EP2240461A1 - Substituted furans and use thereof - Google Patents

Abstract

The present application relates to substituted furan derivatives of the formula (I), to a method for the production thereof, to the use thereof for the treatment and/or prophylaxis of diseases, and to the use thereof for the production of pharmaceuticals for the treatment and/or prophylaxis of diseases, particularly for the treatment and/or prophylaxis of cardiovascular diseases.

Description

 Substituted furans and their use

The present application relates to novel, substituted furan 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 EP receptor stimulates 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 formation or by an 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. 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.

Compared to PGI ₂ , the compounds described in the present application are chemically and metabolically stable, non-prostanoid activators of the IP receptor, which mimic the biological activity of PGI ₂ and can thus be used for the treatment of diseases, in particular of cardiovascular diseases ,

In US 3,442,913 trifluoromethyl-substituted furancarboxylic acids are disclosed as synthesis intermediates. EP 0 258 790 describes furan and thiophenecarboxylic acid propargyl esters as insecticides. US 5,068,237 discloses substituted furans for the treatment of, for example, Alzheimer's disease. JP 10-114765 claims substituted aryl furans as fungicides. In US 2003/0199570, inter alia, substituted furans are disclosed as estrogen receptor modulators for the treatment of inflammatory bowel disease, colitis and Crohn's disease. EP 1 535 915 describes substituted furans and thiophenes as PPAR modulators for the treatment of arteriosclerosis, diabetes mellitus and lipid metabolism disorders. WO 2004/110357 claims, inter alia, substituted furans for the treatment of neurodegenerative, cardiovascular and proliferative diseases as well as eye diseases.

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

in which

represents -CH ₂ - or -C (= O) -,

is O or NR ⁴ ,

in which

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

M for a group of the formula

# - CH-L ¹ - ## or # - L2 L ³ - ##

stands, where

# means the link with E,

## means the point of attachment with Z,

R ⁵ is hydrogen or (C _r C ₄₎ alkyl,

wherein alkyl may be substituted with one substituent selected from the group hydroxy and amino,

L ^{1 is} (C ₁ -C ₇ ) -alkanediyl, (C ₂ -C ₇ ) -alkendiyl or a group of formula * _L ^1A -VL ^IB - ** _;

wherein alkanediyl and alkenediyl may be substituted with 1 or 2 substituents fluorine,

and

embedded image in which

the attachment site with -CHR ⁵ means

** the attachment point with Z means

IA is (C, -C ₅ ) -alkanediyl,

wherein alkanediyl having 1 or 2 substituents independently may be selected from the group consisting of (Ci-C ₄₎ -alkyl and (C _r C ₄₎ alkoxy.

IB is a bond or (C ₁ -C ₃ ) -alkanediyl,

wherein alkanediyl may be substituted by 1 or 2 substituents fluorine,

and

V is O or NR ⁶ ,

wherein

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

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

Q is (C ₃ -C ₇ ) -cycloalkyl, (C ₄ -C ₇ ) -cycloalkenyl, 5- to 7-membered heterocyclyl,

Phenyl or 5- or 6-membered heteroaryl,

wherein cycloalkyl, cycloalkenyl, heterocyclyl, phenyl, and heteroaryl having 1 or 2 substituents independently selected from the group of fluorine, chlorine, (C] _-C4) alkyl, trifluoromethyl, hydroxy, (C _r C ₄₎ -alkoxy, trifluoromethoxy, amino, mono- (Ci-C ₄₎ -alkylamino and di- (Ci -C ₄₎ alkylamino can be substituted,

wherein alkyl is substituted with a substituent selected from the group of hydroxy, (C _{r C4)} alkoxy, amino, mono- (C _r C ₄₎ -alkylamino and di- _(Ci-C4) - alkylamino may be substituted,

and

L ^{3 is} (C _r C ₄ ) -alkanediyl or (C ₂ -C ₄ ) -alkendiyl,

wherein alkanediyl may be substituted by 1 or 2 substituents fluorine,

and

wherein a methylene group of the alkanediyl group may be exchanged for O or NR ⁷ ,

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

Z is a group of the formula

stands, where

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

and

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

R ¹ represents halogen, cyano, nitro, (C _{r C6)} alkyl, trifluoromethyl, (C ₂ -C ₆₎ alkenyl, (C ₂ -C ₄₎ - alkynyl, (C ₃ -C ₇₎ cycloalkyl, (C ₄ -C ₇₎ cycloalkenyl, (C _r C ₆₎ alkoxy, trifluoromethoxy, (C _{r C6)} alkylthio, (Ci-C ₆₎ alkylcarbonyl, amino, mono- (C _{r C6)} - alkylamino, di- (C ₁ -C ₆ ) -alkylamino or (C ₁ -C ₆ ) -alkylcarbonylamino,

in which (C ₁ -C ₆ ) -alkyl and (C ₁ -C ₆ ) -alkoxy in turn have a substituent selected from the group cyano, hydroxy, (C 1 -C ₄ ) -alkoxy, (C 1 -C ₄ ) -alkylthio, amino, mono- (Ci-C ₄₎ -alkylamino and di- (Ci -C ₄₎ alkylamino can be substituted,

or

two radicals R ¹ bound to adjacent carbon atoms of the phenyl ring together form a group of the formula -O-CH ₂ -O-, -O-CHF-O-, -O-CF ₂ -O-, -O-CH ₂ -CH ₂ - Form O- or -O-CF ₂ -CF ₂ -O-,

n is the number O, 1 or 2,

wherein, in the event that R ¹ occurs several times, its meaning may be the same or different,

and

R ^{2 is} phenyl or 5- or 6-membered heteroaryl,

wherein phenyl and heteroaryl having 1 to 3 substituents independently selected from the group halogen, cyano, nitro, formyl, (Ci-C ₆₎ alkyl, trifluoromethyl, (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, trifluoromethoxy, (C _r Q) alkylthio, (C _r C ₆ ) alkylcarbonyl, amino, mono (C _r C ₆ ) -alkylamino, di- (C ₁ -C ₆ ) -alkylamino and (C ₁ -C ₆ ) -alkylCycarbonylamino may be substituted,

wherein alkyl and alkoxy having a substituent selected from the group consisting of cyano, hydroxy, (C _{r C4)} alkoxy, (Ci-C ₄₎ alkylthio, amino, mono (C] _-C4) - alkylamino and di- ( C 1 -C ₄ ) -alkylamino may be substituted,

or

two substituents bonded to adjacent carbon atoms of the phenyl ring together form a group of the formula -O-CH ₂ -O-, -O-CHF-O-, -O-CF ₂ -O-, -O-CH ₂ -CH ₂ -O- or form -O-CF ₂ -CF ₂ -O-,

and

R ^{3 is} methyl, ethyl or trifluoromethyl,

and their salts, solvates and solvates of the salts.

Compounds according to 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 and of the formula (I) encompassed by 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.

Suitable salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. Also included are salts suitable for pharmaceutical Applications themselves are not suitable, but can be used for example for the isolation or purification of the inventive compounds.

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 according to the invention. The term "prodrugs" includes compounds which may themselves be biologically active or inactive, but are reacted during their residence time in the body 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 assays described below, and in particular in vivo enzymatically or chemically to the free carboxylic acids, as the main biologically 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 or ethyl esters (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:

In the context of the invention, alkyl is a linear or branched alkyl radical having 1 to 6 carbon atoms. Preference is given to a linear or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.

Alkenyl in the context of the invention represents a linear or branched alkenyl radical having 2 to 6 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. By way of example and by way of preference: vinyl, allyl, isopropenyl and n-but-2-en-1-yl.

Alkynyl in the context of the invention represents a linear or branched alkynyl radical having 2 to 4 carbon atoms and a triple bond. By way of example and preferably mention may be made of: ethynyl, n-prop-1-yn-1-yl, n-prop-2-yn-1-yl, n-but-2-yn-1-yl and n-but-3-one in-l-yl.

Alkanediyl in the context of the invention is a linear or branched divalent alkyl radical having 1 to 7 carbon atoms. By way of example and preferably mention may be made of: methylene, 1,2-ethylene, ethane-1,1-diyl, 1,3-propylene, propane-1,1-diyl, propane-1,2-diyl, propane-2,2-propylene diyl, 1,4-butylene, butane-1,2-diyl, butane-l, 3-diyl and butane-2,3-diyl.

Alkenediyl in the context of the invention is a linear or branched divalent alkenyl radical having 2 to 7 carbon atoms and up to 2 double bonds. Examples which may be mentioned by way of example and are preferably: ethene-1, 1-diyl, ethene-1,2-diyl, propene-1,1-diyl, propylene-1,2-diyl, propene-1,3-diyl, but-1-one en-1, 4-diyl, but-1-en-1, 3-diyl, but-2-en-1, 4-diyl and buta-1,3-dien-1, 4-diyl.

Alkoxy in the context of the invention is a linear or branched alkoxy radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. By way of example and preferably mention may be made of: methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylthio in the context of the invention is a linear or branched alkylthio radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkylthio radical having 1 to 4 carbon atoms. Examples which may be mentioned are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, n-pentylthio and n-hexylthio.

Alkylcarbonyl in the context of the invention is a linear or branched alkyl radical having 1 to 6 carbon atoms and a carbonyl group attached in position 1. By way of example and by way of preference: methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, isobutylcarbonyl and tert-butylcarbonyl.

Mono-alkylamino in the context of the invention represents an amino group having a linear or branched alkyl substituent which has 1 to 6 carbon atoms. Examples which may be mentioned are: methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.

Di-alkylamino in the context of the invention is an amino group having two identical or different linear or branched alkyl substituents, each having 1 to 6 carbon atoms. Examples which may be mentioned are: 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.

Alkylcarbonylamino in the context of the invention represents an amino group which is linked via a carbonyl group with a linear or branched alkyl substituent having 1 to 6 carbon atoms. By way of example and preferably mention may be made of: methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino, isobutylcarbonylamino and tert-butylcarbonylamino.

Cycloalkyl in the context of the invention is a monocyclic, saturated cycloalkyl group having 3 to 7 carbon atoms. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Cycloalkenyl is in the context of the invention a monocyclic cycloalkyl group having 4 to 7 carbon atoms and a double bond. Examples which may be mentioned by way of example include cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.

Heterocvclyl in the context of the invention is a saturated, monocyclic, heterocyclic radical having 5 to 7 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series Ν, O, S, SO, SO ₂ , where a nitrogen atom also a Ν Oxide can form. Preferred are 5- or 6-membered saturated heterocyclyl radicals having one or two ring heteroatoms from the series N and O. Examples which may be mentioned are pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, hexahydroazepinyl and hexahydro-1, 4-diazepinyl.

Heteroaryl is in the context of the invention for an aromatic heterocycle (heteroaromatic) with 5 or 6 ring atoms and up to 3 heteroatoms from the series N, O and S, wherein a nitrogen atom can also form an N-oxide. Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl and pyrazinyl.

Halogen is in the context of the invention for fluorine, chlorine, bromine and iodine, preferably 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 one another for all radicals which occur repeatedly. Substitution with one, two or three identical or different substituents is preferred. Very particular preference is given to the substitution with a substituent.

In the formulas of the group for which M or Z may stand, the endpoint of the line where *, **, #, ##, •, ••, or ### stands, is not a carbon atom or a CH ₂ group, but is part of the bond to the respective designated atom to which M or Z is bound.

