HK1182697B

HK1182697B - Ring-fused 4 -aminopyrimidines and use thereof as stimulators of soluable guanylate cyclases

Info

Publication number: HK1182697B
Application number: HK13109942.5A
Authority: HK
Inventors: Markus Follmann; Johannes-Peter Stasch; Gorden Redlich; Jens Ackerstaff; Nils Griebenow; Andreas Knorr; Frank Wunder; Volkhart Min-Jian Li
Original assignee: Bayer Intellectual Property Gmbh
Priority date: 2010-07-09
Filing date: 2011-07-05
Publication date: 2017-08-11

Description

Fused-ring 4-aminopyrimidines and their use as stimulators of soluble guanylate cyclase

The present invention relates to novel fused-ring 4-aminopyrimidines, to a process for their preparation, to their use alone or in combination for the treatment and/or prophylaxis of diseases and to their use for the preparation of medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular disorders.

One of the most important cellular transport systems in mammalian cells is cyclic guanosine monophosphate (cGMP). It forms the NO/cGMP system together with Nitric Oxide (NO), which is released from the endothelium and transports hormones and mechanical signals. Guanylate cyclase catalyzes the biosynthesis of cGMP from Guanosine Triphosphate (GTP). The representatives of such families known to date can be divided into two groups, depending on the structural features or on the type of ligand: specific guanylate cyclases, which are stimulated by natriuretic peptides, and soluble guanylate cyclases, which are stimulated by NO. Soluble guanylate cyclase consists of two subunits and it is highly likely that each heterodimer contains one heme that is part of the regulatory site. This is crucial for the activation mechanism. NO can be attached to the iron atom of heme and thus significantly increase the activity of the enzyme. In contrast, heme-free formulations are not stimulated by NO. Carbon monoxide (CO) can also be attached to the central iron atom of heme, but is stimulated less by CO than by NO.

Throughout the formation of cGMP and the resulting regulation of phosphodiesterases, ion pathways and protein kinases, guanylate cyclase plays a key role in different physiological processes, more particularly in the relaxation and proliferation of smooth muscle cells, in platelet aggregation and platelet adhesion and in nerve signaling, and in disorders based on disruption of the above-mentioned processes. Under pathophysiological conditions, the NO/cGMP system can be inhibited, which can lead to, for example, hypertension, platelet activation, increased cell proliferation, endothelial function disorders, atherosclerosis, angina pectoris, heart failure, myocardial infarction, thrombosis, stroke and sexual function disorders.

Due to the desired high efficacy and low levels of side effects, a promising approach is the possible NO-independent treatment of the above mentioned disorders by targeting the influence of the cGMP signaling pathway in organisms.

To date, therapeutic stimulation of soluble guanylate cyclase has been achieved by the use of specialized compounds (e.g., organic nitrates), the role of which is based on NO. NO is formed by biotransformation and activates soluble guanylate cyclase by attacking the central iron atom of heme. One of the important drawbacks of this mode of treatment, in addition to side effects, is the development of tolerance.

Over the last years, there have been some descriptions of compounds that stimulate soluble guanylate cyclase directly, i.e. without prior release of NO, such as 3- (5 '-hydroxymethyl-2' -furyl) -1-benzylidazole [ YC-1; wu et al, Blood 84(1994), 4226; mulschet al., brit.j.pharmacol.120(1997), 681), fatty acids [ Goldberg et al, j.biol.chem.252(1977),1279], diphenyliodonium hexafluorophosphate [ Pettiboneet al, eur.j.pharmacol.116(1985),307], isoliquiritigenin [ Yu et al, brit.j.pharmacol.114(1995),1587] and various substituted pyrazole derivatives (WO 98/16223).

As stimulators for soluble guanylate cyclase, WO 00/06569 discloses fused pyrazole derivatives and WO 03/095451 discloses 3-pyrimidinyl pyrazolopyridines substituted with carbamates. WO 2010/065275 discloses substituted pyrrolopyrimidines and dihydropyridopyrimidines as sGC activators.

It is an object of the present invention to provide novel substances which act as very potent stimulators of soluble guanylate cyclase.

The present invention provides compounds of the general formula (I) and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides or salts thereof,

wherein

A is (C)₁-C₃) An alkanediyl group or a group of the formula,

wherein

Is a site of attachment to the pyrimidine ring,

# is the attachment site to the carbonyl group,

ring Q is a 4-to 6-membered heterocyclic ring,

and is

Wherein (C)₁-C₃) -alkanediyl may be substituted with 1 or 2 substituents independently selected from fluoro, trifluoromethyl, (C)₁-C₄) An alkyl group, a hydroxyl group and an amino group,

wherein (C)₁-C₄) The alkyl group may be substituted with 1 to 3 substituents independently selected from the group consisting of fluoro, trifluoromethyl and hydroxy,

R¹is hydrogen or fluorine, and can be used as the active ingredient,

R²is (C)₁-C₆) An alkyl group or a benzyl group, or a substituted or unsubstituted alkyl group,

wherein (C)₁-C₆) The alkyl group is substituted with one trifluoromethyl substituent,

wherein (C)₁-C₆) The alkyl group may be substituted with 1 to 3 fluoro substituents,

and is

Wherein the benzyl group is substituted with 1 to 3 fluoro substituents.

The compounds of the present invention are compounds of formula (I) and salts thereof, solvates thereof and solvates of salts thereof, compounds of formula (la) and salts thereof, solvates thereof and solvates of salts thereof, which are encompassed by formula (I) and are described in detail hereinafter, and compounds and salts thereof, solvates thereof and solvates of salts thereof, which are encompassed by formula (I) and are described in detail hereinafter as working examples, provided that the compounds encompassed by formula (I) and are described in detail hereinafter are not already salts, solvates and solvates of salts.

The compounds of the invention are also N-oxides of the compounds of formula (I) and salts thereof, solvates thereof and solvates of the salts thereof.

Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds of the invention. Also encompassed are salts which are not only suitable per se for pharmaceutical use but can also be used, for example, for the isolation or purification of the compounds of the invention.

Physiologically acceptable salts of the compounds of the invention include acid addition salts of inorganic acids, carboxylic acids and sulfonic acids, for example the hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, ethanesulfonate, toluenesulfonate, benzenesulfonate, naphthalenedisulfonate, acetate, trifluoroacetate, propionate, lactate, tartrate, malate, citrate, fumarate, maleate and benzoate salts.

Physiologically acceptable salts of the compounds of the invention also include salts of the customary bases, such as, for example and with preference, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts which are derived from ammonia or from organic amines having from 1 to 16 carbon atoms, such as, for example and with preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

In the context of the present invention it is,solvatesRefers to a form of the compound of the present invention which is a solid or liquid complex formed by complexing the compound of the present invention with a solvent molecule. Hydrates are a particular form of solvates in which water is complexed with it. The solvate in the context of the present invention is preferably a hydrate.

The compounds of the invention may, depending on their structure, exist in the form of different stereoisomers, i.e. in the form of configurational isomers or optionally as conformational isomers (enantiomers and/or diastereomers, including atropisomers). Accordingly, the present invention encompasses enantiomers and diastereomers, as well as mixtures of each thereof. The stereoisomeric homogeneous compositions may be separated from said mixtures of enantiomers and/or diastereomers in a known manner; preference is given to using chromatography for this purpose, in particular HPLC chromatography on achiral or chiral phases.

When the compounds of the present invention may exist in tautomeric forms, the present invention encompasses all tautomers.

The invention also encompasses all suitable isotopic variations of the compounds of the invention. Isotopic variations of the compounds of the present invention are understood herein to mean the following compounds: at least one atom within the compounds of the present invention is replaced with another atom having the same atomic number, but a different atomic mass than the atom normally or predominantly present in nature. Examples of isotopes that can be incorporated into the compounds of the invention are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, for example²H (deuterium),³H (tritium),¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³²P、³³P、³³S、³⁴S、³⁵S、³⁶S、¹⁸F、³⁶Cl、⁸²Br、¹²³I、¹²⁴I、¹²⁹I and¹³¹I. specific isotopic variations of the compounds of the present invention, for example, more particularly, those in which one or more radioactive isotopes are incorporated, can be advantageous in, for example, studying the mechanism of action or the distribution of the active ingredient within the body; due to the relative ease of preparation and detection, especially with³H or¹⁴C-isotopically labelled compounds are suitable for this purpose. Furthermore, the inclusion of isotopes (e.g., deuterium) may afford specific therapeutic advantages resulting from greater metabolic stability of the compounds, for example, increased half-life in the body or a reduction in the active dose required; thus, such modifications of the compounds of the invention may also constitute preferred embodiments of the invention in some cases. Isotopic variations of the compounds of the present invention can be obtained by subjecting a compound of the present invention to a process known to those skilled in the art, for example, by the process described below and the procedures described in the working examplesPrepared with the respective reagents and/or isotopic variations corresponding to the starting compounds.

The invention also encompasses prodrugs of the compounds of the invention. The term "prodrug" includes the following compounds: which may or may not be biologically active per se but which is converted to a compound of the invention when resident in the body (e.g. by metabolism or hydrolysis).

In the formulae of the groups which may represent A, the end points of the lines marked by the symbols X or #, do not represent a carbon atom or CH₂A group, but is part of the bond that each atom is attached to a.

In the context of the present invention, unless otherwise indicated, the substituents are defined as follows:

in the context of the present inventionAlkyl radicalIs a straight or branched alkyl group having 1 to 4 carbon atoms. Preferred examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl.

In the context of the present inventionAlkanediyl groupIs a linear divalent alkyl group having 1 to 3 carbon atoms. Examples include: methylene, ethyl-1, 2-diyl or propyl-1, 3-diyl.

In the context of the present inventionHeterocyclic ringsIs a saturated heterocyclic ring having a total of 4 to 6 ring atoms, which contains one or two ring heteroatoms selected from N, O and/or S and is attached via a ring carbon atom. Examples include: azetidinyl, oxetanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, and thiomorpholinyl. Preference is given to azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and tetrahydropyranyl.

If a group in a compound of the present invention is substituted, the group may be mono-or polysubstituted unless otherwise specified. In the context of the present invention, all groups occurring more than once are defined independently of one another. Preferably by one, two or three identical or different substituents.

Preference is given in the context of the present invention to compounds of the general formula (I-1) and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides or salts thereof,

wherein

A is (C)₁-C₃) An alkanediyl group or a group of the formula,

wherein

Is a site of attachment to the pyrimidine ring,

# is the attachment site to the carbonyl group,

ring Q is a 4-to 6-membered heterocyclic ring,

and is

Wherein (C)₁-C₃) -alkanediyl may be substituted with 1 or 2 substituents independently selected from fluoro, trifluoromethyl and (C)₁-C₄) An alkyl group, a carboxyl group,

R¹is hydrogen or fluorine.

