hydrogen atom as a substituent.

B is optionally substituted phenyl or naphthyl. Structures of optionally substituted phenyl or naphthyl moieties of formula I that are of particular interest include structures 2a and 2b:

и

and

Structures 2a and 2b show that the substituents R ¹ can be on any carbon atom in the structure, which has a valency, which in other cases is filled with a hydrogen atom as a substituent, and the bond with the urea group can also be through any carbon atom in the structure, which has a valency, which in other cases is filled with a hydrogen atom as a substituent.

In one group of embodiments of the present invention, B is substituted with at least one halogen substituent. In another group of embodiments, R _x is NR _a R _b , a R _a and R _{b are} independently hydrogen or C ₁ -C ₄ alkyl optionally substituted with hydroxy, and L is a bridging group that means —S— or —O—.

The variable p has a value of 0, 1, 2, 3 or 4, preferably 0 or 1. The variable n has a value of 0, 1, 2, 3, 4, 5 or 6, preferably 0, 1, 2, 3 or 4. The variable m has a value of 0, 1, 2 or 3, preferably 0.

Each R ¹ means independently: halogen C ₁ -C ₅ haloalkyl, NO ₂ , C (O) NR ⁴ R ⁵ , C ₁ -C ₆ alkyl, C ₁ -C ₆ dialkylamine, C ₁ -C ₃ alkylamine , CN, amino, hydroxy or C ₁ -C ₃ alkoxy. R ¹ means more preferably halogen, and of halogens, preferably chlorine or fluorine, and more preferably fluorine.

Each R ² means independently: C ₁ -C ₅ alkyl, C ₁ -C ₅ haloalkyl, C ₁ -C ₃ alkoxy, N-oxo or N-hydroxy. R ² preferably means methyl or trifluoromethyl.

Each R ³ means independently: halogen, R ⁴ , OR ⁴ , S (O) R ⁴ , C (O) R ⁴ , C (O) NR ⁴ R ⁵ , oxo, cyano or nitro (NO ₂ ).

R ⁴ and R ^{5 are} independently selected from hydrogen, C ₁ -C ₆ alkyl, and up to perhalogenated C ₁ -C ₆ alkyl.

Other examples of A include: 3-tert-butyl-phenyl, 5-tert-butyl-2-methoxyphenyl, 5-tert-butyl-2-methoxyphenyl, 5- (trifluoromethyl) -2-phenyl, 3- (trifluoromethyl) -4 -chlorophenyl, 3- (trifluoromethyl) -4-bromophenyl or 5- (trifluoromethyl) -4-chloro-2-methoxyphenyl.

Other examples of B include:

,

,

,

,

,

,

,

,

,

,

,

,

и

,

,

and

Preferably, the urea group —NH — C (O) —NH— and the bridging group, L, are not bonded to adjacent ring carbons of B, but preferably there are 1 or 2 ring carbons separating them.

Examples of R ¹ groups include fluoro, chloro, bromo, methyl, NO ₂ , C (O) NH ₂ , methoxy, SCH ₃ , trifluoromethyl and methanesulfonyl.

Examples of R ² groups include methyl, ethyl, propyl, oxygen and cyano.

Examples of the R ³ groups include trifluoromethyl, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, chlorine, fluorine, bromine, cyano, methoxy, acetyl, trifluoromethanesulfonyl, trifluoromethoxy and trifluoromethylthio.

The group of compounds of interest have the following formula II

where R _a and R _b independently mean hydrogen and C ₁ -C ₅ -alkyl.

In the formula II means

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

,

или

,

,

,

,

or

,

where the urea group, —NH — C (O) —NH—, and the oxygen bridging group are not bonded to adjacent ring carbons of B, but preferably there are 1 or 2 ring carbons separating them,

and A in formula II means

или

or

where the variable n has the value 0, 1, 2, 3, or 4.

R ³ means trifluoromethyl, methyl, ethyl, propyl, butyl, isopropyl, tert-butyl, chlorine, fluorine, bromine, cyano, methoxy, acetyl, trifluoromethanesulfonyl, trifluoromethoxy or trifluoromethylthio.

In a subgroup of such compounds, each R ³ substituent A in formula II is selected from chlorine, trifluoromethyl, tert-butyl or methoxy.

In other subgroups of such compounds, A in formula II means

and B in formula II means phenylene, fluoro substituted phenylene or difluoro substituted phenylene.

Another group of compounds of interest includes compounds having the structure of formula X below, wherein the phenyl ring “B” optionally has a halogen substituent.

For compounds of formula XR ² , m and A are as defined above for formula I. The variable “m” is preferably zero, leaving C (O) NHCH ₃ as the sole substituent on the pyridinyl moiety. A preferred value for A is substituted phenyl, which has at least one R ³ substituent. R ³ preferably means halogen, preferably chlorine or fluorine, trifluoromethyl and / or methoxy.

A subgroup of compounds of interest includes compounds having the structural formulas Z1 and Z2 below:

Preferably used as compounds of formula I in accordance with the invention is 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) -ureido] -3-fluorophenoxy} pyridine-2-carboxylic acid methylamide (BAY 43-9006) or a salt of p-toluenesulfonic acid methylamide 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) ureido] -3-fluorophenoxy} pyridine-2-carboxylic acid (tosylate salt of compound I)). More preferably, the salt of p-toluenesulfonic acid methylamide 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) ureido] -3-fluorophenoxy} pyridine-2-carboxylic acid exists at least 80% in stable polymorphic form I. More preferably, the salt of p-toluenesulfonic acid methylamide 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) -ureido] -3-fluorophenoxy} pyridine-2-carboxylic acid exists at least on 80% in stable polymorphic form and in micronized form.

Micronization can be achieved by standard grinding methods, preferably by air grinding, known to those skilled in the art. The micronized form may have an average particle size of from 0.5 to 10 microns, preferably from 1 to 6 microns, more preferably from 1 to 3 microns. The indicated particle size is the average particle size distribution measured by laser diffraction known to those skilled in the art (measuring device: HELOS, Sympatrc).

