EP2212331A1

EP2212331A1 - Trisubstituted furopyrimidines and the use thereof as activators of the ip receptor

Info

Publication number: EP2212331A1
Application number: EP08850886A
Authority: EP
Inventors: Thomas Lampe; Raimund Kast; Friederike Stoll; Joachim Schuhmacher
Original assignee: Bayer Schering Pharma AG
Current assignee: Bayer Pharma AG
Priority date: 2007-11-16
Filing date: 2008-11-03
Publication date: 2010-08-04
Also published as: JP2011503126A; WO2009062605A1; CA2705689A1; DE102007054786A1; US20100267749A1

Abstract

The invention relates to the novel 4,5,6-trisubstituted furo[2,3-d]pyrimidine derivatives of formula (I), to methods for their production, their use in the treatment and/or prophylaxis of diseases and their use in the production of drugs for the treatment and/or prophylaxis of diseases, especially for the treatment and/or prophylaxis of cardiovascular diseases.

Description

TRISUBSTITUTED FUROPYRAMIDINES AND THEIR USE AS ACTIVATORS OF THE IP RECEPTOR

The present application relates to novel 4,5,6-trisubstituted furo [2,3-d] pyrimidine derivatives, processes for their preparation, their use for the treatment and / or prophylaxis of diseases, and 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 diseases.

Prostacyclin (PGI ₂ ) belongs to the family of bioactive prostaglandins, which are derivatives of arachidonic acid. PGI ₂ is the major product of arachidonic acid metabolism in endothelial cells and has potent vasodilating and anti-aggregating properties. PGI ₂ is the physiological antagonist of thromboxane A ₂ (TxA ₂ ), a potent vasoconstrictor and platelet aggregation stimulator, thus contributing to the maintenance of vascular homeostasis. A reduction in PGI ₂ levels is probably responsible for the development of various cardiovascular diseases [Dusting, GJ. et al., Pharmac. Ther. 1990, 48: 323-344; Vane, J. et al., Eur. J. Vase. Endovasc. Surg. 2003, 26: 571-578].

After release of arachidonic acid from phospholipids via phospholipases A ₂ PGI ₂ is synthesized by cyclooxygenases and then by the PGI ₂ synthase. PGI ₂ is not stored, but released immediately after synthesis, causing its effects locally. PGI ₂ is an unstable molecule that is rapidly (half-life about 3 minutes) non-enzymatically rearranged to an inactive metabolite, 6-keto-prostaglandin Fl alpha [Dusting, GJ. et al., Pharmac. Ther. 1990, 48: 323-344].

The biological effects of PGI ₂ are due to the binding to a membrane-bound receptor, the so-called prostacyclin or IP receptor [Narumiya, S. et al., Physiol. Rev. 1999, 79: 1193-1226]. The IP receptor belongs to the G protein-coupled receptors that are characterized by seven transmembrane domains. In addition to the human IP receptor, rat and mouse prostacyclin receptors have also been cloned [Vane, J. et al., Eur. J. Vase. Endovasc. Surg. 2003, 26: 571-578]. In smooth muscle cells, activation of the IP receptor leads to stimulation of adenylate cyclase, which catalyzes the formation of cAMP from ATP. The increase in the intracellular cAMP concentration is responsible for the prostacyclin-induced vasodilation and the inhibition of platelet aggregation. In addition to the vasoactive properties, PGI ₂ still has anti-proliferative [Schroer, K. et al., Agents Actions Suppl. 1997, 48: 63-91; Kothapalli, D. et al., Mol. Pharmacol. 2003, 64: 249-258; Planchon, P. et al., Life Sei. 1995, 57: 1233-1240] and anti-arteriosclerotic effects [Rudic, RD et al., Circ. Res. 2005, 96: 1240-1247; Egan KM et al., Science 2004, 114: 784-794]. In addition, metastasis formation is inhibited by PGI ₂ [Schneider, MR et al., Cancer Metastasis Rev. 1994, 13: 349-64). Whether these effects are due to stimulation of cAMP production or by IP receptor-mediated activation of other signal transduction pathways in the respective target cell [Wise, H. et al. TIPS 1996, 17: 17-21], such as the phosphoinositide cascade and potassium channels, is unclear.

Although the overall effects of PGI _{2 are} therapeutically useful, clinical use of PGI ₂ is severely limited by its chemical and metabolic instability. More stable PGI ₂ analogs such as iloprost [Badesch, DB et al., J. Am. Coli. Cardiol. 2004, 43: 56S-61S] and treprostinil [Chattaraj, SC, Curr. Opion. Invest. Drugs 2002, 3: 582-586] could be made available, but the duration of these compounds is still very short. Also, the substances can be administered to the patient only via complicated routes of administration, such as by continuous infusion, subcutaneously or via repeated inhalations. These routes of administration can also lead to additional side effects, such as infections or pain at the injection site. The use of the only PGI ₂ derivative orally available to the patient, beraprost [Barst, RJ. et al., J. Am. Coli. Cardiol. 2003, 41: 2119-2125], again limited by its short duration of action.

The object of the present invention is to provide new substances which act as chemically and metabolically stable, orally available activators of the IP receptor and are suitable as such for the treatment of diseases, in particular of cardiovascular diseases.

WO 03/018589 discloses 4-aminofuro [2,3-d] pyrimidines as adenosine kinase inhibitors for the treatment of cardiovascular diseases. Furthermore, in WO 2007/079861 and WO 2007/079862 4-amino, 4-oxy or 4-thio-substituted 5,6-diphenylfuro [2,3-d] pyrimidine derivatives and their use for the treatment of cardiovascular diseases described. Furo [2,3-d] pyrimidines substituted in the 5- and / or 6-position with alkyl and / or alkenyl radicals and their use for the treatment of various diseases are described in DE 1 817 146, WO 03/022852, WO 03 / 080064, WO 2005/092896, WO 2005/121149 and WO 2006/004658.

The present invention relates to compounds of the general formula (I)

in which

R ^{1 is} (C _r C ₆ ) alkyl or a group of the formula -C (= O) -R ^1A or -CH (OH) -R ^1B where

R ^1A (C _r C ₆ ) alkyl, hydroxy, (C _r C ₆ ) alkoxy, (C ₂ -C ₆ ) alkenyloxy, amino, mono (C _r C ₆ ) alkylamino or mono (C ₂ -C ₆ ) alkenylamino

and

R ^{1B is} (C _r C ₆ ) -alkyl,

R ² is hydrogen or (C _r C ₄₎ -alkyl,

R ^{3 represents} a substituent selected from the group consisting of halogen, cyano, nitro, (C ₁ -C ₆ ) -alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₄ ) -alkynyl, (C ₃ -C ₇ ) cycloalkyl, (C ₄ -C ₇₎ cycloalkenyl, (C ₁ -C ₆₎ - alkoxy, trifluoromethyl, trifluoromethoxy, (Ci-C ₆₎ alkylthio, (Ci-C _ö) -acyl, amino, mono-

(C ₁ -C ₆ ) -alkylamino, di (C ₁ -C ₆ ) -alkylamino and (C ₁ -C ₆ ) -acylamino,

where (C ₁ -C ₆ ) -alkyl and (C ₁ -C ₆ ) -alkoxy in each case in each case with cyano, hydroxy, (C 1 -C ₄ ) -alkoxy, (C 1 -C ₄ ) -alkylthio, amino, mono- or di- (C 1 -C ₄ ) -alkylamino may be substituted,

m is the number 0, 1 or 2,

in the case that the substituent R ³ occurs twice, its meanings may be the same or different,

A is O or NR ⁴ , in which

Tet R ⁴ is hydrogen, (C _r _C6) alkyl, (C ₃ -C ₇₎ -cycloalkyl or (C ₄ -C ₇₎ cycloalkenyl significance,

M for a group of the formula

R ⁵

# - CH- L- ## or # - | J- £ Q "V-L- ##

stands in which

# the linkage with the group A and

## means the point of attachment to the group Z,

R ^{5 is} hydrogen or (C 1 -C ₄ ) -alkyl which may be substituted by hydroxyl or amino,

L ^{1 is} (C ₁ -C ₇ ) -alkanediyl or (C ₂ -C ₇ ) -alkendiyl, which may be mono- or di-substituted by fluorine, or a group of formula * -L ^IA -VL ^1B - **, in which

* the point of attachment with the group -CHR ⁵ ,

** the point of attachment to the group Z,

L ^1A (Ci-C ₅₎ -alkanediyl which may be mono- or disubstituted by identical or different (Ci-C ₄₎ -alkyl and / or (C _r C ₄₎ alkoxy,

L ^{1B is} a bond or (C ₁ -C ₃ ) -alkanediyl which may be mono- or disubstituted by fluorine,

and

VO or NR ⁶ , in which

R ⁶ is hydrogen, (C _r _C6) alkyl or (C ₃ -C ₇₎ cycloalkyl,

represent

L ^{2 is} a bond or (C 1 -C ₄ ) -alkanediyl,

L ³ (C _r C ₄ ) alkanediyl which may be mono- or disubstituted by fluorine and in which a methylene group may be replaced by O or NR ⁷ , wherein

R ⁷ is hydrogen, (C _r _C6) alkyl or (C ₃ -C ₇₎ cycloalkyl,

or (C ₂ -C ₄ ) -alkendiyl,

and

Q is (C ₃ -C ₇ ) -cycloalkyl, (C ₄ -C ₇ ) -cycloalkenyl, phenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl, which may each be up to twice, identical or different, with radicals selected from the group fluorine, chlorine, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, hydroxy, (C 1 -C ₄ ) -alkoxy, trifluoromethoxy, amino, mono (C 1 -C ₄ ) - alkylamino and di- (C 1 -C ₄ ) -alkylamino may be substituted,

wherein (Ci-C ₄₎ -alkyl for its part may be substituted by hydroxy, (C _r C ₄₎ alkoxy, amino, mono- or di- (C] _-C4) alkylamino,

and

Z is a group of the formula

stands in which

### the linkage with the group L ¹ or L ³

and

R ⁸ is hydrogen or (C _r C ₄₎ alkyl,

and their salts, solvates and solvates of the salts.

Compounds of the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts comprising the compounds of the formulas below and their salts, solvates and solvates of the salts encompassed by formula (I) and those of the formula (I), hereinafter referred to as exemplary compounds and their salts, solvates and solvates of the salts, as far as the compounds of formula (I), the compounds mentioned below are not already salts, solvates and solvates of the salts.

Depending on their structure, the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore includes the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers, the stereoisomerically uniform components can be isolated in a known manner.

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms. As salts, physiologically acceptable salts of the compounds according to the invention are preferred in the context of the present invention. Also included are salts which are themselves unsuitable for pharmaceutical applications but can 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 mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

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

In the context of the invention, solvates are those forms of the compounds according to the invention which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water. As solvates, hydrates are preferred in the context of the present invention.

In addition, the present invention also includes prodrugs of the compounds of the invention. The term "prodrugs" includes compounds which may themselves be biologically active or inactive, but during their residence time in the body are converted to compounds of the invention (for example metabolically or hydrolytically).

In particular, the present invention in the case of the compounds of the formula (I) in which

Z is a group of the formula

stands,

also hydrolysable ester derivatives of these compounds. These are understood to mean esters which can be hydrolyzed in physiological media, under the conditions of the biological tests described below, and in particular in vivo enzymatically or chemically to the free carboxylic acids, as the biologically mainly active compounds. As such esters, (C 1 -C ₄ ) -alkyl esters in which the alkyl group may be straight-chain or branched are preferred. Particularly preferred are methyl, ethyl or terf.-butyl ester (see also corresponding definitions of the radical R ⁸ ).

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:

(C ₁ -CJ-AlkVl (C ₁ -CQ-AlkVl, (C ₁ -Ca) -AUcVl and (C _r CV) alkyl are in the context of the invention for a straight-chain or branched alkyl radical having 1 to 6, 1 to 5 1 to 4 or 1 to 3 carbon atoms is preferred, a straight-chain or branched alkyl radical having 1 to 4, particularly preferably 1 to 3, carbon atoms being given by way of example and preferably: methyl, ethyl, n-propyl, isopropyl, n-butyl where n-butyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl. in the context of the invention for a straight-chain or branched alkenyl radical having 2 to 6, 2 to 5 or 2 to 4 carbon atoms and one or two double bonds. Preference is given to a straight-chain or branched alkenyl radical having 2 to 4 carbon atoms and one double bond. Examples which may be mentioned are: vinyl, allyl, isopropenyl, n-but-2-en-1-yl, 2-methylprop-2-en-1-yl and n-but-3-en-1-yl.

