DE10256405A1 - New 4-substituted quinoline derivatives, useful for treating bacterial infections, optionally including additional ring nitrogens - Google Patents

Abstract

4-substituted quinoline derivatives (I), their salts, solvates, hydrates and formulations are new. 4-substituted quinoline derivatives of formula (I), their salts, solvates, hydrates and formulations are new. A = oxygen, sulfur, nitrogen, 1-4C (hetero)alkylene or 2-4C alkenylene or alkynylene; X1-X5 = nitrogen or CR2; R1 = hydrogen, hydroxy or (hetero)alkoxy; R2 = hydrogen, halo, hydroxy, (hetero)alkyl, alkenyl or alkynyl; R3 = a group of formula (i)-(viii); R4 = hydroxy, 1-6C alkyl or 1-8C heteroalkyl; R5 = (hetero)alkyl, alkenyl, alkynyl, (hetero)aryl, (alkyl)cycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl; n = 0-3; and m = 0 or 2.

Description

In many countries around the world there is resistance across from the currently used Antibiotics have increased significantly in recent years and at Partly threatening dimensions assumed. The main problem with this is that these pathogens are not just one, but usually multiple Wear resistance. This is especially true for some grief-positive pathogen groups, such as staphylococci, pneumococci and enterococci (S. Ewig et al .; Antibiotic resistance in pathogens of community-acquired respiratory infections; Chemother. J. 2002, 11, 12-26; F. Tenover; Development and spread of bacterial resistance to antimicrobial agents: an overview; Clin. Infect. Dis. 2001 Sep 15, 33 Suppl. 3, 108-115).

A long feared development has recently occurred: The first strain of Staphylococcus aureus was described in the USA, which is not only methicillin resistant, but also highly resistant to vancomycin (Centers for Disease Control and Prevention; Staphylococcus aureus resistant to vancomycin - United States, 2002; MMWR 2002, 51, 565-567).

In addition to hygienic measures in hospitals are therefore also reinforced Efforts are needed to find new antibiotics that are as possible have a new structure and a new mechanism of action, to be effective against these problem germs.

The processes of DNA replication and DNA transcription offer interesting opportunities with essential ones to interfere with bacterial processes. So it is known that the in use today Fluoroquinolones are extremely effective and also a very effective one have good bactericidal activity. These compounds generally inhibit the bacterial enzyme DNA gyrase, which has essential functions in transcription, cell division or cell proliferation (K. Drlica; Mechanism of fluoroquinolone action; Curr. Opinion microbiol. 1999 2, 504-508). However, it has also been described that certain representatives of this group of substances inhibit another enzyme that has an indispensable function DNA replication, topoisomerase IV (A. B. Khodursky et al .; Topoisomerase IV is a target of quinolones in Escherichia coli; Proc. Natl. Acad. Sci. 1995, 92, 11801-11805; E. Pestova et al .; Contribution of topoisomerase IV and DNA gyrase mutations in Streptococcus pneumoniae to resistance to novel fluoroquinolones; Antimicrob. Agents. Chemother. 1999, 43, 2000-2004; E. Varon et al .; ParC and GyrA may be interchangeable initial targets of some fluoroquinolones in Streptococcus pneumoniae; Antimicrob. Agents chemother. 1999, 43, 302-306). This is an enzyme only found in bacteria, which at least has a reaction which cannot be fulfilled by the DNA gyrase, namely the Decatenation of DNA strands.

Bacterial topoisomerase IV is therefore an attractive target enzyme for new antibacterial agents. Since the human cell does not have a homologous topoisomerase high selectivity in principle possible. Like DNA gyrase, topoisomerase IV consists of two subunits, A and B, encoded by the parC and parE genes. Neither for parC nor for parE selective inhibitors are known to date.

The present application describes novel chemical compounds, which are bacterial topoisomerase IV with. high selectivity inhibit and high antibacterial activity, especially against resistant Gram-positive bacteria.

wobei
A ein Sauerstoff-, Schwefel-, Stickstoffatom, ein Alkylen-, Alkenylen, Alkinylen oder eine Heteroalkylen-gruppe ist,
X₁, X₂ und X₃ unabhängig voneinander Stickstoffatome oder Gruppen der Formel CR² sind,
R¹ ein Wasserstoffatom, ein Halogenatom, eine Hydroxy-, eine Alkyloxy-, eine Heteroalkyl- oder eine Heteroalkyloxygruppe ist,
R² ein Wasserstoffatom, ein Halogenatom, eine Hydroxy-, Alkyl-, Alkenyl-, Alkinyl- oder eine Heteroalkylgruppe ist,
R³ aus den folgenden Gruppen ausgewählt ist:

die Reste R⁴ unabhängig voneinander ein Halogenatom, eine Hydroxy-, Amino-, Nitro- oder Thiolgruppe, ein Alkyl-, Alkenyl-, Alkinyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Alkylcycloalkyl-, Heteroalkylcycloalkyl-, Heterocycloalkyl-, Aralkyl- oder ein Heteroaralkylrest sind, wobei jedes, z.B. 0, 1, 2 oder 3 Wasserstoffatome des Ringsystems, an das A gebunden ist, durch R⁴ ersetzt sein kann (auch die Wasserstoffatome der Gruppen U, V, G und/oder E) und/oder zwei der Reste R⁴ zusammen Teil eines Aryl-, Heteroaryl-, Cycloalkyl-, Heterocycloalkyl-, Alkylcycloalkyl-, Heteroalkylcycloalkyl-, Aralkyl- oder ein Heteroaralkylrings sind,
R⁵ ein Alkyl-, Alkenyl-, Alkinyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Alkylcycloalkyl-, Heteroalkylcycloalkyl-, Heterocycloalkyl-, Aralkyl- oder ein Heteroaralkylrest ist,
R^6a, R^6b und R^6c unabhängig voneinander ein Wasserstoffatom, ein Alkyl-, Alkenyl-, Alkinyl-, Heteroalkyl-, Aryl-, Heteroaryl-, Cycloalkyl-, Alkylcycloalkyl-, Heteroalkylcycloalkyl-, Heterocycloalkyl-, Aralkyl- oder ein Heteroaralkylrest sind,
E ein Stickstoffatom oder eine CH-Gruppe ist,
U ein Sauerstoffatom, ein Schwefelatom oder eine Gruppe der Formel C=O, C=CH₂, C=CHR⁴, C=C(R⁴)₂, SO₂, SO, CH₂ oder NH ist,
V ein Stickstoffatom oder eine CH-Gruppe ist,
W eine Hydroxy-, eine Mercapto-, eine Alkoxy- oder eine Heteroalkyloxygruppe ist,
Y¹, Y², Y³ und Y⁴ unabhängig voneinander ein Stickstoffatom oder eine CR⁴-Gruppe sind,
Q¹ und Q⁴ unabhängig voneinander ein Sauerstoffatom, ein Schwefelatom oder eine NH-Gruppe sind,
Q² und Q³ unabhängig voneinander ein Stickstoffatom oder eine CR⁴-Gruppe sind,
G ein Stickstoffatom oder eine CH-Gruppe ist,
n gleich 0, 1, 2 oder 3 ist,
m gleich 0, 1, 2, 3, oder 4 ist,
o gleich 0 oder 1 ist und
p gleich 0, 1, 2 oder 3 ist, wobei p = 1 und gleichzeitig G = N nur für den Fall zugelassen ist, dass R⁴ = O-Alkyl oder R⁴ = S-Alkyl ist;
und wobei p = 1 und gleichzeitig o = 0 nur für den Fall zugelassen ist, dass R⁴ = O-Alkyl oder R⁴ = S-Alkyl ist,
oder ein pharmakologisch akzeptables Salz, Solvat, Hydrat oder eine pharmakologisch akzeptable Formulierung derselben.The present invention relates to compounds of the general formula (I):

in which
A is an oxygen, sulfur, nitrogen atom, an alkylene, alkenylene, alkynylene or a heteroalkylene group,
X ₁ , X ₂ and X _{3 are} independently nitrogen atoms or groups of the formula CR ² ,
R ^{1 is} a hydrogen atom, a halogen atom, a hydroxy, an alkyloxy, a heteroalkyl or a heteroalkyloxy group,
R ^{2 is} a hydrogen atom, a halogen atom, a hydroxyl, alkyl, alkenyl, alkynyl or a heteroalkyl group,
R ^{3 is selected} from the following groups:

the radicals R ⁴ independently of one another are a halogen atom, a hydroxyl, amino, nitro or thiol group, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl -, Aralkyl- or a heteroaralkyl radical, where each, for example 0, 1, 2 or 3 hydrogen atoms of the ring system to which A is attached, can be replaced by R ⁴ (also the hydrogen atoms of the groups U, V, G and / or E) and / or two of the radicals R ⁴ together form part of an aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl or a heteroaralkyl ring,
R ^{5 is} an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl radical,
R ^6a , R ^6b and R ^6c independently of one another are a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl radical .
E is a nitrogen atom or a CH group,
U is an oxygen atom, a sulfur atom or a group of the formula C = O, C = CH ₂ , C = CHR ⁴ , C = C (R ⁴ ) ₂ , SO ₂ , SO, CH ₂ or NH,
V is a nitrogen atom or a CH group,
W is a hydroxy, a mercapto, an alkoxy or a heteroalkyloxy group,
Y ¹ , Y ² , Y ³ and Y ^{4 are} independently a nitrogen atom or a CR ⁴ group,
Q ¹ and Q ^{4 are} independently an oxygen atom, a sulfur atom or an NH group,
Q ² and Q ^{3 are} independently a nitrogen atom or a CR ⁴ group,
G is a nitrogen atom or a CH group,
n is 0, 1, 2 or 3,
m is 0, 1, 2, 3, or 4,
o is 0 or 1 and
p is 0, 1, 2 or 3, where p = 1 and at the same time G = N is only permitted if R ⁴ = O-alkyl or R ⁴ = S-alkyl;
and where p = 1 and at the same time o = 0 is only permitted if R ⁴ = O-alkyl or R ⁴ = S-alkyl,
or a pharmacologically acceptable salt, solvate, hydrate or a pharmacologically acceptable formulation thereof.

The term alkyl or alk refers focus on a saturated, straight-chain or branched hydrocarbon group, the 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, especially preferably has 1 to 6 carbon atoms, e.g. the methyl, ethyl, Propyl, isopropyl, isobutyl, tert-butyl, n-hexyl, 2,2-dimethylbutyl or n-octyl group.

The terms alkenyl and alkynyl refer refer to at least partially unsaturated, straight-chain or branched Hydrocarbon groups containing 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, particularly preferably 2 to 6 carbon atoms have, e.g. B. the ethenyl, allyl, acetylenyl, propargyl, Isoprenyl or hex-2-enyl group. Preferably such Groups 1, 2 or 3, particularly preferably 1 double or triple connections on.

The term heteroalkyl refers refer to an alkyl, an alkenyl or an alkynyl group, in of one or more (preferably 1, 2 or 3) carbon atoms replaces an oxygen, nitrogen, phosphorus or sulfur atom are (preferably oxygen or nitrogen), e.g. an alkyloxy group such as. Methoxy or ethoxy, or a methoxymethyl, nitrile, Methyl carboxy alkyl ester, carboxy alkyl ester or 2,3-dioxyethyl group. The term heteroalkyl also refers to a carboxylic acid or one of a carboxylic acid derived group such as B. acyl, acyloxy, carboxyalkyl, carboxyalkyl esters e.g. Methyl carboxyalkyl ester, carboxyalkylamide, alkoxycarbonyl or alkoxycarbonyloxy.