Also preferred in the context of the present invention are compounds of the formula (I) below as well as salts thereof, solvates thereof, and solvates of salts thereof,

wherein

A is a group of the formula,

wherein

Is a site of attachment to the pyrimidine ring,

# is the attachment site to the carbonyl group,

ring Q is an azetidine ring, an oxetane ring, a pyrrolidine ring, a tetrahydrofuran ring, a piperidine ring or a tetrahydropyran ring

R¹Is hydrogen or fluorine.

R²Is 2,2, 2-trifluoroethyl, 3,3, 3-trifluoropropan-1-yl, 4,4, 4-trifluorobutan-1-yl, 3,3,4,4, 4-pentafluorobutan-1-yl or benzyl,

wherein the benzyl group is substituted with 1 to 3 fluoro substituents.

wherein

A is (C)₁-C₃) Alkanediyl group

Wherein (C)₁-C₃) Alkanediyl may be independently substituted by 1 or 2 substituents selected from fluorine, (C)₁-C₄) Alkyl, hydroxyl and amino substituents,

and is

Wherein (C)₁-C₃) Alkanediyl is substituted with 1 substituent selected from the group consisting of fluorine and trifluoromethyl,

R¹is hydrogen or fluorine, and can be used as the active ingredient,

wherein the benzyl group is substituted with 1 to 3 fluoro substituents.

Also preferred in the context of the present invention are compounds of the formula (I-1) below as well as salts thereof, solvates thereof, and solvates of the salts thereof,

wherein

A is a group of the formula,

wherein

Is a site of attachment to the pyrimidine ring,

# is the attachment site to the carbonyl group,

R¹Is hydrogen or fluorine.

wherein

A is (C)₁-C₃) Alkanediyl group

Wherein (C)₁-C₃) Alkanediyl may be independently substituted by 1 or 2 groups selected from fluoro and (C)₁-C₄) The radical substitution of an alkyl radical,

and is

R¹is hydrogen or fluorine.

Also preferred in the context of the present invention are compounds of the formula (I) below and salts thereof, solvates thereof, and solvates of the salts thereof, wherein

A is alkylene or ethan-1, 2-diyl,

wherein alkylene and eth-1, 2-diyl are substituted with 1 or 2 groups independently selected from fluoro and trifluoromethyl.

wherein

A is a group of the formula,

wherein

Is a site of attachment to the pyrimidine ring,

# is the attachment site to the carbonyl group,

ring Q is a 4-to 6-membered heterocyclic ring.

wherein

A is a group of the formula,

wherein

Is a site of attachment to the pyrimidine ring,

# is the attachment site to the carbonyl group.

Also preferred in the context of the present invention are compounds of formula (I) below, wherein R is R, and salts, solvates, and solvates of salts thereof¹Is fluorine.

Also preferred in the context of the present invention are compounds of formula (I) below, wherein R is R, and salts, solvates, and solvates of salts thereof²Is 3,3,4,4, 4-pentafluorobutan-1-yl.

In the context of the present inventionPreferred are compounds of formula (I) and salts, solvates, and solvates of salts thereof, wherein R is²Is benzyl, wherein the benzyl group is substituted with 1 to 3 fluoro substituents.

Particularly preferred in the context of the present invention are the compounds of formula (I) below:

4-amino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one,

4-amino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one,

4-amino-2- [ 5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one,

4' -amino-2 ' - [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -4, 5-dihydrospiro [ furan-3, 5' -pyrrolo [2,3-d ] pyrimidine ] -6' (7' H) -one,

4-amino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -5-methyl-5, 8-dihydropyrido [2,3-d ] pyrimidin-7 (6H) -one,

4-amino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -5- (trifluoromethyl) -5, 8-dihydropyrido [2,3-d ] pyrimidin-7 (6H) -one,

4-amino-5, 5-dimethyl-2- [1- (3,3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one,

4-amino-2- [ 5-fluoro-1- (3,3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one.

4-amino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -5- (trifluoromethyl) -5, 8-dihydropyrido [2,3-d ] pyrimidin-7 (6H) -one.

Individual radical definitions specified in various combinations or preferred combinations of radicals are also replaced-in a manner independent of the various combinations of specified radicals-by other bound radical definitions as required.

Combinations of two or more of the above-mentioned preferred ranges are particularly preferred.

The invention further provides a process for preparing the compounds of the formula (I) according to the invention, characterized in that

[A] A compound of formula (II)

Wherein R is¹And R²Each as defined above

Conversion to compounds of formula (III) under acidic conditions

Wherein R is¹And R²Each as defined above, is capable of,

a compound of formula (III) with a compound of formula (IV) in an inert solvent in the presence of a suitable base

Wherein A is as defined above and

T¹is (C)₁-C₄) An alkyl group, a carboxyl group,

reaction to give the compound of formula (I)

A, R therein¹And R²Each as defined above.

[B] A compound of formula (III) with a compound of formula (V) in an inert solvent in the presence of a suitable base

Wherein

A¹Is (C)₂-C₃) An alkanediyl group,

Wherein (C)₂-C₃) Alkanediyl may be substituted by 1 or 2 groups independently selected from fluoro, trifluoromethyl and (C)₁-C₄) The substituent of the alkyl group is substituted,

wherein (C)₁-C₄) The alkyl group may be substituted with 1 to 3 substituents independently selected from fluorine, trifluoromethyl and hydroxyl,

and is

T²Is (C)₁-C₄) An alkyl group, a carboxyl group,

reaction to give the compound of formula (I-A)

Wherein A is¹、R¹And R²Each as defined above.

The resulting compounds of formula (I) and (I-a) may optionally be converted to their solvates, salts and/or solvates of their salts with a suitable (I) solvent and/or (ii) acid or base.

The conversion of (II) → (III) is carried out in a two-stage process by methods known to the skilled person, first in methanol at 0 ℃ to +40 ℃ to form an imidate with sodium methoxide, followed by nucleophilic addition of the equivalent of ammonia, e.g. aqueous ammonia or ammonium chloride, in a suitable acid at +50 to +150 ℃ to form the amidine (III).

Suitable acids for forming amidines (III) are inorganic acids, such as hydrogen chloride/hydrochloric acid, sulfuric acid, polyphosphoric acid or phosphoric acid, or organic acids, such as acetic acid, trifluoroacetic acid or formic acid. Hydrochloric acid or acetic acid is preferably used.

Inert solvents used in step (III) + (IV) → (I) of the process are, for example, alcohols such as methanol, ethanol, N-propanol, isopropanol, N-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glyme or diglyme, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N' -Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or water. Mixtures of the solvents mentioned may also be used. Tert-butanol is preferred.

Suitable bases for step (III) + (IV) → (I) of the process are alkali metal hydroxides (e.g. lithium hydroxide, sodium hydroxide or potassium hydroxide), alkali metal carbonates (e.g. lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate), alkali metal bicarbonates (e.g. sodium bicarbonate or potassium bicarbonate), alkali metal alkoxides (e.g. sodium methoxide or potassium methoxide, sodium ethoxide or potassium tert-butoxide), or organic amines (e.g. triethylamine, diisopropylethylamine, pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN)). Preferably potassium tert-butoxide is used.

The reaction (III) + (IV) → (I) is usually carried out in a temperature range of +20 ℃ to +150 ℃, preferably +75 ℃ to +100 ℃, optionally in microwaves. The reaction may be carried out at standard pressure, increased pressure or reduced pressure (e.g. from 0.5 to 5 bar). Generally, standard pressure is used.

Inert solvents for step (III) + (V) → (I-a) of the process are, for example, alcohols such as methanol, ethanol, N-propanol, isopropanol, N-butanol or tert-butanol, ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N' -Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or water. Mixtures of the solvents mentioned may also be used.

Suitable bases for step (III) + (V) → (I-A) of the process are alkali metal hydroxides (e.g. lithium hydroxide, sodium hydroxide or potassium hydroxide), alkali metal carbonates (e.g. lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate), alkali metal bicarbonates (e.g. sodium bicarbonate or potassium bicarbonate), alkali metal alkoxides (e.g. sodium methoxide or potassium methoxide, sodium ethoxide or potassium tert-butoxide), or organic amines (e.g. triethylamine, diisopropylethylamine, pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) or 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN)).

Preference is given to using sodium methoxide in methanol or potassium tert-butoxide in tert-butanol.

The reaction (III) + (V) → (I-a) is usually carried out in a temperature range of +20 ℃ to +150 ℃, preferably +60 ℃ to +100 ℃, optionally in microwaves. The reaction may be carried out at standard pressure, increased pressure or reduced pressure (e.g. from 0.5 to 5 bar). Generally, standard pressure is used.

The methods described above are exemplified with reference to, for example, the synthetic schemes below (scheme 1 and scheme 2):

route scheme 1

1 sodium methoxide, methanol 2, ammonium chloride and acetic acid; b) KOt-Bu, t-BuOH ].

Route map 2：

[ a ] NaOMe, methanol, 65 ℃ C ].

The compounds of the formula (II) are known from the literature (see, for example, WO 03/095451, example 4A) or can be prepared by the following method: reacting a compound of formula (VI) in an inert solvent

Wherein R is¹As defined above, the above-mentioned,

with hydrazine hydrate to give the compound of the formula (VII)

Wherein R is¹As defined above, the above-mentioned,

the compound of formula (VII) is then reacted with isoamyl nitrite in an inert solvent in the presence of a suitable Lewis acid to give the corresponding diazonium salt which is then converted directly to the compound of formula (VIII) using sodium iodide

Wherein R is¹As defined above, the above-mentioned,

subsequently reacting the compound of formula (VIII) with a compound of formula (IX) in an inert solvent in the presence of a suitable base

R²-x¹(IX)，

Wherein R is²As defined above and

X¹are suitable leaving groups, for example tosylate, mesylate or halogen, especially bromine or iodine,

reacting to obtain a compound of formula (X)

Wherein R is¹And R²Each as defined above, is capable of,

the compound of formula (X) is then reacted with copper cyanide in an inert solvent.

Inert solvents used in step (VI) → (VII) of the process are alcohols such as methanol, ethanol, N-propanol, isopropanol, N-or tert-butanol or 1, 2-ethanediol, ethers such as diethyl ether, dioxane, tetrahydrofuran, glyme or diglyme, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N' -Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine, acetonitrile or water. Mixtures of the solvents mentioned may also be used. 1, 2-ethanediol is preferred.

The reaction (VI) → (VII) is usually carried out in a temperature range of +60 ℃ to +200 ℃, preferably +120 ℃ to +180 ℃. The reaction may be carried out at standard pressure, increased pressure or reduced pressure (e.g. from 0.5 to 5 bar). Generally, standard pressure is used.

Inert solvents for reaction (VII) → (VIII) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethylene or chlorobenzene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diglyme, or other solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N' -Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine or acetonitrile. DMF is preferred.

Suitable lewis acids for step (VII) → (VIII) of the process are boron trifluoride-diethyl ether complex, cerium (IV) ammonium nitrate (CAN), stannous (II) chloride, lithium perchlorate, zinc (II) chloride, indium (III) chloride or indium (III) bromide. Boron trifluoride-diethyl ether complex is preferred.