The process of preparing the salt of p-toluenesulfonic acid methylamide 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) -ureido] -3-fluorophenoxy} -pyridine-2-carboxylic acid and its stable polymorphic form I is described in patent applications EP 04023131.8 and EP 04023130.0.

When any part is “substituted”, it can have up to the highest number of the indicated substituents, and each substituent can be located at any suitable position of the part and can be attached via any suitable substituent atom. By "any suitable position" is meant any position of a part that is chemically accessible by means known in the art or studied in it, and which does not create an unstable molecule, for example, which is not acceptable for administration to humans. When two or more substituents are present in any part, each substituent is selected independently of any other substituents and may thus be the same or different.

The term “optionally substituted” is understood to mean that the part is modified to such an extent that it may or may not be substituted, or substituted with a specific substituent (s).

Obviously, the term “hydroxy” for a pyridine substituent includes 2-, 3-, and 4-hydroxypyridine, and also includes prior art structures such as 1-oxo-pyridine, 1-hydroxy-pyridine, or pyridine N-oxide.

Since many forms of these compounds, salts and the like have been used here, individual compounds, salts or the like are also taken into account.

The term C ₁ -C ₆ alkyl, unless otherwise indicated, is understood to mean linear, branched chains or cyclic alkyl groups having from one to six carbon atoms, which may be cyclic, linear or branched with a single or multiple branches. Such groups include, for example, methyl, ethyl, n-propyl, iso-propyl, p-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl and the like.

By the term C ₁ -C ₆ haloalkyl, unless otherwise indicated, is meant a saturated hydrocarbon radical having up to six carbon atoms which are substituted by at least one halogen atom, up to perhalogenated. A radical can be cyclic, linear or branched with a single or multiple branches. The halogen substituent (s) include chlorine, fluorine, bromine or iodine. Fluorine, chlorine and bromine are preferred, and fluorine and chlorine are most preferred. The halogen substituent (s) may be located at any available carbon atom. When more than one halogen substituent is present in this part, they may be the same or different. Examples of such halogenated alkyl substituents include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and 1,1,2,2-tetrafluoroethyl and the like.

The term C ₁ -C ₆ alkoxy, unless otherwise indicated, is understood to mean cyclic, linear or branched chains of alkoxy groups having from one to six saturated carbon atoms, which may be cyclic, linear or branched with a single or multiple branches, and include groups such as methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, pentoxy and the like. Halogenated groups such as 2,2-dichloroethoxy, trifluoromethoxy and the like are also included.

By halo or halogen is meant fluorine, chlorine, bromine or iodine. Fluorine, chlorine and bromine are preferred, and fluorine and chlorine are most preferred.

By C ₁ -C ₃ -alkylamine, unless otherwise indicated, is meant methylamino, ethylamino, propylamino or isopropylamino.

Examples of C ₁ -C ₆ dialkylamine include, but are not limited to, diethylamino, ethyl isopropylamino, methyl isobutylamino and dihexylamino.

The term heteroaryl refers to both monocyclic and bicyclic heteroaryl rings. By monocyclic heteroaryl is meant an aromatic monocyclic ring having from 5 to 6 ring atoms and 1-4 heteroatoms selected from N, O and S, the remaining atoms are carbon. When more than one heteroatom is present in this part, they are selected independently of each other, so that they can be the same or different. Monocyclic heteroaryl rings include, but are not limited to, pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, isothiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine and triazine.

By bicyclic heteroaryl is meant fused bicyclic moieties where one of the rings is selected from monocyclic heteroaryl rings described above and the second ring is either benzene or another monocyclic heteroaryl ring described above. When both rings in the bicyclic moiety are heteroaryl rings, they may be the same or different, as long as they are chemically accessible by means known in the art. Bicyclic heteroaryl rings include 5–5, 5–6, or 6–6 fused bicyclic aromatic structures available through synthesis, including, for example, but not limited to, benzoxazole (fused phenyl and oxazole), quinoline (fused phenyl and pyridine), imidazopyrimidine ( fused imidazole and pyrimidine) and the like.

Where indicated, the bicyclic heteroaryl moieties may be partially saturated. When a partially saturated or monocyclic heteroaryl ring, as described above, is fully or partially saturated, the second ring, as described above, is either fully or partially saturated, or both rings are partially saturated.

The term "heterocyclic group", unless otherwise indicated, means monocyclic and bicyclic moieties containing at least one atom selected from oxygen, nitrogen and sulfur, which are saturated or partially saturated, and include, but are not limited to, tetrahydropyran, tetrahydrofuran, 1,3-dioxolane, 1,4-dioxane, morpholine, thiomorpholine, piperazine, piperidine, piperidinone, tetrahydropyrimidone, pentamethylene sulfide, tetramethylene sulfide, dihydropyran, dihydrofuran, dihydrothiophene and the like.

The term “C ₁ -C ₃ -alkyl-phenyl” includes, for example, 2-methylphenyl, isopropylphenyl, 3-phenylpropyl, or 2-phenyl-1-methylethyl. Examples include 2- [chlorophenyl] ethyl, 3,4-dimethylphenylmethyl and the like.

Unless otherwise specified or indicated, the term “aryl” includes 6-12 membered mono or bicyclic aromatic hydrocarbon groups (eg, phenyl, naphthalene, azulene, indene group) having 0, 1, 2, 3, 4, 5 or 6 substituents.

The compounds of formula (I) may contain one or more asymmetric centers, depending on the location and nature of the various desired substituents. Asymmetric carbon atoms can be in the (R) or (S) configuration, or in the (R, S) configuration. In some cases, asymmetry may also occur as a result of limited rotation around a particular bond, for example, a central bond connecting two substituted aromatic rings of these compounds. Substituents in the ring may also be present in cis or transform. It is understood that all of these configurations (including enantiomers and diastereomers) are included in the scope of the present invention. Preferred compounds are compounds of formula (I) with an absolute configuration that gives the highest desired biological activity. Individual isomers, pure or partially purified isomers or racemic mixtures of the compounds of the invention are also included in the scope of the present invention. The purification of these isomers and the separation of these mixtures of isomers can be performed using standard techniques known in the art.