The expression cycloalkyl or cyclo- refers to a saturated or partially unsaturated cyclic group which has one or more rings which a framework form which have 3 to 14 carbon atoms, preferably 3 to 10 Contains carbon atoms, e.g. the cyclopropyl, cyclohexyl, tetralin or cyclohex-2-enyl group. The cycloalkyl group preferably has 0, 1, 2 or 3 double bonds on.

The term heterocycloalkyl or heterocyclo refers to a cycloalkyl group as defined above, in which one or more (preferably 1, 2 or 3) ring carbon atoms or ring CH or ring CH ₂ groups by an oxygen or nitrogen -, Phosphorus or sulfur atom are replaced and can represent, for example, the piperidine, morpholine, N-methylpiperazine or N-phenylpiperazine group.

The terms alkylcycloalkyl or heteroalkylcycloalkyl refer to groups according to the definitions above both cycloalkyl and heterocycloalkyl as well as alkyl, alkenyl, alkynyl and / or Contain heteroalkyl groups.

Examples of such groups are Alkylcycloalkyl, alkenylcycloalkyl, alkynylcycloalkyl, alkylheterocycloalkyl, Alkenyl heterocycloalkyl, alkynyl heterocycloalkyl, heteroalkylcycloalkyl, Heteroalkenylcycloalkyl, heteroalkynylcycloalkyl, heteroalkylheterocycloalkyl, Hetero alkenyl heterocycloalkyl, heteroalkynyl heterocycloalkyl, where the cyclic groups saturated or are single, double or triple unsaturated.

The expression aryl or ar relates refer to an aromatic group containing one or more rings 5 or 6 to 14 ring carbon atoms, preferably 5 or 6 to Contains 10 ring carbon atoms e.g. a phenyl, naphthyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-ethoxyphenyl, 4-carboxyphenylalkyl or 4-hydroxyphenyl group.

The term heteroaryl refers to an aryl group in which one or more (preferably 1, 2 or 3) carbon atoms, especially ring hydrocarbon atoms, ring CH or ring CH ₂ groups are replaced by an oxygen, nitrogen, phosphorus or sulfur atom, for example the 4-pyridyl, 2-imidazolyl, 3-pyrazolyl - and Isoquinolinyl group.

The terms aralkyl or heteroaralkyl refer to groups according to the definitions above both aryl and heteroaryl as well as alkyl, alkenyl and alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl groups. Examples are arylalkyl, rrylalkenyl, arylalkynyl, rrylheteroalkyl, Aryl heteroalkenyl, aryl heteroalkynyl, heteroaryl heteroalkyl, Heteroaryl heteroalkenyl, heteroaryl heteroalkynyl, arylcycloalkyl, Heteroarylcycloalkyl, aryl heterocycloalkyl, heteroaryl heterocycloalkyl, arylcycloalkenyl, Heteroarylcycloalkenyl, arylcycloalkynyl, heteroarylcycloalkynyl, Aryl heteroalkenyl, heteroaryl heteroalkenyl, aryl heteroalkynyl, Heteroaryl heteroalkynyl, heteroarylalkyl, heteroarylalkenyl and Heteroarylalkynyl groups, the cyclic groups being saturated or are single, double or triple unsaturated. Further examples are, for example, the tetrahydroisoquinolinyl, benzyl, 2- or 3-ethylindolyl, 4-Methylpyridino-, 3-oxo-3,4-dihydro-2H-pyrido [3,2b] [1,4] thiazin-6-ylmethyl-, 2,3-dihydrobenzo- [1,4] dioxin-6 -ylmethyl- or benzo [1,3] dioxol-5-ylmthyl or thiophene-2-ylsulfanylmethyl group.

The terms alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroalkylarylalkyl heteroaralkyl also refer to groups in which one or more hydrogen atoms of such groups are represented by fluorine, chlorine or bromine or iodine atoms or OH, SH, NH ₂ or NO ₂ groups are replaced. These terms also refer to groups substituted with unsubstituted alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl groups.

Compounds of formula (2) can be based on contain one or more centers of chirality during their substitution. The present The invention therefore encompasses both all pure enantiomers and all pure diastereomers, as well as their mixtures in any mixing ratio.

Compounds of the formula (I) are preferred, where A is an O, S or N atom or a group of the formula CH ₂ , CH ₂ CH ₂ , CH ₂ N (alkyl), N (alkyl) CH ₂ , CH ₂ O, OCH ₂ , CH ₂ S, SCH ₂ , CH ₂ CH (OH), CH (OH), CH (OH) CH ₂ , NHCO, CONH, C (= O) CH ₂ or CH ₂ C (= O).

Compounds of the formula (I) are further preferred, one of the groups X ₁ , X ₂ and X _{3 being} a nitrogen atom or a group of the formula CR ² and the other being CH groups.

R ² is particularly preferably a C ₁ -C ₄ alkyloxy group, it being possible for one, two or more, preferably one, hydrogen atom to be replaced by fluorine atoms.

U is more preferably a nitrogen, an oxygen, a sulfur atom or a methylene group.

X ² is more preferably a nitrogen atom or a group of the formula CH.

X ¹ and X ^{3 are more} preferably a group of the formula CH. Again, R ^{1 is} a heteroalkyl group.

Furthermore, n is preferably the same 0 or 1.

Again, R ⁴ is preferably an alkyl, heteroalkyl or heteroaralkyl group.

R ⁵ is more preferably an aralkyl or a heteroaralkyl group.

Again preferably R ^{5 is} a group of formula COR ⁷ , COOR ⁷ or SO ₂ R ⁷ , where R ^{7 is} an alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or a heteroaralkyl group.

More preferably, m is 0, 1 or 2.

The therapeutic use of the Compounds of formula (I), their pharmacologically acceptable salts or solvates and hydrates as well as formulations and pharmaceutical Compositions are also within the scope of the present invention.

The pharmaceutical compositions according to the present Invention contain at least one compound of formula (I) as Active ingredient and optional carrier and / or adjuvants.

Examples of pharmacologically acceptable Salts of the compounds of formula (I) are salts of physiological acceptable mineral acids like hydrochloric acid, sulfuric acid and phosphoric acid or salts of organic acids like methanesulfonic acid, p-toluenesulfonic acid, Lactic acid, Acetic acid, Trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and Salicylic acid. More examples of pharmacologically acceptable salts of the compounds of formula (I) are alkali or alkaline earth salts such as B. sodium, potassium, lithium, Calcium or magnesium salts, ammonium salts or salts of organic Bases such as B. methylamine, dimethylamine, triethylamine, piperidine, Ethylenediamine, lysine, choline hydroxide, meglumine, morpholine or arginine Salts. Compounds of formula (I) can be solvated, especially be hydrated. The hydration can e.g. during the Manufacturing process or as a result of the hygroscopic nature the initially anhydrous compounds of formula (I) occur. If the connections of the formula (I) contain asymmetric carbon atoms, they can either as achiral compounds, diastereomer mixtures, mixtures of enantiomers or as optically pure compounds.

The pro-drugs, which are also the subject of the present invention, contain a compound of the formula (I) and at least one pharmacologically acceptable protective group which are known per se is split off under physiological conditions, for example an alkoxy, aralkyloxy, acyl or acyloxy group, such as for example an ethoxy, benzyloxy, acetyl or acetyloxy group.

Even the use of these active ingredients for the manufacture of pharmaceuticals is the subject of the present Invention. In general, compounds of formula (I) are listed under Apply the known and acceptable modes, either individually or administered in combination with any other therapeutic agent. Such therapeutically useful Means can administered in one of the following ways: orally, e.g. as Dragees, coated Tablets, pills, semi-solids, soft or hard capsules, solutions, emulsions or suspensions; parenterally, e.g. as an injectable solution; rectal as suppositories; by inhalation, e.g. as a powder formulation or spray, transdermally or intranasally. To make such Tablets, pills, semi-solids, coated tablets, coated tablets and hard gelatin capsules can be the therapeutically usable product with pharmacologically inert, inorganic or organic drug carriers be mixed, e.g. with lactose, sucrose, glucose, gelatin, Malt, silica gel, starch or derivatives thereof, talc, stearic acid or its salts, dry skimmed milk and the like. For the manufacture of soft capsules, drug carriers can be used such as. vegetable oils, Use petroleum, animal or synthetic oils, wax, fat, polyols. For the production of liquid solutions and syrups, drug carriers such as e.g. Water, Alcohols, aqueous saline, aqueous dextrose, Polyols, glycerin, vegetable oils, Use petroleum, animal or synthetic oils. For suppositories you can use drug carriers such as. vegetable oils, Use petroleum, animal or synthetic oils, wax, fat and polyols. For aerosol formulations one can use compressed gases that are suitable for this purpose, such as e.g. Use oxygen, nitrogen and carbon dioxide. The pharmaceutical usable agents can also Additives for preservation, stabilization, emulsifiers, sweeteners, Flavorings, salts for change of osmotic pressure, buffers, coating additives and antioxidants contain.

Combinations with other therapeutic Can average include other antimicrobial and antifungal agents.

For prevention and / or treatment of bacterial and / or fungal infections, the dose of the invention can be biological active connection can vary within wide limits can be adjusted to individual needs. In general a dose of 10 mg to 4000 mg per day is suitable, with one preferred dose is 50 to 3000 mg per day. In appropriate cases the dose also below or above the values given above. The daily dose can be as simple Administration or in multiple administrations. A typical single dose contains about 50 mg, 100 mg, 250 mg, 500 mg, 1 g or 2 g of the Active ingredient.

EXAMPLES

Example 1: 2- (3 - {[(2,3-dihydro-benzo [1,4] dioxin-6-ylmethyl) amino] methyl} piperidin-1-yl) -1- (6-methoxyquinolin-4 yl) ethanol.

3-Azidomethylpiperidin-1-carboxylic acid benzyl ester:

Triethylamine (5.6 ml, 40.1 mmol) and then methanesulfonyl chloride (2 ml, 25.7 mmol) were added to a solution of benzyl 3-hydroxymethylpiperidine-1-carbonate (5 g, 20.05 mmol) in dichloromethane (100 ml) at 0 ° C. and then methanesulfonyl chloride (2 ml, 25.7 mmol). After the solution had stirred for 20 min, the reaction mixture was cooled to -60 ° C. and a solution of benzyl 4-oxopiperidine-1-carboxylate (2.33 g, 10 mmol) in diethyl ether (10 ml) was added. The reaction mixture was warmed to room temperature within 30 minutes and water (40mL) was added. The two phases were separated and the aqueous phase extracted twice with 50 ml ethyl acetate. The combined organic phases were washed with 20 ml of saturated sodium chloride solution, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (EtOAc). The resulting oil was dissolved in DMF (45 mL) and sodium azide (2.6g, 40mmol) was added. The reaction mixture was stirred for a further 3 hours at 80 ° C. and then diluted with water (100 ml) and ethyl acetate (200 ml). The two phases were separated and the aqueous phase extracted twice with 50 ml ethyl acetate. The combined organic phases were washed with 20 ml of saturated sodium chloride solution, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane / EtOAc 1/1).
Yield: 6.1 g (18.6 mmol)
¹ H NMR (CDCl3, 300 MHz: 1.28 (m, 1H); 1.51 (m, 1H); 1.60-1.87 (m, 3H); 2.74 br s, 1H); 2.91 (m, 1H); 3.23 (br d, J = 4.5Hz, 2H); 3.98 (td, J = 4.1, 13.2Hz, 1H); 4.06 (br s, 1H); 5.15 (s, 2H); 7.28-7.38 (m, 5H).