In the context of the invention, C 1 -C 4 -alkynyl is a straight-chain or branched alkynyl radical having 2 to 4 carbon atoms and a triple bond, a straight-chain alkynyl radical having 2 to 4 carbon atoms being preferred in-1-yl, n-prop-2-yn-1-yl, n-but-2-yn-1-yl and n-but-3-yn-1-yl. in the context of the invention are a straight-chain or branched divalent alkyl radical having 1 to 4 or 1 to 3 carbon atoms. In each case, a straight-chain alkanediyl radical having 1 to 4 or 1 to 3 carbon atoms is preferred. By way of example and preferably mention may be made of: methylene, ethane-1,2-diyl (1,2-ethylene), ethane-1,1-diyl, propane-1,3-diyl (1,3-propylene), propane-1, l-diyl, propane-l, 2-diyl, propane-2,2-diyl, butane-1,4-diyl (1,4-butylene), butane-1,2-diyl, butane-l, 3-diyl and butane-2,3-diyl. in the context of the invention are a straight-chain or branched divalent alkyl radical having 1 to 7, 1 to 5 or 3 to 7 carbon atoms. In each case, a straight-chain alkanediyl radical having 1 to 7, 1 to 5 or 3 to 7 carbon atoms is preferred. Examples which may be mentioned by way of example and are preferably: methylene, ethane-1,2-diyl (1,2-ethylene), ethane-1,1-diyl, propane-1,3-diyl (1,3-propylene), propane-1, l-diyl, propane-l, 2-diyl, propane-2,2-diyl, butane-1,4-diyl (1,4-butylene), butane-1,2-diyl, butane-l, 3-diyl , Butane-2,3-diyl, pentane-1,5-diyl (1,5-pentylene), pentane-2,4-diyl, 3-methyl-pentane-2,4-diyl and hexane-1,6- diyl (1,6-hexylene).

(C ₂ -Cd) -Alkendiyl and (Cϊ-CCl-alkenediyl in the context of the invention are a straight-chain or branched divalent alkenyl radical having 2 to 4 or 2 to 3 carbon atoms and up to 2 double bonds 2 to 4 or 2 to 3 carbon atoms and one double bond, by way of example and preferably: ethene-1, 1-diyl, ethene-1,2-diyl, propene-1, 1-diyl, propylene-1,2-diyl Propen-1, 3-diyl, but-1-ene-1,4-diyl, but-1-en-1, 3-diyl, but-2-ene-1,4-diyl and buta-1, 3 -diene-l, 4-diyl. in the context of the invention for a straight-chain or branched divalent alkenyl radical having 2 to 7 or 3 to 7 carbon atoms and up to 3

Double bonds. In each case, a straight-chain alkenediyl radical having 2 to 7 or 3 to 7 is preferred

Carbon atoms and a double bond. By way of example and preferably:

Ethene-1, 1-diyl, ethene-1, 2-diyl, propene-1,1-diyl, propylene-1,2-diyl, propen-1, 3-diyl, but-1-ene-1,4- diyl, but-1-en-1, 3-diyl, but-2-ene-1,4-diyl, buta-1,3-dien-1, 4-diyl, pent-2-en-1, 5 diyl, hex-3-ene-1, 6-diyl and hexa-2,4-diene-l, 6-diyl.

In the context of the invention, (C ₁ -Q) -alkoxy and (C ₂ -C 4) -alkoxy represent a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms, preference being given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms called: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.

(C ₂ -C 4) -Alkenyloxy in the context of the invention represents a straight-chain or branched alkenyloxy radical having 2 to 6 carbon atoms and one double bond in the alkenyl group. Preference is given to a straight-chain or branched alkenyloxy radical having 3 or 4 carbon atoms. Examples which may be mentioned are: allyloxy, (n-but-2-en-1-yl) oxy, (2-methylprop-2-en-1-yl) oxy and (n-but-3-en-1-yl ) oxy. in the context of the invention are a straight-chain or branched alkylthio radical having 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched alkylthio radical having 1 to 4 carbon atoms. Exemplary and forward may be mentioned: methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, n-pentylthio and n-hexylthio.

(C ₁ -GO-AcVl [(C _r C ₆ ) alkanoyl], (C ₁ -C ₁ VACvI [(C, -Cs) -AlkEnOyI] and (C _r GiVAcyl [(C, -C ₄ ) alkanoyl ] represent in the context of the invention a straight-chain or branched alkyl radical having 1 to 6, 1 to 5 or 1 to 4 carbon atoms which carries a doubly bonded oxygen atom in the 1-position and is linked via the 1-position straight-chain or branched acyl radical having 1 to 4 carbon atoms, by way of example and preferably: formyl, acetyl, propionyl, n-butyryl, isobutyryl and pivaloyl. in the context of the invention are an amino group having a straight-chain or branched alkyl substituent which has 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms. Examples which may be mentioned by way of example include methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.

Di- (C ₁ -C 6) -alkylamino and di- (C ₁ -C ₄ -alkyl ₎ vinylamine are in the context of the invention an amino group having two identical or different straight-chain or branched alkyl substituents, each having 1 to 6 or 1 to 4 Preference is given to straight-chain or branched dialkylamino radicals each having 1 to 4 carbon atoms, examples of which are preferably: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N- Methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.

Mono- (C 2 -C 12 -alkenylamino means in the context of the invention an amino group having a straight-chain or branched alkenyl substituent which has 2 to 6 carbon atoms and one double bond, preference is given to a straight-chain or branched monoalkenylamino radical having 3 or 4 carbon atoms Allylamino, (n-but-2-en-1-yl) amino, (2-methylprop-2-en-1-yl) -amino and (n-but-3-en-1-yl) -amino may be mentioned as preference , in the context of the invention are an amino group having a straight-chain or branched acyl substituent which has 1 to 6 or 1 to 4 carbon atoms and is linked via the carbonyl group. Preference is given to an acylamino radical having 1 to 4 carbon atoms. Examples which may be mentioned are: formamido, acetamido, propionamido, n-butyramido and pivaloylamido.

(C ₁ -C ₂ VCvClOalkyl ₎ (C ₁ -C ₄ ) cycloalkyl and (C ₁ -C ₄ -cycloalkyl in the context of the invention represent a monocyclic, saturated cycloalkyl group having 3 to 7, 3 to 6 or 4 to 6 carbon atoms. atoms. Preference is given to a cycloalkyl radical having 3 to 6 carbon atoms. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

(C4-C ₂ ) -Ccloalkenyl, (Q-QyCycloalkenyl and (C _j -Cfi) cycloalkenyl in the context of the invention for a monocyclic cycloalkyl group having 4 to 7, 4 to 6 or 5 or 6 carbon atoms and a double bond Preference is given to a cycloalkenyl radical having 4 to 6, particularly preferably 5 or 6, carbon atoms, and may be mentioned by way of example and preferably: cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.

In the context of the invention, 5- to 7-membered heterocyclyl represents a saturated or partially unsaturated heterocycle having a total of 5 to 7 ring atoms which contains one or two ring heteroatoms from the series N and / or O and via ring carbon atoms and or optionally ring nitrogen atoms is linked. Preference is given to a 5- or 6-membered saturated heterocycle having one or two ring heteroatoms from the series N and / or O. Examples which may be mentioned are: pyrrolidinyl, pyrrolinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, dihydropyranyl, tetrahydropyranyl, morpholinyl , Hexahydroazepinyl and hexahydro-1,4-diazepinyl. Preference is given to pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl and morpholinyl.

5- or 6-membered heteroaryl in the context of the invention represents an aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms containing one or two ring heteroatoms from the series N, O and / or S and via ring carbon atoms and / or optionally a ring nitrogen atom is linked. Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl. Thienyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl are preferred.

Halogen in the context of the invention includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.

If radicals are substituted in the compounds according to the invention, the radicals can, unless otherwise specified, be monosubstituted or polysubstituted. In the context of the present invention, the meaning is independent of each other for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred. Particularly preferred is a substitution with one or two identical or different substituents, very particularly preferably the substitution with a substituent.

Preferred in the context of the present invention are compounds of the formula (I) in which

R ^{1 is} (C _r C ₄ ) alkyl or a group of the formula -C (= O) -R ^1A wherein R ^{1A is} (Ci-Gi) -alkyl, hydroxy, (C _r C ₄ ) -alkoxy, allyloxy, mono- (Ci-C ₄ ) -alkylamino or allylamino,

R ^{2 is} hydrogen, methyl or ethyl,

R ^{3 is} a substituent selected from the group fluorine, chlorine, cyano, methyl, ethyl, methoxy, ethoxy, trifluoromethyl and trifluoromethoxy,

m is the number 0, 1 or 2,

A is O or NH,

M for a group of the formula

# - CH- L- ## or # - iΛ-f- Q 4 ~ L- ##

stands in which

# the linkage with the group A

and

## means the point of attachment to the group Z,

R ^{5 is} hydrogen, methyl or ethyl,

L ^{1 is} (C ₃ -C ₇ ) alkanediyl, (C ₃ -C ₇ ) alkylenediyl or a group of formula * -L ^1A -VL ^1B - ** in which

* the point of attachment with the group -CHR ⁵ ,

** the point of attachment to the group Z,

L ^1A (C ₁ -C ₃ ) -alkanediyl which may be monosubstituted or disubstituted by methyl,

L ^1B (C, -C ₃ ) alkanediyl and

VO or N-CH ₃

represent

L ^{2 is} a bond, methylene, ethane-1, 1-diyl or ethane-1, 2-diyl,

L ³ (C ₁ -C ₃ ) alkanediyl or a group of the formula "-W-CH ₂ - *" or

--W-CH ₂ -CH ₂ - ** means in which

The point of attachment to the ring Q,

•• the link to the group Z

and

WO or NR ⁷ , wherein

R ^{7 is} hydrogen or (C ₁ -C ₃ ) -alkyl,

represent

and

Q is cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl or phenyl which are each up to twice, identically or differently, selected from fluorine, methyl, ethyl, trifluoromethyl, hydroxy, methoxy and Ethoxy can be substituted,

and

Z is a group of the formula

stands in which

### means the point of attachment to the group L ¹ or L ³ , and their salts, solvates and solvates of the salts.

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

R ^{1 is} ethyl, n-propyl or a group of the formula -C (= O) -R ^1Λ in which

R ^{1Λ is} ethyl, n-propyl, ethoxy, allyloxy, ethylamino, n-propylamino or allylamino,

R ^{2 is} hydrogen or methyl,

R ^{3 is} fluorine, chlorine or methyl,

m is the number 0 or 1,

A is O or NH,

M for the group of the formula

R ⁵

1

# - CH - L - ## stands in which

# the linkage with the group A

and

## means the point of attachment to the group Z,

R ^{5 is} hydrogen or methyl,

and

L ^{1 is} butan-l, 4-diyl, pentan-l, 5-diyl or a group of the formula * -L ^1A -OL ^1B - **, in which

* the point of attachment with the group -CHR ⁵ ,

** the point of attachment to the group Z,

L ^{1A is} methylene or ethane-1,2-diyl which may be monosubstituted or disubstituted by methyl, NND

L ^1B methylene or ethane-1, 2-diyl

represent

and

Z for the group of the formula

stands in which

### means the point of attachment to the group L ¹ ,

and their salts, solvates and solvates of the salts.

The residue definitions given in detail in the respective combinations or preferred combinations of residues are also replaced by residue definitions of other combinations, regardless of the particular combinations of the residues indicated.

Particularly preferred are combinations of two or more of the preferred ranges mentioned above.

Very particular preference in the context of the present invention is given to the compounds mentioned below:

(<5 R) -6 - ({5 - [(7 £) -3-ethoxy-2-methyl-3-oxoprop-l-en-l-yl] -6-phenylfuro [2,3-d] pyrimidine 4-yl} - oxy) heptanoic acid,

(6Λ) -6- ({5 - [(7)) -3- (ethylamino) -2-methyl-3-oxo-prop-1 -ene-1-yl] -6-phenylfuro [2,3-d] pyrimidine 4-yl) oxy) heptanoic acid

and

(<JR) -6 - ({5 - [(7 ^ -2-methyl-3-oxo-3- (propylamino) prop-l-en-l-yl] -6-phenylfuro [2,3-d] pyrimidin-4-yl) oxy) heptanoic acid e

and their salts, solvates and solvates of the salts. The invention further provides a process for the preparation of the compounds of the formula (I) according to the invention in which Z is -COOH or -C (OO) -COOH, which comprises reacting a compound of the formula (II)

in which R ³ and m have the meanings given above

and

X ^{1 represents} a leaving group such as, for example, halogen, in particular chlorine,

in an inert solvent in the presence of a base with a compound of formula (HI)

, IVk

HA (m),

in which A and M have the meanings given above

and

Z ^{1 is} cyano or a group of the formula - [C (O)] _y -COOR ^8A in which

the number 0 or 1

and

R> 8 ⁸ A ^A denotes (C ₁ -C) -alkyl,

to a compound of the formula (IV)

in which A, M, Z rl, r R 3 and m are each as defined above, and then either

[A] in an inert solvent in the presence of a base and a suitable palladium catalyst with a boronic acid derivative of the formula (V) or an olefin of the formula (VI)

(V) (VI)

in which R ¹ and R ^{2 have} the meanings given above

and

R ^{9 is} hydrogen or (C 1 -C ₄ ) -alkyl or both radicals R ⁹ together form a -CH ₂ -CH ₂ -, -C (CH ₃ ) ₂ -C (CH ₃ ) ₂ - or -CH ₂ -C Form (CH ₃ ) ₂ -CH ₂ -bridge,

to a compound of formula (VE)

in which A, M, Z, R, R, R and m are each as defined above,

couples

or

[B] first in an inert solvent in the presence of a base and a suitable palladium catalyst with a vinylboronic acid derivative of the formula (VEH)

H ₂ C

CX

^* R ^S (VI!),

in which R ^{9 has} the abovementioned meaning, into a compound of the formula (EX)

in which A, M, Z 1, τ R) 3 and m are each as defined above,

subsequently converted by reaction with ozone and subsequent treatment with a sulfide to give a compound of the formula (X)

in which A, M, Z, R and m are each as defined above,

oxidized and then in an inert solvent in the presence of a base with a phosphorus YHd of the formula (XI) or a phosphonate of the formula (XIT)

(XI) (XH)

in which R ¹ and R ^{2 have} the meanings given above and

R ^{1 is} phenyl or o-, m- or p-tolyl,

R ^{1 is} (C ¹ -C ₄ ) -alkyl

and

Y ^'is a halide anion,

to a compound of formula (VIT)

in which A, M, Z ¹ , R ¹ , R ² , R ³ and m are each as defined above,

couples

and the compounds of the formula (VII) finally by hydrolysis of the ester or cyano group Z ¹ into the carboxylic acids of the formula (IA)

in which A, M, R ¹ , R ² , R ³ , m and y each have the meanings given above,

and optionally with the corresponding (i) solvents and / or (ii) bases or acids to their solvates, salts and / or solvates of the salts.