Optical isomers can be obtained by resolving racemic mixtures in accordance with conventional techniques, for example, by forming diastereoisomeric salts using an optically active acid or base, or by forming covalent diastereoisomers. Examples of suitable acids are tartaric, diacetyl tartaric, ditoluoyl tartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual isomers based on their physical and chemical differences using methods known in the art, for example, by chromatography or fractional crystallization. Optically active bases or acids occur when they are released from the separated stereoisomeric salts. Various methods for resolving optical isomers include the use of chiral chromatography (eg, chiral HPLC columns), with or without commonly used derivatization, optimally selected to increase the separation of enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, for example, Chiracel OD and Chiracel OJ among many others selected in the usual way. Enzymatic separation methods, with or without derivatization, are also applicable. Optically active compounds of formula I can also be prepared using chiral synthesis methods using optically active starting materials.

The present invention also relates to practicable forms of the compounds as disclosed herein, such as pharmaceutically acceptable salts, metabolites, and prodrugs. The term “pharmaceutically acceptable salt” is used to mean a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. See, e.g., S. M. Berge, et al. "Pharmaceutical salts," J. Pharm. Sci. 1977, 66, 1-19. Pharmaceutically acceptable salts include salts obtained by reacting a basic compound acting as a base with an inorganic or organic acid to form a salt, for example, a salt of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid. Pharmaceutically acceptable salts also include salts in which the basic compound acts as an acid and is reacted with a suitable base to form, for example, sodium, potassium, calcium, magnesium, ammonium and choline salts. It will also be apparent to those skilled in the art that acid salts of the claimed compounds can be prepared by reacting these compounds with a suitable inorganic or organic acid using any of a number of known methods. Alternatively, alkali and alkaline earth metal salts are prepared by reacting the compounds of the present invention with a suitable base by various known methods.

Representative salts of the compounds of the present invention include conventional non-toxic salts and quaternary ammonium salts, which are obtained, for example, from inorganic or organic acids or bases using methods known in the art. For example, such acidic salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, butyrates, citrates, camphorites, camphorsulfonates, cinnamates, cyclopentane propionates, digluconates, dodecyl sulfates, heptane sulfonates, heptofluorosulfates, heptofluorides, fuma , hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, itaconates, lactates, maleates, mandelates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfate you, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, tartrate, thiocyanate, tosylate, trifluoromethanesulfonate, and undecanoate.

Basic salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. In addition, basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl and dibutyl sulfates; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aryl and arylalkyl halides, like benzyl and phenylethyl bromides, and other monosubstituted arylalkyl halides.

Solvates for the purposes of the invention are those forms of compounds in which the solvent (solvent) molecules form a complex in the solid state and include, but are not limited to, for example, ethanol and methanol. Hydrates are a special form of solvates in which the solvent molecules are water.

Some pharmacologically active agents can be further modified using labile functional groups, which are cleaved after administration in vivo to deliver the parent active agent and the pharmacologically inactive derivatizing group. These derivatives, which are commonly referred to by the term “prodrugs,” can be used, for example, to change the physicochemical properties of the active agent, target delivery of the active agent to a specific tissue, change the pharmacokinetic and pharmacodynamic properties of the active agent, and reduce undesirable side effects. Prodrugs of the present invention include, for example, esters of the corresponding compounds of the present invention, which are well tolerated pharmaceutically acceptable esters, such as alkyl esters, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl esters. Additional esters such as phenyl-C ₁ -C ₅ -alkyl may be used, however methyl ether is preferred.

Methods that can be used to synthesize other prodrugs are described in the following reviews on this topic, which are incorporated herein by reference to descriptions of these synthesis methods:

- Higuchi, T .; Stella, V. eds. Prodrugs As Novel Drug Delivery Systems. ACS Symposium Series. American Chemical Society: Washington, DC (1975).

- Roche, E.B. Design of Biopharmaceutical Properties through Prodrugs and Analogs. American Pharmaceutical Association: Washington, DC (1977).

- Sinkula, A.A .; Yalkowsky, S.H. J Pharm Set. 1975, 64, 181-210.

- Stella, V.J .; Charman, W.N. Naringrekar, V.R. Drugs 1985, 29, 455-473.

- Bundgaard, H., ed. Design of Prodrugs. Elsevier: New York (1985).

- Stella, V.J .; Himmelstein, K.J. J.Med. Chem. 1980, 23, 1275-1282.

- Han, H-K; Amidon, G.L. AAPS Pharmsci 2000, 2, 1-11.

- Denny, W.A. Eur. J. Med. Chem. 2001, 36, 577-595.

- Wermuth, C.G. in Wermuth, C.G. ed. The Practice of Medicinal Chemistry Academic Press: San Diego (1996), 697-715.

- Balant, L.P .; Doelker, E. in Wolff, M.E. ed. Burgers Medicinal Chemistry And Drug Discovery John Wiley & Sons: New York (1997), 949-982.

The metabolites of the compounds of this invention include oxidized derivatives of the compounds of formula I, II, X, Z1 and Z2 in which one or more nitrogen atoms are substituted by a hydroxy group and which include derivatives in which the nitrogen atom of the pyridine group is in the form of oxide, which is indicated by technology with the term "1-oxo-pyridine", or has a hydroxyl substituent, which is indicated in the prior art by the term "1-hydroxy-pyridine".

General cooking methods

The specific processes that are used to obtain the compounds used in the implementation of the invention depend on the target individual compounds. Factors such as the choice of certain substituents play a role in the method to be followed when preparing the individual compounds of the invention. These factors can easily be determined by one of ordinary skill in the art.

Compounds of the invention can be prepared using known chemical reactions and techniques as described in the following published international applications WO 00/42012, WO 03/047579, WO 2005/009961, WO 2004/078747 and WO 05/000284 and European applications EP 04023131.8 and EP 04023130.0.

The compounds of the invention can be prepared by conventional chemical procedures and / or, as described below, from starting materials that are either commercially available or can be prepared by standard, conventional chemical procedures. The main methods for preparing the compounds are given below.