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

A is -CH ₂ - or -C (= O) -,

E is O or NR ⁴ ,

in which

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

M for a group of the formula

# - CH-L ¹ - ## or # - L ² L ³ - ## stands, where

# means the link with E,

## means the point of attachment with Z,

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

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

wherein

♦ the attachment site with -CHR 5 i means

** the attachment point with Z means

L ^{1A is} (C _r C ₃ ) -alkanediyl,

wherein alkanediyl may be substituted with 1 or 2 substituents independently of one another selected from the group consisting of methyl and ethyl,

L ^{1B is} (C ₁ -C ₃ ) -alkanediyl,

and

V is O or NR ⁶ ,

wherein

R ^{6 is} hydrogen, (C ₁ -C ₃ ) -alkyl or cyclopropyl,

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

Q is cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, polypholinyl or phenyl,

wherein cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, Moφholinyl and phenyl may be substituted with 1 or 2 substituents independently selected from the group fluorine, methyl, ethyl, trifluoromethyl, hydroxy, methoxy and ethoxy, and

L ^{3 is} (C _r C ₃ ) -alkanediyl or a group of the formula "-W-CR ⁹ R ¹⁰ - **, -W-CH ₂ -CR ⁹ R ' ⁰ -" or e-CH ₂ -W- CR ⁹ R ¹⁰ - ». stands,

wherein alkanediyl may be substituted by 1 or 2 substituents fluorine,

and

wherein

The point of attachment to the ring Q means

•• the point of attachment with the group Z means

W is O or NR ⁷ ,

wherein

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

R ^{9 is} hydrogen or fluorine,

and

R ^{10 is} hydrogen or fluorine,

Z is a group of the formula

stands, where

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

and

R ^{8 is} hydrogen,

R ^{1 is} fluorine, chlorine, methyl, ethyl, vinyl, trifluoromethyl or methoxy,

n is the number 0, 1 or 2, wherein, in the event that R ¹ occurs several times, its meaning may be the same or different,

and

R ^{2 is} phenyl or 2-pyridyl,

wherein phenyl and 2-pyridyl having 1 or 2 substituents independently selected from the group fluorine, chlorine, cyano, methyl, ethyl, n-propyl, vinyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, methylthio, ethylthio, amino, methylamino and ethylamino can be substituted

and

R ^{3 is} methyl or trifluoromethyl,

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

A is -CH ₂ - or -C (= O) -,

E is O or NR ⁴ ,

in which

R ^{4 is} hydrogen,

M for a group of the formula

R ⁵

# - CH- L ¹ - ## or # - L ² - £ θ ^ "L ³ - ##

stands, where

# means the link with E,

## means the point of attachment with Z,

R ^{5 is} hydrogen or methyl,

L ¹ for butane-1,4-diyl, pentane-l, 5-diyl or a group of the formula * -L ^IA -VL ^IB - ** stands,

wherein

* the link with -CHR ⁵ means

** the attachment point with Z means

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

wherein methylene and ethane-1, 2-diyl may be substituted by 1 or 2 substituents methyl,

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

and

V is O or NR ⁶ ,

embedded image in which

R ^{6 is} methyl,

L ^{2 is} a bond,

Q is phenyl,

and

L ^{3 is} ethane-1, 2-diyl, propane-1,3-diyl or a group of the formula "-W-CR ⁹ R ¹⁰ - * or.-W-CH ₂ -CR ⁹ R ¹⁰ - **,

wherein

The point of attachment to the ring Q means

•• the point of attachment with the group Z means

W stands for O,

R ^{9 is} hydrogen,

and R ^{10 is} hydrogen,

Z is a group of the formula

stands, where

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

and

R ^{8 is} hydrogen,

R ^{1 is} fluorine, chlorine, methyl or trifluoromethyl,

n is the number 0 or 1,

and

R ^{2 is} phenyl,

where phenyl may be substituted by a substituent selected from the group consisting of methyl, ethyl, vinyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy,

and

R ^{3 is} methyl,

and their salts, solvates and solvates of the salts.

Preference is also given to compounds of the formula (I) in which

M for a group of the formula

stands, where

# means the link with E, ## means the point of attachment with Z,

R ^{5 is} hydrogen or methyl,

L ^{1 is} butanedi-1,4-diyl, pentan-l, 5-diyl or a group of the formula * -L ^IA -VL ^1B - **,

wherein

* the link with -CHR ⁵ means

** the attachment point with Z means

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

wherein methylene and ethane-l, 2-diyl may be substituted by 1 or 2 substituents methyl,

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

and

V is O or NR ⁶ ,

wherein

R ^{6 is} methyl.

Preference is also given to compounds of the formula (I) in which

M for a group of the formula

stands, where

# means the link with E,

## means the point of attachment with Z,

L ^{2 is} a bond,

Q is phenyl, and

L ^{3 is} ethane-l, 2-diyl, propane-l, 3-diyl or a group of the formula "-W-CR ⁹ R ¹⁰ - ** or β-W-CH ₂ -CR ⁹ R ¹⁰ -ββ,

wherein

The point of attachment to the ring Q means

•• the point of attachment with the group Z means

W stands for O,

R ^{9 is} hydrogen,

and

R ^{10 is} hydrogen.

Preference is also given to compounds of the formula (I) in which

R ^{2 is} phenyl,

wherein phenyl may be substituted with one substituent selected from the group of methyl, ethyl, vinyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy.

Preference is also given to compounds of the formula (I) in which R ^{3 is} methyl.

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.

Very particular preference is given to combinations of two or more of the abovementioned preferred ranges.

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, which comprises reacting either

[A] compounds of the formula (HA),

in which n, R ¹ and R ³ each have the meanings given above

and

A ^{1 stands} for - (C = O) -

and

X ^{1 is} chlorine or hydroxy,

in an inert solvent optionally in the presence of a suitable acid or base and / or a suitable condensing agent, with a compound of the formula (II-A)

HEM-Z (m-A),

in which E and M each have the meanings given above

and

Z ^{1 is} cyano or a group of the formula COOR ^8A ,

in which

R ¹ 8A is (Ci-GO-alkyl,

to compounds of the formula (IV-A)

in which n, A ¹ , E, M, Z ¹ , R ¹ and R ³ each have the meanings given above, couples,

then in an inert solvent, for example with N-bromosuccinimide, to give compounds of the formula (V-A)

in which n, A ¹ , E, M, Z ¹ , R ¹ and R ³ each have the meanings given above,

brominated and this then in an inert solvent in the presence of a base and a suitable palladium catalyst with a compound of formula (VI)

in which R has the abovementioned meaning,

and

R ^{11 is} hydrogen or both radicals R ¹¹ together form a -C (CHj) ₂ -C (CH ₃ );, - bridge,

to compounds of the formula (VII-A)

in which n, A ¹ , E, M, Z ¹ , R ¹ , R ² and R ^{3 are} each as defined above,

couples

or

[B] Compounds of the formula (HB)

in which n, R ¹ and R ³ each have the meanings given above

and

A ^{1 is} - (C = O) -,

and

R ^{12 is} (CrO-alkyl,

in an inert solvent in the presence of a base and a suitable palladium catalyst with a compound of the formula (VI) to give compounds of the formula (IV-B)

in which n, A ¹ , R ¹ , R ² , R ³ and R ¹² each have the meanings given above,

Coupling and this then by basic or acidic hydrolysis in compounds of formula (V-B)

in which n, A, R, R and R each have the meanings given above,

überfuhrt,

and this then in an inert solvent in the presence of a suitable base and a suitable condensing agent with a compound of formula (Hl-A) to compounds of the formula (VII-A)

in which n, A ¹ , E, M, Z ¹ , R ¹ , R ² and R ³ each have the meanings given above,

implements,

or

[C] Compounds of the formula (H-C)

in which n, R ¹ and R ³ each have the meanings given above,

in an inert solvent in the presence of a base and a suitable palladium catalyst with a compound of the formula (VT) to give compounds of the formula (IV-C)

in which n, R, R and R each have the meanings given above,

coupled, these then in a suitable solvent with a suitable reducing agent to compounds of the formula (VC)

in which n, R> 1, DR ² , u, n "dJ D R 3 each have the meanings given above

and

A ^{2 stands} for -CH ₂ -

and

E ^{1 is} O,

and then this in an inert solvent in the presence of a suitable base with a compound of formula (III-C)

X ² - M - Z ¹ (mc), in which M and Z ¹ each have the meanings given above,

and

X ² for a leaving group such as halogen or Trifluormethansulfonyloxy, in particular bromine or

Trifluoromethanesulfonyloxy stands,

to compounds of the formula (VII-C)

in which n, A ² , E ¹ , M, Z ¹ , R ¹ , R ² and R ^{3 are} each as defined above,

implements, or

[D] compounds of formula (IV-C) in an inert solvent in the presence of a suitable reducing agent with a compound of formula (HI-D)

HE ² -MZ ¹ _{(with D)>}

in which M and Z ¹ each have the meanings given above,

and

E ^{2 is} NR ⁴ ,

in which

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

to compounds of the formula (VII-D)

in which n, A ² , E ² , M, Z ¹ , R ¹ , R ² and R ^{3 are} each as defined above,

implements,

and the respectively resulting compounds of the formulas (VII-A), (VII-C) or (VII-D) then by hydrolysis of the cyano or ester group Z ¹ into the carboxylic acids of the formula (1-1)

in which n, A, E, M, R, R and R 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 the coupling reactions (II-A) + (ffl-A) → (IV-A) and (VB) + (Ul-A) -> (VII-A) 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, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane, 1,2-dichloroethane, trichlorethylene or chlorobenzene, or other solvents such as acetone, Acetonitrile, ethyl acetate, pyridine, dimethyl sulfoxide, dimethylformamide, N, N'-dimethylpropylene urea (DMPU) or N-methylpyrrolidinone (ΝMP). It is also possible to use mixtures of the solvents mentioned. Preference is given to dichloromethane, dimethylformamide or mixtures of these two solvents.

Suitable bases in the coupling reactions are alkali carbonates, e.g. Sodium or potassium carbonate, or organic bases such as triethylamine, N-methylmorpholine, N-methylpiperidine, NN-diisopropylethylamine or 4-NN-dimethylaminopyridine. Preferably, triethylamine is used.

Suitable acids in the coupling reactions are generally sulfuric acid, hydrochloric acid / hydrochloric acid, hydrogen bromide / hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonic acid, methanesulfonic acid or trifluoromethanesulfonic acid. The acid is used here in catalytic amounts.

The couplings (II-A) + (IH-A) → (IV-A) and (VB) + (EI-A) → (VTI-A) are typically in a temperature range of 0 ⁰ C to +60 ⁰ C, preferably carried out at 0 ⁰ C to + 35 ° C. The reactions can be carried out at normal, at elevated or at reduced pressure (for example from 0.5 to 5 bar); generally one works at normal pressure.

In the amide coupling reactions [E = NR ⁴ in (EI-A)] (EA) + (EI-A) → (IV-A) and (VB) + (EI-A) - »(VE-A) are suitable As condensing agents, for example, carbodiimides such as NN-diethyl, NN'-dipropyl, NN'-diisopropyl, NN'-dicyclohexylcarbodiimide (DCC) or N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), phosgene Derivatives such as NN-carbonyldiimidazole (CDI), 1, 2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, acylamino compounds such as 2 Ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or isobutyl chloroformate, propanephosphonic anhydride, cyanophosphonic acid diethyl ester, bis (2-oxo-3-oxazolidinyl) -phosphoryl chloride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate, benzotriazole 1-oxy-tris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), 0- (benzotriazol-1-yl) -NNN ', N'-tetramethyl-uronium tetrafluoroborate (TBTU), O- (benzotriazol-1-yl ) -NNN ', N-tetramethyluronium hexa- fluorophosphate (HBTU), 2- (2-oxo-1 - (2H) -pyridyl) -1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O- (7-azabenzotriazol-1-yl) -NN, N ', N'-tetramethyluronium hexafluorophosphate (ΗATU) or O- (1H-6-chlorobenzotriazol-1-yl) -1,3,3-tetramethyluronium tetrafluoroborate (TCTU), optionally in combination with further auxiliaries such as 1 -Hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu). Preference is given to using 0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) in combination with N, N-diisopropylethylamine and 4-N, N-dimethylaminopyridine.

Suitable inert solvents in the bromination in process step (FV-A) → (VA) are halohydrocarbons such as carbon tetrachloride or 1, 2-dichloroethane or other solvents such as acetonitrile. The bromination is carried out in a temperature range from -20 ⁰ C to + 50 ⁰ C. Suitable brominating agents are elemental bromine and in particular N-bromosuccinimide (ΝBS), optionally with addition of α, α'-azobis (isobutyronitrile) (AIBN) as initiator.

Inert solvents for process steps (VA) + (VT) → (VH-A), (UB) + (VI) → (IV-B) and (HC) + (VT) -> (IV-C) 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 glycol dimethyl ether, hydrocarbons such as benzene, xylene,

Toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethyl sulfoxide, N, N'-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (ΝMP), pyridine, acetonitrile or water. It is also possible mixtures of the above

Use solvent. Preference is given to a mixture of dimethyl sulfoxide and water.

Suitable bases for the (VA) + (VI) → (VH-A), (HB) + (VI) → (IV-B) and (HC) + (VI) → (IV-C) are customary inorganic bases , These include in particular alkali metal 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 hydrogen phosphates such as disodium or dipotassium hydrogen phosphate. Preferably, sodium or potassium carbonate is used.