Inert solvents for process step (II) + (HT) - »(IV) are, for example, ethers, such as diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane, Cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichloroethane, tetrachloroethane, trichlorethylene, chlorobenzene or chlorotoluene, or other solvents such as dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (ΝMP) or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using tetrahydrofuran, toluene, dimethylformamide, dimethyl sulfoxide or mixtures of these.

Optionally, however, the process step (IT) + (HI) - »(FV) can also be carried out without a solvent. AIs base for process step (II) + (HI) -> (IV) are customary inorganic or organic bases. These include preferably alkali metal hydroxides such as lithium, sodium or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, alkali metal alcoholates such as sodium or potassium terf.-butylate, alkali metal hydrides such as sodium or Potassium hydride, amides such as lithium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, organometallic compounds such as butyl lithium or phenyllithium, or organic amines such as triethylamine, N-methylmorpholine, N-methylpiperidine, N, N-diisopropylethylamine or pyridine.

In the case of reaction with alcohol derivatives [A in (HI) = O] also phosphazene bases (so-called "Schwesinger bases") such as P2-t-Bu or P4-t-Bu are useful [see. e.g. R. Schwesinger, H. Schlemper, Angew. Chem. Int. Ed. Engl. 26, 1167 (1987); T. Pietzonka, D. Seebach, Chem. Ber. 124, 1837 (1991)].

In the reaction with amine derivatives [A in (HI) = Ν] tertiary amines, in particular N, N-diisopropylethylamine, sodium tert-butoxide or sodium hydride are preferably used as the base. If appropriate, however, these reactions can also be carried out-without the use of an auxiliary base-if an excess of the amine component (TS) is used. In the reaction with alcohol derivatives [A in (ST) = O], sodium hydride, potassium or cesium carbonate or the phosphazene bases P2-t-Bu and P4-t-Bu are preferred.

The process step (II) + (HI) -> (IV) may optionally be carried out advantageously with the addition of a crown ether.

Li another variant of the process, the reaction (II) + (ST) -> (TV) in a two-phase mixture consisting of an aqueous alkali metal hydroxide solution as a base and one of the above hydrocarbons or halogenated hydrocarbons as a further solvent, under Use of a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate or tetrabutylammonium bromide are performed.

The process step (II) + (IH) -> (TV) is carried out in the reaction with amine derivatives [A in (IH) = Ν] generally in a temperature range from -20 ⁰ C to + 15O ⁰ C, preferably at 0 ⁰ C. to + 100 ⁰ C. in the reaction with alcohol derivatives [a in (TS) = O], the reaction is generally carried out in a temperature range of -20 ⁰ C to +120 ⁰ C, preferably at -10 ⁰ C to +80 ⁰ C carried out.

Inert solvents for process steps (IV) + (V) → (VTT) and (IV) + (VTS) → (TX) are, for example, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol , Ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene Glykoldimethylether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethyl sulfoxide, NN-dimethylpropyleneurea, N-methylpyrrolidone, pyridine, acetonitrile or water. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to a mixture of tetrahydrofuran and water.

Suitable bases for process steps (IV) + (V) → (VII) and (IV) + (Vm) → (JX) are customary inorganic bases. These include in particular alkali hydroxides such as, for example, lithium, sodium or potassium hydroxide, alkali hydrogen carbonates such as sodium or potassium bicarbonate, alkali metal or alkaline earth metal carbonates such as lithium, sodium, potassium, calcium or cesium carbonate, or alkali metal hydrogen phosphates such as disodium or dipotassium hydrogenphosphate. phat. Preferably, sodium or potassium carbonate is used.

The reactions (IV) + (V) → (VII) and (IV) + (Vm) → (DC) are generally in a temperature range of +20 ⁰ C to +150 ⁰ C, preferably at +50 ⁰ C to + 100 ⁰ C performed.

Inert solvents for process step (IV) + (VI) -> (VE) are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents, such as dimethylformamide , Dimethylsulfoxide, N, N'-dimethylpropyleneurea, N-methylpyrrolidone, pyridine or acetonitrile. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using dimethylformamide.

The process step (IV) + (VI) -> (VII) is usually carried out in the presence of a tertiary amine base. Particularly suitable for this purpose are amines such as triethylamine, tri-n-butylamine, N, N-diisopropylethylamine, N-methylpiperidine or N-methylmorpholine. Preference is given to using triethylamine or N, N-diisopropylethylamine.

Optionally, in the reaction (IV) + (VI) -> (VE) an addition of tetraalkylammonium salts, such as tetra-n-butylammonium bromide, be advantageous.

The reaction (IV) + (VI) -> (VE) is usually carried out in a temperature range from +50 ⁰ C to +200 ⁰ C, preferably at +80 ⁰ C to +150 ⁰ C.

The process steps (IV) + (V) → (VE) and (W) + (VEI) → (K) ["Suzuki coupling"] and (IV) + (VI) -> (VE) ["Heck reaction "] occur in the presence of a palladium catalyst. For this purpose, suitable palladium compounds are suitable for such coupling reactions, for example palladium (E) acetate, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (E) chloride, bis (tri-o-tolylphosphine) palladium (E. ) chloride, bis (acetonitrile) palladium (π) chloride and [1,1-bis ¹ (diphenylphosphino) ferrocene] dichloφalladium (II) dichloromethane com- plex [cp. eg J. Hassan et al., Chem. Rev. JO2, 1359-1469 (2002)]. Preferably, bis (triphenylphosphine) palladium (II) chloride or bis (tri-o-tolylphosphine) palladium (π) chloride are used.

The ozonolysis in process step (EX) -> (X) is carried out by known methodology with the aid of an ozone generator preferably in alcohol / dichloromethane mixtures as solvent in a temperature range from -100 ⁰ C to -60 ⁰ C. For the reductive after-treatment of the reaction mixture, preference is given to using sulfides, for example dimethyl sulfide.

Inert solvents for process step (X) + (XI) or (XU) - »(VE) are, for example, ethers, such as diethyl ether, tert-butyl methyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, Xylene, pentane, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylsulfoxide, N, N'-dimethylpropyleneurea or N-methylpyrrolidone. It is likewise possible to use mixtures of the solvents mentioned. Preference is given to using tetrahydrofuran.

Suitable bases for process step (X) + (XI) or (XU) → (VIT) are the bases customary for Wittig or Wittig-Horner reactions of this type. These include in particular alkali metal hydrides such as sodium or potassium hydride, alkali metal alcoholates such as sodium or potassium tert-butoxide, amides such as lithium or potassium bis (trimethylsilyl) amide or lithium diisopropylamide, or organometallic compounds such as butyllithium or phenyllithium. Preferably, sodium hydride is used.

The reactions (X) + (XI) or (XU) -> (VIT) are generally carried out in a temperature range from -20 ⁰ C to + 60 ⁰ C, preferably at 0 ⁰ C to + 40 ⁰ C.

The hydrolysis of the ester or nitrile group Z ¹ in process step (VIT) -> (IA) is carried out by customary methods by treating the esters or nitriles in inert solvents with acids or bases, wherein the latter initially formed salts be converted by treatment with acid into the free carboxylic acids. In the case of tert-butyl ester ester cleavage is preferably carried out with acids.

Suitable inert solvents for these reactions are water or the organic solvents customary for ester cleavage. These preferably include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents such as acetone, dichloromethane, dimethylformamide or dimethyl sulfoxide. It is likewise possible to use mixtures of the solvents mentioned. In the case of basic ester hydrolysis, preference is given to mixtures of water with dioxane, tetrahydrofuran, methanol and / or ethanol, water and / or n-propanol are preferably used in the nitrile hydrolysis. In the case of the reaction with trifluoroacetic acid, preference is given to using dichloromethane and, in the case of reaction with hydrogen chloride, preferably tetrahydrofuran, diethyl ether, dioxane or water.

Suitable bases are the customary inorganic bases. These include preferably alkali or alkaline earth hydroxides such as sodium, lithium, potassium or barium hydroxide, or alkali or alkaline earth metal carbonates such as sodium, potassium or calcium carbonate. Particularly preferred are sodium or lithium hydroxide.

Suitable acids for the ester cleavage are generally sulfuric acid, hydrochloric acid / hydrochloric acid, hydrobromic / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid or mixtures thereof, optionally with the addition of water. Hydrogen chloride or trifluoroacetic acid are preferred in the case of the tert-butyl esters and hydrochloric acid in the case of the methyl esters.

The ester cleavage is generally carried out in a temperature range from 0 ⁰ C to + 100 ⁰ C, preferably at +0 ⁰ C to +50 ⁰ C. The nitrile hydrolysis is generally in a temperature range from +50 ⁰ C to +150 ⁰ C, preferably at +80 ⁰ C to +120 ⁰ C performed.

The reactions mentioned can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar), in general the reaction is carried out at normal pressure.

The compounds of the formula (I) according to the invention in which Z is a group of the formula

stands,

can be prepared by reacting compounds of formula (VII), in which Z ^{1 is} cyano, in an inert solvent with an alkali azide in the presence of ammonium chloride or with trimethylsilyl azide, optionally in the presence of a catalyst.

Inert solvents for this reaction are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or other solvents, such as dimethyl sulfoxide, dimethylformamide, N, N'-dimethylpropyleneurea or N-methylpyrrolidine. lidon. It is likewise possible to use mixtures of the solvents mentioned. Preferably, toluene is used.

In particular, sodium azide in the presence of ammonium chloride or trimethylsilyl azide is suitable as the azide reagent. The latter reaction can advantageously be carried out in the presence of a catalyst. Compounds such as di-n-butyltin oxide, trimethylaluminum or zinc bromide are particularly suitable for this purpose. Preferably, trimethylsilyl azide is used in combination with di-n-butyltin oxide.

The reaction is generally carried out in a temperature range of +50 ⁰ C to +150 ⁰ C, preferably at +60 ⁰ C to +110 ⁰ C. The reaction can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar). As a rule, one works at normal pressure.

The compounds according to the invention of the formula (I) in which Z is a group of the formula

stands,

can be prepared by reacting compounds of the formula (VH) in which Z ^{1 is} methoxy- or ethoxycarbonyl [y = 0], first in an inert solvent with hydrazine, in compounds of the formula (XIH)

in which A, M, R ¹ , R ² , R ³ and m are each as defined above,

and then reacted in an inert solvent with phosgene or a phosgene equivalent, such as NN'-carbonyldiimidazole.

Alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether are suitable as inert solvents for the first step of this reaction sequence. It is also possible to use mixtures of these solvents. Preference is given to Mixture of methanol and tetrahydrofuran used. The second reaction step is preferably carried out in an ether, in particular in tetrahydrofuran. The reactions are generally carried out in a temperature range of 0 ⁰ C to +70 ⁰ C under atmospheric pressure.

The compounds of the formula (I) according to the invention in which L ^{1 represents} a group of the formula * -L ^1A -VL ^1B - **, wherein L ^1A , L ^1B and V have the meanings given above, can alternatively also be prepared thereby in that compounds of the formula (II)

in which X Λ, R r> 3 and m have the meanings given above,

initially in an inert solvent in the presence of a base with a compound of the formula (XIV)

in which A, L ^1A , V and R ⁵ each have the meanings given above

and

is hydrogen or a temporary O or N-protecting group,

to compounds of the formula (XV)

in which A, L, T, V, R> 3, R, 5 and m are each as defined above, then, after elimination of an optionally present protective group T, in an inert solvent in the presence of a base with a compound of the formula (XVI)

_L 1B

X ^{2 /} ^ Z ¹ (XVI),

in which L ^IB and Z ^{1 have} the meanings given above

and

X ^{2 represents} a leaving group such as halogen, mesylate, tosylate or triflate,

or in the case where L ^{IB is} -CH ₂ CH ₂ -, with a compound of the formula (XVH)

H ₂ C ^^ Z ¹ (XVE),

in which Z ^{1 has} the meaning given above,

in compounds of the formula (IV-A)

in which A, L ^1A , L ^1B , V, Z ¹ , R ³ , R ⁵ and m are each as defined above,

converted and then further reacted according to the method described above (see also the following reaction scheme 2).