The reaction (VII) → (VIII) is usually carried out at a temperature in the range of-78 ℃ to +40 ℃, preferably 0 ℃ to +20 ℃. The reaction may be carried out at standard pressure, increased pressure or reduced pressure (e.g. from 0.5 to 5 bar). Generally, standard pressure is used.

Inert solvents for the reaction (VIII) + (IX) → (X) are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethylene or chlorobenzene, ethers such as diethyl ether, dioxane, tetrahydrofuran, glyme or diglyme, or other solvents such as Dimethylformamide (DMF), Dimethylsulfoxide (DMSO), N' -Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine or acetonitrile. DMF is preferred.

Suitable bases for step (VIII) + (IX) → (X) of the process are alkali metal hydrides (e.g. sodium or potassium hydride), alkali metal carbonates (e.g. lithium, sodium, potassium or cesium carbonate), alkali metal bicarbonates (e.g. sodium or potassium bicarbonate), alkali metal alkoxides (e.g. sodium or potassium methoxide, ethoxide or tert-butoxide), amides (e.g., sodium amide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, or lithium diisopropylamide), organometallic compounds (e.g., butyllithium or phenyllithium), or organic amines (e.g., triethylamine, diisopropylethylamine, pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), or 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN)). Cesium carbonate is preferred.

The reaction (VIII) + (IX) → (X) is usually carried out in a temperature range from 0 ℃ to +60 ℃ and preferably from +10 ℃ to +25 ℃. The reaction may be carried out at standard pressure, increased pressure or reduced pressure (e.g. from 0.5 to 5 bar). Generally, standard pressure is used.

Inert solvents used in step (X) → (II) of the process are, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents such as Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N' -Dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP), pyridine or acetonitrile. It is also preferred to use mixtures of the solvents mentioned. DMSO is preferred.

The reaction (X) → (II) is usually carried out in a temperature range of +20 ℃ to +180 ℃, preferably +100 ℃ to +160 ℃, optionally in microwaves. The reaction may be carried out at standard pressure, increased pressure or reduced pressure (e.g. from 0.5 to 5 bar). Generally, standard pressure is used.

The preparation described can be illustrated by the synthetic scheme below (scheme 3):

route map 3

Hydrazine hydrate, 1, 2-ethanediol; b) isoamyl nitrite, NaI, THF; b) 2-fluorobenzyl bromide, Cs₂CO₃,DMF；d):CuCN,DMSO]。

The compounds of formula (VI) are known from the literature [ see, e.g., Winn m., j.med.chem.1993,36, 2676-; EP 634413-A1; CN 1613849-A; EP 1626045-A1; WO 2009/018415], or can be prepared by methods similar to the known methods from the literature or as illustrated in the synthetic scheme below (scheme 4):

route map 4

Sulfuric acid; b) zinc, methanol, glacial acetic acid; c) trifluoroacetic anhydride and dichloromethane.

Compounds of formula (IV) and (V) are commercially available and known from the literature and can be prepared by methods similar to known methods from the literature or as exemplarily shown in the synthetic schemes below (schemes 5 and 6):

route map 5

[a):1.LiHMDS,-78℃,THF,2.NBS；b):NaH,50℃,THF].

Route map 6

[a):NaOMe,MeOH,65℃].

The compounds of the invention are potent stimulators of soluble guanylate cyclase, have valuable pharmacological properties and are therefore suitable for the treatment and/or prevention of disorders in humans and animals.

The compounds of the invention cause vasodilation and inhibit platelet aggregation, as well as cause a decrease in blood pressure and an increase in coronary blood flow. These effects are mediated by direct stimulation of soluble guanylate cyclase and intracellular cGMP elevation. Furthermore, the compounds of the invention potentiate the action of substances that can increase cGMP levels, such as EDRF (endothelial derived relaxin), NO donors, protoporphyrin IX, arachidonic acid or phenylhydrazine derivatives.

The compounds of the invention are suitable for the treatment and/or prophylaxis of cardiovascular disorders, pulmonary disorders, thromboembolic disorders, and fibrotic disorders.

Thus, the compounds of the invention are useful in medicaments for the treatment and/or prophylaxis of cardiovascular disorders, such as hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina, peripheral and cardiovascular disorders, arrhythmias, Sinus and ventricular arrhythmias, and impaired conduction, such as I-III degree atrioventricular block (AB block I-III), supraventricular tachycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmia, torsades de pointes, atrial and ventricular extrasystoles, AV-junctional zone extrasystoles, Sick Sinus syndrome (mock-Sinus syndrome), syncope, AV-reentrant tachycardia, Wolff-Parkinson-White syndrome, Acute Coronary Syndrome (ACS), autoimmune cardiac disorders (pericarditis, angina pectoris, peripheral and cardiovascular disorders, cardiac arrhythmias, Endocarditis, valvular heart disease (valvolitis), aortic inflammation, cardiomyopathy), shock such as cardiogenic shock, septic and anaphylactic shock, aneurysm, boxer canine cardiomyopathy (ventricular premature contraction (PVC)); for the treatment and/or prophylaxis of thromboembolic disorders and ischaemias, such as myocardial ischaemia, myocardial infarction, stroke, myocardial hypertrophy, transient ischaemic attacks, pre-eclampsia, inflammatory cardiovascular disorders, coronary and peripheral arterial spasms, oedema formation, such as pulmonary oedema, cerebral oedema, renal oedema or oedema caused by heart failure, peripheral perfusion impairment (impaired reperfusion injury), arterial and venous thrombosis, microalbuminuria, myocardial insufficiency, endothelial dysfunction; for the prevention of restenosis following, for example, thrombolytic therapy, Percutaneous Transluminal Angioplasty (PTA), transluminal coronary angioplasty (PTCA), heart transplantation, and bypass surgery, as well as microvascular and macrovascular lesions (vasculitis), elevated levels of fibrinogen and low-density LDL, and elevated concentrations of plasminogen activator inhibitor 1 (PAI-1); and for the treatment and/or prevention of erectile dysfunction and female sexual dysfunction.

In the context of the present invention, the term "heart failure" also covers more specific or more relevant types of diseases, such as acute decompensated heart failure, right heart failure, left heart failure, total heart failure (global failure), ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, heart valve defects, heart failure associated with heart valve defects, mitral stenosis, mitral insufficiency, aortic stenosis, aortic insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary stenosis, pulmonary insufficiency, complex heart valve defects, myocarditis, chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, diastolic heart failure, and systolic heart failure.

In addition, the compounds of the present invention are also useful for the treatment and/or prevention of arteriosclerosis, disturbed lipid metabolism, hypolipidaemia (hyprolipoproteinemia), dyslipidaemia, hypertriglyceridaemia, hyperlipidaemia, hypercholesteraemia, betalipoproteinaemia, sitosterolemia, xanthomatosis, erygier's disease, obesity (adiposity), obesity (obesity) and combined hyperlipidaemia, as well as metabolic syndrome.

Furthermore, the compounds of the invention are useful for the treatment and/or prevention of first and second phase raynaud's phenomenon, microcirculation disorders, claudication, peripheral and autonomic neuropathy, diabetic microangiopathy, diabetic retinopathy, diabetic ulcers in the extremities, gangrene, scleroderma, lupus erythematosus, onychomycosis, rheumatic diseases, and for promoting wound healing.

Furthermore, the compounds of the invention are also suitable for the treatment of urinary disorders, such as Benign Prostatic Syndrome (BPS), Benign Prostatic Hyperplasia (BPH), benign prostatic hypertrophy (BPE), Bladder Outlet Obstruction (BOO), lower urinary tract syndrome (LUTS, including Feline Urinary Syndrome (FUS)), genitourinary disorders, including neurogenic overactive bladder (OAB) and (IC), incontinence (UI), such as mixed urinary incontinence, urge urinary incontinence, stress urinary incontinence or overflow urinary incontinence (MUI, UUI, SUI, OUI), pelvic pain, benign and malignant disorders of organs in the male and female urogenital systems.

Furthermore, the present invention is suitable for the treatment and/or prevention of renal disorders, in particular acute and chronic renal insufficiency, and acute and chronic renal failure. In the context of the present invention, the term "renal insufficiency" encompasses acute and chronic clinical manifestations of renal insufficiency, as well as potential or related renal disorders, such as renal hypoperfusion, dialysis-related hypotension (intrarenal hypertension), obstructive uropathy, glomerulopathy, glomerulonephritis, acute glomerulonephritis, glomerulosclerosis, tubulointerstitial disease, renal disorders, such as primary and congenital renal diseases, nephritis, immune renal disorders, such as renal metastasis rejection and immune complex-induced renal disorders, toxicant-induced nephropathy, contrast-induced nephropathy, diabetic and non-diabetic nephropathy, pyelonephritis, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, and nephrotic syndromes with diagnostic features such as abnormal reduction of creatinine and/or water discharge; abnormally elevated blood levels of urea, nitrogen, potassium and/or creatinine; altered activity of renal enzymes (e.g., glutamyl synthase), altered urine osmolality, or altered urine volume; increase in microalbuminuria, massive albuminuria; glomerular and arteriolar lesions; tubular expansion (tubulariation); hyperphosphatemia and/or the need for dialysis. The invention also encompasses the use of the compounds of the invention for the treatment and/or prevention of the sequelae of renal insufficiency, such as emphysema, heart failure, uremia, anemia, electrolyte disorders (e.g. hypercalcemia, hyponatremia), and disorders of bone and carbohydrate metabolism.

In addition, the compounds of the invention are also suitable for the treatment and/or prevention of asthma, Pulmonary Arterial Hypertension (PAH) and other forms of Pulmonary Hypertension (PH) including pulmonary hypertension associated with left heart disease, HIV, sickle cell anemia, thromboembolism (CTEPH), sarcoidosis, Chronic Obstructive Pulmonary Disease (COPD) or pulmonary fibrosis; chronic Obstructive Pulmonary Disease (COPD), Acute Respiratory Distress Syndrome (ARDS), Acute Lung Injury (ALI), alpha-1 antitrypsin deficiency (AATD), pulmonary fibrosis, pulmonary emphysema (e.g., emphysema induced by smoking), and Cystic Fibrosis (CF).

The compounds described in the present invention are also active ingredients for the prophylaxis and treatment of disorders of the central nervous system which are characterized by a deregulation of the NO/cGMP system. More particularly, they are suitable for improving perception, attention, learning ability or memory after cognitive impairment, such as occurs in particular in the following conditions/diseases/syndromes: such as mild cognitive impairment, age-related learning and memory impairment, age-related memory loss, vascular dementia, craniocerebral trauma, stroke, dementia following stroke, posttraumatic craniocerebral trauma, attention-concentration disorder complex, attention-concentration disorder in children with learning and memory difficulties, alzheimer's disease, dementia with lewy bodies, dementia with deterioration of the frontal lobe including pick's syndrome, parkinson's disease, progressive nuclear palsy, dementia with degeneration of the basal ganglia, Amyotrophic Lateral Sclerosis (ALS), huntington's chorea, demyelination, multiple sclerosis, thalamic deformation, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or korsakoff's syndrome. They are also suitable for the treatment and/or prevention of disorders of the central nervous system, such as anxiety, states of stress and depression, CNS-related sexual dysfunctions and disturbed sleep, and of pathological disorders which control the intake of food, stimulants and addictive substances.