3-hydroxymethyl-piperidine-1-carboxylic acid benzyl ester was already published in Arch. Pharm. (Weinheim, Germany) 1990p. 9-12. 3-Aminomethyl-piperidine-1-carboxylic acid benzyl ester:

Triphenylphosphine (8g, 30mmol) was added to a solution of benzyl 3-azidomethylpiperidine-1-carboxylic acid (6.1g, 18.6mmol) in THF (37mL) and water (5mL). After the solution had been stirred at 60 ° C. for 3 hours, the reaction mixture was concentrated and the residue was taken up in 3N HCl (200 ml) and ether (200 ml). The two phases were separated and the aqueous phase extracted twice with 100 ml ethyl acetate. Solid sodium hydroxide (16g, 640mmol) was carefully added until an oil separated. The mixture was diluted with ethyl acetate, the organic phase was dried over MgSO ₄ , filtered and the filtrate was spun in to dryness.
Yield: 2.81 g, 11.3mmol
MS (EI) m / z 249 [M + H] ⁺ 3 - {[(2,3-dihydrobenzo [1,4] dioxin-6-ylmethyl) amino] -methyl} -piperidine-1-carboxylic acid benzyl ester:

1,4-Benzodioxane-6-carbaldehyde (0.9848, 6mmol) and sodium triacetoxyborohydride (1.7g, 8mmol ) added. After the solution had been stirred for 3 hours at room temperature, saturated NaHCO ₃ solution (20 ml) was added. The two phases were separated and the aqueous phase extracted twice with 50 ml dichloromethane each. The combined organic phases were washed with 20 ml of saturated sodium chloride solution, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (EtOAc then McOH / EtOAc 1/9).
Yield: 1.7g, 4.28mmol (oil)
MS (EI) m / z 397 [M + H] ⁺ (2,3-dihydro-benzo [1,4] dioxin-6-ylmethyl) piperidin-3-yl-methylamine:

To a solution 3 - {[(2,3-dihydrobenzo [1,4] dioxin-6-ylmethyl) amino] methyl} piperidine-1-carboxylic acid benzyl ester (0.98g, 2.47mmol) in EtOH (10mL) and AcOEt ( 10 mL), 20% Pd (OH) ₂ on carbon (0.23g) was added and hydrogenated under a hydrogen atmosphere (1bar). The reaction mixture was filtered off and the filtrate was concentrated.
Yield: 0.64g, 2.43mmol
MS (EI) m / z 308 [M + H] ⁺ 6-methoxy-4-oxiranylchinolin:

Trimethylsulfonium iodide (0.954g, 4.67mmol) and potassium hydroxide powder (1.8g, 32mmol) were added to a solution of 6-methoxyquinoline-4-carbaldehyde (0.85g, 4.54mmol) in acetonitrile (13.5mL) and water (6 drops). The reaction mixture was heated to 60 ° C over an hour. The mixture was then cooled to room temperature and benzene (40 ml) was added. The precipitate was filtered off and the filtrate was spun in to dryness. The residue was diluted with water (100 ml) and ethyl acetate (100 ml), the phases were separated and the aqueous phase was extracted twice with 50 ml ethyl acetate. The combined organic phases were dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (EtOAc).
Yield: 0.904g, 4.5mmol
MS (EI) m / z 202 [M + H] ⁺

6-methoxyquinoline-4-carbaldehyde was prepared according to Eur. J. Med: Chem. Chim. Ther. 2000 (35) p-707-714. 2- (3 - {[(2,3-dihydrobenzo [1,4] dioxin-6-ylmethyl) amino] methyl} piperidin-1-yl) -1 (6-methoxy-quinolin-4-yl) ethanol:

A solution of 6-methoxy-4-oxiranylquinoline (0.161g, 0.8mmol) and (2,3-dihydrobenzo [1,4] dioxin-6-ylmethyl) piperidin-3-ylmethylamine (0.210g, 0.8mmol) in ethanol (4mL) was warmed to 80C over 16 hours. The reaction mixture was cooled to room temperature and evaporated to dryness. The residue was purified by column chromatography on silica gel (EtOAc then EtOAc-MeOH 4: 1).
Yield: 0.240g. 0.51mmol (oil)
MS (EI) m / z 464 [M + H] ⁺

Example 2: anti-6-methoxy-4- (3- {3-methoxy-1- [2- (thiophene-2-ylsulfanyl) ethyl] piperidin-4-yl} propyl) quinoline.

4- (2-hydroxy-ethyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester:

Lithium borohydride (1.71g, 79.1mmol) was added at room temperature to a solution of ethyl 1-carboxy-1,2,5,6-tetrahydropyridine-4-acetate (4g, 13.1mmol) in THF (100mL). After the solution had been stirred at 60 ° C. for 2 hours, a solution of 3N HCl (2 ml) was slowly added dropwise. The reaction mixture was diluted with water (10mL) and ethyl acetate (30mL). The two phases were separated and the aqueous phase extracted twice with 50 ml ethyl acetate. The combined organic phases were washed with 20 ml of saturated sodium chloride solution, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane / EtOAc 1-2 then 1-4).
Yield: 3.2g, (12.2mmol)
MS (EI) m / z 262 [M + H] ⁺

Ethyl-1-carboxy-1,2,5,6-tetrahydropyridin-4-acetate was produced according to Chem. Pharm. Bull. 1982, p 1067.

4- [2- (tert-butyldimethylsilanyloxy) ethyl] -3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester:

To a solution of 4- (2-hydroxyethyl) -3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (3.2g, 12.2mmol) in dichloromethane (50mL) were added 4-DMAP (2.98g, 24.4 mmol) and tert-butyldimethylsilyl chloride (2.02g, 13.4mmol) added. After stirring at room temperature for 2 hours, the solution was evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane / EtOAc 6-1).
Yield: 4.6g, (12.1mmol)
δ H (CDCl ₃ , 300 MHz): 0.05 (s, 6H); 0.88 (s, 9H); 2.11 (m, 2H); 2.22 (br t, J = 6.3Hz, 2H); 3.56 (t, J = 5.6Hz, 2H); 3.68 (t, J = 6.6Hz, 2H); 3.94 (m, 2H); 5.15 (s, 2H); 5.3 (m, 1H); 7.31-7.37 (m, 5H).
MS (EI) m / z 376 [M + H] ⁺ anti-4- [2- (tert-butyldimethylsilanyloxy) ethyl] -3-hydroxypiperidine-1-carboxylic acid benzyl ester:

To a solution of 4- [2- (tert-butyldimethylsilanyloxy) ethyl] -3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (4.2g, 11.18mmol) in THF (62mL) was added 9-BBN (2.7 g, 44mmol) added. After the solution had been stirred at 60 ° C. for 24 hours, the mixture was cooled to 0 ° C. and ethanol (6 ml), 3N NaOH (35 ml) and 30% H ₂ O ₂ (35 ml) were slowly added dropwise and the mixture was stirred vigorously for one hour. The mixture was diluted with dichloromethane (100mL) and 10% Na ₂ SO ₃ (40mL). The two phases were separated and the aqueous phase extracted twice with 100 ml dichloromethane. The combined organic phases were washed with 20 ml of saturated sodium chloride solution, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane / EtOAc 4-1).
Yield: 2.9g, (7.36mmol)
δ H (CDCl ₃ , 300 MHz): 0.10 (s, 6H); 0.91 (s, 9H); 1.4-1.64 (m, 5H); 2.46 (br t, J = 7Hz, 1H); 2.62 (m, 1H); 3.27 (m, 1H); 3.56 (m, 1H); 3.81 (dt, J = 6.4; 4.1Hz, 1H); 4.10 (m, 1H); 4.32 (m, 1H); 4.88 (br s, 1H); 5.13 (s, 2H); 7.31-7.37 (m, 5H).
MS (EI) m / z 394 [M + H] ⁺ anti-4- (2-hydroxyethyl) -3-methoxypiperidine-1-carboxylic acid benzyl ester:

Sodium hydride (0.27g, 6.7mmol) was added to an ice-cold solution of benzyl anti-4- [2- (tert-butyldimethylsilanyloxy) ethyl] -3-hydroxy-piperidine-1-carboxylic acid (2.4g, 6.1mmol) in THF (60mL). 60% dispersion in oil) added. After the solution had been stirred for 15 minutes, methyl iodide (0.49mL, 7.93mmol) was added dropwise. After stirring for 3 hours, the reaction mixture was diluted with 10% NaHSO ₄ (50 ml) and ethyl acetate (50 ml). The two phases were separated and the aqueous phase extracted twice with 50 ml ethyl acetate. The combined organic phases were washed with 20 ml of saturated sodium chloride solution, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was dissolved in THF (50 ml) and mixed with trifluoroacetic acid (4ml). After stirring for 1 hour, the reaction mixture was spun in to dryness. The residue was purified by column chromatography on silica gel (EtOAc).
Yield: 1.18g, (4.02mmol)
δ H (CDCl ₃ , 300 MHz): 1.23 (m, 1H); 1.50 (m, 2H); 1.85 (m, 2H); 2.05 (br s, 1H); 2.53 (br s, 1H); 2.76-2.85 (m, 2H); 3.43 (s, 3H); 3.59-3.76 (m, 2H); 4.12 (m, 1H); 4.50 (m, 1H); 5.13 (s, 2H); 7.31-7.35 (m, 5H).
MS (EI) m / z 294 [M + H] ⁺ anti-3-methoxy-4- (2-oxoethyl) piperidine-1-carboxylic acid ester:

A solution of DMSO (0.91mL, 12.8mmol) in dichloromethane (6mL) was added to a solution of oxalyl chloride (0.78mL, 8.94mmol) in dichloromethane (7mL) at -78 ° C. After the solution had been stirred at -78 ° C for 15 minutes, a solution of benzyl anti-4- (2-hydroxyethyl) -3-methoxypiperidine-1-carboxylate (1.18g, 4.02mmol) in dichloromethane (5mL) was slowly added dropwise. After stirring the solution at -78 ° C for an hour, a solution of TEA (5.5mL) in dichloromethane (6mL) was added. The reaction mixture was diluted with dichloromethane (100 ml), washed with 10% NaHSO ₄ (50 ml), dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane / EtOAc 1/1).
Yield: 1.17g, (4.02mmol)
MS (EI) m / z 292 [M + H] ⁺ anti-3-methoxy-4-prop-2-ynylpiperidine-1-carboxylic acid benzyl ester:

A solution of triphenylphosphine (3.16g, 12.06mmol) and anti-3-methoxy-4- (2-oxoethyl) piperidine-1-carboxylic acid benzyl ester (1.17g, 4.02mmol) in dichloromethane (20mL) was added to a solution at -20 ° C Solution of carbon tetrabromide (2.0g, 6.03mmol) in dichloromethane (10mL) added. After the solution had been stirred at room temperature for 40 minutes, it was spun in to dryness. The residue was diluted in ethyl acetate and n-hexane (1: 1), filtered through Celite and evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane / EtOAc 4/1). Yield: 1.6g. This material was dissolved in THF (22mL) and n-BuLi (3.8mL, 8.74mmol 2.3N in hexane) was added dropwise at -78 ° C. After the solution was stirred at -78 ° C for 1 hour, a solution of 10% NaHSO ₄ (20mL) was added.