In an analogous manner, the compounds of the formula (I) according to the invention in which L ^{3 is} a group of the formula ## STR3 ## may be W-CH ₂ -... Or -W-CH ₂ -CH ₂ -**, where W is the above also has the meaning indicated, that compounds of the formula (IT)

(H), in which X, R and m have the meanings given above,

first in an inert solvent in the presence of a base with a compound of the formula (xvm)

in which A, L ² , Q and W each have the meanings given above

and

is hydrogen or a temporary O or N-protecting group,

to compounds of the formula (XIX)

in which A, L ² , Q, T, W, R ³ and m are each as defined above,

these then - after cleavage of an optionally present protective group T - in an inert solvent in the presence of a base with a compound of formula (XX)

X- (CH ₂ ) - Z ¹ (XX),

in which Z ^{1 has} the meaning given above,

n stands for the number 1 or 2

and

X is a leaving group such as halogen, mesylate, tosylate or triflate,

or in the case where L is "-W-CH ₂ CH ₂ - **, with a compound of the formula (XVII) H ₀ C ^ ₇ I (xvπ),

in which Z ^{1 has} the meaning given above,

in compounds of the formula (IV-B)

in which A, L ² , Q, W, Z ¹ , R ³ , m and n are each as defined above,

For the process steps (II) + (XIV) → (XV), (XV) + (XVI) or (XVII) → (IV-A), (IT) + (XVm) → (XIX) and (XIX) + (XX) or (XVII) → (IV-B) find the previously for the reaction (H) + (IH) - »(IV) described reaction parameters such as solvents, bases and reaction temperatures in an analogous manner.

The compounds of the formula (H) in turn can be prepared, for example, by reacting phenacylbromides of the formula (XXI)

in which R ³ and m have the meanings given above,

first with malononitrile in the presence of a base, such as diethylamine, in 2-aminofuronitriles of the formula (XXII)

in which R ³ and m have the meanings given above, then converted with formamide into 4-aminofiiropyrimidines of the formula (XXHI)

in which R ³ and m have the meanings given above,

condensed, then with N-bromosuccinimide to give compounds of the formula (XXIV)

in which R ³ and m have the meanings given above,

brominated and subsequently with isoamyl nitrite in the presence of a chloride source such as hydrogen chloride or copper ()) chloride to give compounds of the formula (H-A)

in which R ³ and m have the meanings given above,

(see also the following reaction scheme 3).

The compounds of the formulas (JU), (V), (VI), (VJS), (XI), (XE), (XIV), (XVI), (XVII), (XVUT), (XX) and (XXI ) are commercially available or known from the literature or they can be prepared in analogy to literature methods.

The preparation of the compounds according to the invention can be exemplified by the following synthesis schemes: Scheme 1: r, Scheme 2:

1B

Base ^, LH-Q i-WH Base

HA X

Base, ₃ / (CH ₂ ) - - Z

Scheme 3: Synthesis of 5-bromo-4-chloro-6-phenylfuro [2,3-d] pyrimidine derivatives

The compounds according to the invention have valuable pharmacological properties and can be used for the prevention and treatment of diseases in humans and animals. The compounds according to the invention are chemically and metabolically stable, non-prostanoid activators of the EP receptor which mimic the biological activity of PGI ₂ .

They are thus particularly suitable for the prophylaxis and / or treatment of cardiovascular diseases such as stable and unstable angina pectoris, hypertension and heart failure, pulmonary hypertension, for the prophylaxis and / or treatment of thromboembolic disorders and ischaemias such as myocardial infarction, stroke, transitori and for inhibiting restenosis such as thrombolytic therapies, percutaneous transluminal angioplasties (PTA), coronary angioplasties (PTCA) and bypass.

The compounds according to the invention are particularly suitable for the treatment and / or prophylaxis of pulmonary hypertension (PH) including its various forms. Thus, the compounds according to the invention are particularly suitable for the treatment and / or prophylaxis of pulmonary arterial hypertension (PAH) and its sub-forms, such as idiopathic, familial and, for example, with portal hypertension, fibrotic diseases, HIV infection or improper medication or Toxins associated with pulmonary arterial hypertension. The compounds according to the invention can also be used for the treatment and / or prophylaxis of other forms of pulmonary hypertension. Thus, they can be used, for example, for the treatment and / or prophylaxis of pulmonary hypertension in left atrial or left ventricular diseases and in left-sided heart valve diseases. In addition, the compounds according to the invention are suitable for the treatment and / or prophylaxis of pulmonary hypertension in chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis, sleep apnea syndrome, diseases with alveolar hypoventilation, altitude sickness and pulmonary developmental disorders.

Furthermore, the compounds according to the invention are suitable for the treatment and / or prophylaxis of pulmonary hypertension due to chronic thrombotic and / or embolic diseases, such as thromboembolism of the proximal pulmonary arteries, obstruction of the distal pulmonary arteries and pulmonary embolism. Furthermore, the compounds according to the invention can be used for the treatment and / or prophylaxis of pulmonary hypertension in connection with sarcoidosis, histiocytosis X or lymphangioleiomyomatosis as well as pulmonary hypertension caused by external vascular compression (lymph node, tumor, fibrosing mediastinitis).

In addition, the compounds according to the invention can also be used for the treatment and / or prophylaxis of peripheral and cardial vascular diseases, of peripheral occlusive diseases (PAOD, PVD) as well as of peripheral circulatory disorders.

Further, the compounds of the present invention may be useful in the treatment of arteriosclerosis, hepatitis, asthmatic diseases, chronic obstructive pulmonary disease (COPD), pulmonary edema, fibrosing lung diseases such as idiopathic pulmonary fibrosis (IPF) and ARDS, inflammatory vascular diseases such as scleroderma and lupus erythematosus, renal failure, arthritis and osteoporosis and for the prophylaxis and / or treatment of cancer, in particular of metastatic tumors.

In addition, the compounds of the invention may also be used as an adjunct to the preservative medium of an organ transplant, such as e.g. in kidneys, lungs, heart or islet cells.

Another object of the present invention is the use of compounds of the invention for the treatment and / or prevention of diseases, in particular the aforementioned diseases. Another object of the present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prevention of diseases, in particular the aforementioned diseases.

Another object of the present invention is a method for the treatment and / or prevention of diseases, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.

The compounds of the invention may be used alone or as needed in combination with other agents. Another object of the present invention are pharmaceutical compositions containing at least one of the compounds of the invention and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned diseases. As suitable combination active ingredients may be mentioned by way of example and preferably:

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

Compounds which inhibit the degradation of cyclic guanosine monophosphate (cGMP) and / or cyclic adenosine monophosphate (cAMP), such as inhibitors of phosphodiesterases (PDE) 1, 2, 3, 4 and / or 5, in particular PDE 5 inhibitors such as sildenafil, Vardenafil and tadalafil;

NO-independent, but heme-dependent guanylate cyclase stimulators, in particular the compounds described in WO 00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;

Guanylate cyclase NO- and heme-independent activators, in particular the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510;

Compounds which inhibit human neutrophil elastase (HNE), such as, for example, Sivelestat, DX-890 (Reltran), Elafin or in particular those described in WO 03/053930, WO 2004/020410, WO 2004/020412, WO 2004/024700, WO 2004/024701, WO 2005/080372, WO 2005/082863 and WO 2005/082864 described compounds;

The signal transduction cascade inhibiting compounds, for example and preferably from the group of kinase inhibitors, in particular from the group of tyrosine kinase and / or serine / threonine kinase inhibitors; • compounds which inhibit soluble epoxide hydrolase (sEH), such as N ₁ N'-dicyclohexylurea, 12- (3 -Adamantan- 1-yl-ureido) dodecanoic acid or 1 -Adamantan- 1 -yl 3- {5- [2- (2-ethoxyethoxy) ethoxy] pentyl} urea;

Compounds affecting the energy metabolism of the heart, such as by way of example and preferably etomoxir, dichloroacetate, ranolazine or trimetazidine;

Agonists of VPAC receptors, such as by way of example and preferably the vasoactive intestinal polypeptide (VIP);

Antithrombotic agents, by way of example and preferably from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances;

Antihypertensive agents, by way of example and preferably from the group of calcium antagonists, angiotensin Aü antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor Antagonists, Rho kinase inhibitors and diuretics; and or

Lipid metabolism-altering agents, by way of example and preferably from the group of thyroid receptor agonists, cholesterol synthesis inhibitors such as by way of example and preferably HMG-CoA reductase or squalene synthesis inhibitors, ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR inhibitors alpha, PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, and lipoprotein (a) antagonists.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a kinase inhibitor such as, for example and preferably, canertinib, imatinib, gefitinib, erlotinib, lapatinib, lestaurtinib, lonafarnib, pegaptinib, pelitinib, semaxanib, tandutinib, tipifarnib, vatalanib, Sorafenib, sunitinib, bortezomib, lonidamine, leflunomide, fasudil or Y-27632.

Antithrombotic agents are preferably understood as meaning compounds from the group of platelet aggregation inhibitors, anticoagulants or profibrinolytic substances.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a platelet aggregation inhibitor such as, for example and preferably, aspirin, clopidogrel, ticlopidine or dipyridamole. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin or Clexane.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a GPUb / IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a factor Xa inhibitor, such as by way of example and preferably rivaraban, DU-176b, fidexaban, razaxaban, fondaparinux, 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 according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.

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

Among the antihypertensive agents are preferably compounds from the group of calcium antagonists, angiotensin AH antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blocker, beta-receptor blocker, mineralocorticoid receptor - Antagonists, Rho-kinase inhibitors and diuretics understood.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alpha-1-receptor blocker, such as by way of example and preferably prazosin.

In a preferred embodiment of the invention, the compounds according to the invention are used in combination with a beta-receptor blocker, such as by way of example and preferably propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipropanol, nadolol, mepindolol, carazalol, Sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, Carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucine dolol administered.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an angiotensin Aü antagonist, such as by way of example and preferably losartan, candesartan, valsartan, telmisartan or embursatan.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an endothelin antagonist such as, by way of example and by way of preference, bosentan, darusentan, ambrisentan or sitaxsentan.

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

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a rho-kinase inhibitor, such as, for example and preferably, Fasudil, Y-27632, SLx-2119, BF-66851, BF-66852, BF-66853, KI-23095, SB-772077, GSK-269962A or BA-1049.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a diuretic, such as by way of example and preferably furosemide.

Among the lipid metabolizing agents are preferably compounds from the group of CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reductase or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR alpha- , PPAR gamma and / or PPAR delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein (a) antagonists understood. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CETP inhibitor, such as by way of example and preferably torcetrapib (CP-529 414), JJT-705 or CETP vaccine (Avant).

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a thyroid receptor agonist such as, by way of example and by way of preference, D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214) ,

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of statins such as, for example and preferably, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an ACAT inhibitor, such as, for example and preferably, avasimibe, melinamide, pactimibe, eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an MTP inhibitor such as, for example and preferably, implitapide, 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, by way of example and by way of preference, pioglitazone or rosiglitazone.

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

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cholesterol absorption inhibitor, such as by way of example and preferably ezetimibe, tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipase inhibitor, such as, for example and preferably, 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, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, cholesta gel or colestimide.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a bile acid reabsorption inhibitor, such as by way of example and preferably ASBT (= IBAT) inhibitors such as e.g. AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a lipoprotein (a) antagonist, such as, by way of example and by way of preference, gemcabene calcium (CI-1027) or nicotinic acid.

Another object of the present invention are pharmaceutical compositions containing at least one inventive compound, usually together with one or more inert, non-toxic, pharmaceutically suitable excipients, and their use for the purposes mentioned above.

The compounds according to the invention can act systemically and / or locally. For this purpose, they may be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctivae otic or as an implant or stent.

For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For the oral administration are according to the prior art working, the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such. Tablets (uncoated or coated tablets, for example with enteric or delayed-release or insoluble coatings which control the release of the compound of the invention), tablets or films / wafers rapidly breaking down in the oral cavity, films / lyophilisates, capsules (e.g. Soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

The parenteral administration can be done bypassing a resorption step (eg, intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or with involvement of resorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For the paren- tereral administration are suitable as application forms, inter alia, injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are suitable, for example Inhalation medicines (including powder inhalers, nebulizers), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets, films / wafers or capsules, suppositories, ear or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg plasters), milk, pastes, foams, powdered powders, implants or stents.

Preference is given to oral or parenteral administration, in particular oral and intravenous administration.

The compounds according to the invention can be converted into the stated administration forms. This can be done in a conventional manner by mixing with inert, non-toxic, pharmaceutically suitable excipients. These adjuvants include, among others. Excipients (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), Stabilizers (eg, antioxidants such as ascorbic acid), dyes (eg, inorganic pigments such as iron oxides) and flavor and / or odoriferous.

In general, it has proven to be advantageous, when administered parenterally, to administer amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg of body weight, in order to achieve effective results. When administered orally, the dosage is about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.

Nevertheless, it may be necessary to deviate from the stated amounts, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. Thus, in some cases it may be sufficient to manage with less than the aforementioned minimum amount, while in other cases, the said upper limit must be exceeded. In the case of the application of larger quantities, it may be advisable to distribute these in several single doses throughout the day.

The following embodiments illustrate the invention. The invention is not limited to the examples. The percentages in the following tests and examples are by weight unless otherwise indicated; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions are based on volume.