Furthermore, the compounds of the present invention are also suitable for regulating blood flow of the brain and therefore as effective agents for preventing and treating migraine. They are also suitable for the prevention and control of sequelae of cerebral infarction (stroke), such as stroke, cerebral ischemia and craniocerebral injury. The compounds of the invention are also useful for controlling the state of pain and tinnitus.

Furthermore, the compounds of the invention have an anti-inflammatory effect and can therefore be used as anti-inflammatory agents for the treatment and/or prevention of the following diseases: sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory disorders of the kidney, chronic inflammatory bowel disease (IBD, crohn's disease, UC), pancreatitis, peritonitis, rheumatic disorders, inflammatory skin disorders, and inflammatory eye disorders.

Furthermore, the compounds of the present invention may also be used for the treatment and/or prevention of autoimmune disorders.

Furthermore, the compounds of the invention are suitable for the treatment and/or prophylaxis of fibrotic disorders of internal organs, such as the lung, the heart, the kidney, the bone marrow and in particular the liver, and of dermatological fibrosis and of the eye. In the context of the present invention, the term "fibrotic disorder" specifically covers the following terms: liver fibrosis, cirrhosis, lung fibrosis, endomyocardial fibrosis, kidney disease, glomerulonephritis, interstitial kidney fibrosis, fibrotic damage due to diabetes, myelofibrosis and similar fibrotic disorders, scleroderma, maculopathy, keloids, hypertrophic scars (including postoperative hypertrophic scars), nevi, diabetic retinopathy, proliferative vitreoretinopathy and disorders of connective tissue (e.g., sarcoidosis).

The compounds of the invention are also suitable for the prevention and treatment of post-operative scars, for example, scars resulting from glaucoma surgery.

The compounds of the present invention are also cosmetically useful for aging and keratinizing skin.

Furthermore, the compounds of the invention are suitable for the treatment and/or prophylaxis of hepatitis, tumors, osteoporosis, glaucoma and gastroparesis.

The present invention also provides the use of a compound of the invention for the treatment and/or prevention of disorders, in particular the disorders mentioned above.

The invention also provides the use of a compound of the invention for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders, renal insufficiency, vascular embolic disorders, fibrous disorders and arteriosclerosis.

The present invention also provides a compound of the invention for use in a method of treatment and/or prevention of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders, renal insufficiency, vascular embolic disorders, fibrous disorders and arteriosclerosis.

The invention also provides the use of a compound of the invention for the preparation of a medicament for the treatment and/or prevention of a disorder, in particular a disorder as mentioned above.

The invention also provides the use of a compound of the invention for the preparation of a medicament for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders, renal insufficiency, vascular embolic disorders, fibrous disorders and arteriosclerosis.

The present invention also provides methods of treating and/or preventing disorders, in particular the disorders mentioned above, using an effective dose of at least one compound of the invention.

The invention also provides methods of treating and/or preventing heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders, renal insufficiency, vascular embolic disorders, fibrous disorders and arteriosclerosis using an effective dose of at least one compound of the invention.

The compounds of the invention may be used alone or, if desired, in combination with other active ingredients. The invention also provides a medicament comprising at least one compound of the invention and one or more further active ingredients, in particular for the treatment and/or prevention of the disorders mentioned above. Preferred examples of suitable active ingredient combinations include:

organic nitrates and NO donors, such as sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine (molsidomine) or SIN-1, and inhaled NO;

compounds which inhibit the breakdown of cyclic guanosine monophosphate (cGMP), for example inhibitors of Phosphodiesterase (PDE)1, 2 and/or 5, in particular PDE 5 inhibitors, such as sildenafil, vardenafil and tadalafil;

an antithrombotic agent, for example and preferably selected from a group consisting of a tubular aggregation inhibitor, an anticoagulant or a plasmin;

hypotensive active ingredients, for example and preferably selected from calcium antagonists, angiotensin AII antagonists, Angiotensin Converting Enzyme (ACE) inhibitors, endothelin antagonists, renin inhibitors, α -receptor blockers, β -receptor blockers, mineralocorticoid receptor antagonists and diuretics; and/or

An active ingredient which alters lipid metabolism, for example and preferably selected from thyroid receptor agonists, cholesterol synthesis inhibitors, for example and preferably selected from HMG-CoA reductase (HMG-CoA) inhibitors or squalene synthesis inhibitors, acyl-CoA-cholesterol acyltransferase (ACAT) inhibitors, cholesterol transfer protein (CETP) inhibitors, triglyceride transfer protein (MTP) inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-sigma agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid resorption inhibitors and lipoprotein (a) antagonists.

An antithrombotic agent is preferably understood to mean a compound selected from the group consisting of platelet aggregation inhibitors, anticoagulants or fibrinolytics.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a platelet aggregation inhibitor, such as, and preferably, aspirin, clopidogrel (clopidogrel), ticlopidine (ticlopidine) or dipyridamole (dipyridamole).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thrombin inhibitor, such as and preferably ximegatran (ximelagatran), dabigatran (dabigatran), melagatran (melagatran), bivalirudin (bivalirudin) or crexate (clexane).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a GPIIb/IIIa antagonist, such as and preferably tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an Xa inhibitor, such as, and preferably, rivaroxaban (BAY 59-7939), DU-176b, apixaban (apixaban), omixaban (otamixaban), fidaxaban (fidaxaban), rizaxaban (fidaxaban), razaxaban (razaxaban), fondaparinux, idraparinux (idraparinux), PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512, or SSR-128428.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with heparin or a heparin derivative having a Low Molecular Weight (LMW).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a vitamin K antagonist, such as and preferably coumarin.

Hypotensive agents are preferably understood to mean compounds selected from the group consisting of: calcium antagonists, angiotensin AII antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists and diuretics.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a calcium antagonist such as, and preferably, nifedipine (nifedipine), amlodipine (amlodipine), verapamil (verapamil) or diltiazem (diltiazem).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an alpha-1-receptor blocker, such as, and preferably, prazosin (prazosin).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a beta-receptor blocker, such as, and preferably, propranolol (propranolol), atenolol (atenolol), timolol (timolol), pindolol (pindolol), alprenolol (alprenolol), oxprenolol (oxprenolol), penbutolol (penbutolol), blanolol (bucanolol), metipranolol (metipranolol), nadolol (nadolol), mepindolol (mepindolol), carazalol, sotalol (sotalol), metoprolol (metoprolol), betaxolol (betaxolol), celiprolol (celoprolol), bisoprolol (bipropolol), carteolol (carteolol), esmolol (esmolol), labolol (betaxolol), valdiolol (valdiolol), celiolol (celolol), pindolol (anedolol), anedolol (anedolol), anediolol (anedolol (anediolol), and anetholol (anetholol).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an angiotensin AII antagonist such as and preferably losartan (losartan), candesartan (candisartan), valsartan (valsartan), telmisartan (telmisartan) or embursatan.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an ACE inhibitor, such as and preferably enalapril (enalapril), captopril (captopril), lisinopril (lisinopril), ramipril (ramipril), delapril (delapril), fosinopril (fosinopril), quinapril (quinopril), perindopril (perindopril) or quadolapril (trandopril).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an endothelin antagonist such as, and preferably, bosentan (bosentan), darussentan (daursentan), ambrisentan (ambrisentan) or sitaxsentan (sitaxsentan).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a renin inhibitor, such as and preferably aliskiren (aliskiren), SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a mineralocorticoid receptor antagonist, such as and preferably spironolactone or eplerenone.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with the following diuretics: loop diuretics such as furosemide (furosemide), torasemide (torasemide), bumetanide (bumetanide) and piretanide (piretanide); potassium sparing diuretics such as amiloride (amiloride) and triamterene (triamterene); aldosterone antagonists such as spironolactone (spironolactone), potassium canrenoate (potassium canrenoate), and eplerenone (eplerenone); and thiazide diuretics such as hydrochlorothiazide (hydrochlorothiazide), chlorthalidone (chlorothalidone), xipamide (xipamide), and indapamide (indapamide).

Agents that alter lipid metabolism are preferably understood to mean compounds selected from the group consisting of: CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase inhibitors or squalene synthesis inhibitors, ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid resorption inhibitors, lipase inhibitors and lipoprotein (a) antagonists.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a Cholesteryl Ester Transfer Protein (CETP) inhibitor, such as and preferably Dacetrapib (dalcetrapib), BAY 60-5521, anacetrapib oder CETP vaccine (CETi-1).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a thyroid receptor agonist such as, and preferably, D-thyroxine, 3,5,3' -triiodothyronine (T3), CGS23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a statin HMG-CoA reductase inhibitor, such as and preferably lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a squalene synthesis inhibitor, such as and preferably BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an ACAT inhibitor such as, and preferably, avasimibe (avasimibe), melinamide (melinamide), patiticum (pactimibe), ibrutinib (eflucimibe) or SMP-797.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an MTP inhibitor, such as and preferably, Enptapide (impliptatide), BMS-201038, R-103757, or JTT-130.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-gamma agonist, such as and preferably pioglitazone (pioglitazone) or rosiglitazone (rosiglitazone).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a PPAR-agonist, such as, and preferably, GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a cholesterol absorption inhibitor, such as and preferably ezetimibe (ezetimibe), tiquinane (tiqueside) or pamaquide (pamaquide).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a lipase inhibitor, such as and preferably orlistat (orlistat).

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a polymeric bile acid adsorbent such as, and preferably, cholestyramine (cholestyramine), colestipol (colestipol), colesevelam (colesevelam), cholestecagel or colestimide.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a bile acid resorption inhibitor, such as, and preferably, an ASBT (═ IBAT) inhibitor, e.g. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with an antagonist of lipoprotein (a), such as and preferably gemcabene calcium (CI-1027) or niacin.

The invention also provides a medicament comprising at least one compound of the invention, usually together with one or more inert, non-toxic pharmaceutically acceptable excipients, and to the use thereof for the purposes mentioned above.

The compounds of the invention may act systemically and/or locally. For this purpose, it can be administered in a suitable manner, for example orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, in the ear canal, or as an implant or stent.

For these routes of administration, the compounds of the invention can be administered in a suitable administration form.