The aqueous phase was extracted three times with 30 ml ethyl acetate, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane / EtOAc 4/1).
Yield: 0.330g, (1.17mmol)
MS (EI) m / z 288 [M + H] ⁺ trifluoromethanesulfonic acid 6-methoxyquinolin-4-yl ester:

2,6-Lutidine (0.5mL, 4.3mmol), 4-dimethylaminopyridine (0.08g, 0.7mmol) and trifluoromethanesulfonic anhydride ( 0.62mL, 3.66mmol) added. After the solution was stirred for 2 hours, water (15 ml) was added dropwise. The two phases were separated and the aqueous phase extracted twice with 50 ml dichloromethane each. The combined organic phases were washed with 20 ml of saturated sodium chloride solution, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane / EtOAc 4/1).
Yield: 0.526g, (1.71mmol)
MS (EI) m / z 308 [M + H] ⁺

anti-3-methoxy-4- [3- (6-methoxy-quinolin-4-yl) -prop-2-ynyl] -piperidine-1-carboxylic acid benzyl ester:

To a mixture of PdCl ₂ (PPh ₃ ) ₂ (0.06g, 0.085mmol) and CuI (0.03g, 0.157mmol) was a degassed solution of trifluoromethanesulfonic acid 6-methoxyquinolin-4-yl ester (0.35g, 1.14mmol) and anti 3-Methoxy-4-prop-2-ynyl-piperidine-1-carboxylic acid benzyl ester (0.33g, 1.17mmol) in DMF (3mL) and TEA (5mL) added. After the solution had been stirred at room temperature for 1 hour, it was evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane / EtOAc 1/1 then 1/2).
Yield: 0.32g, (0.72mmol)
MS (EI) m / z 445 [M + H] ⁺ anti-3-methoxy-4- [3- (6-methoxyquinolin-4-yl) propyl] piperidine-1-carboxylic acid benzyl ester:

To a solution of benzyl anti-3-methoxy-4- [3- (6-methoxyquinolin-4-yl) prop-2-ynyl] piperidine-1-carboxylate (0.33g, 0.72mmol) in EtOH (10mL) and Platinum oxide (0.19 g, 12.8 mmol) was added to ethyl acetate (4 ml) and hydrogenated under a hydrogen atmosphere (1 bar). The catalyst was filtered off and the filtrate was spun in to dryness. The residue was purified by column chromatography on silica gel (EtOAc).
Yield: 0.27g, (0.60mmol)
δ H (CDCl ₃ , 300 MHz): 1.15-1.30 (m, 2H); 1.36 (m, 1H); 1.65-1.93 (m, 4H); 2.56 (br s, 1H); 2.78 (m. 2H); 3.00 (m, 2H); 3.40 (s, 3H); 3.96 (s, 3H); 4.00 (m, 1H); 4.10 (m, 1H); 5.12 (s, 2H); 7-20-7.25 (m, 2H); 7.31-7.38 (m, 6H); 8.04 (d, J = 0 9.2 Hz, 1H); 9.67 (d, J = 4.2 Hz, 1H).
MS (EI) mlz 449 [M + H] ⁺ anti-6-methoxy-4- [3- (3-methoxypiperidin-4-yl) propyl] quinoline:

To a solution of benzyl anti-3-methoxy-4- [3- (6-methoxyquinolin-4-yl) propyl] piperidine-1-carboxylic acid (0.27g, 0.6mmol) in AcOEt (10mL) was added 20% Pd ( OH) ₂ on carbon (0.190g) added and hydrogenated under a hydrogen atmosphere (1bar). The catalyst was filtered off and the filtrate was spun in to dryness.
Yield: 0.13g, (0.413mmol)
MS (EI) m / z 315 [M + H] ⁺ anti-6-methoxy-4- (3- {3-methoxy-1- [2- (thiophene-2-yl-sulfanyl) ethyl] piperidin-4- yl) propyl) quinoline:

Potassium carbonate (0.160g, 1.157mmol) was added to a solution of anti-6-methoxy-4- [3- (3-methoxypiperidin-4-yl) propyl] quinoline (0.130g, 0.413mmol) in DMF (3mL). and 2- (2-bromoethylsulfanyl) thiophene (0.130g, 0.58mmol) were added. After the solution had been stirred at 60 ° C. for 40 minutes, it was spun in to dryness. The residue was purified by column chromatography on silica gel with ethyl acetate then ethyl acetate / MeOH 9/1.
Yield: 0.098g, (0.214mmol)
δ H (CDCl ₃ , 300 MHz): 1.28 (m, 2H); 1.72-2.00 (m, 7H); 2.67 (m, 2H); 2.82 (m, 1H); 2.89-3.04 (m, 5H); 3.17 (m, 1H); 3.36 (s, 3H); 3.94 (s, 3H); 6.96 (dd, J = 3.5; 5.3Hz, 1H); 7.12 (dd, J = 1.5; 3.5Hz, 1H); 7.19 (d, J = 4.4Hz, 1H); 7.22 (d, J = 2.7Hz, 1H); 7.34 (m, 2H); 7.99 (d, J = 9.2Hz, 1H); 8.65 (d, J = 4.4Hz, 1H).
MS (EI) m / z 457 [M + H] ⁺

2- (2-Bromo-ethylsulfanyl) thiophene was chem. Heterocycl. Compd. (Engl. Transl.) 1975 (11) p. 299 manufactured. Example 3: syn-4- [2- (tert-Butyldimethylsilanyloxy) ethyl] -3-hydroxy-piperidine-1-carboxylic acid benzyl ester.

Triphenylphosphine (7.2g, 27.4mmol), 4 were added in succession to an ice-cooled solution of benzyl ester anti-4- [2- (tert-butyldimethylsilanyloxy) ethyl] -3-hydroxypiperidine-1-carboxylic acid (5.4g, 13.7mmol) in THF (110mL) -Nitrobenzoic acid (4.6g, 27.4mmol) and diethyl azodicarboxylate (4.3mL, 27.4mmol) added. After the solution had been stirred for 2 hours, it was spun in to dryness. The residue was purified twice by means of column chromatography on silica gel with ethyl acetate / n-hexane 1/4. The backlog was in McOH (50ml) diluted and mixed with potassium carbonate (0.8g, 5.78mmol). After the solution had been stirred for 1 hour, it was spun in to dryness. The residue was diluted in ethyl acetate (100 ml) and water (50 ml). The two phases were separated and the aqueous phase extracted twice with 50 ml AcOEt. The combined organic phases were washed with 20 ml of saturated sodium chloride solution, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane / EtOAc 1/4 then 1/1).
Yield: 1.67g, (4.24mmol)
δ H (CDCl ₃ , 300 MHz): 0.07 (s, 6H); 0.90 (s, 9H); 1.43 (m, 1H); 1.50-1.80 (m, 5H); 2.83 (m, 1H); 2.98 (m, 1H); 3.65-3.75 (m, 2H); 3.83 (br s, 1H); 4.04-4.12 (m, 2H); 5.12 (s, 2H); 7.31-7.37 (m, 5H).
MS (EI) m / z 394 [M + H] ⁺ syn-4- (2-hydroxy-ethyl) -3-methoxy-piperidine-1-carboxylic acid benzyl ester:

Sodium hydride (0.190g, 4.75mmol, 60% dispersion in.) Was added to an ice-cooled solution of benzyl syn-4- [2- (tert-butyldimethylsilanyloxy) ethyl] -3-hydroxypiperidine-1-carboxylic acid (1.67g, 4.24mmol) in THF (22mL) Ö1) added. After the solution had been stirred for 15 minutes, methyl iodide (0.35mL, 5.66mmol) was added dropwise. After stirring for 7 hours, the reaction mixture was diluted with 10% NaHSO ₄ (50 ml) and ethyl acetate (50 ml). The two phases were separated and the aqueous phase extracted twice with 50 ml ethyl acetate. The combined organic phases were washed with 20 ml of saturated sodium chloride solution, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was dissolved in THF (50 ml) and trifluoroacetic acid (10 ml) was added. After stirring for 1 hour, the reaction mixture was spun in to dryness. The residue was purified by column chromatography on silica gel (EtOAc).
Yield: 0.57g, (1.94mmol)
δ H (CDCl ₃ , 300 MHz): 1.45 (m, 1H); 1.58-1.80 (m, 5H); 2.88 (m, 2H); 3.23-3.41 (m, 4H); 3.71 (m, 2H); 4.15 (m, 1H); 4.40 (m, 1H); 5.15 (dd, J = 12.5; 21Hz, ABq, 2H); 7.31-7.37 (m, 5H).
MS (EI) m / z 294 [M + H] ⁺ syn-3-methoxy-4- (2-oxoethyl) piperidine-1-carboxylic acid benzyl ester:

A solution of DMSO 0.43mL, 6.04mmol) in dichloromethane (3mL) was added to a solution of oxalyl chloride (0.38mL, 4.35mmol) in dichloromethane (3.5mL) at -78 ° C. After the solution had been stirred at -78 ° C for 15 minutes, a solution of benzyl syn-4- (2-hydroxyethyl) -3-methoxYPiperidine-1-carboxylate (0.57g, 1.94mmol) in dichloromethane (3mL) was slowly added dropwise. After the solution had been stirred at -78 ° C. for one hour, a solution of TEA (2.6 ml) in dichloromethane (4 ml) was added. The reaction mixture was diluted with dichloromethane (100 ml), washed with 10% NaHSO ₄ (50 ml), dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane / EtOAc 1/1).
Yield: 0.56g, (1.94mmol)
MS (EI) m / z 292 [M + H] ⁺ syn-3-methoxy-4-prop-2-inylpiperidin-1-carboxylic acid benzyl ester:

A solution of triphenylphosphine (1.58g, 6.03mmol) and syn-3-methoxy-4- (2-oxoethyl) piperidine-1-carboxylic acid benzyl ester (0.56g, 1.94mmol) in dichloromethane (10mL) was added to a solution at -20 ° C Solution of carbon tetrabromide (1.0g, 3.02mmol) in dichloromethane (5mL) added. After the solution had been stirred at room temperature for 40 minutes, it was spun in to dryness. The residue was diluted in ethyl acetate] n-hexane (1/1), filtered through Celite and evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane / EtOAc 4/1). Yield: 1.6g. This material was dissolved in THF (10mL) and n-BuLi (1.3mL, 3.0mmol, 2.3N in hexane) was added dropwise at -78 ° C. After the solution was stirred at -78 ° C for 1 hour, a solution of 10% NaHSO ₄ (20mL) was added. The aqueous phase was extracted three times with 30 ml ethyl acetate, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane / EtOAc 4/1).
Yield: 0.314g, 1.1mmol)
MS (EI) m / z 288 [M + H] ⁺ syn-3-methoxy-4- [3- (6-methoxyquinolin-4-yl) prop-2-ynyl] piperidine-1-carboxylic acid benzyl ester:

To a mixture of PdCl ₂ (PPh ₃ ) ₂ (0.06g, 0.085mmol) and CuI (0.03g, 0.157mmol) a degassed solution of trifluoromethanesulfonic acid 6-methoxyquinolin-4-yl ester (0.35g, 1.14mmol) and syn- 3-Methoxy-4-prop-2-ynyl-piperidine-1-carboxylic acid benzyl ester (0.33g, 1.17mmol) in DMF (3mL) and TEA (5mL) added. After the solution had been stirred at room temperature for 1 hour, it was evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane / EtOAc 1/1 then 1/2).
Yield: 0.35g, 0.78mmol)
MS (EI) m / z 445 [M + H] ⁺ syn-3-methoxy-4- [3- (6-methoxyquinolin-4-yl) propyl] piperidine-1-carboxylic acid benzyl ester:

To a solution of benzyl syn-3-methoxy-4- [3- (6-methoxyquinolin-4-yl) prop-2-ynyl] piperidine-1-carboxylate (0.35g, 0.78mmol) in EtOH ( 10mL) and ethyl acetate (4ml became platinum oxide (0.21g, 0.92mmol) added and under a hydrogen atmosphere (1bar) hydrogenated. The catalyst was filtered off and the filtrate was dried concentrated by rotary evaporation. The residue was by means of column chromatography purified on silica gel (EtOAc).
Yield: 0.185g, (0.41mmol)
δ H (CDCl₃, 300 MHz): 1.43-1.65 (m, 5H); 1.80 (m. 2H); 2.76 (m, 2H); 3.05 (t, J = 7.5 Hz, 2H); 3.29 (m, 4H); 3.96 (s, 3H); 4.17 (m, 1H); 4.45 (m, 1H); 5.14 (dd, J = 13; 19.6Hz, ABq, 2H) ; 7.24 (m, 2H); 7:31 to 7:38 (m, 6H); 8.06 (d, J = 9.2 Hz, 1H); 9.68 (d, J = 4.1Hz, 1H).
MS (EI) m / z 448.9 [M + H]⁺  syn-6-methoxy-4- [3- (3-methoxypiperidin-4-yl) propyl] quinoline:

20% Pd (OH) was added to a solution of benzyl syn-3-methoxy-4- [3- (6-methoxyquinolin-4-yl) propyl] piperidine-1-carboxylate (0.185g, 0.41mmol) in AcOEt (10mL) _{2 added} on carbon (0.110g) and hydrogenated under a hydrogen atmosphere (1bar). The catalyst was filtered off and the filtrate was spun in to dryness.
Yield: 0.14g, (0.412mmol)
MS (EI) m / z 315 [M + H] ⁺ syn-6-methoxy-4- (3- {3-methoxy-1- [2- (thiopen-2-yl-sulfanyl) ethyl] piperidin-4 yl} propyl) quinoline:

To a solution of syn-6-methoxy-4- [3- (3-methoxypiperidin-4-yl) propyl] quinoline (0.128g, 0.412mmol) in DMF (3mL) was added potassium carbonate (0.160g, 1.157mmol) and 2 - (2-Bromoethylsulfanyl) thiophene (0.130g, 0.58mmol) added. After the solution had been stirred at 60 ° C. for 40 minutes, it was spun in to dryness. The residue was purified by column chromatography on silica gel with ethyl acetate then ethyl acetate / MeOH 9/1.
Yield: 0.110g, (0.24mmol)
δ H (CDCl ₃ , 300 MHz): 1.47 (m, 3H); 1.61 (m, 2H); 1.78 (m, 2H); 2.08 (m. 2H); 2.67 (m, 2H); 2.82 (m, 1H); 2.89-3.08 (m, 5H); 3.27 (br s, 1H); 3.34 (s, 3H); 3.96 (s, 3H); 6.96 (dd, J = 3.5; 5.3Hz, 1H); 7.12 (dd, J = 1.5; 3.5Hz, 1H); 7.19 (d, J = 4.4Hz, 1H); 7.22 (d, J = 2.7Hz, 1H); 7.34 (m, 2H); 8.02 (d, J = 9.2Hz, 1H); 8.66 (d, J = 4.4Hz, 1H).
MS (EI) m / z 457 [M + H] ⁺

Example 4: 4 - [(Benzo [1.3] dioxol-5-ylmethyl) amino] -1- [2- (6-methoxy-quinazolin-4-yl) ethyl] cyclohexanol.

8 - ([2- (6-methoxy-quinazolin-4-yl) ethyl] -1,4-dioxaspiro [4.5] decan-8-ol

To a solution of 8- (6-methoxy-quinazolin-4-ylethynyl) -1,4-dioxa-spiro [4.5] decan-8-ol (0.96g, 2.88mmol) in EtOH (40mL) and THF (10ml) platinum oxide (0.46 g) was added and hydrogenated under a hydrogen atmosphere (1 bar). The reaction mixture was stirred in the presence of activated carbon (5 g) and filtered off. The filtrate was spun in to dryness. The residue was purified by column chromatography on silica gel (EtOAc then EtOAc: MeOH 9/1).
Yield: 0.623g (1.81mmol), foam
MS (EI) m / z 344 [M + H] ⁺

8- (6-methoxy-quinazolin-4-ylethynyl) -1,4-dioxa-spiro [4.5] decan-8-o1 was prepared according to J. Chem. Soc. Perk. Trans. 1, 2000, 3382. 4-hydroxy-4- [2- (6-methoxy-quinazolin-4-yl) ethyl] cyclohexanone:

A solution of 8 - ([2- (6-methoxy-quinazolin-4-yl) ethyl] -1,4-dioxa-spiro [4.5] decan-8-ol (0.623g, 1.81mmol) in AcOH-THF -H ₂ O (3-2-2, 10mL) was stirred for 30 hours at 60 ° C. The reaction mixture was evaporated to dryness, the residue was diluted with sodium bicarbonate (100mL) and ethyl acetate (100 mL), the phases were separated and the aqueous phase was extracted twice with 50 ml of ethyl acetate, the combined organic phases were dried over MgSO ₄ , filtered and evaporated to dryness.
Yield: 0.425g (1.41mmol) foam.
MS (EI) m / z 301 [M + H] ⁺ 4 - [(Benzo [1.3] dioxol-5-ylmethyl) amino] -1- [2- (6-methoxyquinazolin-4-yl) ethyl] - cyclohexanol:

To a solution of 4-hydroxy-4- [2- (6-methoxyquinazolin-4-yl) ethyl] cyclohexanone (0.068, 0.2mmol) in dichloromethane (1mL) were added piperonylamine (0.030mL, 0.24mmol) and Sodium triacetoxyborohydride (0.088, 0.377mmol) added. The reaction mixture was stirred overnight, then filtered through a hydromatrix (wetted with a NaHCO ₃ solution, 2 ml) and washed with dichloromethane. The filtrate was spun in to dryness. The residue was purified by column chromatography on silica gel (dichloromethane: MeOH 9/1 then dichloromethane: MeOH 9/1 and 2% triethylamine).
Yield: 0.074g (0.17mmol) foam.
MS (EI) m / z 436 [M + H] ⁺

Example 5: Benzo [1,3] dioxol-5-ylmethyl- {4- [2- (6-methoxyquinolin-4-yl) ethyl] cyclohexyl} amine.

8-ethynyl-l, 4-dioxa-spiro [4.5] decane:

To a solution of triphenylphosphine (19.6g, 74.6mmol) and 1,4-dioxa-spiro [4.5] dec-8-carbaldehyde (5g, 29.37mmol) in dichloromethane (100mL) was added a solution of carbon tetrabromide at -30 ° C ( 12.4 g, 37.4mmol) in dichloromethane (40mL) added. After the solution had been stirred at room temperature for 2 hours, it was spun in to dryness. The residue was diluted in ethyl acetate and n-hexane (1: 3; 500 ml), filtered through Celite and evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane / EtOAc 4/1). Yield: 6.08g (18.6mmol). This material was dissolved in THF (90mL) and n-BuLi (16.5mL, 38mmol 2.3N in hexane) was added dropwise at -78 ° C. After the solution was stirred at -78 ° C for 1 hour, a solution of 10% NaHSO ₄ (50mL) was added. The aqueous phase was extracted three times with 50 ml ethyl acetate, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane / EtOAc 5/1).
Yield: 2.74g (16.5mmol)
δ H (CDCl ₃ , 300 MHz): 1.61 (m, 2H); 1.70-1.94 (m, 6H); 2.07 (d, J = 2.5Hz, 1H); 2.51 (m, 1H); 3.96 (s, 4H). 4- (1,4-dioxaspiro [4.5] dec-8-ylethynyl) -6-methoxyquinoline:

A degassed solution of trifluoromethanesulfonic acid 6-methoxyquinolin-4-yl ester (0.95g, 3.1mmol) and 4 was added to a mixture of PdCl ₂ (PPh ₃ ) ₂ (0.110 g, 0.157mmol) and CuI (0.055 g, 0.288mmol) - (1,4-Dioxa-spiro [4.5] dec-8-ylethynyl) -6-methoxy-quinoline (0.514g, 3.1mmol) in DMF (6mL) and TEA (12mL) added. After the solution had been stirred at room temperature for 1 hour, it was evaporated to dryness. The residue was purified by column chromatography on silica gel (EtOAc).
Yield: 0.83g (2.56mmol)
MS (EI) m / z 324 [M + H] ⁺ 4- [2- (1,4-dioxaspiro [4.5] dec-8-yl) ethyl] -6-methoxyquinoline:

To a solution of 4- (1,4-dioxa-spiro [4.5] dec-8-yl-ethynyl) -6-methoxyquinoline (0.83g, 2.53mmol) in EtOH (30mL) and ethyl acetate (10ml) was added platinum oxide (( 0.462 g) was added and the mixture was hydrogenated under a hydrogen atmosphere (1 bar), the catalyst was filtered off and the filtrate was evaporated to dryness, and the residue was purified by column chromatography on silica gel (EtOAc then EtOAc-methanol 9-1).
Yield: 0.77g (2.35mmol)
MS (EI) m / z 328 [M + H] ⁺ 4- [2- (6-methoxy-quinolin-4-yl) ethyl] cyclohexanone:

A solution of 4- [2- (1,4-dioxa-spiro [4.5] dec-8-yl) ethyl] -6-methoxy-quinoline (0.77g, 2.35mmol) in AcOH-THF-H ₂ O (3-2-2, 10mL) was stirred at 60 ° C for 10 hours. The reaction mixture was spun in to dryness. The residue was diluted with AcOEt (100mL), washed with NaHCO ₃ (100mL), dried over MgSO ₄ , filtered and evaporated to dryness.
Yield: 0.631g (2.23mmol)
MS (EI) m / z 284 [M + H] ⁺ benzo [1,3] dioxol-5-ylmethyl- {4- [2- (6-methoxy-quinolin-4-yl) ethyl] cyclohexyl} - amine:

To a solution of 4- [2- (6-methoxy-quinolin-4-yl) ethyl] cyclohexanone (0.05g, 0.176mmol) in dichloromethane (0.5mL) were added piperonylamine (0.038mL, 0.3mmol) and sodium triacetoxyborohydride ( 0.05g) added. The reaction mixture was stirred overnight, then filtered through a hydromatrix (wetted with a NaHCO ₃ solution, 2 ml) and washed with dichloromethane. The filtrate was spun in to dryness. The residue was purified by column chromatography on silica gel (AcOEt then AcOEt: MeOH 9/1).
Yield: 0.069g (0.165mmol)
MS (EI) m / z 419 [M + H] ⁺

Example 6: 2- {3 - [(2,3-dihydro-benzo [1,4] dioxin-6-ylmethyl) amino] pyrrolidin-1-yl} -1- (6-methoxyquinolin-4-yl) ethanol.