Urea preparations of formula I can be prepared by condensation of two arylamine moieties and in the presence of phosgene, diphosgene, triphosgene, carbonyldiimidazole or equivalents in a solvent that does not react with any of the starting materials, as described in one or more of these publications. Alternatively, compounds of formula I can be synthesized by reacting amines with isocyanates, as described in one or more of the published international applications mentioned above.

Isocyanates are commercially available or can be synthesized from heterocyclic amines by methods well known to those skilled in the art (e.g., treating an amine with phosgene or a phosgene equivalent such as trichloromethyl chloroformate (diphosgene), bis (trichloromethyl) carbonate (triphosgene) or N, N'- carbonyldiimidazole; or alternatively, the Curtius rearrangement of amides or carboxylic acid derivatives such as ester, acid halide or anhydride).

Arylamines are commercially available or can be synthesized by methods well known to those skilled in the art. Arylamines are usually synthesized by reduction of nitroaryls using metal catalysts such as Ni, Pd or Pt about H ₂ or a hydride transfer agent such as format, cyclohexadiene or borohydride (Rylander. Hydrogenation Methods; Academic Press: London, UK (1985)). Nitroaryl can also be directly reduced using a concentrated hydride source such as LiAlH ₄ (Seyden-Penne. Reductions by the Alumino- and borohydrides in Organic Synthesis; VCH Publishers: New York (1991)), or using a zero valence metal such like Fe, Sn, or Ca, usually in an acidic environment, there are many methods for the synthesis of nitroaryls (March. Advanced Organic Chemistry, 3rd Ed .; John Wiley: New York (1985). Larock. Comprehensive Organic Transformations; VCH Publishers: New York (1989) ) Nitroaryls are usually formed by electrophilic nitration of aromatic compounds using HNO ₃ or, alternatively, a source of NO ⁺ ₂ .

Pyridin-1-oxides of the formula I, wherein the pyridine ring carries a hydroxy substituent at the nitrogen atom, and A, B, L are generally defined above, can be obtained from the corresponding pyridines under oxidizing conditions known in the art. Some examples are as follows:

- peroxides, such as meta-chloroperbenzoic acid in chlorinated solvents, such as dichloromethane, dichloroethane or chloroform (Markgraf et al., Tetrahedron 1991.47, 183);

- (Me ₃ SiO) ₂ in the presence of a catalytic amount of rhenium acid in chlorinated solvents such as dichloromethane (Coperet et al., Terahedron Lett. 1998, 39, 761);

- perfluoro-cis-2-butyl-3-propylocaziridine in some combinations of halogenated solvents (Amone et al., Tetrahedron 1998, 54, 7831);

- a complex of hypofluoric acid - acetonitrile in chloroform (Dayan et al., Synthesis 1999, 1427);

- the ocean in the presence of a base, such as KOH, in water (Robker et al., J. Chem. Res., Synop. 1993, 10, 412);

- magnesium monoperoxyphthalate in the presence of glacial acetic acid (Klemm et al., J. Heterocylic Chem. 1990, 6, 1537);

- hydrogen pyroxide in the presence of water and acetic acid (Lin A.J., Org. Prep. Proced. Int. 1991, 23 (1), 114);

dimethyldiethylene oxide in acetone (Boyd et al., J. Chem. Soc., Perkin Trans. 1991, 9, 2189).

In addition, special methods for the preparation of diarylureas and intermediates are previously described elsewhere in the patent literature and can be adapted for the compounds of the present invention. For example, Miller S. et al., "Inhibition of p38 Kinase using Symmetrical and Unsymmetrical Diphenyl Ureas" PCT Application WO 9932463, Miller, S et al. "Inhibition of raf Kinase using Symmetrical and Unsymmetrical Substituted Diphenyl Ureas" PCT application WO 9932436, Dumas, J. et al., "Inhibition of p38 Kinase Activity using Substituted Heterocyclic Ureas" PCT application WO 99 32111, Dumas, J. et al., "Method for the Treatment of Neoplasm by Inhibition of raf Kinase using N-Heteroaryl-N '- (hetero) arylureas" PCT Application WO 99 32106, Dumas, J. et al., "Inhibition of p38 Kinase Activity using Aryl- and Heteroaryl-Substituted Heterocyclic Ureas "PCT Application WO 99 32110, Dumas, J., et al.," Inhibition of raf Kinase using Aryl- and Heteroaryl-Substituted Heterocyclic Ureas "PCT Application WO 99 32455, Riedl, B ., et al., "O-Carboxy Aryl Substituted Diphenyl Ureas as p38 Kinase Inhibitors" PCT Application WO 0042012, Riedl, B., et al., "O-Carboxy Aryl Substituted Diphenyl Ureas as p38 Kinase Inhibitors" PCT Application WO 0041698, Dumas, J. et al. "Heteroaryl ureas containing nitrogen hetero-atoms as p38 kinase inhibitors" US application. publ. US2002000065296, Dumas, J. et al. "Preparation of N-aryl-N '- [(acylphenoxy) phenyl] ureas as raf kinase inhibitors" PCT Application WO 0262763, Dumas, J. et al. "Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas" PCT application WO 02 85857, Dumas, J. et al. "Preparation of quinolyl, isoquinolyl or pyridyl-ureas as inhibitors of raf kinase for the treatment of tumors and / or cancerous cell growth," US Application. publ. US20020165394. All of the above patent applications are incorporated herein by reference.