As palladium catalyst for the process steps (VA) + (VI) → (VH-A), (HB) + (VI) → (WB) and (HC) + (VI) → (IV-C) ["Suzuki Coupling "], for example, palladium on activated carbon, palladium (H) acetate, tetrakis (triphenylphosphine) palladium (0), bis-

(Triphenylphosphine) palladium (H) chloride, bis (acetonitrile) palladium (π) chloride and [1,1'-bis (diphenylphosphino) ferrocene] dichloφalladium (H) -dichloromethane complex suitable [see. eg J. Hassan et al., Chem. Rev. 102, 1359-1469 (2002)]. The reactions (VA) + (VI) → (VD-A), (HB) + (VI) → (IV-B) and (FI-C) + (VI) → (IV-C) are generally used in one Temperature range of +20 ⁰ C to +150 ⁰ C, preferably carried out at +50 ⁰ C to +100 ⁰ C.

Suitable inert solvents for process step (FV-C) → (VC) are alcohols such as methanol, ethanol, n-propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or halogenated hydrocarbons such as dichloromethane, trichloromethane, Carbon tetrachloride or 1,2-dichloroethane, or other solvents such as dimethylformamide. It is also possible to use mixtures of the solvents mentioned. Preference is given to using tetrahydrofuran.

Suitable reducing agents for the process step (FV-C) - »(VC) borohydrides, such as sodium borohydride, sodium triacetoxyborohydride, lithium borohydride or sodium cyanoborohydride, aluminum hydrides such as lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride or diisobutylaluminum hydride or borane-tetrahydrofuran Complex used.

Reaction (IV-C) → (VC) is generally carried out in a temperature range of 0 ⁰ C to +60 ⁰ C, preferably from 0 ⁰ C to +40 ⁰ C.

Inert solvents for process step (VC) + (EH-C) - (VFI-C) 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, carbon tetrachloride, 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 or dimethylformamide.

Optionally, however, the process step (V-C) + (FH-C) -> (VFI-C) can also be carried out without a solvent.

Suitable bases for the process step (VC) + (HI-C) - »(VFI-C) 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 tert-butoxide, 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 phenyl lithium, or organic amines such as triethylamine, N-Methylmoφholin, N-methylpiperidine, N, N-diisopropylethylamine or pyridine.

Furthermore, in the reaction (VC) + (III-C) -> (VII-C) also phosphazene bases (so-called "Schwesinger bases") such as P2-t-Bu or P4-t-Bu expedient [cf. , e.g. R. Schwesinger, H. Schlemper, Angew. Chem. Int. Ed. Engl. 26, 1167 (1987); T. Pietzonka, D. Seebach, Chem. Ber. 124, 1837 (1991)].

The process step (V-C) + (EI-C) -> (VII-C) may optionally be carried out advantageously with the addition of a crown ether.

In a process variant, the reaction (VC) + (DI-C) -> (VH-C) also in a two-phase mixture consisting of an aqueous alkali hydroxide solution as the base and one of the above hydrocarbons or halogenated hydrocarbons as further Solvent, be carried out using a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate or tetrabutylammonium bromide.

The process step (VC) + (HI-C) -> (VII-C) is generally carried out in a temperature range from -20 ⁰ C to +120 ⁰ C, preferably at 0 ⁰ C to + 60 ⁰ C.

Suitable inert solvents for process step (IV-C) + (IH-D) - »(VII-D) are alcohols such as methanol, ethanol, n-propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or Diethylene glycol dimethyl ether, or halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, or other solvents such as dimethylformamide. It is also possible to use mixtures of the solvents mentioned. Preference is given to using tetrahydrofuran.

Boron hydrides, such as, for example, sodium borohydride, sodium triacetoxyborohydride, lithium borohydride or sodium cyanoborohydride, if appropriate with addition of acids such as formic acid or acetic acid, or Lewis acids, are suitable as reducing agents for process step (IV-C) + (DI-D) → (VD-D) such as titanium (IV) tetrachloride or titanium (IV) isopropylate.

Alternatively, the reaction (IV-C) + (DI-D) -> (VD-D) can be carried out with ammonium formate or formic acid, or under a hydrogen atmosphere with catalysts such as Raney-Νickel, palladium, palladium on activated carbon or platinum.

The reaction (FV-C) + (DI-D) -> (VII-D) is generally carried out in a temperature range from 0 ⁰ C to +60 ⁰ C, preferably from 0 ⁰ C to +40 ⁰ C.

The hydrolysis of the cyano or ester group Z ^{1 of} the compounds (VII-A), (VII-C) or (VH-D) to compounds of the formula (I-1) and the ester of the formula (IV-B ) to carboxylic acids of the formula (VB) is carried out by customary methods by treating the esters or nitriles in inert solvents with acids or bases, wherein in the latter, the salts initially formed are converted by treatment with acid in the free carboxylic acids. In the case of the 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 a basic ester hydrolysis, preference is given to using mixtures of water with dioxane, tetrahydrofuran, methanol and / or ethanol, in the nitrile hydrolysis preferably water and / or n-propanol. In the case of the reaction with trifluoroacetic acid, preference is given to using dichloromethane and, in the case of the 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 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, if appropriate 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 Esterspaltung is generally carried out in a temperature range of 0 ⁰ C to +100 ⁰ C, preferably at +0 ⁰ C to +50 ⁰ C.

The reactions mentioned can be carried out at normal, elevated or reduced pressure (for example from 0.5 to 5 bar). In general, one works 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 the formula (VII-A), (VE-C) or (VE-D) in which Z ^{1 is} cyano in an inert solvent with an alkali azide in the presence of ammonium chloride or with Trimethylsilylazid 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 (DMPU). or N-methylpyrrolidone (ΝMP). 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 ° C to +110 ⁰ C. The reaction can be carried out at normal, elevated or reduced pressure (eg from 0.5 to 5 bar). In general, you work 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 the formulas (VII-A), (VII-C) or (VE-D) in which Z ^{1 is} methoxy- or ethoxycarbonyl first in an inert solvent with hydrazine in compounds of the formula (II) VEI)

in which n, A, E, M, R ¹ , R ² and R ^{3 have} the meanings given above,

and then reacted in an inert solvent with phosgene or a phosgene equivalent, such as N, N'-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. Preferably, a mixture of methanol and tetrahydrofuran is 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 according to the invention of the formula (I) in which L ^{1 is} a group of the formula * -L ¹ -VL ^1B - **, where L ^1A , L ^1B and V have the meanings indicated above, can alternatively also be prepared thereby in that compounds of the formula (IX)

in which n, A, E, ^IA , V, R ¹ , R ² , R ³ and R ^{5 are} each as defined above,

in the presence of a base, if appropriate in an inert solvent, with a compound of the formula (X)

"2. 1B -, 1 χ - ^L - ^z (X),

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

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

or in the case where L ^{1B is} -CH ₂ CH ₂ -, with a compound of the formula (XI)

H ₂ C ^ Z ¹ (XI),

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

in compounds of the formula (VII-I)

in which n, A, E, L ^1A , L ^1B , V, Z ¹ , R ¹ , R ² , R ³ and R ^{5 are} each as defined above,

überfuhrt and then further implemented according to the method described above.

For the process steps (IX) + (X) or (XI) -> (VII-I), the above for the reactions (HA) + (mA) → (IV-A) and (II-B) + (UI -A) → (IV-B) described reaction parameters such as solvents, bases and reaction temperatures in an analogous manner application.

The compounds of the formula (I) according to the invention in which L ^{3 is} a group of the formula --W-CR ⁹ R ¹⁰ - ** or.-W-CH ₂ -CR ⁹ R ¹⁰ - **, wherein W, R ⁹ and R ^{10 have} the meanings given above, can alternatively also be prepared by reacting compounds of the formula (XS)

in which n, A, E, L ² , Q, W, R ¹ , R ² and R ^{3 are} each as defined above,

in the presence of a base, optionally in an inert solvent, with a compound of the formula (Xffl)

X ² - (CH ₂ ) - CR ⁹ RZ ¹ (Xm),

in which R ⁹ , R ¹⁰ , X ² and Z ¹ each have the meanings given above,

m is the number 0 or 1,

or in the case where L ^{3 is} "-W-CH ₂ CH ₂ - **, with a compound of the formula (XI)

in compounds of the formula (VII-2)

in which n, m, A, E, L ² , Q, W, Z ¹ , R ¹ , R ² , R ³ , R ⁹ , R ¹⁰ and m are each as defined above,

transferred and then further implemented according to the method described above.

For the process steps (X) + (XIH) or (XI) - »(VII-2), the above for the reactions (π-A) + (mA) → (IV-A) and (HB) + (EI -A) → (IV-B) described reaction parameters such as solvents, bases and reaction temperatures in an analogous manner application.

Other compounds of the invention may optionally also be prepared by conversions of functional groups of individual substituents, in particular those listed under R ¹ and R ² , starting from the compounds of the formula (I) obtained by the above methods. These transformations are carried out by conventional methods known to those skilled in the art and include, for example, reactions such as nucleophilic and electrophilic substitutions, oxidations, reductions, hydrogenations, transition metal-catalyzed coupling reactions, elimination, alkylation, amination, esterification, ester cleavage, etherification, ether cleavage, formation of Carbonamides, as well as introduction and removal of temporary protecting groups. The compounds of the formulas (HA), (HB), (UC), (IH-A), (HI-C), (IH-D) and (VI) are commercially available, known from the literature or can be prepared in analogy to processes known from the literature (see also Reaction Schemes 1 and 2).

The preparation of the compounds according to the invention can be illustrated by the following synthesis schemes:

Scheme 1

Base, Pd cat

Scheme 2

Scheme 3

Scheme 4 Base, Pd cat

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 IP receptor.

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 of the invention may 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 cardiac vascular diseases, of peripheral occlusive diseases (PAOD, PVD) as well as of peripheral circulatory disorders.

Furthermore, the compounds according to the invention can be used for the treatment of arteriosclerosis, hepatitis, asthmatic diseases, chronic obstructive pulmonary diseases (COPD), pulmonary edema, pulmonary fibroids 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 the 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.

Another object of the present invention are the inventive compound of formula (I) for use in a method for the treatment and / or prophylaxis of angina pectoris, pulmonary hypertension, thromboembolic diseases and peripheral occlusive diseases.

The compounds according to the invention can be used alone or as needed in combination with other active substances. Another object of the present invention are medicaments, 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 SESf-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), Elafrn 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 the soluble epoxide hydrolase (sEH), such as NN'-dicyclohexylurea, 12- (3-adamantan-1-yl-ureido) -dodecanoic acid or 1-adamantan-1-yl-3- {5- [2 - (2-ethoxyethoxy) ethoxy] pentyl} urea;

• connections affecting the energy metabolism of the heart, such as exemplary and preferably etomoxir, dichloroacetate, ranolazines or trimetazidines;

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

Antithrombotic agents, by way of example and preferably from the group of thrombocyte 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, by way of example and by way of preference, 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 of the invention are used in combination with a GPBb / IIIa antagonist, as exemplified and preferably 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 Aü antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor B-relaxer, beta-receptor blocker, mineralocorticoid receptor Tor 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 by way of preference, 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 AQ 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 preferably 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 of 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 by way of 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 by way of example and preferably implitapide, BMS-201038, R-103757 or JTT-130.

In a preferred embodiment of the invention, the compounds according to 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, for example and preferably, ASBT (= IBAT) inhibitors such as 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 compound of the invention, 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, conjunctival, 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 (for example Hart - or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be accomplished by bypassing a resorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or by resorting to absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneal). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For other routes of administration are, for example inhalation medicaments (including Pulverinhala- tors, Nebulizer), nasal drops, solutions or sprays, lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous Suspensions (lotions, shake mixtures), lipophilic suspensions, Ointments, creams, transdermal therapeutic systems (eg patches), 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

Boc tert-butoxycarbonyl br s broad singlet (by NMR)

Bu Butyl

C concentration

DBU l, 8-diazabicyclo [5.4.0] undec-7-ene

TLC thin layer chromatography

DCI direct chemical ionization (in MS) dd doublet of doublet (in NMR)

DIBAH diisobutylaluminum hydride

DIEA diisopropylethylamine ("Hünig-Base")

4-DMAP 4-N, N-dimethylaminopyridine

DME 1, 2-dimethoxyethane

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide dt doublet from triplet (by NMR) d. Th. Of theory (at yield) ee enantiomeric excess

EI electron impact ionization (in MS)

ESI electrospray ionization (in MS)

Et ethyl

Mp melting point

GC gas chromatography sat. saturated h hour (s)

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

HPLC high pressure liquid chromatography conc. concentrated

LC-MS liquid chromatography-coupled mass spectrometry

Me methyl min minute (s)

Ms methanesulfonyl (mesyl)

MS mass spectrometry

NBS N-bromosuccinimide

NMR nuclear magnetic resonance spectrometry

Pd / C palladium on charcoal qu quintet (by NMR) rac. racemic

RP reverse phase (reverse phase, with FIPLC)

RT room temperature

R, retention time (by HPLC)

TFA trifluoroacetic acid

THF tetrahydrofuran

LC-MS. HPLC and GC methods:

GC-MS (Method I): Instrument: Micromass GCT, GC6890; 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 ^o C / min → 310 ° C (hold for 3 min).