A. Examples

Abbreviations:

Section. absolutely

Ac acetyl

Ac ₂ O acetic anhydride aq. Aqueous, aqueous solution

C concentration

TLC thin layer chromatography

DCI direct chemical ionization (in MS)

DIBAH diisobutylaluminum hydride

DMF NN-dimethylbromamide

DMSO dimethyl sulfoxide d. Th. Of theory (at yield) ee enantiomeric excess

EI electron impact ionization (in MS) eq equivalent (s)

ESI electrospray ionization (in MS)

Mp melting point

GC-MS gas chromatography-coupled mass spectrometry sat. saturated h hour (s)

HATU O- (7-azabenzotriazol-1-yl) -N, NN ', N'-tetramethyluronium hexafluorophosphate

HPLC high pressure liquid chromatography cat. catalytically conc. concentrated

LC-MS liquid chromatography-coupled mass spectrometry

Me Methyl min minute (s)

MS mass spectrometry

NBS N-bromosuccinimide

NMR nuclear magnetic resonance spectrometry rac. racemic

RP reverse phase (reversed phase, for HPLC)

RT room temperature R, retention time (by HPLC)

TFA trifluoroacetic acid

THF tetrahydrofuran

HPLC. LC-MS and GC-MS methods:

Method 1 (HPLO:

Instrument: HP 1100 with DAD detection; Column: Kromasil 100 RP-18, 60 mm x 2.1 mm, 3.5 μm; Eluent A: 5 ml HClO ₄ (70%) / liter water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 6.5 min 90% B → 6.7 min 2% B → 7.5 min 2% B; Flow: 0.75 ml / min; Column temperature: 30 ^° C .; UV detection: 210 nm.

Method 2 CLC-MS):

Instrument: Micromass platform LCZ with HPLC Agilent Series 1100; Column: Thermo Hypersil GOLD 3μ 20mm x 4mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 5.5 min 10% A; Oven: 50 ^° C .; Flow: 0.8 ml / min; UV detection: 210 nm.

Method 3 (LC-MS):

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow: 0.0 min 1 ml / min → 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ^° C .; UV detection: 210 nm.

Method 4 (LC-MS):

Device Type MS: Waters ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Onyx Monolithic Cl 8, 100 mm x 3 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A → 2 min 65% A → 4.5 min 5% A → 6 min 5% A; Flow: 2 ml / min; Oven: 40 ^° C; UV detection: 210 nm. Method 5 TLC-MS):

Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Gemini 3μ 30 mm x 3.00 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A - »4.5 min 5% A; Flow: 0.0 min 1 ml / min - »2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ^° C .; UV detection: 210 nm.

Method 6 (GC-MSV

Instrument: Micromass GCT, GC 6890; Column: Restek RTX-35, 15 m × 200 μm × 0.33 μm; constant flow with helium: 0.88 ml / min; Oven: 70 ^° C; Inlet: 250 ^° C; Gradient: 70 ⁰ C, 30 ° C / min → 310 ⁰ C (3 min hold).

Method 7 (LC-MS):

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Onyx Monolithic Cl 8, 100 mm x 3 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 2 min 65% A -> 4.5 min 5% A → 6 min 5% A; Flow: 2 ml / min; Oven: 40 ^° C; UV detection: 208-400 nm.

Method 8 (LC-MS):

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex syn ergi 2.5 μ MAX-RP 100A Mercury, 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A → 0.1 min 90% A → 3.0 min 5% A → 4.0 min 5% A → 4.01 min 90% A; Flow: 2 ml / min; Oven: 50 ^° C .; UV detection: 210 nm.

Method 9 (LC-MS):

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: Phenomenex Synergi 2.5 μ MAX-RP 100A Mercury, 20 mm x 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A -> 0.1 min 90% A → 3.0 min 5% A -> 4.0 min 5% A → 4.1 min 90% A; Flow: 2 ml / min; Oven: 50 ^° C .; UV detection: 208-400 nm. Starting compounds and intermediates;

Example IA

2-amino-5-phenyl-3-furonitrile

68.6 ml (663 mmol) of diethylamine were added dropwise at RT to a mixture of 60.0 g (301 mmol) of bromoacetophenone and 25.89 g (391.86 mmol) of malononitrile in 130 ml of DMF (cooling required to maintain the temperature). At the end of the addition, the cooling was removed, the mixture was stirred at RT for 1 h and then added to 385 ml of water. It was diluted with a further 125 ml of water and stirred at RT for 20 min. The precipitated solid was filtered off, washed twice with 125 ml of water, sucked dry and washed with petroleum ether. The residue was dried under high vacuum. There were obtained 33.3 g (50.1% of theory) of the target compound as crystals.

HPLC (Method 1): R, = 4.27 min

MS (DCI): m / z = 202 (M + NH ^, 185 (M + H) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 7:51 to 7:45 (m, 2H), 7:39 to 7:32 (m, 3H), 6:54 (s, IH), 4.89 (br s, IH.).

Example 2A

6-phenylfuro [2,3-d] pyrimidin-4-amine

110 g (597 mmol) of 2-amino-5-phenyl-3-furonitrile were suspended in 355 ml (9 mol) of formamide and heated for 1.5 h (bath temperature about 210 ⁰ C). The mixture was then cooled to RT and stirred into water. The precipitated solid was filtered off with suction and washed with water. The still moist product was stirred in dichloromethane, filtered off with suction and dried in vacuo. This gave 106 g (80% of theory) of the target compound. LC-MS (Method 2): R, = 3.1 min .; m / z = 212 (M + H) ⁺

HPLC (Method 1): R, = 3.63 min.

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 8.20 (s, IH), 7.8 (d, 2H), 7.55-7.32 (m, 6H).

Example 3A

5-Bromo-6-phenylfuro [2,3-d] pyrimidin-4-amine

80 g (378.7 mmol) of 6-phenylfuro [2,3-d] pyrimidin-4-amine in 770 ml of carbon tetrachloride at 60 ⁰ C heated. 84.3 g (473.4 mmol) of N-bromosuccinimide were added and the mixture was stirred at reflux overnight. After cooling, the mixture was filtered off, the filter cake was stirred successively with dichloromethane and acetonitrile and filtered again. The filter cake was then dried in vacuo. 86 g of the target product were obtained (78.2% of theory).

MS (DCI): m / z = 290/292 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.28 (s, IH), 8.03 (d, 2H), 7.60-7.50 (m, 5H).

Example 4A

5-bromo-4-CMOR-6-phenylfuro [2,3-d] pyrimidine

54 g (186 mmol) of 5-bromo-6-phenylfuro [2,3-d] pyrimidin-4-amine were initially charged in 135 ml of chloroform, 70 ml of 4N hydrogen chloride in dioxane (280 mmol) and heated to reflux. 50 ml (372 mmol) of isoamyl nitrite were added dropwise with evolution of gas. After the end of the addition, the mixture was stirred at reflux for 3 hours before the cooled reaction mixture was poured into water and extracted with dichloromethane. The organic phase was washed with sat. Washed with sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. geengt. The crude product was purified by chromatography on silica gel (eluent: dichloromethane). The product was stirred in methanol for further purification, filtered off with suction and dried under high vacuum. 32 g of the target product were obtained (55.5% of theory).

LC-MS (Method 3): R, = 2.54 min .; m / z = 309/310 (M + H) ⁺

HPLC (Method 1): R _t = 5.08 min.

¹ H-NMR (400 MHz, CDCl _3): δ = 8.79 (s, IH), 8:23 to 8:20 (m, 2H), 7:58 to 7:51 (m, 3H).

Example 5A

(2E, 6 /?) - 6-hydroxyhept-2-enoic acid tert. butyl

Solution A: 10.71 g (267.7 mmol) of 60% sodium hydride were dissolved in 150 ml of abs. Suspended THF and dropwise with cooling with 43.3 ml (276.7 mmol) of P, P-Dimethylphosphonoessigsäure- tert. butyl ester added. The mixture was stirred at RT, after about 30 min, a solution was formed.

To a cooled to -78 ⁰ C solution of 17.87 g (178.5 mmol) of (R) -γ-valerolactone [(5R) -5-methyldihydrofuran-2 (3H) -one] in 200 ml abs. TΗF, 187.4 ml (187.4 mmol) of a 1 M solution of DEBAΗ in TΗF were added dropwise. The solution was stirred for 1 h at -78 ° C and then added to the solution A prepared above. After the end of the addition, the mixture was slowly warmed to RT and stirred at RT overnight. The reaction mixture was added to 300 ml of ethyl acetate and stirred with 50 ml of concentrated potassium sodium tartrate solution. After phase separation, the aqueous phase was re-extracted with ethyl acetate. The organic phases were combined, with sat. Sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 5: 1). This gave 32.2 g (90.1% of theory) of the target product which contained small amounts of the cis isomer.

MS (DCI): m / z = 218 (M + N +,) *

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 6.70 (dt, IH), 5.73 (d, IH), 4.44 (d, IH), 3.58 (m, IH), 2.28- 2.13 (m, 2H) , 1.47-1.40 (m, 2H), 1.45 (s, 9H), 1.04 (d, 3H). Example 6A

(-) - 6-hydroxyheptanoic acid tert-butyl ester

32.2 g (160.8 mmol) of (2.E, 6 /?) - 6-hydroxyhept-2-enoic acid tert-butyl ester were dissolved in 200 ml of ethanol and treated with 1.7 g of 10% palladium on carbon. The mixture was stirred at RT under a hydrogen atmosphere (atmospheric pressure) for 2 hours and then filtered through Celite. The filtrate was concentrated in vacuo. From the residue, after chromatography on silica gel (eluent: cyclohexane / ethyl acetate 10: 1 → 6: 1), 15.66 g of the target product (48.1% of theory) were obtained.

MS (DCI): m / z = 220 (M + NH,) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 3.85-3.75 (m, IH), 2.22 (t, 2H), 1.68-1.54 (m, 2H), 1:53 to 1:30 (m, 4H), 1:45 ( s, 9H), 1.18 (d, 3H).

[α] _D ²⁰ = -21 °, c = 0.118, chloroform.

Example 7A

(6R) -6 - [(5-bromo-6-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] heptanoic acid terf.-butyl ester

10.0 g (32.30 mmol) of 5-bromo-4-chloro-6-phenylfuro [2,3-d] pyrimidine and 10.8 g (53.30 mmol) of (-) - 6-hydroxyheptanoic acid tert-butyl ester were dissolved in 20 ml of DMF initially charged and mixed at 0 ⁰ C with 2.1 g (53.30 mmol) of 60% sodium hydride. The reaction mixture was then warmed to RT and stirred at this temperature for 45 min. The reaction mixture was then added with water and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel with a gradient of cyclohexane and ethyl acetate (20: 1 → 10: 1). Received 6.8 g of the target product (44% of theory). LC-MS (Method 4): R, = 4.87 min; m / z = 475 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.60 (s, IH), 8.06 (d, 2H), 7.64-7.50 (m, 3H), 5.48 (m, IH), 2.18 (t , 2H), 1.76 (m, 2H), 1.61-1.28 (m, 7H), 1.33 (s, 9H).

[α] _D ²⁰ = -56 °, c = 0.450, chloroform.

Example 8A

(ÖΛ) -6 - [(6-phenyl-5-vinylfuro [2,3-d] pyrimidin-4-yl) oxy] heptanoic / erϊ.-butyl ester

Under argon atmosphere 3.0 g (6.31 mmol) of (6R) -6 - [(5-bromo-6-phenylfiiro [2,3-d] pyrimidin-4-yl) oxy] heptanoic acid tert-butyl ester in Dissolved 20 ml of THF and treated with 6.3 ml of 2 N aqueous sodium carbonate solution. After adding 1.458 g (9.47 mmol) of 2-vinylboronic acid pina- colester and 0.443 g (0.63 mmol) of bis (triphenylphosphine) palladium (II) chloride, the mixture was stirred at reflux overnight. After cooling, the reaction mixture was filtered through Celite, the filtrate was concentrated and the residue was dried under high vacuum. The crude product was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 10: 1 → 8: 1). Obtained 2.08 g of the target product (70.8% of theory).

LC-MS (Method 5): R, = 3.58 min; m / z = 423 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.61 (s, IH), 7.37 (d, 2H), 7.60-7.50 (m, 3H), 6.39 (dd, IH), 6.28 (dd, IH), 5.59 (dd, IH), 5.52 (m, IH), 2.19 (t, 2H), 1.85-1.69 (m, 2H), 1.58-1.48 (m, 2H), 1.45-1.37 (m, 2H) , 1.39 (d, 3H), 1.32 (s, 9H).

[α] _D ²⁰ = -47.4 °, c = 0.330, chloroform.

Example 9A

(OER) -6 - [(5-formyl-6-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] heptanoic acid ter-butyl ester /.-

1.55 g (3.55 mmol) of (6R) -6 - [(6-phenyl-5-vinylfliro [2,3-d] pyrimidin-4-yl) oxy] heptanoic acid Fe / α-butyl ester were dissolved in 17.3 ml of methanol and ethyl acetate Dissolved 17.3 ml of dichloromethane and cooled to -78 ° C.

Ozone gas was generated in the ozonizer and passed through the reaction mixture in the oxygen stream for about 10 minutes, whereby it turned green-blue. After switching off the ozonizer, the excess ozone was expelled from the reaction solution by the gas stream. Subsequently, the still cold, light-green reaction mixture was mixed with 8 ml of dimethyl sulfide and slowly warmed to RT. It was then concentrated and the residue dried under high vacuum. The

Crude product was purified by chromatography on silica gel (eluent: cyclohexane / ethyl acetate 10: 1). 0.81 g of the target product were obtained (53.1% of theory).