Suitable administration forms for oral administration are those which operate according to the prior art, which release the compounds of the invention rapidly and/or in a modified manner and which contain the compounds of the invention in crystalline and/or amorphous and/or dissolved form, for example tablets (uncoated or coated tablets, for example with a gastric-resistant or delayed-dissolving or insoluble coating which controls the release of the compounds of the invention), tablets which disintegrate rapidly in the oral cavity or films/tablets, films/lyophilizates or capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished without an absorption step (e.g., by intravenous, intraarterial, intracardiac, intravertebral, or intralumbar routes) or with an absorption step (e.g., by intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal routes). Administration forms suitable for parenteral administration include preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For other routes of administration, suitable examples are inhalable pharmaceutical forms (including powders, sprays), nasal drops, solutions or sprays, tablets, films/slabs or capsules for the tongue, sublingual or buccal administration, suppositories, otic or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams (creams), transdermal therapeutic systems (e.g. patches), creams, pastes, foams, sprinkles, implants or stents.

Oral or parenteral administration, in particular oral administration, is preferred.

The compounds of the invention can be converted into the administration forms mentioned. This can be done in a manner known per se by mixing with inert, non-toxic pharmaceutically acceptable excipients. These excipients include carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (e.g. sodium lauryl sulfate, polyoxysorbitan oleate), binders (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilizers (e.g. antioxidants, e.g. ascorbic acid), dyes (e.g. inorganic pigments, e.g. iron oxide) and fragrances and/or odor correctors.

In general, to achieve effective results, it has been found advantageous to administer the drug in an amount of from about 0.001 to 1mg/kg body weight, preferably from about 0.01 to 0.5mg/kg body weight, for parenteral administration. For oral administration, the dosage is from about 0.01 to 100mg/kg body weight, preferably from about 0.01 to 20mg/kg body weight and most preferably from 0.1 to 10mg/kg body weight.

However, in some cases the dosage may be deviated from if desired, depending in particular on the following factors: body weight, route of administration, individual response to the active ingredient, nature of the formulation and time of administration or interval of administration. Thus, in some cases, it may be sufficient to lower than the minimum mentioned, while in other cases the upper limit mentioned must be exceeded. For administration in relatively large amounts, it is advisable to divide these doses into several separate doses over the course of a day.

The working examples which follow illustrate the invention. The present invention is not limited to these examples.

Percentages in the tests and examples below, unless otherwise indicated, are percentages by weight; the parts are weight parts. The solvent ratio, dilution ratio and concentration values for the liquid/liquid solution are all based on volume.

A.Examples

Abbreviations and acronyms:

aq. aqueous solution

calc calculated value

DCI direct chemical ionization (in MS)

DMF dimethyl formamide

DMSO dimethyl sulfoxide

eq. equivalent

ESI electrospray ionization (in MS)

Et Ethyl group

h hours

HPLC high pressure high performance liquid chromatography

HRMS high resolution mass spectrum

conc. concentrated

LC/MS liquid chromatogram coupled mass spectrum

LiHMDS lithium hexamethyldisilazide

Me methyl group

min for

MS Mass Spectrometry

NMR nuclear magnetic resonance spectrum

Pd₂dba₃Tris (dibenzylideneacetone) dipalladium

Ph phenyl

RT Room temperature

R_tRetention time (in HPLC)

t-Bu tert-butyl

THF tetrahydrofuran

UV ultraviolet spectrum

Ratio of v/v (solution) volume to volume

XPHOS dicyclohexyl (2',4',6' -triisopropylbiphenyl-2-yl) phosphine

LC/MS method:

method 1(LC-MS):

the instrument comprises the following steps: waters ACQUITY SQD UPLC system; column: waters Acquity UPLC HSS T31.8 μ 50x1 mm; eluent A, 1l of water +0.25ml of 99% formic acid, eluent B:1l acetonitrile +0.25ml 99% formic acid; gradient: 0.0 min 90% a → 1.2 min 5% a → 2.0 min 5% a; the furnace temperature is 50 ℃; flow rate: 0.40 ml/min; and (4) UV detection: 210-400 nm.

Method 2(LC-MS):

MS instrument: waters ZQ; HPLC apparatus: agilent 1100 Series; UV DAD; column: ThermoHypersil GOLD 3 μ 20mm x 4 mm; eluent A is 1l of water and 0.5ml of 50% formic acid, eluent B is 1l of acetonitrile and 0.5ml of 50% formic acid; gradient: 0.0 min 100% a → 3.0 min 10% a → 4.0 min 10% a; furnace temperature: 55 ℃; flow rate: 2 ml/min; and (4) UV detection: 210 nm.

Method 3(LC-MS):

the instrument comprises the following steps: waters ACQUITY SQD UPLC system; column: waters Acquity UPLC HSS T31.8 μ 30x2 mm; eluent A:1l of water +0.25ml of 99% formic acid, eluent B of 1l of acetonitrile +0.25ml of 99% formic acid; gradient: 0.0 min 90% a → 1.2 min 5% a → 2.0 min 5% a; furnace temperature: 50 ℃; flow rate: 0.60 ml/min; and (4) UV detection: 208-400 nm.

Raw materials and intermediates:

example 1A

1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboximidamide hydrochloride

The synthesis of this compound is described in WO 2003/095451, example 6A.

Example 2A

2, 6-dichloro-5-fluoronicotinamide

A suspension of 25g (130.90mmol)2, 6-dichloro-5-fluoro-3-cyanopyridine in concentrated sulfuric acid (125ml) was stirred at 60-65 ℃ for 1 hour. After cooling to room temperature, the contents of the flask were poured into ice water and extracted three times with ethyl acetate (100ml each). The combined organic phases were washed with water (100ml) and then with saturated aqueous sodium bicarbonate solution (100ml), dried and concentrated on a rotary evaporator. The resulting material was dried under high vacuum.

Yield: 24.5g (90% of theory)

¹H NMR(400MHz,DMSO-d₆):＝7.95(br s,1H),8.11(br s,1H),8.24(d,1H)。

Example 3A

2-chloro-5-fluoronicotinamide

A suspension of 21.9g (335.35mmol) zinc in methanol (207ml) was mixed with 44g (210.58mmol)2, 6-dichloro-5-fluoronicotinamide at room temperature. Acetic acid (18.5ml) was then added and the mixture was heated to reflux with stirring for 24 hours. The contents of the flask, except for zinc, were then poured out, followed by addition of ethyl acetate (414ml) and saturated aqueous sodium bicarbonate solution (414ml), followed by vigorous stirring. Subsequently, the reaction mixture was filtered through celite with suction and washed three times with ethyl acetate (517 ml each). The organic phase was removed and the aqueous phase was washed with ethyl acetate (258 ml). The combined organic phases were washed once with saturated aqueous sodium bicarbonate (414ml), dried and concentrated under reduced pressure. To the thus-obtained crystals was added methylene chloride (388ml), and the resulting mixture was stirred for 20 minutes. The mixture is filtered off again with suction, washed with diethyl ether and drained.

Yield: 20.2g (53% of theory)

¹H NMR(400MHz,DMSO-d₆):＝7.87(br s,1H),7.99(dd,1H),8.10(br s,1H),8.52(d,1H)。

Example 4A

2-chloro-5-fluoronicotinonitrile (nicotinonitril)

81.2ml (582.25mmol) triethylamine was added to a suspension of 46.2g (264.66mmol) 2-chloro-5-fluoronicotinamide in dichloromethane (783ml) and the mixture was cooled to 0 ℃. 41.12ml (291.13mmol) of trifluoroacetic anhydride are then slowly added dropwise with stirring, and the mixture is stirred at 0 ℃ for 1.5 hours. Subsequently, the reaction solution was washed twice with saturated aqueous sodium bicarbonate solution (391 ml each), dried and concentrated under reduced pressure.

Yield 42.1g (90% of theory).

¹H NMR(400MHz,DMSO-d₆):＝8.66(dd,1H),8.82(d,1H)。

Example 5A

5-fluoro-1H-pyrazolo [3,4-b ] pyridin-3-amines

A suspension of 38.5g (245.93mmol) 2-chloro-5-fluoronicotinonitrile was first added to 1, 2-ethanediol (380ml) and then hydrazine hydrate (119.6ml,2.459 mol). The resulting mixture was heated under reflux for 4 hours with stirring. The product precipitated during cooling. Water (380ml) was added to the yellow crystals, and the mixture was stirred at room temperature for 10 minutes. The suspension was then filtered with suction through a sintered filter (frit) and washed with water (200ml) and-10 ℃ THF (200 ml). The residue was dried under high vacuum with phosphorus pentoxide.

Yield 22.8g (61% of theory)

¹H NMR(400MHz,DMSO-d₆):＝5.54(s,2H),7.96(dd,1H),8.38(m,1H),12.07(m,1H)。

Example 6A

5-fluoro-3-iodo-1H-pyrazolo [3,4-b ] pyridine

10g (65.75mmol) of 5-fluoro-1H-pyrazolo [3,4-b ] pyridin-3-amine are initially taken up in THF (329ml) and the mixture is cooled to 0 ℃. Then 16.65ml (131.46mmol) of boron trifluoride diethyl etherate were gradually added. The reaction mixture was further cooled to-10 ℃. A solution of 10.01g (85.45mmol) of isoamyl nitrite in THF (24.39ml) was then gradually added and the resulting mixture was stirred for another 30 minutes. The mixture was diluted with cold diethyl ether (329ml) and the resulting solid was filtered off. The diazonium salt thus prepared was added in portions to a solution of 12.81g (85.45mmol) of sodium iodide in acetone (329ml) at 0 ℃ and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water (1.8 l) and extracted twice with ethyl acetate (487 ml each time). The collected organic phases were washed with saturated aqueous sodium chloride (244ml), dried, filtered and concentrated. 12.1g (purity 86%, 60% of theory) of the desired compound are obtained in the form of a solid. The crude product was converted without further purification.

LC-MS (method 1) R_t1.68 minutes; MS (ESIpos) 264(M + H)⁺

Example 7A

5-fluoro-1- (2-fluorobenzyl) -3-iodo-1H-pyrazolo [3,4-b ] pyridine

12.1g (39.65mmol) of the compound from example 6A were initially taken in DMF (217ml) and then 8.25g (43.62mmol) of 2-fluorobenzyl bromide and 14.21g (43.62mmol) of cesium carbonate were added. The mixture was stirred at room temperature for two hours. The reaction mixture was then poured into water (1.17l) and extracted twice with ethyl acetate (502 ml). The collected organic phases were washed with saturated aqueous sodium chloride (335ml), dried, filtered and concentrated. The residue is chromatographed on silica gel (eluent: 97:3 petroleum ether/ethyl acetate) and the product fractions are then concentrated. 9.0g (61% of theory) of the desired compound are obtained in the form of a solid. The resulting solid was added to ethyl acetate and washed with 10% aqueous sodium thiosulfate solution, then with saturated aqueous sodium chloride solution, dried and concentrated.