LC-MS (method D: instrument type MS: Micromass ZQ; instrument type HPLC: Waters Alliance 2795; column: Phenomenex Synergi 2.5 μ MAX-RP 100A Mercury 20 mm x 4 mm; eluent A: 1 1 water + 0.5 ml 50% formic acid , Eluent B: 1 1 acetonitrile + 0.5 ml 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.

LC-MS (Method 3): Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Gemini 3 μ 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.

LC-MS (Method 4): Instrument: Micromass QuattroPremier with Waters UPLC Acquity; Column: Thermo Hypersil GOLD l, 9μ 50 x 1 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 -> 1.5 min 10% A - »2.2 min 10% A Furnace: 50 ^° C; Flow: 0.33 ml / min; UV detection: 210 nm. LC-MS (Method 5): 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 nr.

LC-MS (Method 6): Device type MS: Waters ZQ; Device Type HPLC: Agilent 1100 Series; UV DAD; 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 ^ 3.0 min 10% A ^ 4.0 min 10% A ^ 4.1 min 100%; Flow: 2.5 ml / min; Oven: 55 ° C; UV detection: 210 nm.

LC-MS (Method 7): Instrument: Micromass Quattro Micro MS with HPLC Agilent Series 1100; Column: Thermo Hypersil GOLD 3μ 20 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 100% A-> 3.0 min 10% A -> 4.0 min 10% A- * 4.01 min 100% A (flow 2.5 ml / min) - »5.00 min 100% A; Oven: 50 ^° C .; Flow: 2 ml / min; UV detection: 210 nm.

Initial connections and intermediates:

Example IA

(2j £, 6Λ) -6-Hydroxyhept-2-enoic acid tert-butyl ester

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

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

MS (DCI): m / z = 218 (M + NΗ ^

¹ H-NMR (400 MHz, DMSO-d 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 2A

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

32.2 g (160.8 mmol) of (2 E, 6Λ) -6-hydroxyhept-2-enoic acid tert-butyl ester are dissolved in 200 ml of ethanol and treated with 1.7 g of 10% palladium on carbon. The mixture is stirred at RT under a hydrogen atmosphere (normal pressure) for 2 h and then filtered through Celite. The filtrate is 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) are 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 3A

6-oxoheptanoic acid tert-butyl ester

10.0 g (about 90% pure, 62.4 mmol) of 6-oxoheptanoic be presented in 71.8 ml of cyclohexane and treated with 20.46 g (93.6 mmol) of tert-butyl 2,2,2-trichloroacetimidat and 15 ml of dichloromethane. To the solution, 0.55 ml is (6.24 mmol) of trifluoromethanesulfonic acid was slowly added dropwise at -10 ⁰ C. The resulting suspension is stirred overnight while warming to RT. The insoluble precipitate is removed by filtration and the filtrate washed twice with saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography on silica gel (cyclohexane / ethyl acetate 5: 1). From the product thus obtained precipitates on standing solid overnight, which is removed by filtration. 4.51 g of product (36.1% of theory) are obtained.

GC-MS (Method 1): R, = 4.1 min; m / z = 144 (M-56) ⁺

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

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 2.46-2.42 (m, 2H), 2.20-2.15 (m, 2H), 2.08 (s, 3H), 1.47-1.40 (m, 4H), 1.41 (s, 9H). Example 4A

(+/-) - aminoheptanoic acid tert-butyl ester

3.85 g (49.9 mmol) of ammonium acetate and 345 mg (5.49 mmol) of sodium cyanoborohydride are added at RT to a solution of 1.0 g (4.99 mmol) of tert-butyl 6-oxoheptanoate in 5 ml of methanol. The mixture is stirred at RT overnight before being diluted with water. The aqueous phase is saturated with sodium chloride and extracted three times with dichloromethane. By adding saturated aqueous sodium carbonate solution, the pH of the aqueous phase is adjusted to 11-12, and the aqueous phase is extracted three times with ethyl acetate. All organic phases are combined, dried over magnesium sulfate and carefully concentrated in vacuo. The crude product is purified by chromatography on silica gel (gradient of dichloromethane / isopropanol 20: 1 to 3: 1, with 1% ammonia). The product fractions are pooled and stored at -20 ⁰ C. 470 mg of product (46.7% of theory) are obtained.

MS (DCI): m / z = 202 (M + H) ⁺

¹ H-NMR (500 MHz, DMSOd ₆ ): δ = 2.95-2.89 (m, IH), 2.19 (t, 2H), 1.52-1.43 (m, 2H), 1.41 (s, 9H), 1.35-1.25 ( m, 4H), 1.04 (d, 3H).

Example 5A

fi5S ^ -6-bromoheptanoic tert-butyl

6.0 g (29.6 mmol) of (-) - tert-butyl 6-hydroxyheptanoate are dissolved under argon in 60 ml of absolute dichloromethane and added dropwise within 2 h to a solution of 13.77 g (32.6 mmol) of triphenylphosphine in 90 ml of absolute toluene 0 ⁰ C dropped. After completion of the addition, the cooling is removed and the mixture is stirred for 2 h at RT before the reaction mixture is filtered through Celite (rinsed with dichloromethane). The filtrate will washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product is purified by chromatography on silica gel (cyclohexane / ethyl acetate 50: 1). 4.79 g of product (60.9% of theory) are obtained.

MS (DCI): m / z = 265/267 (M + H) ⁺ , 282/284 (M + NH,) ⁺

¹ H-NMR (400 MHz, DMSO-Ci ₆ ): δ = 4.28 (m, IH), 2.21 (t, 2H), 1.80-1.72 (m, 2H), 1.67 (d, 3H), 1.58-1.41 ( m, 4H), 1.40 (s, 9H).

[α] _D ²⁰ = + 30.0 °, c = 0.550, chloroform.

Example 6A

f6 /? j-6-Azidoheptansäure tert-butyl

2.0 g (7.45 mmol) fö $ -6-Brornheptansäure tert-butyl ester and 2.94 g (45.3 mmol) of sodium azide are mixed in 28.7 ml of DMF and stirred vigorously overnight at 70 ⁰ C. After cooling, the reaction mixture is diluted with plenty of dichloromethane and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and carefully concentrated in vacuo. The crude product is purified by chromatography on silica gel (cyclohexane / ethyl acetate 50: 1). 1.63 g of product (95.3% of theory) are obtained.

MS (DCI): m / z = 228 (M + H) ⁺ , 245 (M + NBL,) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 3.55 (m, IH), 2.19 (t, 3H), 1.55-1.25 (m, 6H and s, 9H), 1.18 (d, 3H).

Example 7A

f6 /? j-6-amino heptanoic acid tert-butyl

To 1.42 g (6.25 mmol) of tert-butyl fo7-> 6-azidoheptanoate, dissolved in 200 ml of THF, 70 mg of Pd / C (10% strength) are added under argon. The mixture is stirred vigorously under hydrogen atmosphere at atmospheric pressure and RT overnight. It is filtered through Celite (washed with dichloromethane) and the filtrate is carefully concentrated in vacuo. The crude product is purified by chromatography on silica gel (gradient of dichloromethane / isopropanol 20: 1 to 3: 1, with 1% ammonia). The product fractions are pooled and stored at -20 ⁰ C. 677 mg of product (53.9% of theory) are obtained.

MS (DCI): m / z = 202 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 2.20 (m, IH), 2.18 (t, 2H), 1.51-1.42 (m, 2H), 1.40 (s, 9H), 1.35-1.27 (m, 4H), 0.94 (d, 3H).

Example 8A

3-nitrophenoxy-methyl acetate

50 g (359.4 mmol) of 3-nitrophenol and 175.67 g (539 mmol) of cesium carbonate are initially charged in 1.0 l of acetone and admixed with 71.5 g (467.3 mmol) of methyl bromoacetate. The mixture is stirred for 1 h at 50 ⁰ C and poured after cooling to 7.5 1 of water. The suspension is stirred for 30 minutes, then filtered with suction and the filter residue washed with water. The solid is dried in a drying oven at 50 ^° C. and 100 mbar. This gives 64.3 g (84.7% of theory) of the target compound.

MS (DCI): m / z = 229 (M + NH,) ⁺

¹ H-NMR (300 MHz, CDCl _3): δ = 7.90 (dd, IH), 7:43 (t, IH), 7:48 (t, IH), 7.28 (dd, IH), 4.75 (s, 2H), 3.86 (s, 3H).

Example 9A

3-aminophenoxy-methyl acetate

To 13 g (61.6 mmol) of methyl 3-nitrophenoxyacetate in 150 ml of methanol, 1.3 g of palladium on activated carbon (10%) are added under argon. The mixture is stirred for 18 h at RT under a hydrogen atmosphere (atmospheric pressure). The catalyst is filtered off through kieselguhr and the filtrate is concentrated in vacuo. After drying in a high vacuum, 10.7 g (95.9% of theory) of the target compound are obtained.

MS (DCI): m / z = 182 (M + H) ⁺ , 199 (M + NH,) ⁺

¹ H-NMR (400 MHz, CDCl _3): δ = 7:10 to 7:02 (m, IH), 6:35 to 6:23 (m, 2H), 4:58 (s, 2H), 3.79 (s, 3H), 3.65 (br s , 2H).

Example IQA

4-Bromo-2-methyl-5-phenylfuran-3-carbaldehyde

200 mg (1.07 mmol) of 2-methyl-5-phenyl-3-furaldehyde are dissolved under argon in 4 ml of acetonitrile and treated at -20 ° in five portions with a total of 210 mg (1.1.8 mmol) of N-bromosuccinimide. After 30 min the meantime diluted with acetonitrile reaction mixture from -20 ⁰ C is heated to RT and concentrated in vacuo The residue is purified by chromatography on silica gel (cyclohexane / ethyl acetate 20: 1). 211.6 mg of target product are obtained (74.3% of theory).

GC-MS (Method 1): R, = 6.57 min; m / z = 264/266 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 9.95 (s, IH), 7.91 (d, 2H), 7.56-7.44 (m, 3H), 2.69 (s, 3H).

Example IIA

4- (4-methoxyphenyl) -2-methyl-5-phenylfuran-3-carbaldehyde

Under argon, 400.0 mg (1.51 mmol) of 4-bromo-2-methyl-5-phenylfuran-3-carbaldehyde, 275.1 mg (1.81 mmol) of 4-methoxyphenylboronic acid and 63.5 mg (0.91 mmol) of bis (triphenylphosphine) palladium (II) chloride mixed in 1.75 ml of DMSO and treated with 1.5 ml of 2N aqueous sodium carbonate solution. The mixture is vigorously stirred for a total of 4 hours at 80 ^° C. (another 92 mg of 4-methoxyboronic acid are added after about 2 hours). After cooling, the crude product is separated directly by preparative RP-HPLC (gradient acetonitrile / water) and isolated 296.4 mg of target product (67.2% of theory).

LC-MS (Method 2): R, = 2.38 min; m / z = 293 (M + H) ⁺

¹ H-NMR (500 MHz, DMSOd ₆ ): δ = 9.78 (s, IH), 7.36-7.25 (m, 6H), 7.01 (d, 2H), 3.79 (s, 3H), 2.69 (s, 3H) ,

Example 12A

[4- (4-methoxyphenyl) -2-methyl-5-phenylfuran-3-yl] methanol

To a solution of 175 mg (0.60 mmol) of 4- (4-methoxyphenyl) -2-methyl-5-phenylfuran-3-carbaldehyde in 0.7 ml of ethanol are added at RT in several portions 22.6 mg (0.6 mmol) of sodium borohydride. After 40 minutes, the reaction mixture is mixed with water and extracted with dichloromethane. The organic phase is washed with saturated aqueous sodium chloride solution, dried and concentrated in vacuo. 160.4 mg of target product are obtained (91.3% of theory). LC-MS (Method 3): R, = 2.66 min; m / z = 277 (MH ₂ O) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 7.34-7.17 (m, 7H), 6.98 (d, 2H), 4.72 (t, IH), 4.12 (d, 2H), 3.80 (s, 3H), 2.39 (s, 3H).