LC-MS (method 5): R _t = 3.31 min; m / z = 425 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.32 (s, IH), 8.68 (s, IH), 8.65 (d, 2H), 7.68-7.60 (m, 3H), 5.52 (m, IH), 2.19 (t, 2H), 1.89-1.70 (m, 2H), 1.58-1.50 (m, 2H), 1.48-1.38 (m, 2H), 1.42 (d, 3H), 1.35 (s, 9H) ,

[α] _D ²⁰ = -52 °, c = 0.460, chloroform.

Example IQA

N-Ethyl-2-methyl acrylamide

0.50g (5.8 mmol) of methacrylic acid were dissolved in 4 ml DMF, cooled to 0 ⁰ C, and 4:42 g (11.62 mmol) of HATU was added. The mixture was stirred for 10 min at 0 ⁰ C before 2.0 ml (11.62 mmol) of NN-diisopropylethylamine and 8.7 ml (17.4 mmol) of a 2 M solution of ethylamine in methanol were added. The reaction mixture was warmed to RT and stirred overnight. It was then diluted with ethyl acetate and washed with water and sat. Sodium chloride solution washed. The organic phase was dried over sodium sulfate, concentrated and the residue stood dried in a high vacuum. The crude product was purified by chromatography on silica gel (eluent: dichloromethane / methanol 100: 1). To remove remaining residues of DMF and NN-diisopropylethylamine, the product obtained was taken up in ethyl acetate and washed thrice with sat. Washed ammonium chloride solution. The organic phase was then dried over sodium sulfate, concentrated in vacuo and the residue was thoroughly dried under high vacuum. 0.91 g of the target product were obtained (about 65% purity, 90.7% of theory).

GC-MS (Method 6): R, = 2.59 min; m / z = 113 (M ⁺ ).

Example IIA

N-propyl-2-methyl acrylamide

The title compound was prepared in a manner analogous to the procedure of Example 10A.

GC-MS (Method 6): R, = 3.01 min; m / z = 127 (M ⁺ ).

Exemplary embodiments:

example 1

(6Λ) -6 - ({5 - [(Hi) -pent-l-en-l-yl] -6-phenylnαro [2,3-d] pyrimidin-4-yl} oxy) heptanoic acid fer /.- butyl ester

Under argon atmosphere, 100 mg (0.21 mmol) of (6 /?) - 6 - [(5-bromo-6-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] heptanoic acid tert. Butyl ester dissolved in 2.0 ml of TΗF and successively treated with 1.05 ml of 2 N aqueous sodium carbonate solution, 53.9 mg (0.47 mmol) of 1-pentenylboronic acid and 14.8 mg (0.021 mmol) of bis (triphenylphosphine) palladium (π) chloride. The mixture was stirred at reflux overnight, then filtered through Celite after cooling. The filtrate was concentrated and the residue was purified by chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 10: 1). 73.9 mg of the target product were obtained (75.0% of theory).

LC-MS (Method 4): R, = 5.22 min; m / z = 465 (M + Η) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.57 (s, IH), 7.78 (d, 2H), 7.60-7.48 (m, 3H), 6.69 (dt, IH), 6.53 (d, IH) , 5.53 (m, IH), 2.25 (q, 2H), 2.19 (t, 2H), 1.79-1.65 (m, 3H), 1.55-1.45 (m, 3H), 1.39 (d, 3H), 1.35 (s , 9H), 0.96 (t, 3H).

[α] _D ²⁰ = -49 °, c = 0.225, chloroform.

Example 2

(OER) -6 - ({5 - [(7 £) -3-oxopent-l-en-l-yl] -6-phenylfuro [2,3-d] pyrimidin-4-yl} oxy) heptanoic acid rer butyl ester

53.9 mg (0.259 mmol) (2-oxobutane) -phosphonic acid diethyl ester were dissolved in 4.0 ml THF, cooled to 0 ⁰ C and treated with 10.3 mg (0.259 mmol, 60% strength) sodium hydride. The mixture was stirred for 5 min. Before 100 mg (0.236 mmol) of (6 /?) - 6 - [(5-formyl-6-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] heptanoic acid ter / .- butyl ester were added. After warming to RT, the reaction mixture was further stirred overnight. Thereafter, water was added and extracted with ethyl acetate. The organic phase was washed with sat. Sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by preparative RP-HPLC (eluent: acetonitrile / water gradient). Obtained were 81.2 mg of the target product (72% of theory).

LC-MS (method 5): R _t = 3.44 min; m / z = 479 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.68 (s, IH), 7.78 (d, 2H), 7.70-7.58 (m, 3H), 7.43 (d, 2H), 5.07 (m, IH) , 2.75-2.67 (m, 2H), 2.19 (t, 2H), 1.90-1.75 (m, 2H), 1.57-1.50 (m, 2H), 1.44 (d, 3H), 1.35 (s, 9H), 1.05 (t, 3H).

[α] _D ²⁰ = -61 °, c = 0.11, chloroform.

Example 3

(ΌR) -6 - ({5 - [(/ £) -3- (ethoxy) -3-oxoprop-l-en-l-yl] -6-phenylfuro [2,3-d] pyrimidin-4-yl } oxy) - heptanoic acid-tert. butyl

29.1 mg (0.13 mmol) of phosphonoacetic acid triethyl ester were dissolved in 2.0 ml of THF, cooled to 0 ⁰ C and treated with 5.2 mg (0.13 mmol, 60% strength) of sodium hydride. The mixture was stirred for 5 minutes before 50 mg (0.118 mmol) of (6 /?) - 6 - [(5-formyl-6-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] heptanoic acid ter or - butyl esters were added. After warming to RT, the reaction mixture was further stirred overnight. Thereafter, water was added and extracted with ethyl acetate. The organic phase was washed with sat. Sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by preparative RP-HPLC (eluent: acetonitrile / water gradient). Obtained were 35.0 mg of the target product (60.1% of theory).

LC-MS (Method 7): R, = 4.99 min; m / z = 495 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.67 (s, IH), 7.78-7.61 (m, 6H), 7.16 (d, IH), 5.50 (m, IH), 4.23-4.17 (m, 2H), 2.18 (t, 2H), 1.86-1.75 (m, 2H), 1.60-1.51 (m, 2H), 1.41 (d, 3H), 1.34 (s, 9H), 1.26 (t, 3H ).

[α] _D ²⁰ = -56 °, c = 0.225, chloroform.

Example 4

(6R) -6- ({5 - [{IE) -2- (allyloxy) -3-oxoprop-1-en-1-yl] -6-phenylfuro [2,3-d] pyrimidin-4-yl } oxy) - heptanoic acid-tert. butyl

122.4 mg (0.518 mmol) of diethyl phosphonoessigsäureallylester were dissolved in 8.0 ml THF, cooled to 0 ⁰ C and treated with 20.3 mg (0.518 mmol, 60% strength) sodium hydride. The mixture was stirred for 5 minutes before 200 mg (0.471 mmol) of (6Λ) -6 - [(5-formyl-6-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] heptanoic acid tert. butyl ester were added. After warming to RT, the reaction mixture was further stirred overnight. Thereafter, water was added and extracted with ethyl acetate. The organic phase was washed with sat. Washed sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by preparative RP-HPLC purified (eluent: acetonitrile / water gradient). Obtained were 225.1 mg of the target product (94.3% of theory).

LC-MS (Method 5): R, = 3.53 min; m / z = 507 (M + H) ⁺

¹ H NMR (400 MHz, DMSO-Cl ₆ ): δ = 8.67 (s, IH), 7.78-7.61 (m, 6H), 7.20 (d, IH), 6.40-5.95 (m, IH), 5.52 ( m, IH), 5.35 (dd, IH), 5.27 (dd, IH), 4.69 (d, 2H), 2.18 (t, 2H), 1.85-1.75 (m, 2H), 1.59-1.50 (m, 2H) , 1.48-1.36 (m + 1, total 5H), 1.33 (s, 9H).

[α] _D ²⁰ = -56 °, c = 0.100, chloroform.

Example 5

(2 £) -3- (4 - {[(7 /?) -? 6- / er .- butoxy-l-methyl-6-oxohexyl] oxy} -6-phenylfuro [2,3-d] pyrimidine 5-yl) - acrylic acid

220.0 mg (0:46 mmol) (6R) -6 - ({5 - [(7 _J £) -3- (allyloxy) -3-oxoprop-l-en-l-yl] -6-phenylfuro [2,3- d] -pyrimidin-4-yl) oxy) heptanoic acid tert-butyl ester and 57 μl (0.643 mmol) morpholine were dissolved under argon in 7.0 ml THF and treated with 5.0 mg (0.004 mmol) tetrakis (triphenylphosphine) palladium ( 0). The reaction mixture was stirred at RT for 3 h and then filtered through Celite. The filter residue was washed with dichloromethane, and the combined filtrates were washed with water and sat. Sodium chloride solution washed. The organic phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative RP-HPLC (eluent: acetonitrile / water gradient). This gave 182 mg of the target product (85.0% of theory).

LC-MS (Method 8): R, = 2.51 min; m / z = 467 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.55 (br.s, IH), 8.55 (s, IH), 7.75 (d, 2H), 7.69-7.57 (m, 4H), 7.05 (d, IH), 5.54 (m, IH), 2.18 (t, 2H), 1.88-1.72 (m, 2H), 1.55-1.50 (m, 2H), 1.45-1.37 (m + t, total 5H), 1.33 ( s, 9H).

[α] _D ²⁰ = -49 °, c = 0.175, chloroform. Example 6

(6Λ) -6 - ({5 - [(7 £) -3-ethoxy-2-methyl-3-oxoprop-l-en-l-yl] -6-phenylfuro [2,3-d] pyrünidin-4 -yl} - oxy) heptanoic acid tert-butyl ester

Under an argon atmosphere, 100 mg (0.21 mmol) of (δ) -6 - [(5-bromo-6-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] heptanoic acid tert-butyl ester , 0.13 ml (1.052 mmol) of ethyl methacrylate, 13.6 mg (0.042 mmol) of tetra-n-butylammonium bromide, 0.55 ml (3.16 mmol) of N, N-diisopropylethylamine and 6.6 mg (0.008 mmol) of dichlorobis (tri-o-tolylphosphine) palladium (II) in 3.0 ml of DMF and heated to 110 ⁰ C overnight. After cooling to RT, the reaction mixture was diluted with ethyl acetate, washed with water and sat. Sodium chloride solution, dried over sodium sulfate and concentrated. The residue was dried under high vacuum and the crude product was purified by preparative RP-HPLC (eluent: water / acetonitrile gradient). 51.9 mg of the target product were obtained (48.5% of theory).

LC-MS (Method 8): R, = 3.06 min; m / z = 509 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.61 (s, IH), 7.74 (d, 2H), 7.60-7.47 (m, 3H), 5.39 (m, IH), 4.25 (q, 2H) , 2.16 (t, 2H), 1.71-1.65 (m, 2H), 1.65 (s, 3H), 1.54-1.43 (m, 2H), 1.40-1.29 (m, 17H).

[α] _D ²⁰ = -51.2 °, c = 0.365, chloroform.

Example 7

(Ό /?) - 6 - ({5 - [(i £) -3-oxo-hex-l-en-l-yl] -6-phenylfuro [2,3-d] pyrimidin-4-yl} oxy) heptanoic acid -fer./.- butyl ester

Under argon atmosphere, 100 mg (0.21 mmol) of ((5α) -6 - [(5-bromo-6-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] heptanoic acid tert. butyl ester, 103.2 mg (1.052 mmol) of 1-hexene-3-one, 13.6 mg (0.042 mmol) of tetra-n-butylammonium bromide, 0.44 ml (3.16 mmol) of triethylamine, and 6.6 mg (0.008 mmol) of dichlorobis (tri-o-tolylphosphine). palladium (II) in 3.0 ml of DMF and heated to 110 ^° C. After 4 h, a further 0.04 eq of dichlorobis (tri-o-tolylphosphine) -palladium (II) and 0.55 ml (3.16 mmol) of N, N were added to the reaction mixture. The mixture was then further stirred overnight at 110 ^° C. After cooling to RT, the reaction mixture was diluted with ethyl acetate, washed with water and saturated sodium chloride solution, dried over sodium sulphate and concentrated, the residue was dried in a high vacuum and the crude product was purified by preparative RP-HPLC (eluent: water / acetonitrile gradient) to give 51.9 mg of the target product (48.5% of theory).

LC-MS (Method 5): R, = 3.51 min; m / z = 493 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.67 (s, IH), 7.78 (d, 2H), 7.69-7.59 (m, 4H), 7.41 (d, IH), 5.56 (m, IH) , 2.65 (dt, 2H), 2.19 (t, 2H), 1.90-1.75 (m, 2H), 1.64-1.51 (m, 4H), 1.49-1.36 (m, 2H), 1.45 (d, 3H), 1.32 (s, 9H), 0.91 (t, 3H).

[α] _D ²⁰ = -60 °, c = 0.115, chloroform.

Example 8

(6R) -6- ({5 - [(/ 2s) -3- (ethylamino) -3-oxoprop-1 -ene-1-yl] -6-phenylfuro [2,3-d] pyrimidin-4-yl } oxy) - heptanoic acid tert-butyl ester

50 mg (0.107 mmol) of (2E) -3- (4 - {[(7R) -6-tert.-butoxy-1-methyl-6-oxohexyl] oxy} -6-phenylfuro [2,3-d ] Pyrimidin-5-yl) acrylic acid were dissolved in 1.0 ml of DMF, cooled to 0 ⁰ C and treated with 81.5 mg (0.214 mmol) HATTJ. The mixture was stirred for 10 min at ⁰ ° C. before 37 μl (0.214 mmol) of N, N-diisopropylethylamine and 161 μl (0.214 mmol) of a 2 M solution of ethylamine in methanol were added. The reaction mixture was stirred at RT overnight, then diluted with ethyl acetate and washed with water and sat. Sodium chloride solution washed. The organic phase was dried over sodium sulfate, concentrated and the residue dried under high vacuum. The crude product was purified by chromatography on silica gel (eluent: dichloromethane / methanol 200: 1). 38.4 mg of the target product were obtained (72.6% of theory).

