N-biarylamides

Abstract

The invention relates to N-biarylamides, methods for production and use thereof for the production of medicaments for the treatment and/or prophylaxis of diseases and for improvement in cognition, concentration power, learning power and/or memory.

Claims

1. A method for treating impairments of perception, concentration, learning and/or memory in a patient suffering from Alzheimer's disease or schizophrenia, comprising administering to the patient a compound represented by Formula (I): ##STR00038## in an amount effective to stimulate an alpha7 nicotinic acetylcholine receptor (7 nAChR), in which R.sup.1 is a group of the formula NR.sup.2CONR.sup.3R.sup.4, NR.sup.2COCOOR.sup.5, NHSO.sub.2R.sup.6, SO.sub.2NHR.sup.7 or NHCOR.sup.8, where R.sup.2 is hydrogen or C.sub.1-C.sub.6-alkyl, R.sup.3 and R.sup.4 are independently of one another hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl or phenyl, which is optionally substituted by up to 3 radicals independently of one another selected from the group of halogen, cyano, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, trifluoromethyl and trifluoromethoxy, or R.sup.3 and R.sup.4 together with the nitrogen atom to which they are bonded form a 5- to 6-membered heterocyclyl, R.sup.5 is hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl or aryl, where C.sub.1-C.sub.6-alkyl is optionally substituted by aryl, R.sup.6 is C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl, 5- to 6-membered heterocyclyl, aryl or 5- to 6-membered heteroaryl, where C.sub.1-C.sub.6-alkyl is optionally substituted by aryl, R.sup.7 is hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl, 5- to 6-membered heterocyclyl, aryl or 5- to 6-membered heteroaryl, where C.sub.1-C.sub.6-alkyl is optionally substituted by aryl, R.sup.8 is C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.6-alkyl or phenyl, where C.sub.1-C.sub.6-alkyl is substituted by C.sub.1-C.sub.6-alkoxy and phenyl by 1 to 3 radicals independently of one another selected from the group of halogen, cyano, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, trifluoromethyl and trifluoromethoxy, or a salt thereof.

2. The method of claim 1, further comprising co-administering a second active ingredient for the treatment of Alzheimer's disease or schizophrenia.

3. The method of claim 1, wherein the administering is by an oral, transdermal, parenteral or inhalation route.

4. The method of claim 1, wherein the compound is selected from the group consisting of: [(4-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylcarbonyl]amino}biphenyl-4-yl)amino]-(oxo)acetic acid hydrochloride; (3R)-N-{4-[(Methylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride; (3R)-N-{3-[(Methylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride; (3R)-N-{4-[(Ethylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride; (3R)-N-{4-[(Phenylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride; (3R)-N-{4-[(Benzylsulfonyl)amino]biphenyl-4-yl }quinuclidine-3-carboxamide; (3R)-N-[4-(Aminosulfonyl)biphenyl-4-yl]quinuclidine-3-carboxamide hydrochloride; (3R)-N-(4-[(Isopropylamino)sulfonyl]biphenyl-4-yl)quinuclidine-3-carboxamide hydrochloride; (3R)-N-{4-[(Benzylamino)sulfonyl]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride; (3R)-N-(4-{[(Methylamino)carbonyl]amino}biphenyl-4-yl)quinuclidine-3-carboxamide; (3R)-N-(4-{([(Cyclopentylamino)carbonyl]amino}biphenyl-4-yl)quinuclidine-3-carboxamide hydrochloride; (3R)-N-(4-{([(Ethylamino)carbonyl]amino}biphenyl-4 -yl)quinuclidine-3-carboxamide; (3R)-N-[4-({[(3 -Methoxyphenyl)amino]carbonyl }amino)biphenyl4-yl]quinuclidine-3-carboxamide hydrochloride; (3R)-N-{4-[(3 -Chlorobenzoyl)amino]biphenyl-4-yl }quinuclidine-3-carboxamide hydrochloride; (3R)-N-{4-[(3-Fluorobenzoyl)amino]biphenyl-4-yl }quinuclidine-3-carboxamide hydrochloride; (3R)-N- {4-[(2-Methoxyacetyl)amino]biphenyl-4-yl }quinuclidine-3-carboxamide hydrochloride; and (3R)-N- {4-[(Cyclopentylcarbonyl)amino]biphenyl-4-yl }quinuclidine-3-carboxamide hydrochloride; or a salt thereof.

5. A method for treating impairments of perception, concentration, learning and/or memory in a patient suffering from Alzheimer' s disease or schizophrenia, comprising administering to the patient a pharmaceutical composition comprising: i) a compound represented by Formula (I): ##STR00039## in an amount effective to stimulate an alpha7 nicotinic acetylcholine receptor (7 nAChR), in which R.sup.1 is a group of the formula NR.sup.2CONR.sup.3R.sup.4, NR.sup.2COCOOR.sup.5, NHSO.sub.2R.sup.6, SO.sub.2NHR.sup.7 or NHCOR.sup.8, where R.sup.2 is hydrogen or C.sub.1-C.sub.6-alkyl, R.sup.3 and R.sup.4 are independently of one another hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl or phenyl, which is optionally substituted by up to 3 radicals independently of one another selected from the group of halogen, cyano, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, trifluoromethyl and trifluoromethoxy, or R.sup.3 and R.sup.4 together with the nitrogen atom to which they are bonded form a 5- to 6-membered heterocyclyl, R.sup.5 is hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl or aryl, where C.sub.1-C.sub.6-alkyl is optionally substituted by aryl, R.sup.6 is C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl, 5- to 6-membered heterocyclyl, aryl or 5-to 6-membered heteroaryl, where C.sub.1-C.sub.6-alkyl is optionally substituted by aryl, R.sup.7 is hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.3-C.sub.8-cycloalkyl, 5- to 6-membered heterocyclyl, aryl or 5- to 6-membered heteroaryl, where C.sub.1-C.sub.6-alkyl is optionally substituted by aryl, R.sup.8 is C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.6-alkyl or phenyl, where C.sub.1-C.sub.6-alkyl is substituted by C.sub.1-C.sub.6-alkoxy and phenyl by 1 to 3 radicals independently of one another selected from the group of halogen, cyano, C.sub.1-C.sub.6-alkyl, C.sub.1-C.sub.6-alkoxy, trifluoromethyl and trifluoromethoxy, or a salt thereof; and ii) a pharmaceutically acceptable carrier.