3 - [(2,3-dihydro-benzo [1,4] dioxin-6-ylmethyl) -amino] -pyrrolidine-1-carboxylic acid benzyl ester

Sodium bicarbonate (7g) and benzyl chloroformate (2.8 mL) were added to a solution of 3-aminopyrrolidine dihydrochloride (3.2 g, 20.1 mmol) in water (100 ml) and acetone (150 mL). The reaction mixture was stirred for 10 hours and then evaporated to dryness. The residue was diluted with AcOEt (100mL). The two phases were separated and the aqueous phase extracted twice with 50 ml AcOEt. The combined organic phases were washed with 20 ml of saturated sodium chloride solution, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was dissolved in dichloromethane (30 ml) and 1,4-benzodioxane-6-carbaldehyde (1.6 g) and after 20 minutes sodium triacetoxyborohydride (4g) were added. The reaction mixture was stirred overnight then diluted with sodium bicarbonate (80 ml). The two phases were separated and the aqueous phase extracted twice with 50 ml dichloromethane each. The combined organic phases were washed with 20 ml of saturated sodium chloride solution, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (AcOEt: MeOH 9/1).
Yield: 3.75g (10.1mmol)
δ H (CDCl ₃ , 300 MHz): 1.57 (br s, 1H), 1.77 (m, 1H), 2.07 (m, 1H); 3.21 (m, 1H); 3.37 (m, 2H); 3.61 (m, 2H), 3.70 (s, 2H); 4.25 (s, 4H); 5.14 (s, 2H); 6.76-6.84 (m, 3H); 7.30-7.38 (m, 5H). (2,3-dihydro-benzo [1,4] dioxin-6-ylmethyl) pyrrolidin-3-yl-amine:

To a solution 3 - [(2,3-dihydro-benzo [1,4] dioxin-6-yl-methyl) amino] pyrrolidin-1-carboxylic acid benzyl ester (3.75g, 10.1mmol) in EtOH (20mL) and AcOEt (20 mL), 20% Pd (OH) ₂ on carbon (1g) was added and hydrogenated under a hydrogen atmosphere (1bar). The reaction mixture was filtered off and the filtrate was concentrated.
Yield: 2.15g (9.2mmol)
MS (EI) m / z 235 [M + H] ⁺ 2- {3 - [(2,3-dihydrobenzo [1,4] dioxin-6-ylmethyl) amino] pyrrolidin-1-yl} - 1- (6-methoxy-quinolin-4-yl) ethanol:

A solution of 6-methoxy-4-oxiranylquinoline (0.201g, 1mmol) and (2,3-dihydrobenzo [1,4] dioxin-6-ylmethyl) pyrrolidin-3-ylamine (0.234g, 1mmol) in ethanol (2mL ) was heated to 80 ° C for 16 hours. The reaction mixture was cooled to room temperature and evaporated to dryness. The residue was purified by column chromatography on silica gel (EtOAc then EtOAc-MeOH 5: 1).
Yield: 0.208g (0.477mmol)
MS (EI) m / z 436.5 [M + H] ⁺

Example 7: 2- {4 - [(2,3-dihydro-benzo [1,4] dioxin-6-yl-amino) methyl] piperidin-1-yl} -1- (6-methoxyquinolin-4-yl) ethanol.

4 - [(2,3-dihydro-benzo [1,4] dioxin-6-ylamino) -methyl] -piperidine-1-carboxylic acid tert-butyl ester:

Sodium bicarbonate (1g, 12mmol) and 1,4-benzodioxan-6-amine (1g, 6.61mmol.) Were added to a solution of tert-butyl 4-methanesulfonyloxymethylpiperidine-1-carboxylic acid (1.26g, 4.3 mmol) in acetonitrile (15 ml) ) in acetonitrile (2mL) added. The reaction mixture was stirred at 80 ° C. for 4 days and then evaporated to dryness. The residue was diluted with AcOEt (100ml) and extracted with water. The aqueous phase was extracted twice with 50 ml of AcOEt. The combined organic phases were washed with 20 ml of saturated sodium chloride solution, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (AcOEt: n-hexane 1/1).
Yield: 0.4 (1.14mol)
MS (EI) m / z 349 [M + H] ⁺

4-methanesulfonyloxymethylpiperidine-1-carboxylic acid tert-butyl ester according to Bioorg. Med. Chem. Lett 2000, 79.

(2,3-dihydrobenzo [1,4] dioxin-6-yl) piperidin-4-ylmethyl-amine

A solution of 4 - [(2,3-dihydro-benzo [1,4] dioxin-6-ylamino) methyl] piperidine-1-carboxylic acid tert-butyl ester (0.4g, 1.15mmol) in trifluoroacetic acid (5 mL ) was stirred for 20 minutes at room temperature then evaporated to dryness. The residue was diluted in AcOEt (100ml) and extracted with 0.25N NaOH (20mL). The aqueous phase was extracted twice with 50 ml of AcOEt. The combined organic phases were washed with 20 ml of saturated sodium chloride solution, dried over MgSO ₄ , filtered and evaporated to dryness.
Yield: 0.284g (1.15mmol)
MS (EI) m / z 249 [M + H] ⁺ 2- {4 - [(2,3-dihydrobenzo [1,4] dioxin-6-ylamino) methyl] piperidin-1-yl} -1- (6-methoxy-quinolin-4-yl) ethanol:

A solution of 6-methoxy-4-oxiranylquinoline (0.1g, 0.497mmol) and (2,3-dihydrobenzo [1,4] dioxin-6-yl) piperidin-4-ylmethylamine (0.120g, 0.497mmol) in ethanol (4mL) was heated to 80 ° C over 48 hours. The reaction mixture was cooled to room temperature and evaporated to dryness. The residue was purified by column chromatography on silica gel (dichloromethane-MeOH 9: 1).
Yield: 0.05g (0.112mmol)
MS (EI) m / z 450 [M + H] ⁺ Example 8: 4- (4-methoxy-benzylamino) -1- [2- (6-methoxyquinazolin-4-yl) ethyl] cyclohexanol.

To a solution of 4-hydroxy-4- [2- (6-methoxyquinazolin-4-y1) ethyl] cyclohexanone (0.06g, 0.2mmol) in dichloromethane (1mL) was added 4-methoxybenzylamine (0.026mL, 0.24mmol) and then Sodium triacetoxaborohydride (0.08g, 0.377 mmol) added. The reaction mixture was stirred overnight, then filtered through a hydromatrix (wetted with a NaHCO ₃ solution, 2 ml) and washed with dichloromethane. The filtrate was spun in to dryness. The residue was purified by column chromatography on silica gel (dichloromethane / MeOH 9/1 then dichloromethane / MeOH 9/1 and 2% triethylamine).
Yield: 0.052g (0.124mmol)
MS (EI) m / z 422 [M + H] ⁺ Example 9: 4- (3-fluorobenzylamino) -1- [2- (6-methoxyquinazolin-4-yl) ethyl] cyclohexanol.

The compound was prepared analogously to Example 8 starting from 3-fluorobenzylamine (0.026mL, 0.24mmol).
Yield: (0.052g, 0.124mmol)
MS (EI) m / z 410 [M + H] ⁺

Example 10: 4- [2- (6-methoxy-quinolin-4-yl) ethyl] -1-phenethylpiperidin-4-ol.

4-ethynyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester:

To a solution of (trimethylsilyl) acetylene (1.8mL, 12.8mmol) in THF (30mL) was added dropwise around -78C n-BuLi (5mL, 11.5mmol, 2.3N in hexane). After stirring for 30 minutes, a solution of tert-butyl 4-oxo-piperidine-1-carboxylate (2 g, 10 mmol) in THF (14 ml) was added dropwise. After stirring at -78 ° C for 15 minutes, the solution was warmed to room temperature and a solution of 10% NaHSO ₄ (20mL) was added. The aqueous phase was extracted three times with 30 ml ethyl acetate, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was dissolved in methanol (40mL) and sodium bicarbonate (1g, 11.9mmol) was added. After one hour the reaction mixture was spun in to dryness. The residue was diluted with water (50mL) and AcOEt (1.00mL). The aqueous phase was extracted twice with 100 ml AcOEt. The combined organic phases were washed with 20 ml of saturated sodium chloride solution, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (hexane / EtOAc 2/1).
Yield: 2.05g (9.1mmol)
¹ H NMR (CDCl ₃ , 300 MHz): 1.47 (s, 9H); 1.68-1.76 (m, 2H); 1.87-2.06 (m, 2H); 2.55 (s, 1H); 3.24-3.32 (m, 2H); 3.75-3.81 (m, 2H).

4-Hydroxy-4- (6-methoxy-quinazolin-4-ylethynyl) -piperidine-1-carboxylic acid tert-butyl ester:

To a mixture of PdCl ₂ (PPh ₃ ) ₂ (0.110 g, 0.157mmol) and CuI (0.055 g, 0.288mmol) a degassed solution of 4-ethynyl-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (0.72g, 3.19mmol) and 4-chloro-6-methoxy-quinazoline (0.59g, 3.03mmol) in Et ₃ N (12mL) and DMF (6mL) added. After the solution After stirring for 1 hour at room temperature, it was evaporated to dryness. The residue was dissolved in AcOEt (100mL) and extracted with water (50mL). The combined organic phases were washed with 20 ml of saturated sodium chloride solution, dried over MgSO ₄ , filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel (EtOAc).
Yield: 1.1g (2.86mmol)
MS (EI) m / z 384 [M + H] ⁺

4-Hydroxy-4- (6-methoxy-quinazolin-4-yl-ethyl) -piperidine-1-carboxylic acid tert-butyl ester:

Platinum oxide (1g, 0.92mmol) was added to a solution of tert-butyl 4-hydroxy-4- (6-methoxyquinazolin-4-ylethynyl) piperidine-1-carboxylic acid (1.1g, 2.86mmol) in EtOH (10mL) and hydrogenated under a hydrogen atmosphere (1 bar). The catalyst was filtered off and the filtrate was spun in to dryness. The residue was purified by column chromatography on silica gel (EtOAc: MeOH 10-1).
Yield: 0.48 g (1.24mmol)
MS (EI) m / z 388 [M + H] ⁺

4- [2- (6-methoxy-quinazolin-4-yl) -ethyl] -piperidin-4-ol:

A solution of 4-hydroxy-4- (6-methoxy-quinazolin-4-yl-ethyl) piperidine-1-carboxylic acid tert-butyl ester (0.48g, 1.24mmol) in trifluoroacetic acid (5 mL) was at room temperature for one hour stirred then evaporated to dryness. The residue was in sat. Sodium bicarbonate solution then stirred in to dryness. The residue was dissolved in dichloromethane-methanol (9-1; 50 ml) and filtered. The filtrate was then spun in to dryness.
Yield: 0.06g, 0.208mmol)
MS (EI) m / z 288 [M + H] ⁺ 4- [2- (6-methoxyquinolin-4-yl) ethyl] -1-phenethylpiperidin-4-ol:

To a solution of 4- [2- (6-methoxyquinolin-4-yl) ethyl] piperidin-4-ol (0.09g, 0.314mmol) in DMF (2mL) was added potassium carbonate (0.180g, 1.3mmol) and (2nd -Bromethyl) benzene (0.1mL, 0.732mmol) added. The reaction mixture was stirred at 60 ° C. for 40 minutes and then evaporated to dryness. The residue was dissolved in dichloromethane-methanol (9-1; 20 ml) and filtered. The filtrate was then spun in to dryness. The residue was purified by column chromatography on silica gel (dichloromethane: MeOH 9-1).
Yield: 0.082g (0.21mmol)
MS (EI) m / z 391 [M + H] ⁺

Example 11: 4- [2- (6-methoxy-quinazolin-4-yl) ethyl] -1 - [[2-thiophene-2-ylsulfanyl) ethyl] piperidin-4-ol.

4-Hydroxy-4- (6-methoxyquinolin-4-ylethynyl) -piperidine-1-carboxylic acid tert-butyl ester:

The compound was prepared analogously to Example 10 starting from trifluoromethanesulfonic acid 6-methoxyquinolin-4-yl ester (0.360 g, 1.17 mmol).
Yield: 0.360 g (0.932mmol)
MS (EI) m / z 383 [M + H] ⁺ 4-hydroxy-4- (6-methoxy-quinolin-4-ylethyl) piperidine-1-carboxylic acid tert-butyl ester:

The compound was prepared analogously to Example 10 starting from 4-hydroxy-4- (6-methoxyquinolin-4-ylethynyl) piperidine-1-carboxylic acid tert-butyl ester (0.360 g, 0.932 mmol).
Yield: 0.294g (0.761mmol)
MS (EI) m / z 387 [M + H] ⁺ 4- [2- (6-methoxyquinolin-4-yl) ethyl] piperidin-4-ol:

The compound was prepared analogously to Example 10 starting from 4-hydroxy-4- (6-methoxyquinolin-4-ylethynyl) piperidine-1-carboxylic acid tert-butyl ester (0.294 g, 0.761 mmol).
Yield: 0.185g (0.647mmol)
MS (EI) m / z 287 [M + H] ⁺ 4- [2- (6-methoxy-quinazolin-4-yl) ethyl] -1 - [[2-thiophen-2-ylsulfanyl) -ethyl] -piperidin-4-ol:

The compound was prepared analogously to Example 10 starting from 2- (2-bromoethylsulfanyl) thiophene (0.67g, 3mmol).
Yield: 0.213g (0.496mmol)
MS (EI) m / z 430 [M + H] ⁺

Example 12: 2- {4 - [(2,3-dihydrobenzo [1,4] dioxin-6-yl-ethyl) amino] azepan-1-yl} -1- (6-methoxy-quinolin-4- yl) ethanol.