LC-MS (Method 9): R, = 2.70 min; m / z = 494 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-dβ): δ = 8.61 (s, IH), 8.12 (t, IH), 7.75 (d, 2H), 7.65-7.52 (m, 4H), 6.93 (d, IH ), 5.44 (m, IH), 3.29-3.18 (m, 2H), 2.18 (t, 2H), 1.98-1.89 (m, IH), 1.78-1.69 (m, IH), 1.55-1.48 (m, 2H ), 1.47 (d, 3H), 1.42-1.35 (m, 2H), 1.35 (s, 9H), 1.10 (t, 3H).

[α] _D ²⁰ = -49 °, c = 0.15, chloroform.

Example 9

(<5Λ) -6 - ({5 - [(7 ^ -3- (allylamino) -3-oxoprop-l-en-l-yl] -6-phenylfuro [2,3-d] pyrimidin-4-yl } oxy) - heptanoic acid terf. butyl ester

The title compound was obtained in a manner analogous to the procedure of Example 8.

LC-MS (Method 5): R, = 3.18 min; m / z = 506 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.63 (s, IH), 8.34 (t, IH), 7.73 (d, 2H), 7.66-7.54 (m, 4H), 6.99 (i.e. , IH), 5.93-5.84 (m, IH), 5.46 (m, IH), 5.20-5.09 (m, 2H), 3.91-3.79 (m, 2H), 2.18 (t, 2H), 1.97-1.89 (m, IH), 1.88-1.70 (m, IH), 1.53-1.48 (m, 2H), 1.48 (d, 3H), 1.41-1.35 (m, 2H), 1.35 (s, 9H).

[α] _D ²⁰ = -58 °, c = 0.105, chloroform.

Example 10

(? 6 /) - 6 - ({5 - [(7 £) -3- (ethylamino) -2-methyl-3-oxoprop-l-en-l-yl] -6-phenylruro [2,3-d ] pyrimidin-4-yl) oxy) heptanoic acid terf. butyl

Under an argon atmosphere, 2500 mg (0.53 mmol) of (6R) -6 - [(5-bromo-6-phenylfuro [2,3-d] pyrimidin-4-yl) oxy] heptanoic acid tert. butyl ester, 457 mg (65% strength, 2.63 mmol) of N-ethyl-2-methylacrylamide, 33.9 mg (0.105 mmol) of tetra-n-butylammonium bromide, 1.4 ml (7.9 mmol) of N, N-diisopropylethylamine and 15.6 mg (0.021 mmol) of dichlorobis (tri-o-tolylphosphine) palladium (II) mixed in 5.0 ml of DMF and heated to 110 ⁰ C overnight. After cooling to RT, the reaction mixture was diluted with ethyl acetate, washed with water and sat. Sodium chloride solution, dried over sodium sulfate and concentrated. The residue was dried under high vacuum and the crude product was purified by preparative HPLC (column: Daicel Chiralpak IA 5 μm, 250 mm × 20 mm, flow: 15 ml / min, temperature: 30 ^° C., eluent: methyl tert-butyl ether / Acetonitrile 80:20). 30 mg of the target product were obtained (11.2% of theory).

¹ H-NMR (500 MHz, DMSO-d ₆ ): δ = 8.58 (s, IH), 8.02 (t, IH), 7.78 (d, 2H), 7.57-7.45 (m, 3H), 7.37 (s, IH), 5.36 (m, 2H), 3.30-3.23 (m, 2H), 2.17 (t, 2H), 1.70-1.62 (m, 2H), 1.68 (s, 3H), 1.52- 1.47 (m, 2H) , 1.39-1.31 (m, 14H), 1.11 (t, 3H).

[α] _D ²⁰ = -58 °, c = 0.050, chloroform.

Example 11

(ΌR) -6 - ({5 - [(7 ^ -2-methyl-3-oxo-3- (propylamino) prop-l-en-l-yl] -6-phenylfuro [2,3-d] pyrimidine 4-yl) oxy) heptanoic acid tert-butyl ester

Yield: 26 mg (9.5% of theory)

¹ H-NMR (500 MHz, DMSOd ₆ ): δ = 8.58 (s, IH), 8.03 (t, IH), 7.79 (d, 2H), 7.57-7.45 (m, 3H), 7.38 (s, IH) , 5.38 (m, IH), 3.28-3.18 (m, 2H), 2.16 (t, 2H), 1.71-1.62 (m, 2H), 1.68 (s, 3H), 1.58- 1.45 (m, 4H), 1.39 -1.30 (m, 14H), 1.10 (t, 3H).

[α] _D ²⁰ = -50 °, c = 0.050, chloroform.

General Procedure A: Cleavage of tert-butyl esters to the corresponding carboxylic acids

To a solution of ter /.- butyl ester in dichloromethane (concentration 0.1 to 1.0 mol / 1; lent additional optional a drop of water) is Added at 0 ⁰ C to RT dropwise trifluoroacetic acid (TFA), until a ratio of dichloromethane / TFA from ca 2: 1 to 1: 2 is reached. The mixture is stirred for 1-18 h at RT and then concentrated in vacuo. Alternatively, the reaction mixture is diluted with dichloromethane, with water and sat. Sodium chloride solution, dried and concentrated in vacuo. If necessary, the crude product can be purified, for example, by preparative RP-HPLC (eluent: acetonitrile / water gradient).

The following exemplary embodiments were obtained in accordance with the general provision A:

(D, Example Structure Analytical Data

20 LC-MS (Method 8): R, = 1.88 min; m / z = 452 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 11.95 (s, IH), 8.58 (s, IH), 8.05 (t,

IH), 7.78 (d, 2H), 7.58-7.44 (m, 3H),

7.38 (s, IH), 5.36 (m, IH), 3.25 (m,

2H), 2.19 (t, 2H), 1.71-1.62 (m, 2H),

1.67 (s, 3H), 1.54-1.46 (m, 2H), 1.42-

1.32 (m, 2H), 1.35 (d, 3H), 1.13 (t, 3H).

[α] _D ²⁰ = -22 °, c = 0.085, chloroform.

21 LC-MS (Method 8):

R, = 1.99 min; m / z = 466 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 11.95 (s, IH), 8.57 (s, IH), 8.05 (t, IH), 7.79 (d, 2H), 7.57-7.45 (m, 3H),

7.36 (s, IH), 5.36 (m, IH), 3.18 (q,

2H), 2.19 (t, 2H), 1.72-1.62 (m, 2H),

1.68 (s, 3H), 1.55-1.45 (m, 4H), 1.40-

1.33 (m, 2H), 1.35 (d, 3H), 0.89 (t, 3H).

[α] _D ²⁰ = -17 °, c = 0.075, chloroform.

B. Evaluation of Pharmacological Activity

The pharmacological activity of the compounds according to the invention can be demonstrated in the following assays:

BI. Binding studies with prostacyclin receptors (EP receptors) of human thrombocyte membranes

To obtain platelet membranes, 50 ml of human blood (buffy coats with CDP stabilizer, Maco Pharma, Langen) are centrifuged for 20 min at 160 × g. The supernatant (platelet-rich plasma, PRP) is removed and then centrifuged again at 2000 xg for 10 min at room temperature. The sediment is dissolved in 50 mM tris (hydroxymethyl) amino methane, which is adjusted with 1N hydrochloric acid to a pH of 7.4, re-suspended and stored at -20 ⁰ C overnight. The following day, the suspension is centrifuged at 80,000 xg and 4 ° C for 30 minutes. The supernatant is discarded. The sediment is re-suspended in 50 mM tris- (hydroxymethyl) -aminomethane / hydrochloric acid, 0.25 mM ethylenediaminetetraacetic acid (EDTA), pH 7.4 and then centrifuged again at 80,000 × g and 4 ° C. for 30 minutes. The membrane bransediment is added to binding buffer ((50 mM Tris-hydroxymethyl) aminomethane / hydrochloric acid, 5 mM magnesium chloride, pH 7.4) and stored at -70 ⁰ C until the binding assay.

For the binding experiment, 3 mM ³ H-iloprost (592 GBq / mmol, Amersham Bioscience) are incubated for 60 min with 300-1000 μg / ml human platelet membranes per batch (maximum 0.2 ml) in the presence of the test substances at room temperature. After stopping, the membranes are mixed with cold binding buffer and washed with 0.1% bovine serum albumin. After addition of Ultima Gold scintillator, the radioactivity bound to the membranes is quantified by means of a scintillation counter. Non-specific binding is defined as radioactivity in the presence of 1 μM iloprost (Cayman Chemical, Ann Arbor) and is typically <25% of the total bound radioactivity. The binding data (IC ₅₀ values) are determined by means of the program GraphPad Prism Version 3.02.

Representative results for the compounds according to the invention are listed in Table 1: Table 1

B-2. EP receptor stimulation on whole cells

The IP agonist activity of test substances is determined using the human erythroleukemia cell line (HEL), which endogenously expresses the IP receptor [Murray, R., FEBS Letters 1989, 1: 172-174]. For this purpose, the suspension cells (4 x 10 ⁷ cells / ml) in buffer [10 mM HEPES (4- (2-hydroxyethyl) -1-piperazinethansulfonsäure) / PBS (phosphate-buffered saline, Fa. Oxoid, UK)], 1 mM Calcium chloride, 1 mM magnesium chloride, 1 mM EBMX (3-isobutyl-l-methylxanthine), pH 7.4, with the respective test substance for 5 minutes at 30 ⁰ C incubated. Subsequently, the reaction is stopped by addition of 4 ° C cold ethanol and the mixtures stored for a further 30 minutes at 4 ° C. Thereafter, the samples are centrifuged at 10,000 xg and 4 ° C. The resulting supernatant is discarded and the sediment used to determine the concentration of cyclic adenosine monophosphate (cAMP) in a commercially available cAMP radioimmunoassay (IBL, Hamburg). IP agonists increase the cAMP concentration in this test, IP antagonists are ineffective. The effective concentration (EC _5O values) is determined using the program GraphPad Prism Version 3.02.

B-3. Thrombocyte aggregation inhibition in vitro

To determine the antiplatelet activity, blood from healthy volunteers of both sexes is used. One part of 3.8% sodium citrate solution as coagulant is mixed with 9 parts of blood. The blood is centrifuged at 900 rpm for 20 min. The pH of the recovered platelet-rich plasma is adjusted to pH 6.5 with ACD solution (sodium citrate / citric acid / glucose). The platelets are then centrifuged off, taken up in buffer and centrifuged again. The thrombocyte ene precipitate is taken up in buffer and additionally re-suspended with 2 mmol / l calcium chloride.

For the aggregation measurements, aliquots of the platelet suspension are incubated with the test substance at 37 ° C. for 10 min. Subsequently, the aggregation by addition of ADP and determined by the turbidimetric method according to Born in the aggregometer at 37 ° C [Born GVR, J. Physiol. (London) 168, 178-179 (1963)].

B-4. Blood pressure measurement on anesthetized rats

Male Wistar rats weighing 300-350 g are anesthetized with thiopental (100 mg / kg i.p.). After tracheostomy, the femoral artery is catheterized for blood pressure measurement. The substances to be tested are administered as a solution orally by gavage or via the femoral vein intravenously in a suitable vehicle.

B-fifth PAH model in anesthetized dog

In this animal model of pulmonary arterial hypertension (PAH), Mongrel dogs with a body weight of about 25 kg are used. The anesthesia is induced by slow intravenous administration of 25 mg / kg of sodium thiopental (Trapanal ^®) and (ferin Alio ^®) 00:15 mg / kg alcuronium chloride and maintained throughout the experiment by means of a continuous infusion of 0.04 mg / kg / hr fentanyl ^® , 0.25 mg / kg / h droperidol (dehydrobenzperidol ^® ) and 15 μg / kg / h alcuronium chloride (Alloferin ^® ). Reflective effects on the heart rate by lowering blood pressure are minimized by autonomic blockade [continuous infusion of atropine (about 10 μg / kg / h) and propranolol (about 20 μg / kg / h)]. After intubation, the animals are ventilated via a respirator with a constant breathing volume, so that an end-tidal CO ₂ concentration of about 5% is achieved. Ventilation takes place with room air, enriched with approx. 30% oxygen (normoxie). To measure the hemodynamic parameters, a catheter filled with fluid is implanted in the femoral artery to measure blood pressure. A dual lumen Swan-Ganz catheter ^® is jugularis on the V. in the pulmonary artery is flooded (distal lumen for measuring the pulmonary arterial pressure, proximal lumen for measuring the central venous pressure). Left ventricular pressure is measured after the introduction of a Mikro-Tip catheter (Millar Instruments ^®) through the carotid artery into the left ventricle and derived from the dP / dt value as a measure of contractility. Substances are administered iv via the femoral vein. The hemodynamic signals are recorded and evaluated by means of pressure transducers / amplifiers and PONEMAH ^® as data acquisition software.