Synthetic transformations that can be used in the synthesis of compounds of formula I and in the synthesis of intermediates involved in the synthesis of compounds of formula I are known or available to those skilled in the art. A set of synthetic transformations can be found in collections, such as:

- J. March. Advanced Organic Chemistry, 4th ed .; John Wiley: New York (1992);

- R.C. Larock. Comprehensive Organic Transformations, 2nd ed .; Wiley-VCH: New York (1999);

- F.A. Carey RJ. Sundberg. Advanced Organic Chemistry, 2nd ed .; Plenum Press: New York (1984);

- T.W. Greene; P.G.M. Wuts. Protective Groups in Organic Synthesis, 3rd ed .; John Wiley: New York (1999);

- L.S. Hegedus. Transition Metals in the Synthesis of Complex Organic Molecules, 2nd ed .; University Science Books: Mill Valley, CA (1994);

- L.A. Paquette, Ed. The Encyclopedia of Reagents for Organic Synthesis; John Wiley: New York (1994);

- A.R. Katritzky; O. Meth-Cohn; CW. Rees, eds. Comprehensive Organic Functional Group Transformations; Pergamon Press: Oxford, UK (1995);

- G. Wilkinson; F. G. A. Stone; E.W. Abel, Eds. Comprehensive Organometallic Chemistry; Pergamon Press: Oxford, UK (1982);

- B.M.Trost; I. Fleming. Comprehensive Organic Synthesis; Pergamon Press: Oxford, UK (1991);

- A.R. Katritzky; CW. Rees eds. Comprehensive Heterocylic Chemistry; Pergamon Press: Oxford, UK (1984);

- A.R. Katritzky; CW. Rees E.F.V. Scriven, eds. Comprehensive Heterocylic Chemistry II; Pergamon Press: Oxford, UK (1996); and

- C. Hansen; P.G. Sammes; J.B. Taylor, Eds. Comprehensive Medicinal Chemistry: Pergamon Press: Oxford, UK (1990).

In addition, periodicals on synthesis methodologies and related topics include Organic Reactions; John Wiley: New York; Organic Syntheses; John Wiley: New York; Reagents for Organic Synthesis: John Wiley: New York; The Total Synthesis of Natural Products; John Wiley: New York; The Organic Chemistry of Drug Synthesis; John Wiley: New York; Annual Reports in Organic Synthesis; Academic Press: San Diego CA; and Methoden der Organischen Chemie (Houben-Weyl); Thieme: Stuttgart, Germany. Moreover, synthetic transformation databases include Chemical Abstracts, which can be searched using either CAS OnLine or SciFinder, Handbuch der Organischen Chemie (Beilstein), which can be searched using SpotFire and REACCS.

Additional therapeutic agents

The compounds of formula I in accordance with the present invention can be combined with additional therapeutic agents currently used to treat, prevent or control pulmonary hypertension, such as, but not limited to, anticoagulants, diuretics (diuretics), cardiac glycosides, calcium blockers channels (calcium antagonists), vasodilators, prostacyclin analogues, endothelin antagonists, phosphodiesterase inhibitors, endopeptidase inhibitors, lipid-lowering agents, thromboxane inhibitors and other therapeutic agents known to reduce pulmonary arterial pressure.

Examples of anticoagulants include, but are not limited to, for example, warfarin, useful for treating patients with pulmonary hypertension who have an increased risk of thrombosis and thromboembolism.

Examples of calcium channel blockers (calcium antagonists) include, but are not limited to, diltiazem, felodipine, amlodipine, and nifedipine, which are especially useful for vasoreactive patients in catheterization of the right heart.

Examples of vasodilators include, but are not limited to, for example, prostacyclin, epoprostenol, treprostinil, and nitric oxide (NO).

Examples of phosphodiesterase inhibitors include, but are not limited to, in particular phosphodiesterase V inhibitors such as, for example, tadalafil, sildenafil and vardenafil.

Examples of endothelin antagonists include, but are not limited to, for example, bosentan and sitaxentan, preferably bosentan.

Examples of prostacyclin analogs include, without limitation of generality, for example, ilomedin, treprostinil and epoprostenol.

Examples of hypolipidemic agents include, but are not limited to, for example, HMG CoA reductase inhibitors such as simvastatin, pravastatin, atorvastatin, lovastatin, itavastatin, fluvastatin, pitavastatin, rosuvastatin, ZD-4522 and cerivastatin.

Examples of diuretics (diuretics) include, but are not limited to, for example, chlortalidone, indapamide, bendroflumethiazide, metolazone, cyclopentiazide, polythiazide, mefruzide, ximapide, chlorothiazide and hydrochlorothiazide, especially useful for controlling peripheral edema.

Examples of other therapeutic agents known to reduce pulmonary blood pressure include, but are not limited to, for example, ACE inhibitors such as enalapril, ramipril, captopril, cilazapril, trandolapril, fosinopril, quinapril, moexipril, lisinopril and perindopril, or AT II inhibitors. such as losartan, candesartan, irbesartan, embusartan, valzartan and telmisartan, or iloprost, betaprost, L-arginine, omapatrilate, oxygen, especially useful in patients with hypoxemia alone or exercise-induced hypoxemia, or digoxy n, especially useful for improving the function of the right ventricle in patients with right ventricular failure.

In addition, the compounds and combinations of the present invention can be combined with kinase inhibitors and / or elastase inhibitors.

Examples of kinase inhibitors include, but are not limited to, generalities, for example, BMS-354825, canertinib, erlotinib, gefitinib, imatinib, lapatinib, forest tortinib, lonafarnib, pegaptinib, pelitinib, semaxanib, tandutinib, tipipharnibylbimbilibid, b and glivek. Gleevec is preferred.

Directions

The compounds and combinations of the present invention can be used to manufacture a medicament for the treatment, prevention and management of pulmonary hypertension. The present invention also provides methods of treating, preventing and managing pulmonary hypertension, comprising administering effective doses of at least one compound of formula I and, if necessary, at least one additional therapeutic agent according to the invention. By “effective dose” is meant an amount of a compound that is suitable to achieve the desired result, for example, for treating, preventing, or controlling a disease or condition.

The term "pulmonary hypertension" according to this invention includes, but is not limited to, primary pulmonary hypertension, secondary pulmonary hypertension, hereditary pulmonary hypertension, precapillary pulmonary hypertension, pulmonary arterial hypertension, idiopathic pulmonary hypertension, thrombotic pulmonary hypertension and pulmonary hypertension associated with or associated with left ventricular dysfunction, mitral valve disease, persistent (constrictive) pericarditis, aortic stenosis, cardiomyopathy, mediastinal fibrosis, pulmonary vein abnormal drainage, pulmonary vein occlusion disease, collagen vascular disease, congenital heart disease, pulmonary venous hypertension, chronic obstructive pulmonary disease, interstitial pulmonary disease, interstitial lung disease, inter , alveolar hyperventilation, prolonged exposure at high altitudes, lung disease in newborns, alveolar capillary dysplasia, sickle -kletochnoy disease (anemia Herrick), other bleeding disorders, chronic thromboembolism, connective tissue disease, lupus, schistosomiasis, sarcoidosis or pulmonary capillary haemangiomatosis.