Example 13A

4-bromo-2-methyl-5-phenylfuran-3-carbonsäuremethylester

1.0 g (4.63 mmol) 2-Methyl-5-phenylfuran-3-acetonitrile are suspended carbonsäuremethylester (available commercially or by methanolysis of 2-methyl-5-phenylfuran-3-carbonyl chloride available) in 5 ml and cooling at -20 ⁰ C with 905 mg (5.09 mmol) of N-bromosuccinimide. After the end of the addition, the mixture is warmed to 0 ^° C. and after 30 minutes to RT, before being evaporated to dryness in vacuo. From the residue, the product is isolated by preparative RP-HPLC (acetonitrile / water). 1.13 g of target product are obtained (83.1% of theory).

LC-MS (Method 3): R, = 2.97 min; m / z = 294/296 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.90 (d, 2H), 7.54-7.40 (m, 3H), 3.84 (s, 3H), 2.63 (s, 3H).

Example 14A

4- (4-methoxyphenyl) -2-methyl-5-phenylfuran-3-carbonsäuremethylester

Under argon, 1260 mg (4.27 mol) of 4-bromo-2-methyl-5-phenylfuran-3-carboxylic acid methyl ester are dissolved in 5.0 ml of DMF and treated successively with 713.6 mg (4.70 mmol) 4 Methoxyphenylboronsäure, 4.3 ml (8.6 mmol) of 2N aqueous sodium carbonate solution and 150 mg (0.21 mmol) of bis (triphenylphosphine) palladium (II) chloride added. The mixture is heated with vigorous stirring for 3 h at 80 ⁰ C. After cooling, the crude mixture is diluted with dichloromethane / methanol, filtered through kieselguhr (washed with dichloromethane / methanol). The filtrate is concentrated to dryness, stirred with dichloromethane and filtered again. The filtrate is concentrated and the residue is purified by chromatography on silica gel (cyclohexane / ethyl acetate 50: 1). Obtained are 1110 mg of target product (80.7% of theory).

LC-MS (Method 3): R, = 3.13 min; m / z = 345 (M + Na) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 7.32-7.21 (m, 5H), 7.18 (d, 2H), 6.97 (d, 2H), 3.81 (s, IH), 3.59 (s, 3H), 2.63 (s, 3H).

Example 15A

4- (4-methoxyphenyl) -2-methyl-5-phenylfuran-3-carboxylic acid

250 mg (0.776 mmol) of methyl 4- (4-methoxyphenyl) -2-methyl-5-phenylfuran-3-carboxylate are dissolved in 6 ml of THF / methanol 1: 1 and treated at RT with 2.5 ml of 1N sodium hydroxide solution. The solution is stirred for 1 h at RT (hardly any conversion). After addition of 5 ml of 10% sodium hydroxide solution, the suspension is warmed to 5O ⁰ C and stirred vigorously for 1 h. After cooling, 10 ml of 1N sodium hydroxide solution and the aqueous phase are extracted with 30 ml of methyl tert-butyl ether. The organic phase is separated and discarded. The aqueous phase is washed with conc. Hydrochloric acid carefully acidified and the resulting suspension is extracted with methyl tert-butyl ether. The organic phase is monitored with saturated aqueous sodium chloride solution, dried over sodium sulfate, concentrated in vacuo and the solid is dried in a high vacuum. 113.0 mg of target product are obtained (47.3% of theory).

LC-MS (Method 4): R, = 1.31 min; m / z = 309 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 12.33 (brs, IH), 7.30-7.20 (m, 5H), 7.19 (d, 2H), 6.95 (d, 2H), 3.80 (s, 3H ), 2.63 (s, 3H). Example 16A

6-Methoxy-6-oxohexyl-2-methyl-5-phenyl-furan-3-carboxylate

994 mg (6.8 mmol) of 6-hydroxyhexanoic acid methyl ester are dissolved in 5 ml of dichloromethane under argon and treated with 0.76 ml (5.44 mmol) of triethylamine and 55 mg (0.45 mmol) of 4-NN-

Dimethylaminopyridine, cooled to 0 ⁰ C and treated with 1.0 g (4.53 mmol) of 2-methyl-5-phenylfuran-3-carbonyl chloride. The cooling is removed and the mixture is added for 2 h

0 ⁰ C stirred before the reaction mixture is added to water and extracted three times with dichloromethane. The combined organic phases are washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo.

The crude product is purified by chromatography on silica gel (cyclohexane / ethyl acetate 10: 1 to 9: 1). 660.2 mg of target product are obtained (44.1% of theory)

LC-MS (method 5): R, = 2.71 min; m / z = 331 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 7.72 (d, 2H), 7.46-7.41 (m, 2H), 7.35-7.30 (m, IH), 7.14 (s, IH), 4.21 (t, 2H), 3.59 (s, 3H), 2.62 (s, 3H), 2.35 (t, 2H), 1.73-1.66 (m, 2H), 1.63-1.57 (m, 2H), 1.45-1.37 (m, 2H) ,

The following example can be obtained in an analogous manner starting from 2-methyl-5-phenylfuran-3-carbonyl chloride and (-) - 6-hydroxyheptanoic acid tert-butyl ester:

Example 17A

(7i-J-6-tert-butoxy-1-methyl-6-oxohexyl 2-methyl-5-phenylfuran-3-carboxylate

LC-MS (Method 2): R, = 3.00 min; m / z = 387 (M + H) ^{+ 1} H-NMR (400 MHz, DMSO- (I ₆ ): δ = 7.72 (d, 2H), 7.44 (t, 2H), 7.35-7.30 (m, IH), 7.12 (s, IH), 5.00 (m , IH), 2.62 (s, 3H), 2.19 (t, 2H), 1.70-1.48 (m, 4H), 1.39 (s, 9H), 1.39-1.30 (m, 2H), 1.29 (d, 3H).

[α] o 20 _ = -37.4 °, c = 0.580, chloroform.

Example 18A

6-methoxy-6-oxohexyl-4-bromo-2-methyl-5-phenylfuran-3-carboxylate

250.0 mg (0.76 mmol) of 6-memoxy-6-oxohexyl-2-methyl-5-phenylfuran-3-carboxylate are suspended in 0.8 ml of acetonitrile and treated at RT with 161.2 mg (0.91 mmol) of N-bromosuccinimide. The mixture is stirred for 1 h at RT, before being concentrated in vacuo. From the crude mixture, the product is isolated by chromatography on silica gel (cyclohexane / ethyl acetate 20: 1 to 15: 1). 236.2 mg of target product are obtained (76.3% of theory).

LC-MS (Method 2): R, = 2.64 min; m / z = 408 (M + H) ⁺ .

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 7.39 (d, 2H), 7.55-7.41 (m, 3H), 4.25 (t, 2H), 3.59 (s, 3H), 2.62 (s, 3H) , 2.35 (t, 2H), 1.73-1.68 (m, 2H), 1.64-1.55 (m, 2H), 1.48-1.41 (m, 2H).

The following example can be obtained in analogous manner starting from (7 / α-6-tert-butoxy-1-methyl-6-oxohexyl 2-methyl-5-phenylfuran-3-carboxylate:

Example 19A

(7-α-tert-Butoxy-1-methyl-6-oxohexyl 4-bromo-2-methyl-5-phenylfuran-3-carboxylate

LC-MS (Method 2): R, = 3.08 min; m / z = 485/487 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 7.92-7.88 (m, 2H), 7.58-7.42 (m, 3H), 5.05 (m, IH), 2.62 (s, 3H), 2.19 (t, 2H), 1.70-1.50 (m, 4H), 1.41-1.37 (m, 2H), 1.39 (s, 9H), 1.39 (d, 3H).

[α] _D ²⁰ = -21.6 °, c = 0.575, chloroform.

Example 2OA

7- {[(2-Methyl-5-phenylfuran-3-yl) carbonyl] amino} heptanoic acid methyl ester

2.0 g (9:06 mmol) -carbonyl chloride 2-Methyl-5-3 -phenylfuran dissolved under argon in 10 ml dichloromethane and cooled to 0 ⁰ C. Is added at 0 ⁰ C with 3:55 g (18.1 mmol) of 7- aminoheptanoic acid methylester hydrochloride and 3.79 ml (27.2 mmol) of triethylamine. The reaction mixture is warmed slowly to RT, added after 2 h to water and extracted three times with dichloromethane. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried on magnesium sulfate and concentrated to dryness in vacuo. From the crude mixture, the product is isolated by chromatography on silica gel (cyclohexane / ethyl acetate 10: 1 to 6: 1). 1.26 g of target product are obtained (40.3% of theory).

LC-MS (Method 3): R, = 2.70 min; m / z = 344 (M + H) ⁺

¹ H-NMR (400 MHz, _DMSO-d6): δ = 8:01 (t, IH), 7.62 (d, 2H), 7:44 (t, 2H), 7:34 to 7:29 (m, IH), 7.25 (s, IH) , 3.59 (s, 3H), 3.20 (qu, 2H), 2.59 (s, 3H), 2.31 (t, 2H), 1.59-1.48 (m, 4H), 1.35-1.28 (m, 4H).

The following example can be obtained analogously from 2-methyl-5-phenylfuran-3-carbonyl chloride and methyl 6-aminohexanoate hydrochloride:

Example 21A

6 - {[(2-Methyl-5-phenylfuran-3-yl) carbonyl] amino} hexanoic acid methyl ester

LC-MS (Method 5): R, = 2.18 min; m / z = 330 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.01 (t, IH), 7.61 (d, 2H), 7.45 (t, 2H), 7.35-7.29 (m, IH), 7.24 (s , IH), 3.58 (s, 3H), 2.59 (s, 3H), 2.31 (t, 3H), 1.61-1.45 (m, 4H), 1.35-1.28 (m, 2H).

Example 22A

7 - {[(4-bromo-2-methyl-5-phenylfiiran-3-yl) carbonyl] amino} -heptanoic

1543 mg (4:49 mmol) of 7 - {[(2-Methyl-5-phenylfuran-3-yl) carbonyl] amino} heptanoic acid are suspended in 4.5 ml 1, 2-dichloroethane, cooled to 0 ⁰ C, and (960 mg 5:39 mmol) of N-bromosuccinimide. After 40 minutes, concentrate the reaction mixture in vacuo and separate the residue by chromatography on silica gel (cyclohexane / ethyl acetate 10: 1 to 6: 1). 594.0 mg of target product are obtained (31.3% of theory).

LC-MS (method 5): R, = 2.41 min; m / z = 422/424 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 8.13 (t, IH), 7.88 (d, 2H), 7.49 (t, 2H), 7.44-7.38 (m, IH), 3.59 (s, 3H) , 3.22 (q, 2H), 2.55 (s, 3H), 2.30 (t, 2H), 1.59-1.46 (m, 4H), 1.39-1.27 (m, 4H).

Example 23A

6 - {[(4-bromo-2-methyl-5-phenylfuran-3-yl) carbonyl] amino} hexanoic acid methyl ester

642.0 mg (1.95 mmol) of methyl 6 - {[(2-methyl-5-phenylfuran-3-yl) carbonyl] amino} hexanoate are suspended in 8 ml of acetonitrile and concentrated at RT in three portions with a total of 416.3 mg (2.34 mmol) of N- Bromsuccinimid spiked. The mixture is concentrated in vacuo after 35 min and the residue is separated by chromatography on silica gel (cyclohexane / ethyl acetate 8: 1 to 2: 1). 579.0 mg of target product are obtained (72.8% of theory).