LC-MS (method 2) R_t2.57 min

MS(ESIpos):m/z＝372(M+H)⁺

¹H NMR(400MHz,DMSO-d₆):＝5.73(s,2H),7.13-7.26(m,3H),7.33-7.41(m,1H),7.94(dd,1H),8.69-8.73(m,1H)。

Example 8A

5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridine-3-carbonitrile

A suspension of 16.03g (43.19mmol) of 5-fluoro-1- (2-fluorobenzyl) -3-iodo-1H-pyrazolo [3,4-b ] pyridine (example 7A) and 4.25g (47.51mmol) of copper cyanide was initially taken up in DMSO (120ml) and stirred at 150 ℃ for 2 hours. After cooling, the contents of the flask were cooled to about 40 ℃ and poured into a solution of concentrated aqueous ammonia (90ml) and water (500ml), ethyl acetate (200ml) was added and the mixture was stirred briefly. The aqueous phase was removed and extracted twice with ethyl acetate (200ml each). The combined organic phases were washed twice with 10% aqueous sodium chloride solution (100ml each), dried over sodium sulfate and concentrated under reduced pressure. The crude product was converted without further purification.

Yield 11.1g (91% of theory)

¹H NMR(400MHz,DMSO-d₆):＝5.87(s,2H),7.17-7.42(m,4H),8.52(dd,1H),8.87(dd,1H)。

Example 9A

5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboximidamide acetate

11.1g (41.07mmol) of 5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridine-3-carbonitrile (example 8A) are added to 2.22g (41.07mmol) of sodium methoxide in methanol (270ml) and the mixture is stirred at room temperature for 2H. Then 2.64g (49.29mmol) ammonium chloride and acetic acid (9.17ml) were added and the mixture was heated to reflux overnight. It was then concentrated to dryness, and the residue was then added to water (100ml) and ethyl acetate (100ml) and adjusted to pH 10 with 2N aqueous sodium hydroxide solution. The resulting mixture was stirred vigorously at room temperature for about 1 hour. The resulting suspension was filtered with suction and washed with ethyl acetate (100ml), with water (100ml) and again with ethyl acetate (100 ml). The residue was dried under high vacuum with phosphorus pentoxide.

Yield 9.6g (78% of theory)

MS(ESIpos):m/z＝288(M+H)⁺

¹H NMR(400MHz,DMSO-d₆):＝1.85(s,3H),5.80(s,2H),7.14-7.25(m,3H),7.36(m,1H),8.42(dd,1H),8.72(dd,1H)。

Example 10A

3, 3-dicyano-2, 2-dimethylpropionic acid methyl ester

In THF (91ml), 1.816g (45.411mmol) of sodium hydride (60% in mineral oil) were gradually mixed with 3g (45.411mmol) of malononitrile. 5.876ml (45.411mmol) methyl 2-bromo-2-methylpropionate were then added and the mixture was stirred at room temperature overnight. Thereafter an additional 5.876ml (45.411mmol) methyl 2-bromo-2-methylpropionate were added and the resulting mixture was heated at 50 ℃ overnight. A further 1.762ml (13.623mmol) of methyl 2-bromo-2-methylpropionate were then added and the mixture was heated at 50 ℃ for a further 4 hours. The resulting mixture was then mixed with saturated aqueous sodium bicarbonate and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. 8.9g of crude product are obtained, which is purified by chromatography on silica gel (4:1 cyclohexane-ethyl acetate).

Yield 6.47g (85% of theory)

¹H NMR(400MHz,DMSO-d₆):[ppm]＝1.40(s,6H),3.74(s,3H),5.27(s,1H)。

Example 11A

3-Bromometrahydrofuran-3-carboxylic acid methyl ester

5.0g (38.419mmol) of methyl tetrahydrofuran-3-carboxylate (prepared analogously to the method of J.org.chem.1996, 2690) are dissolved in 200ml of THF and cooled to-78 ℃ and 76.83ml of a 1M solution of lithium bis (trimethylsilyl) amide in THF are added. After 30 minutes at-78 ℃ 10.26g (57.63mmol) of N-bromosuccinimide suspended in 50ml of THF are gradually added. After this time, the resulting mixture was allowed to warm to room temperature overnight. The resulting mixture was then mixed with water and extracted with ethyl acetate. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, then dried over sodium sulfate, filtered and concentrated. The crude product is purified by chromatography on silica gel (eluent: dichloromethane). 491mg (6% of theory) of the target compound are obtained.

¹H NMR(400MHz,CDCl₃):[ppm]＝2.49(ddd,1H),2.74(ddd,1H),3.83(s,3H),4.03-4.10(m,1H),4.11-4.17(m,2H),4.31(d,1H)。

Example 12A

3- (Dicyanomethyl) tetrahydrofuran-3-carboxylic acid methyl ester

440mg (11.00mmol) of sodium hydride (60% in mineral oil) are initially introduced into 30ml of THF, and 726mg (11.00mmol) of malononitrile are then added in portions. Thereafter, 2.3g (11.00mmol) of the compound obtained in example 11A in THF (50ml) were added. The resulting mixture was stirred at room temperature for 6 hours, and then heated at 50 ℃ overnight. After cooling, the mixture was mixed with saturated aqueous sodium bicarbonate and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, then dried over sodium sulfate, filtered and concentrated. The residue (2.66g) was dried under high vacuum for 1 hour and then converted without further purification.

Example 13A

2-methoxy-4-methyl-6-oxo-1, 4,5, 6-tetrahydropyridine-3-carbonitrile

The synthesis of this compound is described in: heterocycles, 1985; 1135-1141.

example 14A

2-methoxy-6-carbonyl-4- (trifluoromethyl) -1,4,5, 6-tetrahydropyridine-3-carbonitrile

7.47g (138.39mmol) of sodium methoxide in methanol (85ml) are first cooled with ice and then 6.04g (91.44mmol) of malononitrile are added in portions. Subsequently, 11.84g (76.84mmol) of methyl 4,4, 4-trifluorocrotonate was added dropwise with stirring, and the resulting mixture was stirred at room temperature for 30 minutes and then heated to reflux for 1 hour. After this time, the mixture was concentrated to dryness under reduced pressure. The residue was mixed with water and extracted four times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Further purification was performed by chromatography on silica gel (3:1 cyclohexane-ethyl acetate). 1.95g of the expected compound (11% of theory) are obtained.

LC-MS (method 1) R_t0.61 min; MS (ESIpos) 221(M + H) M/z⁺

Example 15A

5-fluoro-3-iodo-1H-pyrazolo [3,4-b ] pyridine

The synthesis is described in: WO 2006/130673, scheme D.

Example 16A

3-iodo-1- (3,3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3,4-b ] pyridine

10.00g (40.813mmol) of the compound from example 15A were initially introduced into DMF (170ml) and 12.30g (44.894mmol) of 1,1,1,2, 2-pentafluoro-4-iodobutane and 14.628g (44.894mmol) of cesium carbonate in DMF (30ml) were added. The resulting mixture was stirred at room temperature for 2 days. Subsequently, another 12.30g (44.894mmol) of 1,1,1,2, 2-pentafluoro-4-iodobutane and 14.628g (44.894mmol) of cesium carbonate were added and the resulting mixture was stirred at room temperature for 2 days. Thereafter, 3.485g (12.720mmol)1,1,1,2, 2-pentafluoro-4-iodobutane and 4.145g (12.720mmol) cesium carbonate were added and the resulting mixture was stirred at room temperature overnight. After this period, 5.00g (18.250mmol) of 1,1,1,2, 2-pentafluoro-4-iodobutane and 5.946g (18.250mmol) of cesium carbonate were added and the resulting mixture was stirred at room temperature for 6 days. The mixture was then stirred at 70 ℃ for 2 days. The solid is filtered off with suction and washed with DMF, and the liquid is then concentrated under high vacuum. The residue was purified by preparative HPLC (methanol: water (with 0.1% formic acid) gradient). 5.48g (34% of theory) of the title compound are obtained in the form of a solid.

LC-MS (method 3) R_t1.23 min

MS(ESIpos):m/z＝392(M+H)⁺

1H NMR(400MHz,DMSO-d6):＝2.87-3.00(m,2H),4.81(t,2H),7.33(dd,1H),7.97(dd,1H),8.65(dd,1H)。

Example 17A

1- (3,3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3,4-b ] pyridine-3-carbonitrile

A suspension of 5.480g (14.012mmol) of the compound from example 16A and 1.380g (15.414mmol) of cuprous cyanide is initially added to DMSO (50ml) and stirred at 150 ℃ for 3 hours. After cooling, the resulting mixture was filtered through celite and washed with ethyl acetate and THF. It was then washed four times with saturated aqueous ammonium chloride and concentrated aqueous ammonia (3:1, v/v) and then with saturated aqueous sodium chloride. The organic phase is dried over sodium sulfate, filtered and concentrated, then dried under high vacuum.

Yield 3.59g (88% of theory)

LC-MS (method 1) R_t1.04 min

MS(ESIpos):m/z＝291(M+H)⁺

1H NMR(400MHz,DMSO-d6):＝2.97-3.10(m,2H),4.94(t,2H),7.55(dd,1H),8.51(dd,1H),8.81(dd,1H)。

Example 18A

1- (3,3,4,4, 4-Pentafluorobutyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboximidamide acetate

3.59g (12,371mmol) of the compound of example 17A in methanol (20ml) are added to 0.668g (12.371mmol) of sodium methoxide in methanol (40ml) and the mixture is stirred at room temperature for 2 hours. Then 0.794g (14,845mmol) ammonium chloride and acetic acid (2.762ml) were added and the resulting mixture was heated to reflux overnight. After this time, the mixture was concentrated to dryness, and the residue was mixed with ethyl acetate and 1N sodium hydroxide solution. The resulting mixture was stirred vigorously at room temperature for about 1 hour. The resulting solid was filtered off with suction and washed with ethyl acetate and water. The residue was dried under high vacuum. 0.507g (11% of theory, 100% purity) was obtained. For each wash fraction, the phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated, then dried under high vacuum. Another 2.76g (43% of theory, purity 71%) are obtained.

LC-MS (method 1) R_t0.58 min

MS(ESIpos):m/z＝308(M+H)⁺

1H NMR(400MHz,DMSO-d₆):＝1.84(s,3H),2.95-3.08(m,2H),4.85(t,2H),7.39(dd,1H),8.63-8.67(m,2H)。

Example 19A

5-fluoro-3-iodo-1- (3,3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3,4-b ] pyridine

5.0g (19.010mmol) of 5-fluoro-3-iodo-1H-pyrazolo [3,4-b ] pyridine are initially taken in DMF (100ml), followed by 20.83g (76.042mmol) of 1,1,1,2, 2-pentafluoro-4-iodobutane, and 14.86g (45.65mmol) of cesium carbonate and 0.63g (3.802mmol) of potassium iodide. The mixture was stirred at 140 ℃ overnight. The mixture was then cooled and combined with the product from a previous experiment conducted similarly to 200mg 5-fluoro-3-iodo-1H-pyrazolo [3,4-b ] pyridine. The solid is filtered off with suction and washed with DMF, and the liquid is then concentrated under high vacuum. The residue was purified by preparative HPLC (methanol: water gradient). 4.34g (52% of theory) of the title compound are obtained in the form of a solid.