Any form of pulmonary hypertension can be treated in accordance with the present invention, including, but not limited to, mild hypertension, for example, associated with increases in average blood pressure of about 20-30 mm Hg. at rest, moderate hypertension, for example, associated with increases in average blood pressure of about 30-39 mm Hg at rest, and severe hypertension, for example, associated with increases in average blood pressure of 40 mm Hg and above at rest.

Pulmonary hypertension includes pulmonary arterial hypertension (RAS) and includes primary pulmonary hypertension (PPH), idiopathic RAS (IPAH), hereditary RAS (FPAH). For pulmonary hypertension, several classification systems have been published, including the Nomenclature and Classification of Pulmonary Hypertension (PH) Evian (1998) and the Revised Nomenclature and Classification of PH (2003). See Lewis et al., Chest, 2004, 126, 73-10, which is incorporated herein by reference in its entirety. Any pH disease listed in these classification schemes can be treated, managed or prevented in accordance with the present invention. Risk factors and diagnostic criteria for pH are described in McGoon et al., Chest, 126, 14-34, 2004, which is incorporated herein by reference in its entirety.

The following list is the 2003 classification proposed at the Third International Conference on Pulmonary Hypertension: RAS, IPAH, FPAH, collagen vascular disease, congenital systemic pulmonary shunts (large vessels, small vessels, operated or not operated), portal hypertension, drug and toxic hypertension, other (glycogenosis, Gaucher disease, hereditary hemorrhagic telangiectasia (Randu-Weber-Osler disease), hemoglobinopathy, myeloproliferative disease, splenectomy) significant involvement of veins and capillaries, pulmonary venous hypertension, pulmonary capillary hemangiomatosis, left-sided atrioventricular heart block, left-sided valvular heart disease, pulmonary hypertension associated with hypoxemia, chronic obstructive pulmonary disease (COPD), interstitial pulmonary disease, sleep disturbance, disturbance alveolar hypoventilation, prolonged exposure to high altitudes, pH due to chronic thrombotic and / or embolic disease, thromboembolic obstruction functions of proximal pulmonary arteries, thromboembolic obstruction of distal pulmonary arteries, pulmonary embolism (tumor, parasites, foreign material), sarcoidosis, histiocytosis X, lymphangiomatosis, pulmonary vascular compression (adenopathy, tumor, fibrosing mediastinitis).

Each of the aforementioned diseases may be associated with an increased risk of pulmonary hypertension, including those with, for example, congenital heart disease (for example, Eisenmenger syndrome); disease of the left heart; pulmonary vein disease (e.g., fibrotic narrowing of the tissue or occlusion of pulmonary veins and venules); pulmonary artery disease; diseases causing alveolar hypoxia; fibrotic lung diseases; Williams syndrome; persons with intravenous injuries associated with drug use; pulmonary vasculitis (such as Wegener, Goodpaschur and Hurg-Strauss syndromes); emphysema; chronic bronchitis; kyphoscoliosis; cystic fibrosis; Pickwick syndrome and sleep apnea syndrome; pulmonary fibrosis; sarcoidosis; silicatosis; CREST (Calcinosis Raynaud Esophagus Sclerosis Teleangiectasiae - fibrosclerotic skin changes, stroma of the internal organs and symptoms of obliterating endarteritis in the form of common Raynaud's syndrome) (skin calcification, Raynaud's syndrome; impaired motility of the esophagus; acrosclerosis and telangiectasia) and other diseases. For example, a person with a BMPR2 mutation (a bone morphogenetic protein receptor II) has a 10-20% risk of acquiring FPAH over a lifetime. Persons with hemorrhagic inherited telangiectasia have also been identified as at risk of IPAH, especially those carrying mutations in ALK1. See McGoon et al., Chest, 2004, 126, 14-34.

According to the invention, the term “treatment” refers to the administration of the pharmaceutical composition after the establishment of symptoms of pulmonary hypertension, while “prevention” refers to the administration to the establishment of symptoms, in particular to patients at risk of pulmonary hypertension. The term "management" covers the prevention of relapse of pulmonary hypertension in a patient suffering from pulmonary hypertension.

Introduction

Compounds or combinations of drugs of the present invention can be administered in any form by any effective route, including, for example, oral, parenteral, enteric, intravenous, intraperitoneal (intraperitoneal), topical, transdermal (for example, using any standard patch), ophthalmic, nasal, local, non-oral, such as aerosol, inhalation, subcutaneous (subcutaneous), intramuscular, buccal, sublingual, rectal, vaginal, intraarterial and intrathecal and etc. They can be administered alone or in combination with any component, active or inactive.

Oral administration is preferred.

The compounds or combinations of drugs of the present invention can be converted in a known manner into conventional dosage forms, which can be liquid or solid, for example, but not limited to, conventional enteric-coated tablets and tablets, capsules, pills, powders, granules, elixirs , tinctures, solutions, suspensions, syrups, solid or liquid aerosols and emulsions.

Examples of solid dosage forms for oral administration are described in provisional application US No. 60/605,752 and 60/658,827.

The combinations of the present invention may be administered at any time and in any effective form. For example, the compounds can be administered simultaneously, for example, as a single composition or dosage unit (for example, a pill or liquid containing both compositions), or they can be administered as separate compositions, but at the same time (for example, when one of the drugs is administered intravenously, and the other is administered orally or intramuscularly). Medications can also be administered sequentially at different points in time. The agents can be conventionally converted to preparatives to achieve the desired release rates over long periods of time, for example, 12-hour, 24-hour. This can be achieved by using substances and / or their derivatives that have a suitable metabolic half-life and / or by using controlled release dosage forms.

Combinations of drugs can be synergistic, for example, when the combined effect of drugs is such that the combined effect is greater than the algebraic sum of their individual effects. Accordingly, reduced doses of drugs can be administered, for example, with a reduction in toxicity or other harmful or undesirable effects, and / or the same doses can be used that are used for separate administration of substances, but with greater efficiency.