LC-MS (Method 3): R, = 2.68 min; m / z = 408/410 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 8.14 (t, IH), 7.87 (d, 2H), 7.50 (t, 2H), 7.43-7.39 (m, IH), 3.59 (s , 3H), 3.21 (qu, 2H), 2.55 (s, 3H), 2.32 (t, 2H), 1.61-1.45 (m, 4H), 1.49-1.31 (m, 2H),

Example 24A

(+/-) - 6 - {[(2-Methyl-5-phenylfuran-3-yl) carbonyl] amino} heptanoic acid tert-butyl ester

219.2 g (0.99 mmol) of 2-methyl-5-phenylfuran-3-carbonyl chloride are dissolved under argon in 1.0 ml of dichloromethane and cooled to 0 ⁰ C. It is mixed at 0 ⁰ C with 200 mg (0.99 mmol) (+/-) - aminoheptanoic acid tert-butyl ester and 0.21 ml (1.49 mmol) of triethylamine. The reaction mixture is warmed slowly to RT, added after 2 h to water and extracted three times with dichloromethane. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness in vacuo. From the crude mixture, the product is isolated by preparative RP-HPLC (acetonitrile / water). 194.6 mg of target product are obtained (50.8% of theory).

LC-MS (Method 6): R, = 2.75 min; m / z = 386 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.71 (d, IH), 7.61 (d, 2H), 7.45 (t, 2H), 7.33-7.29 (m, 2H), 3.95 (m, IH), 2.59 (s, 3H), 2.19 (t, 2H), 1.54-1.42 (m, 4H), 1.38 (s, 9H), 1.35-1.24 (m, 2H), 1.12 (d, 3H).

The following example can be obtained in an analogous manner starting from 2-methyl-5-phenylfuran-3-carbonyl chloride and (6R) -6-aminoheptanoic acid tert-butyl ester:

Example 25A

(-) - föR _/ ) -6 - {[(2-Methyl-5-phenyl-furan-3-yl) carbonyl] -amino} -heptanoic acid tert -butyl ester

LC-MS (Method 4): R _t = 1.49 min; m / z = 386 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d _6): δ = 7.71 (d, IH), 7.62 (d, 2H), 7:45 (t, 2H), 7:33 to 7:28 (m, 2H), 3.95 (m, IH), 2.59 (s, 3H), 2.19 (t, 2H), 1.54-1.42 (m, 4H), 1.38 (s, 9H), 1.36-1.24 (m, 2H), 1.12 (d, 3H).

[α] _D ²⁰ = -23.1 °, c = 0.485, chloroform.

Example 26A

(+/-) - 6 - {[(4-bromo-2-methyl-5-phenylfuran-3-yl) carbonyl] amino} heptanoic acid tert-butyl ester

190.0 mg (0.493 mmol) of (+/-) - 6 - {[(2-methyl-5-phenylfuran-3-yl) carbonyl] amino} heptanoic acid tert-butyl ester are suspended in 2 ml of acetonitrile and concentrated at RT in three Portions with a total of 105.3 mg (0.591 mmol) of N-bromosuccinimide were added. After stirring for 25 minutes, the mixture is diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in water Vacuum concentrated. The residue is separated by preparative RP-HPLC (acetonitrile / water). 124.5 mg of target product are obtained (50.4% of theory).

LC-MS (Method 6): R, = 2.87 min; m / z = 464/466 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.99 (d, IH), 7.87 (d, 2H), 7.51 (t, 2H), 7.44-7.39 (m, IH), 3.93 (m, IH), 2.54 (s, 3H), 2.20 (t, 2H), 1.55-1.30 (m, 6H), 1.20 (s, 9H), 1.12 (d, 3H).

The following example can be obtained in analogous manner starting from (-) - f <5α-J-6 - {[(2-methyl-5-phenyl-furan-3-yl) -carbonyl] -amino} -heptanoic acid tert-butyl ester:

Example 27A

heptanoic acid tert-butyl ester {[(4-bromo-2-methyl-5-phenylfuran-3-yl) carbonyl] amino} - (-) - ^ 6 / j-6?

LC-MS (Method 7): R, = 2.85 min; m / z = 464/466 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.99 (d, IH), 7.87 (d, 2H), 7.50 (t, 2H), 7.44-7.39 (m, IH), 3.92 (m, IH), 2.54 (s, 3H), 2.20 (t, 2H), 1.55-1.30 (m, 6H), 1.20 (s, 9H), 1.12 (d, 3H).

[α] _D ²⁰ = -14.4 °, c = 0.515, chloroform.

EXAMPLES

example 1

6-methoxy-6-oxohexyl-4- (4-memoxyphenyl) -2-methyl-5-phenylfuran-3-carboxylate

Under argon, 150 mg (0.366 mol) of 6-methoxy-6-oxohexyl-4-bromo-2-methyl-5-phenylfuran-3-carboxylate are dissolved in 0.8 ml of DMSO and treated successively with 66.8 mg (0.440 mmol) of 4-methoxyphenylboronic acid, Added 76.0 mg (0.55 mmol) of potassium carbonate, 80 .mu.l of methanol and 14.4 mg (0.022 mmol) of bis (triphenylphosphine) palladium (ir) chloride. The mixture is heated with vigorous stirring for about 4.5 h at 80 ⁰ C (reaction control by LC-MS). After cooling, the crude mixture is separated directly by preparative RP-HPLC and the product is isolated. Obtained are 50.2 mg of target product (31.4% of theory).

LC-MS (Method 3): R, = 3.37 min; m / z = 437 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 7.30-7.20 (m, 5H), 7.20 (d, 2H), 6.98 (d, 2H), 3.96 (t, 2H), 3.81 (s, 3H), 3.58 (s, 3H), 2.65 (s, 3H), 2.23 (t, 2H), 1.43-1.32 (m, 4H), 1.04-0.95 (m, 2H)

The following examples can be prepared analogously:

Example 2

7 - ({[4- (4-methoxyphenyl) -2-methyl-5-phenylfuran-3-yl] carbonyl} amino) heptanoic acid

Starting from 7 - {[(4-bromo-2-methyl-5-phenylfuran-3-yl) carbonyl] aimno} heptanoic acid methyl ester and 4-methoxyphenylboronic acid; 84 mg target product (51.6% of theory).

LC-MS (Method 2): R, = 2.43 min; m / z = 450 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Ci ₆ ): δ = 7.34 (t, IH), 7.31-7.28 (m, 5H), 7.23 (d, 2H), 6.98 (d, 2H), 3.79 (s, 3H), 3.58 (s, 3H), 3.05 (q, 2H), 2.55 (s, 3H), 2.28 (t, 2H), 1.50-1.40 (m, 2H), 1.30-1.04 (m, 6H).

Example 3

7 - ({[4- (4-ethylphenyl) -2-methyl-5-phenylfuran-3-yl] carbonyl} amino) heptanoic acid

Starting from 7 - {[(4-bromo-2-methyl-5-phenylfuran-3-yl) carbonyl] amino} heptanoic acid methyl ester and 4-ethylphenylboronic acid; 72.8 mg of target product (45.8% of theory) are obtained.

LC-MS (Method 2): R, = 2.69 min; m / z = 448 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 7.39 (t, IH), 7.30-7.20 (m, 8H), 3.59 (s, 3H), 3.04 (qu, 2H), 2.65 (qu, 2H) , 2.45 (s, 3H), 2.27 (t, 2H), 1.50-1.142 (m, 2H), 1.30-1.15 (m, 4H), 1.22 (t, 3H), 1.15- 1.06 (m, 2H).

Example 4

6 - ({[4- (4-methoxyphenyl) -2-methyl-5-phenylfuran-3-yl] carbonyl} amino) hexanoic acid methyl ester

Starting from 6 - {[(4-bromo-2-methyl-5-phenylfuran-3-yl) carbonyl] amino} hexanoic acid methyl ester and 4-methoxyphenylboronic acid; 43.9 mg of target product (45.7% of theory) are obtained.

LC-MS (Method 5): R, = 2.51 min; m / z = 436 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 7.38 (t, IH), 7.32-7.28 (m, 5H), 7.23 (d, 2H), 6.98 (d, 2H), 3.80 (s, 3H), 3.59 (s, 3H), 3.04 (qu, 2H), 2.55 (s, 3H), 2.24 (t, 2H), 1.49-1.40 (m, 2H), 1.32-1.22 (m, 2H), 1.11 -1.03 (m, 2H).

Example 5

6 - ({[4- (4-ethylphenyl) -2-methyl-5-phenylfuran-3-yl] carbonyl} amino) hexanoic acid methyl ester

Starting from 6 - {[(4-bromo-2-methyl-5-phenylfuran-3-yl) carbonyl] amino} hexanoic acid methyl ester and 4-ethylphenylboronic acid; 36.7 mg of target product (35.3% of theory) are obtained.

LC-MS (Method 2): R, = 2.60 min; m / z = 434 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-Cl ₆ ): δ = 7.41 (t, IH), 7.32-7.20 (m, 9H), 3.59 (s, 3H), 3.04 (qu, 2H), 2.67 (qu, 2H), 2.44 (s, 3H), 2.24 (t, 2H), 1.49-1.41 (m, 2H), 1.30-1.23 (m, 2H), 1.22 (t, 3H), 1.15- 1.08 (m, 2H) ,

Example 6

(7 /?) - 6-tert-Butoxy-1-methyl-6-oxohexyl 4- (4-methoxyphenyl) -2-methyl-5-phenylfuran-

3-carboxylate

Under argon, 120 mg (0.258 mol) of (7R> 6-tert-butoxy-1-methyl-6-oxohexyl 4-bromo-2-methyl-5-phenylfuran-3-carboxylate in 300 ul DMSO and dissolved successively with 47.0 mg (0.309 mmol) of 4-methoxyphenylboronic acid, 260 μl of 2N aqueous sodium carbonate solution and 10.9 mg (0.015 mmol) of bis (triphenylphosphine) palladium (II) chloride are added and the mixture is heated to 80 ^° C. with vigorous stirring for about 1.5 hours (Reaction control by LC-MS) After cooling, the crude mixture is separated directly by preparative RP-HPLC and the product isolated to give 71.4 mg of the target product (80% purity, 45.0% of theory).

LC-MS (Method 2): R, = 3.15 min; m / z = 493 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 7.30-7.20 (m, 5H), 7.18 (d, 2H), 6.98 (d, 2H), 4.78 (m, IH), 3.80 (s, 3H) , 2.64 (s, 3H), 2.11 (t, 2H), 1.71-1.57 (m, 2H), 1.38 (s, 9H), 1.40-1.25 (m, approx. 2H), 1.06-0.97 (m, approx. 2H), 1.02 (d, 3H).

The following example can be prepared in an analogous manner starting from (7R,) - 6-tert-butoxy-1-methyl-6-oxohexyl 4-bromo-2-methyl-5-phenylfuran-3-carboxylate and 4-ethylphenylboronic acid:

Example 7

(7i?) - 6-tert-Butoxy-1-methyl-6-oxohexyl 4- (4-ethylphenyl) -2-methyl-5-phenylfuran-3-carboxylate

47.3 mg of target product are obtained (29.9% of theory).

LC-MS (method 5): R, = 3.52 min; m / z = 513 (M + Na) ^{+ 1} H NMR (400 MHz, DMSO-d "): δ = 7.28-7.21 (m, 6H), 7.18 (d, 2H), 4.77 (m, IH), 2.67 (qu, 2H), 2.62 (s, 3H), 2.11 (t, 2H), 1.38 (s, 9H), 1.38-1.30 (m, 3H), 1.23 (t, 3H), 1.20-1.11 (m, 2H), 1.06-0.96 (m, 2H) , 0.98 (d, 3H).

[α] _D ²⁰ = -33.7 °, c = 0.485, chloroform.

Example 8

6 - {[4- (4-methoxyphenyl) -2-methyl-5-phenylfuran-3-yl] methoxy} hexanoic acid ethyl ester

160 mg (0.544 mmol) of [4- (4-methoxyphenyl) -2-methyl-5-phenylfuran-3-yl] methanol and 157.6 mg (0.707 mmol) of ethyl 6-bromohexanoate are dissolved in 1.0 ml of absolute DMF, to 0 ° C. Cooled and treated dropwise with 0.6 ml (0.6 mmol) of phosphazene base P4-t-Bu (1 M solution in hexane). The mixture is treated after 1 h at 0 ⁰ C with water and the solution with IN hydrochloric acid solution is approximately neutral (pH about 7). It is extracted with dichloromethane, the organic phase is dried with sodium sulfate and concentrated in vacuo. The product is isolated by preparative RP-HPLC (acetonitrile / water). 44.3 mg of target product (18.7% of theory) are obtained.

MS (DCI); m / z = 454 (M + NHL,) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 7.33-7.19 (m, 7H), 6.98 (d, 2H), 4.09 (s, 2H), 4.03 (qu, 2H), 3.80 (s, 3H) , 3.30 (qu, 2H), 2.39 (s, 3H), 2.26 (t, 2H), 1.55-1.42 (m, 4H), 1.29-1.20 (m, 2H), 1.15 (UH).