LC-MS (method 3) R_t1.30 min

MS(ESIpos):m/z＝410(M+H)⁺

1H NMR(400MHz,DMSO-d6):＝2.84-3.00(m,2H),4.79(t,2H),7.93(dd,1H),8.71(dd,1H)。

Example 20A

5-fluoro-1- (3,3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3,4-b ] pyridine-3-carbonitrile

A suspension of 4.34g (10.609mmol) of the compound from example 19A and 1.045g (11.670mmol) of cuprous cyanide is initially introduced into DMSO (30ml) and stirred at 150 ℃ for 2 hours. After cooling, the resulting mixture was filtered through celite, washed with ethyl acetate and THF, and then extracted 4 times with saturated aqueous ammonium chloride and concentrated aqueous ammonia (3:1 v/v). The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure.

Yield 3.19g (97% of theory)

1H NMR(400MHz,DMSO-d6):＝2.94-3.09(m,2H),4.93(t,2H),8.54(dd,1H),8.88(dd,1H)。

Example 21A

5-fluoro-1- (3,3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3,4-b ] pyridine-3-carboximidamide acetate

3.19g (10,351mmol) of the compound from example 20A are added to 0.559g (10.351mmol) of sodium methoxide in methanol (25ml) and the mixture is stirred at room temperature for 2 hours. Thereafter, 0.664g (12.421mmol) of ammonium chloride and acetic acid (2.31ml) were added and the resulting mixture was heated to reflux overnight. After this time, the mixture was concentrated to dryness and the residue was mixed with ethyl acetate and 1N sodium hydroxide solution. The phases were separated. The aqueous phase was extracted again with ethyl acetate. The combined organic phases were combined and concentrated.

Yield 2.67g (37% of theory, approximately 56% purity)

LC-MS (method 1) R_t0.68 min

MS(ESIpos):m/z＝326(M+H)⁺

Working examples are as follows:

example 1

4-amino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one

Step a)

1.51g (37.84mmol) of sodium hydride (60% in mineral oil) are initially introduced into 10ml of DMSO. Thereafter, 2.5g (37.843mmol) of malononitrile in DMSO (10ml) were gradually added dropwise with cooling and the resulting mixture was stirred for 10 minutes. 3.582ml (37.843mmol) of methyl bromoacetate in DMSO (10ml) are subsequently added dropwise at room temperature. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction was then stopped by addition of saturated aqueous ammonium chloride solution, followed by addition of ethyl acetate. The phases were separated and the aqueous phase was extracted again with ethyl acetate. The combined organic phases were washed again with saturated aqueous ammonium chloride solution. Then dried over sodium sulfate, filtered and concentrated to dryness. The crude product was used without further purification in step b):

step b)

1.04g (3.403mmol) of the compound from example 1A are initially introduced into tert-butanol, and 458mg (4.083mmol) of potassium tert-butoxide are then added. Subsequently, 470mg (3.403mmol) of the crude product from step a) in tert-butanol were added and the resulting mixture was heated to reflux overnight. After cooling, water and ethyl acetate were added and the phases were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed once with water and once with saturated aqueous sodium chloride solution. Then dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by preparative HPLC (acetonitrile: water (+ 0.05% formic acid) gradient). After the product fractions were concentrated, DMF, water and acetonitrile were added, an insoluble residue was formed and filtered off. After washing the solid obtained with acetonitrile, 23mg of the expected compound (2% of theory) are obtained.

LC-MS (method 1) R_t0.82 min; MS (ESIpos) 376(M + H) M/z⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]＝3.34(s,2H),5.81(s,2H),6.85(s br,2H),7.13-7.25(m,3H),7.33-7.40(m,2H),8.63(dd,1H),8.99(dd,1H),10.95(s br,1H)。

Example 2

4-amino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one

5.887g (19.256mmol) of the compound from example 1A are initially introduced into tert-butanol (50ml) and 2.593g (23.107mmol) of potassium tert-butoxide are added. Subsequently, 3.2g (19.256mmol) of the compound of example 10A in tert-butanol (25ml) were added dropwise and the resulting mixture was heated to reflux overnight. The next day, another 0.64g (3.851mmol) of the compound of example 10A was added and the resulting mixture was heated to reflux for an additional day. After cooling, the precipitate is filtered off and washed with diethyl ether. The precipitate obtained is subsequently suspended in water, filtered off again and washed with diethyl ether. After drying under high vacuum, 6.65g of the expected compound are obtained (85% of theory).

LC-MS (method 1) R_t0.90 min; MS (ESIpos) 404(M + H) M/z⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]＝1.35(s,6H),5.82(s,2H),6.82(br s,2H),7.14-7.25(m,3H),7.33-7.40(m,2H),8.63(dd,1H),9.03(dd,1H),10.98(s br,1H)。

Example 3

4-amino-2- [ 5-fluoro-1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one

In analogy to the preparation of example 2, 4.18g (12.035mmol) of the compound of example 9A are reacted with 2.20g (13.239mmol) of the compound of example 10A. 3.72g of the expected compound (73% of theory) are obtained.

LC-MS (method 1) R_t0.98 min; MS (ESIpos) 422(M + H)⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]＝1.34(s,6H),5.81(s,2H),6.85(br s,2H),7.13-7.25(m,3H),7.36(m,1H),8.69(dd,1H),8.84(dd,1H),10.96(s br,1H)。

Example 4

4' -amino-2 ' - [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -4, 5-dihydrospiro [ furan-3, 5' -pyrrolo [2,3-d ] pyrimidine ] -6' (7' H) -one

In analogy to the preparation of example 2, 2.257g (7.382mmol) of the compound of example 1A are reacted with 1.434g (7.382mmol) of the compound of example 12A. This gave 566mg of the expected compound (17% of theory).

LC-MS (method 1) R_t0.84 min; MS (ESIpos) 432(M + H) M/z⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]＝2.20-2.37(m,2H),3.71(d,1H),3.90(q,1H),4.10(d,1H),4.25-4.31(m,1H),5.82(s,2H),6.57(br s,2H),7.12-7.25(m,3H),7.33-7.41(m,2H),8.64(dd,1H),9.02(dd,1H),11.96(s br,1H)。

Example 5

4-amino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -5-methyl-5, 8-dihydropyrido [2,3-d ] pyrimidin-7 (6H) -one

2.174g (7.112mmol) of the compound from example 1A and 1.3g (7.823mmol) of the compound from example 13A are initially introduced into 20ml of methanol, and 422mg (7.823mmol) of sodium methoxide are added in portions at room temperature. The resulting mixture was stirred at room temperature for 10 minutes and then heated to reflux overnight. After cooling, acetic acid (0.5ml) and water (20ml) were added to the mixture and it was cooled in an ice bath. The precipitate is filtered off with suction, washed with water and methanol and then dried under high vacuum. 2.51g of the expected compound (87% of theory) are obtained.

LC-MS (method 1) R_t0.85 min; MS (ESIpos) 404(M + H) M/z⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]＝1.04(d,3H),2.31(d,1H),2.79(dd,1H),3.13-3.19(m,1H),5.81(s,2H),6.93(br s,2H),7.12-7.25(m,3H),7.34-7.37(m,2H),8.62(dd,1H),9.14(dd,1H),10.56(s,1H)。

Example 6

4-amino-2- [1- (2-fluorobenzyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -5- (trifluoromethyl) -5, 8-dihydropyrido [2,3-d ] pyrimidin-7 (6H) -one

694mg (2.271mmol) of the compound according to example 1A and 500mg (2.271mmol) of the compound according to example 14A are initially introduced into 10ml of tert-butanol, and 305mg (2.725mmol) of potassium tert-butoxide are added in portions at room temperature. The resulting mixture was stirred at room temperature for 10 minutes, and then heated to reflux for 2 days. After cooling, water and ethyl acetate were added to the mixture. The precipitate is filtered off with suction. The filtrate is concentrated, a little ethyl acetate and diethyl ether are added and the precipitate formed is filtered off with suction. The combined solids from the two substeps were then dried under high vacuum. 588mg of the expected compound (53% of theory) are obtained.

LC-MS (method 1) with Rt 0.92 min; MS (ESIpos) 458(M + H)⁺

1H NMR(400MHz,DMSO-d6):[ppm]＝2.63(d,1H),3.19(dd,1H),4.16-4.20(m,1H),5.83(s,2H),7.13-7.40(m,7H),8.63(dd,1H),9.15(dd,1H),10.85(s,1H)。

Example 7

4-amino-5, 5-dimethyl-2- [1- (3,3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one

500mg (1.361mmol) of the compound from example 18A are initially introduced into tert-butanol (7.5ml) and 183mg (1.361mmol) of potassium tert-butoxide are added. Subsequently, 226mg (1.361mmol) of the compound of example 10A in tert-butanol (2.5ml) were added dropwise and the resulting mixture was heated to reflux overnight. After cooling, ethyl acetate and water were added, the phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue is stirred with methanol and the solid is filtered off with suction. The solid was washed vigorously with methanol, and the combined filtrates were concentrated and then purified by preparative HPLC (acetonitrile: water (+ 0.05% formic acid) gradient). 127mg of the title compound (21% of theory) are obtained.

LC-MS (method 1) R_t0.93 min; MS (ESIpos) 442(M + H) M/z⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]＝1.36(s,6H),2.91-3.04(m,2H),4.88(t,2H),6.83(br s,2H),7.38(dd,1H),8.63(dd,1H),9.02(dd,1H),11.01(s br,1H)。

Example 8

4-amino-2- [ 5-fluoro-1- (3,3,4,4, 4-pentafluorobutyl) -1H-pyrazolo [3,4-b ] pyridin-3-yl ] -5, 5-dimethyl-5, 7-dihydro-6H-pyrrolo [2,3-d ] pyrimidin-6-one

520mg (1.350mmol) of the compound from example 21A are initially introduced into tert-butanol (10ml) and 181mg (1.620mmol) of potassium tert-butoxide are added. 224mg (1.350mmol) of the compound of example 10A in tert-butanol (2.5ml) were then added and the resulting mixture was heated to reflux overnight. Subsequently, an additional 112mg (0.675mmol) of the compound of example 10A were added and the resulting mixture was heated to reflux for 7.5 hours. After cooling, water and ethanol were added and the mixture was placed in an ultrasonic bath for 1 hour. This process forms a precipitate which is filtered off with suction and washed with water. The filter cake was stirred with a small amount of ethanol (2-3ml) and filtered again with suction. The resulting solid was dried under high vacuum. 212mg of the title compound (34% of theory) are obtained.