The compounds or combinations of the drug substances of the present invention can also be combined with any other suitable additive or pharmaceutically acceptable carrier. Such additives include any of the substances already mentioned, as well as any of the commonly used substances, such as those described in Reminfiton: The Science and Practice of Pharmacy (Gennaro and Gennaro, eds., 20th edition, Lippincott Williams & Wilkins, 2000); Theory and Practice of Industrial Pharmacy (Lachman et al., Eds., 3rd edition, Lippincott Williams & Wilkins, 1986); Encyclopedia of Pharmaceutical Technology (Swarbrick and Boylan, eds., 2nd edition, Marcel Dekker, 2002). They may be referred to herein by the term “pharmaceutically acceptable carriers” to indicate that they are combined with an active drug and can be safely administered to a person for therapeutic purposes.

In addition, the compounds or combinations of drugs of the present invention can be administered with other active substances or used in conjunction with other methods of treatment (therapies) that are used to treat any of the above diseases and / or conditions.

Other therapies according to the invention include, but are not limited to, for example, physical or mechanical therapy, such as electrical stimulation, acupuncture, magnetotherapy or topical application of polyurethane films.

The present invention also provides combinations of at least one compound of formula I and at least one other therapeutic agent mentioned above, suitable for treating a disease or condition. "Combinations" for the purposes of the invention include:

- individual compositions or dosage forms that contain at least one compound of formula I and at least one other therapeutic agent mentioned above;

- combined packages containing at least one compound of formula I and at least one other therapeutic agent mentioned above, to be administered simultaneously or sequentially;

- kits that contain at least one compound of the formula I and at least one other therapeutic agent mentioned above, packaged separately from each other as dosage units or as independent dosage units, with and without indications that they to be administered simultaneously or sequentially; and

- separate independent dosage forms of at least one compound of formula I and at least one other therapeutic agent mentioned above, which act together to achieve a therapeutic effect, for example, treating the same disease when administered simultaneously or sequentially .

The dosage of each of the combination substances may be selected relative to another and / or depending on the type of disease and / or clinical presentation of the disease in order to provide the desired therapeutic activity. For example, the active substances in combination may be present and administered in a fixed combination. By “fixed combination” is meant pharmaceutical formulations in which the components are in a fixed ratio that provides the desired effectiveness. These values can be determined according to the standard methodology for an individual patient, when various parameters are used to select the appropriate dosage (for example, type of disease, patient age, clinical picture of the disease, patient's health status, weight, etc.), or the values can be standard.

The amount of active ingredient administered can vary widely according to factors such as the type of compound and dosage unit used, method and time of administration, treatment period, age, gender and general condition of the patient being treated, etiology and degree of development of the condition being treated, metabolic rate and excretion of the drug, possible combinations of drugs and the interaction between drugs, etc.

It is preferable to use a compound of formula I in an amount of from 20 to 2000 mg, preferably from 40 to 800 mg, and more preferably from 50 to 600 mg.

Particular preference is given to the amount of 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) ureido] phenoxy} pyridine-2-carboxylic acid methylamide p-toluenesulfonic acid salt in the pharmaceutical composition from 27 to 2740 mg, preferably from 54 to 1096, more preferably 68 to 822 mg.

In another preferred embodiment, the compound of formula I is administered in combination with at least one additional therapeutic agent in an amount that can be determined by those skilled in the art according to their professional judgment.

The pharmaceutical composition according to the present invention is administered one or more, preferably up to three, and more preferably up to two times per day. Oral administration is preferred. With each introduction, the number of simultaneously taken tablets or capsules should not exceed two.

However, in some cases, deviation from the indicated amounts may be useful, depending on body weight, individual tolerance of the active component, type of preparation, and time or interval over which administration is carried out. For example, in some cases, quantities less than the aforementioned minimum may be sufficient, while in other cases, the indicated upper limit must be exceeded. In the case of the introduction of relatively large quantities, it may be appropriate to divide them into several separate doses throughout the day.

The combination may contain effective amounts of at least one compound of formula I and at least one other therapeutic agent mentioned above, which helps to achieve greater therapeutic efficacy compared to when one of the two compounds is used separately. The combination may be useful for the treatment, prevention, or management of pulmonary hypertension when the therapeutic effect is not observed with separate use of the substances or when an enhanced effect is observed when the combination is administered.

The relative content of each compound in combination can also be selected based on their respective mechanisms of action and disease biology. The relative content of each compound can vary widely and the present invention includes combinations for the treatment, prevention, or management of pulmonary hypertension, in which the amounts of the compounds of formula I and other therapeutic agents can be adjusted in the usual way, so that one of them is in large quantities.

The release of one or more combination substances may also be controlled, where appropriate, in order to provide the desired therapeutic activity in the case of a simple dosage form, combination package, kit or separate, independent dosage forms.

It is preferable to use a combination comprising a compound of formula I and at least one compound selected from the group consisting of phosphodiesterase V inhibitors, endothelin antagonists, prostacyclin analogs, kinase inhibitors and elastase inhibitors. It is more preferable to use a combination containing 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) -ureido] -3-fluorophenoxy} pyridine-2-carboxylic acid methylamide (BAY 43-9006) or a p-toluenesulfonic salt 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) -ureido] -3-fluorophenoxy} -pyridin-2-carboxylic acid methylamide acids and at least one compound selected from the group consisting of tadalafil, sildenafil , vardenafil, bosentan, sitaxentan, ilomedin, treprostinil and epoprostenol. Most preferred is the use of a combination containing 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) ureido] -3-fluorophenoxy} pyridine-2-carboxylic acid methylamide or methyl p-toluenesulfonic acid salt of 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) -ureido] -3-fluorophenoxy} pyridine-2-carboxylic acid and bosentan or vardenafil.

Examples:

The effects of the compounds and combinations of drugs according to this invention were tested in vitro on isolated rat pulmonary arteries and in vivo on rats with pulmonary hypertension exposed to monocrotaline.