Example 9

[3 - ({[4- (4-Methoxyphenyl) -2-methyl-5-phenyl-furan-3-yl] -carbonyl} -amino) -phenoxy] -acetic acid methyl ester

110 mg (0.357 mmol) of 4- (4-methoxyphenyl) -2-methyl-5-phenylfuran-3-carboxylic acid are dissolved in 0.5 ml of DMF and admixed with 149.2 mg (0.392 mmol) of HATU. The mixture is added for 10 min

RT was stirred before 80.8 mg (0.446 mmol) of methyl 3-aminophenoxyacetate, 4.4 mg (0.036 mmol) of 4-N, N-dimethylaminopyridine and 75 .mu.l (0.428 mmol) of diisopropylethylamine were added. The reaction mixture is stirred at RT overnight before being added to water.

The aqueous phase is extracted three times with ethyl acetate, and the combined organic extracts are dried

Phases over magnesium sulfate and concentrated in vacuo. From the crude mixture, the product is isolated by preparative RP-HPLC (acetonitrile / water). 120 mg target product (slightly contaminated, about 70% of theory) are obtained.

LC-MS (Method 2): R, = 2.49 min; m / z = 472 (M + H) ⁺

¹ H-NMR (400 MHz, DMSOd ₆ ): δ = 9.85 (s, IH), 7.38-7.05 (m, 10H), 6.98 (d, 2H), 6.61 (d, IH), 4.73 (s, 2H) , 3.78 (s, 3H), 3.32 (s, 3H), 2.58 (s, 3H).

Example 10

(+/-) - 6 - ({[4- (4-Methoxyphenyl) -2-methyl-5-phenyl-furan-3-yl] -methyl} -amino) -heptanoic acid-tert-butyl ester

150 mg (513 mmol) of 4- (4-methoxyphenyl) -2-methyl-5-phenylfuran-3-carbaldehyde are dissolved in 0.5 ml of absolute THF and treated with 113.6 mg (0.564 mmol) of (+/-) - aminoheptanoic acid tert. butyl ester and 0.30 ml (1.026 mmol) of titanium (IV) isopropylate. The mixture is stirred at RT overnight before being cooled to 10 ^° C. and 38.8 mg (1026 mmol) of sodium borohydride added become. After about 1 h, 0.58 ml of ethanol are slowly added dropwise with cooling. The mixture is warmed to RT and stirred for 2 h, before adding a little water. The precipitated, white precipitate is filtered off with suction and washed three times with water, twice with methanol and dichloromethane. The filtrate is diluted with water and the organic phase separated. The aqueous phase is extracted twice with dichloromethane. Combine all organic phases, dry over magnesium sulfate and concentrate in vacuo. The product is purified by preparative RP-HPLC (acetonitrile / water). 26.6 mg of target product are obtained (10.9% of theory).

LC-MS (Method 3): R, = 2.17 min; m / z = 478 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO- (I ₆ ): δ = 7.34-7.15 (m, 7H), 6.99 (d, 2H), 3.81 (s, 3H), 2.45-2.32 (m, ca. 2H) , 2.35 (s, 3H), 2.15 (t, 2H), 1.45-1.35 (m, 2H), 1.39 (s, 9H), 1.28-1.12 (m, 4H), 0.87 (d, 3H).

Example 11

(+/-) - 6 - ({[4- (4-Methoxyphenyl) -2-methyl-5-phenyl-furan-3-yl] carbonyl} -amino) -heptanoic acid-tert-butyl ester

Under argon, 122 mg (0.263 mol) of (+/-) - 6 - {[(4-bromo-2-methyl-5-phenylfuran-3-yl) carbonyl] amino} heptanoic acid tert-butyl ester in 615 μl of DMSO dissolved and successively treated with 47.9 mg (0.315 mmol) of 4-methoxyphenylboronic acid, 54.5 mg (0.55 mmol) of potassium carbonate, 62 .mu.l of methanol and 11.1 mg (0.016 mmol) of bis (triphenylphosphine) palladium (II) chloride. The mixture is heated with vigorous stirring for 2 h at 80 ⁰ C. Another 24 mg (0.158 mmol) of 4-methoxyphenylboronic acid are added and the reaction mixture is stirred for a further 1.5 h at 80 ° C. After cooling, the crude mixture is separated directly by preparative RP-HPLC and the product is isolated. 55.1 mg of target product are obtained (42.7% of theory).

LC-MS (Method 2): R, = 2.80 min; m / z = 492 (M + H) ⁺

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.32-7.20 (m, 7H), 7.12 (d, IH), 6.99 (d, 2H), 3.81 (s, 3H), 3.81-3.72 ( m, IH), 2.46 (s, 3H), 2.11 (t, 3H), 1.42-1.36 (m, 2H), 1.38 (s, 9H), 1.29-1.19 (m, 2H), 1.11-1.03 (m, 2H), 0.94 (d, 3H).

Separation of Enantiomers: The racemic mixture (40 mg) (+/-) - 6 - ({[4- (4-methoxyphenyl) -2-methyl-5-phenyl-furan-3-yl] -carbonyl} -amino) -heptanoic acid-tert. butyl ester is dissolved in a mixture of 2 ml of isohexane and 0.2 ml of ethanol and separated by chromatography on a chiral phase into the enantiomers; Column: Daicel Chiralpak AD-H, 5 μm, 250 mm x 30 mm; Flow: 15 ml / min; Detection: 220 nm; Injection volume: 1.1 ml; Temperature: 30 ^° C .; Eluent: 95% isohexane / 5% ethanol. The following examples are isolated:

Example 12

(+) - (15 ^ - ({[4- (4-Methoxyphenyl) -2-methyl-5-phenyl-furan-3-yl] -carbonyl} -amino) -heptanoic acid-tert-butyl ester

Obtained 7.0 mg target product (35% of theory).

¹ H-NMR (400 MHz, CDCl _3): δ = 7:35 to 7:15 (m, 7H), 7:04 (d, 2H), 5:04 (d, IH), 3.95-3.88 (M approx. IH) 3.90 (s , 3H), 2.72 (s, 3H), 2.16 (t, 3H), 1.52-1.40 (m, ca. 2H), 1.46 (s, 9H), 1.30-1.02 (m, ca. 4H), 0.89 (i.e. , 3H).

[α] _D ²⁰ = + 42.5 °, c = 0.35, chloroform.

and

Example 13

(-) - (^ /? J-6 - ({[4- (4-Methoxyphenyl) -2-methyl-5-phenyl-furan-3-yl] carbonyl} -amino) -heptanoic acid tert -butyl ester

9.0 mg of target product (45% of theory) are obtained.

¹ H-NMR (400 MHz, CDCl _3): δ = 7:35 to 7:15 (m, 7H), 7:03 (d, 2H), 5:03 (d, IH), 3.95-3.88 (m, IH) 3.90 (s, 3H ), 2.72 (s, 3H), 2.16 (t, 3H), 1.52-1.40 (m, ca. 2H), 1.46 (s, 9H), 1.30-1.02 (m, 4H), 0.88 (d, 3H).

[α] _D ²⁰ = -31.8 °, c = 0.450, chloroform.

Alternatively, (-) - fö / -j-6- ({[4- (4-methoxyphenyl) -2-methyl-5-phenyl-furan-3-yl] carbonyl} -amino) -heptanoic acid tert-butyl ester is also detectable establish the following rule:

Under argon 80.0 mg (0.172 mmol) of (-) - (15R> 6 - {[(4-bromo-2-methyl-5-phenylfuran-3-yl) carbonyl] amino} heptanoic acid tert-butyl ester in 450 Dissolved and treated successively with 31.4 mg (0.207 mmol) of 4-Methoxyphenylboronsäure, 172 ul of 2N aqueous sodium carbonate solution and

6.0 mg (0.009 mmol) of bis (triphenylphosphine) palladium (II) chloride. The mixture is heated with vigorous stirring for 2.5 h at 100 ⁰ C. After cooling, from the

Reaction mixture directly isolated by preparative RP-HPLC the product. 70.5 mg of target product are obtained (83.3% of theory).

[α] _D ²⁰ = -28.3 °, c = 0.450, chloroform.

General Procedure A: Hydrolysis of methyl or ethyl esters to corresponding carboxylic acid derivatives

To a solution of a methyl or ethyl ester in THF or THF / methanol (1: 1) (concentration about 0.05 to 0.5 mol / 1) at RT 1.5 to 10 eq. Sodium hydroxide is added as IN aqueous solution. The mixture is stirred for a period of 0.5-18 h at RT and then neutralized with 1N hydrochloric acid or slightly acidified. If a solid precipitates, the product can be isolated by filtration, washing with water and drying in a high vacuum. Alternatively, the target compound is isolated directly from the crude product, optionally after extractive work-up with dichloromethane or ethyl acetate, by preparative RP-HPLC (eluent: Water / acetonitrile gradient) or by stirring with an inert solvent. The following examples are made in accordance with General Procedure A: =

(T,

(m, (t)

General Procedure B: Cleavage of tert-butyl esters to corresponding carboxylic acid derivatives

To a solution of the tert-butyl ester in dichloromethane (concentration 0.1 to 1.0 mol / 1, additionally optionally a drop of water) is added dropwise at 0 ⁰ C to RT TFA until a ratio of dichloromethane / TFA of about 2: 1 to about 1: 2 is reached. The mixture is stirred for 1-18 h at RT and then concentrated in vacuo. Alternatively, dilute with dichloromethane, wash with water and saturated aqueous sodium chloride solution, dry and concentrate in vacuo. If necessary, the reaction product can be purified by preparative RP-HPLC (eluent: acetonitrile / water gradient).

The following examples are prepared according to General Procedure B:

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 Prostacvclin receptors (LP 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 to a pH of 7.4 with 1N hydrochloric acid, resuspended, 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-hydroxvmethyl) 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. IP 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 IBMX (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 lead to an increase in the cAMP concentration in this test, IP antagonists are ineffective. The effective concentration (EC ₅₀ 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 The platelet-rich plasma obtained 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 platelet 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 is induced by addition of ADP and determined by the turbidimetric method according to Born in the aggregometer at 37 ° C [Born G.V.R., 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 (approximately 10 μg / kg / h) and propranolol (approximately 20 μg / kg / h)]. After intubation, the animals are ventilated by a constant-volume ventilator to reach an end-tidal CC> ₂ concentration of approximately 5%. 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 a thromboxane A ₂ - analogue as a stimulus to be 0:21 to 0:32 ug / kg / min U-46619 [9, l l-dideoxy-9α, l lα-epoxy-methano-prostaglandin F _2o (Sigma.)] Infused 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 transducers / 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 compound of 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 of 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.