LC-MS (method 1) R_t1.01 minutes; MS (ESIpos) 460(M + H) M/z⁺

¹H NMR(400MHz,DMSO-d₆):[ppm]＝1.36(s,6H),2.92-3.04(m,2H),4.87(t,2H),6.88(br s,2H),8.71(s br,1H),8.85(dd,1H),11.01(s br,1H)。

B.Measurement of drug efficacy

The pharmacological effects of the compounds of the invention can be shown in the assays below:

B-1.in vitro vasodilatory action

Rabbits were stunned from the neck and then exsanguinated. The aorta was removed, adherent tissue removed and divided into 1.5mM wide rings, which were individually placed under pre-stress in a 5ml organ bath containing a Krebs-Henseleit solution of carbopol-gold rinse (carbogen-scattered) with the following composition (in mM each) at 37 ℃: sodium chloride 119; potassium chloride: 4.8; calcium chloride dihydrate: 1; magnesium sulfate heptahydrate: 1.4; potassium dihydrogen phosphate: 1.2; sodium bicarbonate: 25; glucose: 10. contractile force was measured with Statham UC2 cells, amplified and digitized using an A/D sensor (DAS-1802HC, Keithley instruments Munich), and then recorded in parallel in a linear recorder. Phenylephrine is added cumulatively to the bath at increasing concentrations in order to produce contractions. After several control cycles, the substance to be investigated is added in each next round at each increasing dose and the degree of contraction is compared with the degree of contraction obtained in the upper round of the run. This was used to calculate the concentration (IC) required to reduce the magnitude of the control value by 50%₅₀Value). The standard administration volume was 5 μ l; the DMSO content in the bath solution corresponds to 0.1%.

Representative IC's of the Compounds of the invention₅₀The values are shown in the following table (table 1):

table 1:

example numbering	IC₅₀[nM]
		2	48
3	9.3
		4	24

B-2.Effect on recombinant Ornithine cyclase receptor cell lines

The cellular effects of the compounds of the invention are determined on recombinant ornithine cyclase receptor cell lines, such as f.wunderet al, anal.biochem.339104 — 112 (2005).

Representative values (MEC ═ minimum effective concentration) for the compounds of the invention are shown in the following table (table 2):

table 2:

example numbering	MEC[μM]
		2	0.001
3	0,001
		4	0,003

B-3.Radio telemetric measurement of rat blood pressure for conscious, spontaneous hypertension

A commercially available telemetry system from DATA SCIENCES INTERNATIONAL DSI, USA was used to make blood pressure measurements on conscious rats as described below.

The system consists of 3 main components:

-an implantable transmitter (a)Remote measuring emitter

A receiver (a)Receiver) connected to the multiplexer (DSI Data exchange matrix)

-a data acquisition computer.

The telemetry system makes it possible to continuously record blood pressure, heart rate and physical activity of a conscious animal in its general habitat.

Animal material

The tests were carried out in adult female spontaneously hypertensive rats (SHR Okamoto) weighing >200 g. SHR/NCrl from Okamoto Kyoto medical school (1963) is a hybrid of male Wistar Kyoto rats with greatly elevated blood pressure and female rats with slightly elevated blood pressure, and was delivered to F13 of the national Institutes of Health (u.s.national Institutes of Health).

After implantation of the emitter, the experimental animals were housed individually in Makrolon type 3 cages. It can freely obtain conventional feed and water.

The day/night rhythm in the laboratory was altered by room lighting at 6:00am and at 7:00 pm.

Emitter implantation

The TA11PA-C40 telemetry transmitter used was surgically implanted in the experimental animals under sterile conditions at least 14 days prior to the first experimental application. Animals fitted with instruments in this manner can be used repeatedly after wound healing and placement of the implant.

For implantation, fasted animals were anesthetized with pentobarbital (Nembutal, Sanofi:50mg/kg intraperitoneal) and then shaved and disinfected over a large area of their abdomen. After opening the abdominal cavity along the white line, the liquid-filled measuring catheter of the system is inserted into the descending aorta in the cranial direction above the bifurcation point and is cemented with tissue glue (VetBonD d)^TMAnd 3M) fixing. The transmitter housing is secured to the abdominal wall muscles within the abdominal cavity, and the wound is closed layer by layer.

To prevent infection, antibiotics (Tardomyocel COMP, Bayer,1ml/kg, subcutaneous injection) were administered post-operatively.

Substances and solutions

Unless otherwise stated, the substances to be investigated were each administered orally to a group of animals by gavage (n-6). The test substances are dissolved in a suitable solvent mixture or suspended in 0.5% methylcellulose (Tylose) in accordance with an administration volume of 5ml/kg body weight.

Animals of the solvent-treated group were used as a control group.

Test procedure

The telemetric measuring means was assigned to 24 animals. Each experiment is recorded with the experiment number (V years, months, days).

The instrumented rats that survived the system were each assigned a separate receiving antenna (1010Receiver, DSI).

The implanted transmitter may be externally activated by an integrated magnetic switch. It is switched to transmission in the experiment preparation phase. The signal transmission may be via a data acquisition system (Dataquest)^TMFor WINDOWS, DSI) are recorded online and processed accordingly. The data are each stored in a file created for this purpose and with the experiment number.

In the standard procedure, the following indices were measured in each case with a period of 10 seconds:

-systolic pressure (SBP)

Diastolic pressure (DBP)

Mean Arterial Pressure (MAP)

Heart Rate (HR)

-Activity (ACT).

Measurements were taken repeatedly at 5 minute intervals under computer control. The source data obtained as absolute values are corrected in the diagram with the currently measured barometric pressure (ambient pressure reference monitor; APR-1) and stored as separate data. Other technical details are given in the large number of documents of the manufacturer company (DSI).

Unless otherwise stated, the test article was administered at 9.00am on the day of the experiment. After dosing, the parameters described above were measured over a 24 hour period. .

Evaluation of

After the experiment was finished, analytical software (DATAQUEST) was used^TMTm ANALYSIS) to classify the collected individual data. Blank values were assumed to be 2 hours prior to dosing, so the data set chosen covered the time from 7.00am on the day of the experiment to 9.00am on the next day.

The data were smoothed over an adjustable period of time by measuring the average (15 minute average) and transferred as a text document to a storage medium. The measurements pre-classified and compressed in this way were transferred to Excel templates and tabulated. For daily experiments, the data obtained are stored in a dedicated file with the experiment number. The results and test protocol are archived in paper form sorted by number.

Reference to the literature

Klaus Witte,Kai Hu,Johanna Swiatek,Claudia Müssig，Georg Ertl andLemmer:Experimental heart failure in rats:effects on cardiovascularcircadian rhythms and on myocardialβ-adrenergic signaling.Cardiovasc Res 47(2):203-405,2000；Kozo Okamoto:Spontaneous hypertension in rats.Int Rev ExpPathol 7:227-270,1969；Maarten van den Buuse:Circadian Rhythms of BloodPressure,Heart Rate,and Locomotor Activity in Spontaneously Hypertensive Ratsas Measured With Radio-Telemetry.Physiology&Behavior 55(4):783-787,1994

C.Working examples for pharmaceutical compositions

The compounds of the present invention can be converted into the following pharmaceutical preparations.

And (3) tablet preparation:

composition (A):

100mg of a compound of the invention, 50mg of lactose (monohydrate), 50mg of corn starch (native), 10mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2mg of magnesium stearate.

The tablet has the weight of 212mg, the diameter of 8mm and the curvature radius of 12 mm.

Preparation:

a mixture of the compound of the invention, lactose and starch was granulated with a 5% (w/w) aqueous solution of PVP. The resulting granules were dried and then blended with magnesium stearate for 5 minutes. The mixture is compressed using a conventional tablet press (see above for tablet forms). The pressure guideline value for tableting was 15 kN.

Suspending agents for oral administration:

composition (A):

1000mg of a compound of the invention, 1000mg of ethanol (96%), 400mg(xanthan gum from FMC, Pennsylvania, USA) and 99g water.

A single dose of 100mg of a compound of the invention corresponds to 10ml of an oral suspension.

Preparation:

suspending the Rhodigel in ethanol; the compounds of the invention are added to the suspension. Water was added with stirring. The resulting mixture was stirred for about 6 hours until swelling of the Rhodigel was complete.

Solutions for oral administration:

composition (A):

500mg of a compound according to the invention, 2.5g of polysorbate and 97g of polyethylene glycol 400. A single dose of 100mg of a compound of the invention corresponds to 20g of an oral solution.

Preparation:

the compounds of the invention are suspended in a mixture of polyethylene glycol and polysorbate under agitation. The stirring operation is continued until the dissolution of the compound of the present invention is completed.

Intravenous administration solution:

the compounds of the invention are dissolved in a physiologically acceptable solvent (e.g., isotonic saline, 5% glucose solution, and/or 30% PEG 400 solution) at a concentration below saturation solubility. The solution was sterile filtered and dispensed into sterile and pyrogen-free injection containers.

Claims

1. Compounds of formula (I) and salts thereof,

wherein

A is C₁-an alkanediyl group,

and is

Wherein C is₁-alkanediyl is substituted with 1 or 2 substituents independently selected from (C)₁-C₄) An alkyl group, a carboxyl group,

R¹is a fluorine compound, and is characterized in that,

R²is a benzyl group, and the benzyl group,

and is

Wherein the benzyl group is substituted with 1 to 3 fluoro substituents.

2. A process for the preparation of a compound of formula (I) as defined in claim 1, characterized in that

[A] Reacting a compound of formula (II) under acidic conditions

Wherein R is¹And R²Each as defined in claim 1

Conversion to a compound of formula (III)

Wherein R is¹And R²Each as defined in claim 1, respectively,

reacting a compound of formula (III) with a compound of formula (IV) in an inert solvent in the presence of a suitable base

Wherein A is as defined in claim 1 and

T¹is (C)₁-C₄) An alkyl group, a carboxyl group,

to give a compound of the formula (I)

A, R therein¹And R²Each as defined in claim 1, respectively,

and the resulting compound of formula (I) is optionally converted to a salt thereof with a suitable (ii) acid or base.

3. Use of a compound of formula (I) as defined in claim 1 for the preparation of a medicament for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, ischemia, vascular disorders, renal failure, thrombotic disorders, fibrotic disorders and arteriosclerosis.

4. The use of claim 3, wherein the hypertension is pulmonary hypertension.

5. A medicament comprising a compound of formula (I) as defined in claim 1 together with inert, non-toxic pharmaceutically acceptable excipients.

6. A medicament comprising a compound of formula (I) as defined in claim 1 and a further active ingredient selected from: organic nitrate, NO donor, cGMP-PDE inhibitor, antithrombotic agent, hypotensive agent and lipid metabolism regulator.

7. The medicament according to claim 5 or 6 for the treatment and/or prophylaxis of heart failure, angina pectoris, hypertension, ischemia, vascular disorders, renal failure, thrombotic disorders, fibrotic disorders and arteriosclerosis.

8. The medicament of claim 7, wherein the hypertension is pulmonary hypertension.