Isolated Small Pulmonary Arteries

Male Wistar rats (250-300 g) were anesthetized with ether, and the lungs were removed. The left pulmonary arterial vessel was dissected and placed in ice-cold Krebs-Henseleit (KH) buffer of the following composition (in mmol / L): NaCl 112, KCl 5.9, CaCl ₂ 2.0, MgCl ₂ 1.2, NaH ₂ PO ₄ 1.2, NaHCO ₃ 25, glucose 11.5 and, if necessary, the compound / combination to be tested, in a concentration of from 10 ^-10 to 10 ^-4 mol / L.

To measure isometric stress, segments in the form of a ring of 2 mm in length were installed in a small-volume chamber of the myograph. Two wires (40 μm in diameter) were introduced through the lumen of the segments and fixed according to the method described by Mulvany and Halpern (Circulation Research 1977; 41: 19-26). After a 30-minute period of establishing equilibrium in an oxygen-saturated KN solution at 37 ° C and pH 7.4, the segments were reduced to a lumen diameter optimal for the development of active stress, which was determined based on the stress coefficient of the inner circumference of the segment wall by setting the length of their inner circumference at 90 % of the length that the vessels would have if they were exposed to a passive voltage equivalent to the voltage produced by transmural pressure of 30 mm Hg

Subsequently, the segments were washed three times with a solution of KN and left to achieve equilibrium for 30 minutes. Then, the contractility of the segment was tested by initial exposure to a solution with a high concentration of K ⁺ (120 mmol / L, K ⁺ -KH solution, which is identical to the KH solution except that NaCl was replaced by KCl on an equimolar basis).

The vessels were then subjected to preliminary contraction using a K ⁺ -KN solution (50 mmol / L). When the contraction stabilized, a dose-response curve was built up with accumulation for the test compound / combination. The stabilized contraction caused by the K ⁺ -KN solution (50 mmol / L) is defined as 100% voltage. Relaxation is expressed as percentage stress.

Pulmonary artery pressure in rats exposed to monocrotaline

Male Sprague Dawley rats (250-300 g) were subcutaneously exposed to monocrotalin at a dose of 60 mg / kg (day zero). On the 14th day after the injection of monocrotaline, the compound / combination to be tested was administered. On day 28, hemodynamic parameters were measured, that is, pressure in the right ventricle, blood system pressure, heart rate, saturation of arterial and venous blood with oxygen, and compared with parameters of unexposed control animals.

Results:

Rats exposed to monocrotalin (MCT) were randomized to receive 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) ureido] -3-fluorophenoxy} pyridine-2-carboxylic acid methylamide at a dose of 3 mg / kg or medication medium (placebo) through a tube once a day after moderate pulmonary arterial hypertension has been established, starting from 14 days after the injection of the MST and until the 28th day. In animals with MCT-induced pulmonary arterial hypertension, treatment with 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) ureido] -3-fluorophenoxy} pyridine-2-carboxylic acid methylamide significantly decreased systolic pressure of the right ventricle animals treated with the drug medium (control: 25 ± 0.56; p-toluenesulfonic acid methylamide salt of 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) -ureido] -3-fluorophenoxy} -pyridin-2- carboxylic acid: 36.50 ± 1.50 mmHg versus placebo: 71.02 ± 5.38 mmHg) (mean ± SEM (standard error of the mean)). This effect of 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) -ureido] -3-fluorophenoxy} -pyridin-2-carboxylic acid methylamide p-toluenesulfonic acid salt was simultaneously accompanied by complete inhibition of left ventricular hypertrophy (right volume ratio ventricle / left ventricle + interventricular septum control: 0.26 ± 0.01; p-toluenesulfonic acid methylamide salt 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) -ureido] -3-fluorophenoxy} -pyridine- 2-carboxylic acid: 0.26 ± 0.01 versus placebo: 0.54 ± 0.04.

Example 1: immediate release tablets and optionally a subsequent film coating (see table).

1.2. Mode of production

Step a) Granulation

Micronized 4 {4- [3- (4-chloro-3-trifluoromethylphenyl) -ureido] -3-fluorophenoxy} pyridine-2-carboxylic acid methylamide, microcrystalline cellulose, croscarmellose sodium and hypromellose are mixed for 2 minutes in a mixer with large shear to obtain a powder mixture. Lauryl sodium sulfate is dissolved in water. The powder mixture is granulated with the solution during wet granulation using a high shear mixer. The granulation process is completed when the granulate reaches a “snowball consistency”. The wet granulation mass is granulated using a 4 mm grater and then dried in a fluidized bed dryer at an inlet air temperature of 80-100 ° C. until a residual moisture content of 0.3 to 0.7 wt.% Is achieved (loss on drying). Dry granules are sieved using a 2 mm sieve.

Step b) compressing the tablets

The granulate is mixed with magnesium stearate and croscarmellose sodium using a drum mixer for 5 to 10 minutes. The mixture is divided into separate portions and compressed into tablets using a standard rotary tablet press at a typical tablet speed of 25,000 to 250,000 tablets / hour.

Step c) film coating

Alternative I:

Hypromellose, polyethylene glycol (Macrogol), titanium dioxide and iron oxide III red are combined with purified water to obtain a homogeneous coating suspension, which is sprayed onto the tablets in a perforating drum coating device.

Alternative II:

The commercially available Opadry Red YS2-15531 is combined with purified water to obtain a homogeneous coating suspension, which is sprayed onto the tablets in a perforating drum coater.

Claims (4)

1. The use of a compound of formula II or a pharmaceutically acceptable salt, solvate or hydrate thereof for the manufacture of a medicament for the treatment, prevention or management of pulmonary hypertension,
wherein said compound of formula II is

where R _a and R _b independently mean hydrogen and C ₁ -C ₄ -alkyl,
A means

and
B means phenylene, fluoro substituted phenylene or difluoro substituted phenylene. 2. The use according to claim 1, where
R _a means hydrogen,
R _b means methyl,
A means

and
B means phenylene or fluoro substituted phenylene. 3. The use according to claim 1, where the compound of formula II also has the structure of one of the following formulas Z1 or Z2 or its salt, solvate or hydrate:

or

4. The use according to claim 3, where the compound of formula II is a tosylate salt of the compounds of formula Z1.