Lv. 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

A is -CH ₂ - or -C (O) -,

E is O or NR ⁴ ,

in which

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

M for a group of the formula

stands, where

# means the link with E,

## means the point of attachment with Z,

R ⁵ is hydrogen or (C _r C ₄₎ alkyl,

wherein alkyl may be substituted with one substituent selected from the group hydroxy and amino,

L ^{1 is} (C ₁ -C ₇ ) -alkanediyl, (C ₂ -C ₇ ) -alkendiyl or a group of the formula * -L ^1A -VL ^1B - **,

wherein alkanediyl and alkenediyl may be substituted with 1 or 2 substituents fluorine, and

wherein

* the link with -CHR ⁵ means

** the attachment point with Z means

L ^{1A is} (C 1 -C ₅ ) -alkanediyl,

wherein alkanediyl may be substituted with 1 or 2 substituents independently of one another selected from the group consisting of (C 1 -C ₄ ) -alkyl and (C 1 -C ₄ ) -alkoxy,

L ^1B represents a bond or (Ci-C ₃₎ -alkyl,

wherein alkanediyl may be substituted by 1 or 2 substituents fluorine,

and

V is O or NR ⁶ ,

wherein

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

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

Q is (C ₃ -C ₇ ) -cycloalkyl, (C ₄ -C ₇ ) -cycloalkenyl, 5- to 7-membered heterocyclyl, phenyl or 5- or 6-membered heteroaryl,

wherein cycloalkyl, cycloalkenyl, heterocyclyl, phenyl and heteroaryl with

1 or 2 substituents independently selected from the group of fluorine, chlorine, (C _{r C4)} alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₄₎ - alkoxy, trifluoromethoxy, amino, mono (Ci-C ₄₎ - Alkylamino and di- (C 1 -C ₄ ) -alkylamino may be substituted,

wherein alkyl having a substituent selected from the group

Hydroxy, (Ci-C ₄₎ -alkoxy, amino, mono- (Ci-C ₄₎ -alkylamino and di- _(Ci-C4) - alkylamino may be substituted, and

, L ³ is (CrC ₄₎ -alkanediyl or (C ₂ -C ₄₎ alkenediyl,

wherein alkanediyl may be substituted by 1 or 2 substituents fluorine,

and

wherein a methylene group of the alkanediyl group may be exchanged for O or NR ⁷ ,

wherein

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

Z is a group of the formula

stands, where

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

and

R ⁸ is hydrogen or (C _r C ₄₎ alkyl,

R ^{1 is} halogen, cyano, nitro, (C ¹ -C ₆ ) -alkyl, trifluoromethyl, (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,

Trifluoromethoxy, (C ₁ -C ₆ ) -alkylthio, Amino, mono

(Ci-C ₆₎ -alkylamino, di- (C iC ₆₎ alkylamino or (C ₁ -C ₆₎ alkylcarbonylamino,

wherein (C _{r C6)} alkyl and (C _{r C6)} -alkoxy in turn with a substituent selected from the group consisting of cyano, hydroxy, (Ci-C ₄₎ alkoxy, (Ci-C ₄₎ alkylthio, Amino, mono- (C 1 -C ₄ ) -alkylamino and di- (C 1 -C ₄ ) -alkylamino,

or

two radicals R ¹ bound to adjacent carbon atoms of the phenyl ring together form a group of the formula -O-CH ₂ -O-, -O-CHF-O-, -O-CF ₂ -O-,

Form -O-CH ₂ -CH ₂ -O- or -O-CF ₂ -CF ₂ -O-,

n is the number O, 1 or 2,

wherein, in the event that R ¹ occurs several times, its meaning may be the same or different,

and

R ^{2 is} phenyl or 5- or 6-membered heteroaryl,

wherein phenyl and heteroaryl having 1 to 3 substituents independently selected from the group halogen, cyano, nitro, formyl, (Ci-C ₆ ) alkyl, trifluoromethyl, (C ₂ -C ₆ ) alkenyl, (C ₂ -C ₄ ) alkynyl, (C ₃ -C ₇₎ cycloalkyl, (C ₄ -C ₇₎ - cycloalkenyl, (C _r C ₆₎ alkoxy, trifluoromethoxy, (Ci-C ₆₎ -alkylthio, (C ₁ -C ₆ ) -

Alkylcarbonyl, amino, mono (Ci-C ₆ ) alkylamino, di (Ci-C ₆ ) alkylamino and can be substituted

wherein alkyl and alkoxy having a substituent selected from the group consisting of cyano, hydroxy, (Ci-C ₄₎ alkoxy, (Ci-C ₄₎ alkylthio, amino, mono- (C ₁ -C ₄₎ alkylamino and di- ( C 1 -C ₄ ) -alkylamino may be substituted,

or

two substituents bonded to adjacent carbon atoms of the phenyl ring together form a group of the formula -O-CH ₂ -O-, -O-CHF-O-, -O-CF ₂ -O-, -O-CH ₂ -CH ₂ -O- or form -O-CF ₂ -CF ₂ -O-,

and

R ^{3 is} methyl, ethyl or trifluoromethyl,

and their salts, solvates and solvates of the salts.

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

represents -CH ₂ - or -C (= O) -,

is O or NR ⁴ ,

in which

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

M for a group of the formula

# - CH- U - ## or # - l_2 -f Q4- L3 - ##

stands, where

# means the link with E,

## means the point of attachment with Z,

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

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

wherein

the attachment site with -CHR ⁵ means

** the attachment point with Z means

IA is (C _r C ₃₎ alkanediyl,

wherein alkanediyl may be substituted with 1 or 2 substituents independently of one another selected from the group consisting of methyl and ethyl,

IB is (C _r C ₃ ) -alkanediyl,

and

V is O or NR ⁶ , wherein

R ⁶ is hydrogen, (C ₁ -C ₃ ) -alkyl or cyclopropyl,

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

Q is cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl or

Phenyl stands,

wherein cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl and phenyl having 1 or 2 substituents independently selected from the group fluorine, methyl, ethyl, trifluoromethyl, hydroxy, methoxy and

Ethoxy can be substituted,

and

L ^{3 is} (C _r C ₃ ) -alkanediyl or a group of the formula --W-CR ⁹ R ¹⁰ - **, -W-CH ₂ -CR ⁹ R ¹⁰ - ** or --CH ₂ -W- CR ⁹ R ¹⁰ - ** stands,

wherein alkanediyl may be substituted by 1 or 2 substituents fluorine,

and

wherein

The point of attachment to the ring Q means

•• the point of attachment with the group Z means

W is O or NR ⁷ ,

wherein

R ⁷ is hydrogen, (C, -C ₃₎ -alkyl or cyclopropyl,

R ^{9 is} hydrogen or fluorine,

and

R ^{10 is} hydrogen or fluorine, Z is a group of the formula

stands, where

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

and

R ^{8 is} hydrogen,

R ^{1 is} fluorine, chlorine, methyl, ethyl, vinyl, trifluoromethyl or methoxy,

n is the number 0, 1 or 2,

wherein, in the event that R ¹ occurs several times, its meaning may be the same or different,

and

R ^{2 is} phenyl or 2-pyridyl,

where phenyl and 2-pyridyl having 1 or 2 substituents independently of one another are selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, n-propyl, vinyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, methylthio, ethylthio, amino,

Methylamino and ethylamino may be substituted,

and

R ^{3 is} methyl or trifluoromethyl,

and their salts, solvates and solvates of the salts.

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

A is -CH ₂ - or -C (= O) -,

E is O or NR ⁴ ,

in which R ^{4 is} hydrogen,

for a group of the formula

R ⁰

# - CH- L ¹ - ## or # - I_2 - (- Q4- L ³ - ##

stands, where

the point of attachment with E means

## means the point of attachment with Z,

R is hydrogen or methyl,

is butane-1,4-diyl, pentane-l, 5-diyl or a group of the formula * -L ^1A -VL ^1B - **,

embedded image in which

the attachment site with -CHR ⁵ means

the point of attachment with Z means

IA is methylene or ethane-1, 2-diyl,

wherein methylene and ethane-l, 2-diyl may be substituted by 1 or 2 substituents methyl,

IB is methylene or ethane-1, 2-diyl,

and

V is O or NR ⁶ ,

embedded image in which

R ^{6 is} methyl,

stands for a bond,

stands for phenyl, and

L ³ for ethane-1, 2-diyl, propane-1,

3-diyl or a group of the formula: -W-CR ⁹ R ¹⁰ -... or-W-CH ₂ -CR ⁹ R ¹ "- •

wherein

The point of attachment to the ring Q means

•• the point of attachment with the group Z means

W stands for O,

R ^{9 is} hydrogen,

and

R ^{10 is} hydrogen,

Z is a group of the formula

stands, where

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

and

R ^{8 is} hydrogen,

R ^{1 is} fluorine, chlorine, methyl or trifluoromethyl,

n is the number 0 or 1,

and

R ^{2 is} phenyl,

where phenyl may be substituted by a substituent selected from the group consisting of methyl, ethyl, vinyl, trifluoromethyl, methoxy, ethoxy and trifluoromethoxy, and

R ^{3 is} methyl,

and their salts, solvates and solvates of the salts.

4. A process for the preparation of compounds of formula (I) as defined in claims 1 to 3, wherein Z is -COOH, characterized in that either

[A] compounds of the formula (H-A),

in which n, R ¹ and R ³ each have the meanings given in claims 1 to 3

and

A ^{1 stands} for - (C = O) -

and

X ^{1 is} chlorine or hydroxy,

in an inert solvent optionally in the presence of a suitable acid or base and / or a suitable condensing agent with a

Compound of formula (HI-A)

HEZ ¹ _(mA);

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

and

Z ^{1 is} cyano or a group of the formula COOR ^8A ,

in which R ^8A represents (C _{r C4)} alkyl,

to compounds of the formula (TV-A)

in which n, A ¹ , E, M, Z ¹ , R ¹ and R ³ each have the meanings given above,

couples,

then in an inert solvent, for example with N-bromosuccinimide, to give compounds of the formula (V-A)

in which n, A ¹ , E, M, Z ¹ , R ¹ and R ³ each have the meanings given above,

brominated and this then in an inert solvent in the presence of a base and a suitable palladium catalyst with a compound of formula (VI)

in which R ^{2 has} the meaning given in claims 1 to 3

and

R ^{11 is} hydrogen or both radicals R ¹¹ together form a -C (CH ₃ ) ₂ -C (CH ₃ ) ₂ bridge, to compounds of the formula (VII-A)

in which n, A ¹ , E, M, Z ¹ , R ¹ , R ² and R ^{3 are} each as defined above,

couples

or

[B] Compounds of the formula (H-B)

in which n, R ¹ and R ³ each have the meanings given in claims 1 to 3

and

A ^{1 is} - (C = O) -,

and

R ¹² is (C _{r C4)} alkyl,

in an inert solvent in the presence of a base and a suitable palladium catalyst with a compound of the formula (VI) to give compounds of the formula (IV-B)

in which n, A ¹ , R ¹ , R ² , R ³ and R ¹² each have the meanings given above,

Coupling and this then by basic or acidic hydrolysis in compounds of formula (V-B)

in which n, A ¹ , R ¹ , R ² and R ³ each have the meanings given above,

convicted

and this then in an inert solvent in the presence of a suitable base and a suitable condensing agent with a compound of formula (HI-A) to give compounds of formula (VII-A)

in which n, A ¹ , E, M, Z ¹ , R ¹ , R ² and R ^{3 are} each as defined above,

implements,

or

[C] Compounds of the formula (HC)

in which n, R ¹ and R ³ each have the meanings given in claims 1 to 3,

in an inert solvent in the presence of a base and a suitable palladium catalyst with a compound of the formula (VI) to give compounds of the formula (IV-C)

in which n, R ¹ , R ² and R ³ each have the meanings given in claims 1 to 3,

coupled, these then in a suitable solvent with a suitable reducing agent to compounds of the formula (V-C)

in which n, R, RJ ² . and "dJ τ R> 3 each have the meanings given above

and

A ^{2 stands} for -CH ₂ -

and E ^{1 is} O,

and then this in an inert solvent in the presence of a suitable base with a compound of formula (III-C)

X ² - MZ ¹ _(mc))

in which M and Z ¹ each have the meanings given above

and

X ^{2 is} a leaving group such as, for example, halogen or trifluoromethanesulfonyloxy, in particular bromine or trifluoromethanesulfonyloxy,

to compounds of the formula (VII-C)

in which n, A ² , E ¹ , M, Z ¹ , R ¹ , R ² and R ^{3 are} each as defined above,

implements,

or

[D] compounds of the formula (IV-C) in an inert solvent in the presence of a suitable reducing agent with a compound of the formula (EI-D)

HE ² - MZ ¹ _(m.Dχ

in which M and Z ¹ each have the meanings given above

and

E ^{2 is} NR ⁴ ,

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

to compounds of the formula (VII-D)

in which n, A ² , E ² , M, Z ¹ , R ¹ , R ² and R ^{3 are} each as defined above,

implements,

and the respectively resulting compounds of the formulas (VII-A), (VII-C) or (VII-D) then by hydrolysis of the cyano or ester group Z ¹ into the carboxylic acids of the formula (I-1)

in which n, A, E, M, R, R and R 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.

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

A compound of formula (I) as defined in any one of claims 1 to 3 for use in a method for the treatment and / or prophylaxis of angina pectoris, pulmonary hypertension, thromboembolic disorders and peripheral occlusive diseases.

7. Use of a compound of the formula (I) as defined in any one of claims 1 to 3, for the preparation of a medicament for the treatment and / or prophylaxis of

Angina pectoris, pulmonary hypertension, thromboembolic disorders and peripheral occlusive diseases.

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

9. A medicament comprising a compound of the formula (I) as defined in any one of claims 1 to 3, in combination with a further active ingredient.

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

11. A method for the treatment and / or prophylaxis of angina pectoris, pulmonary hypertension, thromboembolic disorders and peripheral occlusive diseases in humans and animals using an effective amount of at least one compound of formula (I) as defined in any one of claims 1 to 3 , or a drug as defined in any one of claims 8 to 10.