To induce acute pulmonary hypertension, either hypoxia or a continuous infusion of thromboxane A ₂ or a thromboxane A ₂ analogue is used as the stimulus. Acute hypoxia is induced by gradual lowering of the oxygen in the ventilation air to about 14%, so that the mPAP increases to values of> 25 mm Hg. In the case of a thromboxane A ₂ analogue stimulus, 0.21-0.32 μg / kg / min U-46619 [9, 11-dideoxy-9α, 11α-epoxy-methano-prostaglandin F _2α (Sigma)] is infused to obtain to increase the mPAP to> 25 mm Hg. B-sixth PAH model in anesthetized Göttinger Minipig

In this animal model of pulmonary arterial hypertension (PAH), Göttingen mini-pigs with a body weight of approx. 25 kg are used. The anesthesia is induced by 30 mg / kg Ketamine (Ketavet ^®) in, followed by an intravenous administration of 10 mg / kg of sodium thiopental (Trapanal ^®); it is maintained during the experiment by inhalation anesthesia from enflurane (2-2.5%) in a mixture of room air enriched with approximately 30-35% oxygen / N ₂ O (1: 1.5). To measure the hemodynamic parameters, a catheter filled with fluid is implanted in the carotid artery to measure blood pressure. A dual lumen Swan-Ganz catheter ^® is jugularis on the V. in the pulmonary artery is flooded (distal lumen for measuring the pulmonary arterial pressure, proximal lumen for measuring the central venous pressure). Left ventricular pressure is measured after the introduction of a Mikro-Tip catheter (Millar Instruments ^®) through the carotid artery into the left ventricle and derived from the dP / dt value as a measure of contractility. Substances are administered iv via the femoral vein. The hemodynamic signals are recorded and evaluated by means of pressure-sensitive devices / amplifiers and PONEMAH ^® as data acquisition software.

To induce acute pulmonary hypertension, a continuous infusion of a thromboxane A ₂ analogue is used as the stimulus. Here, 0.12-0.14 μg / kg / min of U-46619 [9, 11-dideoxy-9α, 11α-epoxymethano-prostaglandin F _2α (Sigma)] is infused to increase the mPAP to> 25 mm Hg.

C. Embodiments of Pharmaceutical Compositions

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

Tablet:

Composition:

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

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

The mixture of the compound according to the invention, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are mixed after drying with the magnesium stearate for 5 minutes. This mixture is compressed with a conventional tablet press (for the tablet format see above). As a guideline for the compression, a pressing force of 15 kN is used.

Orally administrable suspension:

Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel ^® (xanthan gum of the firm FMC, Pennsylvania, USA) and 99 g of water.

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

production:

The rhodigel is suspended in ethanol, the compound according to the invention is added to the suspension. While stirring, the addition of water. Until the completion of the swelling of Rhodigels is stirred for about 6 h. Orally administrable solution:

Composition:

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

production:

The compound according to the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring is continued until complete dissolution of the compound according to the invention.

iv solution:

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

Claims

claims

1. Compound of formula (I)

in which

R ^{1 is} (C, -C ₆ ) alkyl or a group of the formula -C (= O) -R ^1A or -CH (OH) -R ^1B , wherein

R ^1A (C _r C ₆ ) alkyl, hydroxy, (C _r C ₆ ) alkoxy, (C ₂ -C ₆ ) alkenyloxy, amino, mono- (C ₁ -C ₆ ) alkylamino or mono (C ₂ -C ₆ ) alkenylamino

and

R ^{1B is} (C _r C ₆ ) -alkyl,

R ^{2 is} hydrogen or (C 1 -C ₄ ) -alkyl,

R ^{3 is} a substituent selected from the group halogen, cyano, nitro, (Ci-Q) -

Alkyl, (C ₂ -C ₆ ) -alkenyl, (C ₂ -C ₄ ) -alkynyl, (C ₃ -C ₇ ) -cycloalkyl, (C ₄ -C ₇ ) -cycloalkenyl, (Ci-Co) - AIkOXy, trifluoromethyl, trifluoromethoxy, (Ci- _C6) acyl, amino, mono- (Ci-C ₆₎ alkylamino, di- (Ci -C ₆₎ alkylamino and (C _r _C6) -

Acylamino stands,

in which (Ci-Cg) -alkyl and (C] -C ₆ ) -alkoxy in each case with cyano, hydroxy, (Ci-C ₄ ) -alkoxy, (Ci-C ₄ ) -alkylthio, amino, mono- or di- (C 1 -C ₄ ) -alkylamino may be substituted,

m is the number 0, 1 or 2,

A is O or NR ⁴ , in which R ^{4 is} hydrogen, (C 1 -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl or (C ₄ -C ₇ ) -cycloalkenyl,

for a group of the formula

stands in which

# the linkage with the group A

and

## means the point of attachment to the group Z,

R ^{5 is} hydrogen or (C 1 -C ₄ ) -alkyl which may be substituted by hydroxy or amino,

L ^{1 is} (C ₁ -C ₇ ) -alkanediyl or (C ₂ -C ₇ ) -alkendiyl, which may be mono- or di-substituted by fluorine, or a group of formula * -L ^1A -VL ^1B - **, in which

* the point of attachment with the group -CHR ⁵ ,

** the point of attachment to the group Z,

L ^1A (C 1 -C ₅ ) -alkanediyl which may be monosubstituted or disubstituted, identically or differently, with (C 1 -C ₄ ) -alkyl and / or (C 1 -C ₄ ) -alkoxy,

L ^{1B is} a bond or (C _r C ₃ ) -alkanediyl which may be monosubstituted or disubstituted by fluorine,

and

VO or NR ⁶ , in which

R ⁶ is hydrogen, (C _r _C6) alkyl or (C ₃ -C ₇₎ cycloalkyl, represent

L ^{2 is} a bond or (C 1 -C ₄ ) -alkanediyl,

R ^{7 represents} hydrogen, (C 1 -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,

or (C ₂ -C ₄ ) -alkendiyl,

and

Q is (C ₃ -C ₇ ) -cycloalkyl, (C ₄ -C ₇ ) -cycloalkenyl, phenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl, each of which may be up to twice, identical or different, by radicals selected from the series comprising fluorine, chlorine, (C _r _C4) alkyl, trifluoromethyl, hydroxy, (C _r C ₄₎ - alkoxy, trifluoromethoxy, amino, mono (Ci-C ₄₎ -alkylamino and di- ( may be substituted Cp C ₄₎ alkylamino,

where (C 1 -C ₄ ) -alkyl in turn contains hydroxyl, (C 1 -C ₄ ) -alkoxy, amino,

Mono- or di- (C _r C ₄₎ alkylamino may be substituted,

and

Z is a group of the formula

stands in which

### the linkage with the group L ¹ or L ³

and R ^{8 is} hydrogen or (C ₁ -C ₄ ) -alkyl,

and their salts, solvates and solvates of the salts.

2. A compound of formula (I) according to claim 1, in which

R ^{1 is} (Ci-C ₄ ) -alkyl or a group of the formula -C (= O) -R ^1A , wherein

R ^1A (C _r C ₄₎ alkyl, hydroxy, (C _r _C4) alkoxy, allyloxy, mono- _(Ci-C4) -alkyl- amino or allylamino means

R ^{2 is} hydrogen, methyl or ethyl,

m is the number 0, 1 or 2,

A is O or NH,

M for a group of the formula

stands in which

# the linkage with the group A

and

## means the point of attachment to the group Z,

R ^{5 is} hydrogen, methyl or ethyl,

L ¹ (C ₃ -C ₇ ) -alkanediyl, (C ₃ -C ₇ ) -alkendiyl or a group of formula * _L ^1A -VL ^1B - **, wherein

* the point of attachment with the group -CHR ⁵ , ** the point of attachment to the group Z,

L ^1B (C, -C ₃ ) alkanediyl

and

VO or N-CH ₃

represent

L ^{2 is} a bond, methylene, ethane-1, 1-diyl or ethane-1, 2-diyl,

L ^{3 is} (Ci-C ₃ ) alkanediyl or a group of the formula "-W-CH ₂ - ** or ^ -W-CH ₂ -CH ₂ - **, in which

The point of attachment to the ring Q,

•• the link to the group Z

and

WO or NR ⁷ , wherein

R ^{7 is} hydrogen or (C _r C ₃ ) -alkyl,

represent

and

Q is cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl or phenyl, each of which may be up to twice, identically or differently, with

Radicals selected from the group fluorine, methyl, ethyl, trifluoromethyl, hydroxy, methoxy and ethoxy may be substituted,

and

Z is a group of the formula

stands in which

### means the point of attachment to the group L ¹ or L ³ ,

and their salts, solvates and solvates of the salts.

A compound of the formula (I) according to claim 1 or 2, in which

R ^{1 is} ethyl, n-propyl or a group of the formula -C (= O) -R ^1A where

R ^{1A is} ethyl, n-propyl, ethoxy, allyloxy, ethylamino, n-propylamino or allylamino,

R ^{2 is} hydrogen or methyl,

R ^{3 is} fluorine, chlorine or methyl,

m is the number 0 or 1,

A is O or NH,

M for the group of the formula

# the linkage with the group A

and

## means the point of attachment to the group Z,

R ^{5 is} hydrogen or methyl,

and

L ¹ butane-1,4-diyl, pentane-l, 5-diyl or a group of the formula

* -L ^1A -OL ^1B - ** means in which * Is the point of attachment to the group -CHR ^5,

** the point of attachment to the group Z,

L ^{1A is} methylene or ethane-1,2-diyl which may be monosubstituted or disubstituted by methyl,

and

L ^{1 B is} methylene or ethane-1, 2-diyl

represent

and

Z for the group of the formula

stands in which

### means the point of attachment to the group L ¹ ,

and their salts, solvates and solvates of the salts.

4. A process for the preparation of compounds as defined in claims 1 to 3, in which Z is -COOH or -C (= O) -COOH, which comprises reacting a compound of the formula (II)

in which R ³ and m have the meanings given in claims 1 to 3

and

in an inert solvent in the presence of a base with a compound of the formula

(M) HA Z ¹ (m),

in which A and M have the meanings given in claims 1 to 3

and

Z ^{1 is} cyano or a group of the formula - [C (O)] _y -COOR ^8A in which

y is the number 0 or 1

and

R ^{8A is} (C 1 -C ₄ ) -alkyl,

to a compound of the formula (IV)

in which A, M, Z ¹ , R ³ and m are each as defined above,

and then either

(V) (VI)

in which R ¹ and R ^{2 have} the meanings given in claims 1 to 3

and R ^{9 is} hydrogen or (C 1 -C ₄ ) -alkyl or both radicals R ⁹ together form a -CH ₂ -CH ₂ -, -C (CHj) ₂ -C (CH ₃ ) Z- or -CH ₂ -C ( CH ₃ ) ₂ -CH ₂ bridge,

to a compound of formula (VET)

in which A, M, Z ¹ , R ¹ , R ² , R ³ and m are each as defined above,

couples

or

[B] first in an inert solvent in the presence of a base and a suitable palladium catalyst with a vinyl boronic acid derivative of the formula

(Vm)

in which R ^{9 has} the abovementioned meaning,

into a compound of the formula (EX)

in which A, M, Z τ \, R τ> 3 and m each have the meanings given above, subsequently converted by reaction with ozone and subsequent treatment with a sulfide to give a compound of the formula (X)

in which A, M, Z ¹ , R ³ and m are each as defined above,

oxidized and then in an inert solvent in the presence of a base with a phosphorus YHd of the formula (XI) or a phosphonate of the formula (Xu)

(XI) (xπ)

in which R ¹ and R ^{2 have} the meanings given in claims 1 to 3 and

R> io is phenyl or o-, m- or p-tolyl,

R ^{1 is} (C ¹ -C ₄ ) -alkyl

and

represents a halide anion,

to a compound of formula (VE)

(Vπ) in which A, M, Z ¹ , R ¹ , R ² , R ³ and m are each as defined above,

couples

and the compounds of the formula (VII) finally by hydrolysis of the ester or i cyano group Z ¹ into the carboxylic acids of the formula (IA)

in which A, M, R ¹ , R ² , R ³ , m and y each have the meanings given above,

If necessary, these are reacted with the appropriate (i) solvents and / or (ii) bases or acids to give their solvates, salts and / or solvates of the salts.

5. A compound as defined in any one of claims 1 to 3 for the treatment and / or prophylaxis of diseases.

6. Use of a compound as defined in any one of claims 1 to 3 for the manufacture of a medicament for the treatment and / or prophylaxis of angina pectoris, pulmonary hypertension, thromboembolic disorders and peripheral occlusive diseases.

7. A medicament containing a compound as defined in any one of claims 1 to 3, in combination with an inert, non-toxic, pharmaceutically suitable excipient.

8. A medicament containing a compound as defined in any one of claims 1 to 3, in combination with another active ingredient.

9. Medicament according to claim 7 or 8 for the treatment and / or prophylaxis of angina pectoris, pulmonary hypertension, thromboembolic disorders and peripheral occlusive diseases.

10. A method for the treatment and / or prophylaxis of angina pectoris, pulmonary hypertension, thromboembolic disorders and peripheral obstructive diseases in men and animals using an effective amount of at least one compound A compound as defined in any one of claims 1 to 3 or a pharmaceutical composition as defined in any one of claims 7 to 9.