4-tetrahydronaphthalen-1-carboxylic acid tert-butyl ester:

A mixture of 5-oxoazepane-1,4-dicarboxylic acid 1-tert-butyl ester-4-ethyl ester (5.7 g, 20 mmol; prepared as described in Synthetic Communications 1992, 22, 1249) was added to a mixture of 3N NaOH (50 ml) and THF (25 ml) heated under reflux for 3 h. The reaction mixture was cooled and neutralized with dilute HCl. The mixture was extracted with ethyl acetate and the organic phases were dried over MgSO ₄ and concentrated.
Yield: 4.2 g (100%)
¹ H NMR (CDCl ₃ , 300 MHz): 1.46 (s, 9H); 1.80 (br, 2H); 2.60-2.7 (m, 4H); 3.4-3.6 (m, 4H). 4-aminoazepan-1-carboxylic acid tert-butyl ester:

Ammonium acetate (3.5 g) and sodium cyanoborohydride (295 mg, 1eq) were added to a solution of tert-butyl 4-oxoazepan-1-carboxylic acid (1g, 4.68 mmol) in methanol (50 ml). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was dissolved in saturated potassium carbonate solution and ethyl acetate. The aqueous phase was extracted with ethyl acetate (2 × 50 ml), the combined organic phases were dried over magnesium sulfate and concentrated. 1 g (100%) of product was obtained, which was used without purification.
¹ H NMR (CDCl ₃ , 300 MHz): 1.46 (s, 9H); 1.5-1.75 (m, 2H); 1.8-2.05 (m, 4H); 2.4 (br, 2H); 2.95-3.05 (m, 1H); 3.1-3.6 (m, 4H).
MS (EI) m / z 215.6 [M + H] ⁺ 4 - [(2,3-dihydrobenzo [1,4] dioxin-6-ylmethyl) -amino] -azepane-1-carboxylic acid tert-butyl ester:

A solution of 4-aminoazepane-1-carboxylic acid tert-butyl ester (428 mg, 2 mmol) and 2,3-dihydrobenzo [1,4] dioxin-6-carbaldehyde (330μl, 2mmol) in dichloroethane (10 ml) was added Acetic acid (500μl) and sodium cyanoborohydride (126 mg) were added. The mixture was stirred overnight at room temperature, diluted with saturated potassium carbonate solution and extracted with dichloromethane. The organic phases were dried over magnesium sulfate and concentrated. The product was purified by chromatography on silica gel (ethyl acetate).
Yield: 370 mg (51%)
¹ H NMR (CDCl ₃ , 300 MHz): 1.46 (s, 9H); 1.5-1.75 (m, 2H); 1.8-2.05 (m, 4H); 2.65 (m, 1H); 3.1-3.6 (m, 4H); 3.70 (s, 2H); 4.26 (s, 4H); 6.8-6.9 (m, 3H).
MS (EI) m / z 363.6 [M + H] ⁺ azepan-4-yl- (2,3-dihydrobenzo [1,4] dioxin-6-ylmethyl) amine:

4 - [(2,3-Dihydrobenzo [1,4] dioxin-6-ylmethyl) amino] azepane-1-carboxylic acid tert-butyl ester (370 mg, 1 mmol) was added in a mixture of 10 ml of water and 2 ml conc. HCl dissolved and stirred at room temperature for 24h. The reaction mixture was neutralized with solid potassium carbonate and extracted with ethyl acetate. Chromatography on silica gel (dichloromethane / MeOH 9: 1) gave 220 mg of pure product (85%).
¹ H NMR (CDCl ₃ , 300 MHz): 1.8-2.0 (m, 1H); 2.0-2.3 (m, 4H); 2.3-2.6 (m, 2H); 3.2-3.4 (m, 4H); 3.6-6.7 (m, 1H); 3.95 (dd, 2H); 4.2-4.3 (m, 5H); 6.8-7.1 (m, 3H).
MS (EI) m / z 263.4 [M + H] ⁺ 2- {4 - [(2,3-dihydrobenzo [1,4] dioxin-6-ylmethyl) -amino] -azepan-1-yl} -1- (6-methoxy-quinolin-4-yl) ethanol:

A mixture of azepan-4-yl- (2,3-dihydro-benzo [1,4] -dioxin-6-ylmethyl) amine (60 mg), 6-methoxy-4-oxiranylquinoline (50 mg), lithium perchlorate (25 mg ) and potassium carbonate (35 mg) was heated in DMF (1 ml) at 80 ° C overnight. The reaction mixture was purified by chromatography on silica gel (dichloromethane / MeOH 9: 1 (+ 2% NEt ₃ ).
¹ H NMR (CDCl ₃ , 300 MHz): 1.5-2.0 (m, 7H); 2.45 (dd, 1H); 2.55-3.05 (m, 8H); 3.5-3.8 (m, 2H); 3.85 (s, 3H); 4.15 (s, 4H); 5.25-5.35 (m, 1H); 6.6-6.8 (m, 2H); 7.11 (dd, 1H); 7.30 (dd, 1H); 7.55 (dd, 1H); 7.97 (d. 1H); 8.7 (d, 1H).
MS (EI) m / z 464.6 [M + H] ⁺

Example 13: [1- (2,3-Dihydro-benzo [1,4] dioxin-6-ylmethyl) azepan-4-yl] (6-methoxyquinolin-4-ylmethyl) amine:

4 - [(6-Methoxy-quinolin-4-ylmethyl) -amino] -azepane-1-carboxylic acid tert-butyl ester:

A solution of 4-aminoazepane-1-carboxylic acid tert-butyl ester (568 mg, 2.65 mmol) and 6-methoxyquinoline-4-carbaldehyde (497 mg (2.7 mmol) in dichloroethane (10 ml) and acetic acid (1 ml) was mixed with Sodium cyanoborohydride (170 mg, 2.7 mmol) was added. The reaction mixture was stirred overnight at room temperature, poured onto saturated sodium carbonate solution and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated. The product was purified by chromatography on silica gel (ethyl acetate).
Yield: 515 mg (51%)
¹ H NMR (CDCl ₃ , 300 MHz): 1.47 (s, 9H); 1.5-2.0 (m, 8H); 2.8-2.9 (m, 1H); 3.2-3.65 (m, 5H); 3.97 (s, 3H); 4.22 (s, 2H); 5.25-5.35 (m, 1H); 6.6-6.8 (m, 2H); 7.11 (dd, 1H); 7.35-7.45 (m, 3H); 8.02 (d, J = 9.2Hz, 1H); 8.73 (d, J = 1.4Hz, 1H).
MS (EI) m / z 386.5 [M + H] ⁺

Azepan-4-yl- (6-methoxy-quinolin-4-ylmethyl) amine:

A solution of 4 - [(6-methoxyquinolin-4-ylmethyl) amino] azepan-1-carboxylic acid tert-butyl ester (700 mg, 1.8 mmol) in dichloromethane (1 ml) was added at room temperature to TFA (1 ml) , The reaction mixture was stirred at room temperature for 3 h, concentrated and taken up in aqueous NaOH. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate. The product was purified by chromatography on silica gel (DCM / MeOH 9: 1 (1% NH ₄ OH)).
Yield: 477 mg (92%)
¹ H NMR (CDCl ₃ , 300 MHz): 1.7-2.3 (m, 6H); 3.0-3.3 (m, 4H); 3.35-3.45 (m, 1H); 3.97 (s, 3H); 4.2 (s, 2H); 7.28 (d, 1H); 7.35-7.45 (m, 2H); 8.02 (d, J = 9.2Hz 1H); 8.73 (d, J = 1.4Hz, 1H).
MS (EI) m / z 286.3 [M + H] ⁺ [1- (2,3-dihydrobenzo [1,4] dioxin-6-ylmethyl) azepan-4-yl] - (6-methoxyquinolin-4-ylmethyl ) amine:

A solution of azepan-4-yl- (6-methoxyquinolin-4-yl-methyl) amine (90 mg, 0.32 mmol) and 2,3-dihydrobenzo [1,4] dioxin-6-carbaldehyde (51.8 mg, 0.32 mmol ) in dichloroethane / THF (1: 1, 0.7 ml), sodium triacetoxyborohydride (100 mg, 0.47 mmol) was added. The reaction mixture was stirred for 3 hours at room temperature, concentrated and chromatographed on silica gel (ethyl acetate, methanol).
Yield: 56 mg (41%)
¹ H NMR (CDCl ₃ , 300 MHz): 1.40-2.05 (m, 6H); 2.35-2.80 (m, 3H); 2.8-2.9 (m, 1H); 3.41 (2, 2H); 3.99 (s, 3H); 4.15 (s, 2H); 4.20 (s, 4H); 6.70-6.80 (m, 3H); 7.37 (dd, J = 2.76, J = 9.1, 1H); 7.45 (d, J = 2.76, 1H); 7.51 (d, J = 4.4, 1H); 7.92 (d, J = 9.12, 1H); 8.65 (d, J = 4.4, 1H).
MS (EI) m / z 434.7 [M + H] ⁺

In an analogous way:
(6-methoxyquinolin-4-ylmethyl) - (1-phenethylazepan-4-yl) amine (25% yield, MS (EI) m / z 390.5 [M + H] ⁺ ),
(6-methoxyquinolin-4-ylmethyl) - [1- (3-phenylpropyl) azepan-4-yl] amine (25% yield, MS (EI) m / z 404.9 [M + H] ⁺ ) and
(1-Heptylazepan-4-yl) - (6-methoxyquinolin-4-ylmethyl) amine (43% yield, MS (EI) m / z 384.4 [M + H] ⁺ ). Example 14: 1- {4 - [(6-methoxyquinolin-4-ylmethyl) amino] azepan-1-yl} -3-phenylpropenone.

A solution of azepan-4-yl- (6-methoxyquinolin-4-yl-methyl) amine (90 mg, 0.32 mmol) in THF / DCE was treated with cinnamic acid chloride (52.5 mg, 1eq). The reaction mixture was stirred for 3 h at room temperature, concentrated and purified by chromatography on silica gel (DCM / MeOH 9: 1 (+ 1% NH4OH)).
Yield: 37 mg (38%)
MS (EI) m / z 416.6 [M + H] ⁺

Example 15: tert-butyl 1- [2-hydroxy-2- (6-methoxyquinolin-4-yl) ethyl] -4-phenethyl- [1,4] diazepane-5-carboxylate

1- [2-hydroxy-2- (6-methoxy-quinolin-4-yl) ethyl] - [1,4] diazepane-5-carboxylic acid tert-butyl ester:

A mixture of 6-methoxy-4-oxiranylquinoline (400 mg, 2 mmol), [1,4] -diazepane-5-carboxylic acid tert-butyl ester (400 mg, 2 mmol, prepared as described in J. Chem. Research (S ), 1991, 306, 2876), lithium perchlorate (211 mg, 2 mmol) and potassium carbonate (275 mg, 2 mmol) in DMF (5 ml) were heated to 100 ° C. over 4 hours. The reaction mixture was diluted with water and ethyl acetate, the aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate and concentrated. The product was purified by chromatography on silica gel (DCM / MeOH 9: 1).
Yield: 330 mg (41%)
MS (EI) m / z 402.5 [M + H] ⁺ 1- [2-hydroxy-2- (6-methoxy-quinolin-4-yl) ethyl] -4-phenethyl [1,4] diazepan-5-carboxylic acid tert-butyl ester:

To a solution of 1- [2-hydroxy-2- (6-methoxy-quinolin-4-yl) ethyl] - [1,4] diazepan-5-carboxylic acid tert-butyl ester (100 mg, 0.25 mmol) and Phenylacetaldehyde (29.2 µl, leq) in THF (700 µl), sodium triacetoxyborohydride (79 mg (1.5 eq) was added. After 2 hours, another equivalent of phenylacetaldehyde was added and the reaction mixture was heated to 40 ° C. After a further 2 hours, the reaction mixture was concentrated to dryness us purified by chromatography on silica gel (ethyl acetate, methanol)
Yield: 67 mg (54%)
MS (EI) m / z 506 [M + H] ⁺ 1- [2-hydroxy-2- (6-methoxyquinolin-4-yl) ethyl] -4-phenethyl- [1,4] diazepane-5- carboxylic acid:

1- [2-Hydroxy-2- (6-methoxo-quinolin-4-y1) ethyl] -4-phenethyl- [1,4] diazepane-5-carboxylic acid tert-butyl ester (55 mg) was dissolved in 4M HCl suspended in dioxane and stirred at room temperature for 3.5 h. The reaction mixture was concentrated and purified by means of preparative HPLC.
Yield: 3.9 mg
MS (EI) m / z 450 [M + H] ⁺

In an analogous way, too
1- [2-Hydroxy-2- (6-methoxy-quinolin-4-yl) ethyl] -4- (3-phenylpropyl) - [1,4] diazepane-5-carboxylic acid tert-butyl ester and
1- [2-Hydroxy-2- (6-methoxyquinolin-4-yl) ethyl] -4- (3-phenylpropyl) - [1,4] diazepan-5-carboxylic acid synthesized starting from dihydrocinnamaldehyde.

Likewise, starting from heptanal
4-heptyl-1- [2-hydroxy-2- (6-methoxyquinolin-4-yl) ethyl] - [1,4] diazepan-5-carboxylic acid tert-butyl ester and
4-Heptyl-1- [2-hydroxy-2- (6-methoxyquinolin-4-yl) ethyl] - [1,4] diazepan-5-carboxylic acid. Example 16: 2- [5-hydroxymethyl-4- (3-phenylpropyl) - [1,4] diazepan-1-yl] -1- (6-methoxyquinolin-4-yl) ethanol.

A solution of 1- [2-hydroxy-2- (6-methoxyquinolin-4-yl) ethyl] -4- (3-phenylpropyl) - [1,4] diazepane-5-carboxylic acid tert-butyl ester (80mg ) in THF was added lithium aluminum hydride (28 mg) and stirred for 1 hour at room temperature. A few drops of saturated Rochelle salt solution were added to the reaction mixture, the mixture was stirred for 15 minutes and the precipitate was filtered off.
Yield: 39 mg (57%)
MS (EI) m / z 450 [M + H] ⁺

In an analogous manner, starting from 4-heptyl-1- [2-hydroxy-2- (6-methoxyquinolin-4-yl) ethyl] - [1,4] diazepan-5-carboxylic acid tert-butyl ester, 2- ( 4-Heptyl-5-hydroxy-methyl- [1,4] diazepan-1-yl) -1- (6-methoxyquinolin-4-yl) ethanol produced in 33% yield (MS (EI) m / z 430 [M + H] ⁺ ).

Example 17: 2- [2- (3,4-Dimethoxyphenyl) ethyl] -5- [2-hydroxy-2- (6-methoxyquinolin-4-yl) ethyl] tetrahydropyrrolo [3,4-c] pyrrole -1,3-dion.

1- [2- (3,4-dimethoxyphenyl) -ethyl] -pyrrole-2,5-dione:

Homoveratrylamine (13.8 ml, leq) was added dropwise to a solution of maleic anhydride (8 g, 81 mmol) in acetic acid (50 ml) at room temperature. The reaction is exothermic. The reaction mixture was then stirred at 100 ° C. overnight. 20 ml of acetic anhydride were added and the mixture was stirred at 100 ° C. for a further 2 h. The reaction mixture was concentrated in vacuo, taken up in water and extracted with ethyl acetate. The organic phases were dried over sodium sulfate and concentrated. The residue was crystallized with hexane / ethyl acetate.
Yield: 7.7 g (36%)
¹ H NMR (CDCl ₃ , 300 MHz): 2.74 (t, J = 7.26, 2H); 3.62 (t, J = 7.26, 2H); 3.7 (s, 3H); 3.72 (s, 3H); 6.64 (dd, J = 2.01, J = 8.1, 1H); 6.75 (d, J = 2.01, 1H); 6.82 (d, J = 8.1, 1H); 6.99 (s, 2H). 5-benzyl-2- [2- (3,4-dimethoxy-phenyl) -ethyl] -tetrahydropyrrolo- [3,4-c] pyrrole-1,3-dione:

320 μl of a 10th solution were added to a solution of benzylpentyloxymethyltrimethylsilanylmethylamine (2.47 g) and 1- [2- (3,4-dimethoxyphenyl) ethyl] pyrrole-2,5-dione (2 g, 7.7 mmol) in dichloroethane (25 ml) % Solution of TFA added dropwise in dichloroethane. The reaction is exothermic. The reaction mixture was stirred at room temperature overnight, washed with aqueous bicarbonate solution, dried over sodium sulfate and concentrated. The product was purified by chromatography on silica gel (hexane / ethyl acetate 1: 1).
Yield: 2.6 g (86%)
MS (EI) m / z 395.2 [M + H] ⁺ )

2- [2- (3,4-Dimethoxyphenyl) ethyl] tetrahydropyrrolo [3,4-c] pyrrole-1,3-dione:

A solution of 5-benzyl-2- [2- (3,4-dimethoxyphenyl) ethyl] tetrahydropyrrolo [3,4-c] pyrrole-1,3-dione (1 g, 2.5 mmol) in methanol (20 ml ) and acetic acid (1 ml) was hydrogenated overnight over Pd / C (10%, 270 mg). The reaction mixture was filtered over dicalite and concentrated. The product was purified by chromatography on silica gel (eluent DCM / MeOH 9: 1).
Yield: 560 mg
MS (EI) m / z 305 [M + H] ⁺ ) 2- [2- (3,4-dimethoxyphenyl) ethyl] -5- [2-hydroxy-2- (6-methoxyquinolin-4-yl) ethyl ] -tetrahydropyrrolo [3,4-c] pyrrole-1,3-dione:

A mixture of 6-methoxy-4-oxiranylquinoline (50 mg, 0.25 mmol), 2- [2- (3,4-dimethoxyphenyl) ethyl] tetrahydropyrrolo- [3,4-c] pyrrole-1,3- Dione (75.6 mg, 0.25 mmol), lithium perchlorate (23.4 mg, 0.25 mmol) and potassium carbonate (35.4 mg, 0.25 mmol) in DMF (1 ml) were heated to 100 ° C for 72 hours. The reaction mixture was diluted with water and ethyl acetate, the aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate and concentrated. The product was purified by chromatography on silica gel (EtOAc, McOH).
Yield: 16.5 mg (10%)
MS (EI) m / z 506 [M + H] ⁺ )

Claims (15)

Compounds of formula (I):

where A is an oxygen, sulfur, nitrogen atom, an alkylene, alkenylene, alkynylene or a heteroalkylene group, X ₁ , X ₂ and X _{3 are} independently nitrogen atoms or groups of the formula CR ² , R ^{1 is} a hydrogen atom Halogen atom, a hydroxy, an alkyloxy, a heteroalkyl or a heteroal is kyloxy group, R ^{2 is} a hydrogen atom, a halogen atom, a hydroxyl, alkyl, alkenyl, alkynyl or a heteroalkyl group, R ^{3 is selected} from the following groups:

the radicals R ⁴ independently of one another are a halogen atom, a hydroxyl, amino, nitro or thiol group, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl -, Aralkyl- or a heteroaralkyl radical, each hydrogen atom of the ring system being bonded to the A, can be replaced by R ⁴ or two of the radicals R ⁴ together form part of an aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, Are heteroalkylcycloalkyl, aralkyl or a heteroaralkyl ring, R ^{5 is} an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkyl-cycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl radical, R ^6a , R ^6b and R ^6c independently of one another are a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or a heteroaralkyl radical, E is a nitrogen atom or one Is a CH group, U is an oxygen atom, a sulfur atom or a group of the formula C = O, C = CH ₂ , C = CHR ⁴ , C = C (R ⁴ ) ₂ , SO ₂ , SO, CH ₂ or NH, V is a nitrogen atom or a CH group, W is a hydroxy, a mercapto, an alkoxy or a heteroalkyloxy group, Y ¹ , Y ² , Y ³ and Y ^{4 are} independently a nitrogen atom or a CR ⁴ group, Q ¹ and Q ^{4 are} independently an oxygen atom, a sulfur atom or an NH group, Q ² and Q ^{3 are} independently a nitrogen atom or e are a CR ⁴ group, G is a nitrogen atom or a CH group, n is 0, 1, 2 or 3, m is 0, 1, 2, 3 or 4, o is 0 or 1 and p is 0, 1, 2 or 3, where p = 1 and at the same time G = N is only permitted if R ⁴ = O-alkyl or R ⁴ = S-alkyl; and wherein P = 1 and at the same time o = 0 is only permitted in the event that R ⁴ = O-alkyl or R ⁴ = S-alkyl, or a pharmacologically acceptable salt, solvate, hydrate or a pharmacologically acceptable formulation thereof. Compounds according to claim 1, wherein A is an O, S or N atom or a group of the formula CH ₂ , CH ₂ CH ₂ , CH ₂ N (alkyl), N (alkyl) CH ₂ , CH ₂ O, OCH ₂ , CH ₂ S, SCH ₂ , CH ₂ CH (OH), CH (OH), CH (OH) CH ₂ , NHCO, CONH, C (= O) CH ₂ or CH ₂ C (= O). Compounds according to claim 1 or 2, wherein one of the groups X ₁ , X ₂ and X _{3 is} a nitrogen atom or a group of the formula CR ² and the other are CH groups. Compounds according to any one of claims 1 to 3, wherein R ^{2 is} a C ₁ -C ₄ alkyloxy group, wherein one or more hydrogen atoms can be replaced by fluorine atoms. Compounds according to one of claims 1 to 4, wherein U is an oxygen, a sulfur atom or an NH or Is methylene group. Compounds according to any one of claims 1 to 5, wherein X ^{2 is} a nitrogen atom or a group of the formula CH. Compounds according to any one of claims 1 to 6, wherein X ¹ and X ^{3 are} a group of the formula CH. Compounds according to any one of claims 1 to 7, wherein R ^{1 is} a heteroalkyl group. Compounds according to one of claims 1 to 8, wherein n is the same Is 0 or 1. Compounds according to any one of claims 1 to 9, wherein R ^{4 is} an alkyl, heteroalkyl or heteroaralkyl group. Compounds according to any one of claims 1 to 10, wherein R ^{5 is} an aralkyl or a heteroaralkyl group. Compounds according to one of claims 1 to 11, wherein R ^{5 is} a group of the formula COR ⁷ , COOR ⁷ or SO ₂ R ⁷ , where R ^{7 is} an alkyl, alkenyl, alkynyl, hetero-alkyl, cycloalkyl, heterocycloalkyl, alkylcyclo-alkyl, Heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl or a heteroaralkyl group. Compounds according to one of claims 1 to 12, where m is 0, 1 or 2. Pharmaceutical compositions containing a compound according to one of the claims 1 to 13 and optional carriers and / or contain adjuvants. Use of a compound or a pharmaceutical A composition according to any one of claims 1 to 14 for treatment of bacterial infections.