6. The method of claim 5, further comprising co-administering a second active ingredient for the treatment of Alzheimer's disease or schizophrenia.

7. The method of claim 5, wherein the administering is by an oral, transdermal, parenteral or inhalation route.

Description

EXAMPLE 1A

(rac)-1-Azabicyclo[2.2.2]octane-3-carbonitrile

(1) ##STR00009##

(2) 20.4 g (163 mmol) of 3-quinuclidinone and 41.4 g (212 mind) of (4-toluenesulfonyl)methyl isocyanide are introduced into 435 ml of 1,2-dimethoxyethane and 16 ml of dry ethanol while cooling in ice. 45.7 g (407 mmol) of potassium tert-butoxide are slowly added in such a way that the temperature does not rise above 10 C. The mixture is then heated at 40 C. for 2.5 h. After cooling to RT, the resulting solid is filtered off. The filtrate is concentrated and chromatographed on neutral alumina (mobile phase: dichloromethane.fwdarw.ethyl acetate.fwdarw.ethyl acetate/methanol 50:1). 22.9 g (quant.) of the racemic product are obtained in slightly impure form.

EXAMPLE 2A

(R)-1-Azabicyclo[2.2.2]octane-3-carbonitrile

(3) ##STR00010##

(4) Enantiomer separation of the racemate from Example 1A takes place by HPLC on a chiral phase; [column: Daicel Chiralpak AD 250 mm20 mm; eluent: 5% water, 87% acetonitrile, 8% acetonitrile with 2% diethylamine; flow rate: 10 ml/mm; detection: 220 nm; volume injected: 0.3 ml]. 8.7 g of the title compound (87% of theory) are isolated from the separation of 20 g of racemic 1-azabicyclo[2.2.2]octane-3-carbonitrile.

(5) R.sub.t=6.19 min [Chiralpak AD 250 mm4.6 mm, 10 m; eluent: 5% water, 95% acetonitrile with 2% diethylamine; temperature: 30 C.; flow rate: 1.0 ml/min].

EXAMPLE 3A

(R)-1-Azabicyclo[2.2.2]octane-3-carboxylic acid

(6) ##STR00011##

(7) 7.50 g (55.1 mmol) of (R)-1-azabicyclo[2.2.2]octane-3-carbonitrile (Example 2A) are heated together with 78 ml of conc. hydrochloric acid under reflux for 4 h. The solvent is removed under reduced pressure, and remaining water is removed by distillation with toluene several times. 12.9 g of the title substance, which still contains inorganic salts, are obtained and reacted without further purification.

EXAMPLE 4A

(3R)N-(4-Bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide

(8) ##STR00012##

(9) 9.17 g (47.8 mmol) of (R)-1-azabicyclo[2.2.2]octane-3-carboxylic acid (Example 3A) are heated together with 160 ml of thionyl chloride under reflux for 1 h. Excess thionyl chloride is removed under reduced pressure, and residues are removed by azeotropic distillation together with toluene. The acid chloride obtained in this way is stirred together with 8.19 g (47.6 mmol) of 4-bromoaniline and 24.6 ml (190.4 mmol) of N,N-diisopropylethylamine in 59 ml of DMF at RT for 72 h. The solvent is removed under reduced pressure, and the crude product is purified by chromatography on silica gel 60 (mobile phase: dichloromethane.fwdarw.dichloromethane/methanol/triethylamine 70:30:2). The product fractions are combined and concentrated in vacuo, and the residue is dried under high vacuum. 5.5 g (37% of theory) of the title compound are isolated. The absolute configuration was assigned by single-crystal analysis of the crystal structure.

(10) .sup.1H-NMR (200 MHz, DMSO-d.sub.6): =10.06 (s, 1H), 7.70-7.40 (m, 4H), 3.30-3.10 (m, 1H), 2.94-2.45 (m, 6H), 2.15-2.04 (m, 1H), 1.73-1.45 (m, 3H), 1.45-1.15 (m, 1H).

(11) HPLC (Method 1): R.sub.t=3.84 min.

(12) MS (ESIpos): m/z=309 (M+H).sup.+.

EXAMPLE 5A

(3R)-Quinuclidine-3-carbonyl chloride hydrochloride

(13) ##STR00013##

(14) 8.18 g (64.43 mmol) of oxalyl chloride are added dropwise to a solution of 2.0 g (12.89 mmol) of (R)-1-azabicyclo[2.2.2]octane-3-carboxylic acid (Example 3A) in 10 ml of toluene. After stirring at room temperature for 18 h, the reaction mixture is concentrated in vacuo and codistilled with toluene twice. Drying under high vacuum results in 2.31 g (85.2% of theory) of the title compound, which is reacted further without further purification.

EXAMPLE 6A

(3R)N-(4-Nitrobiphenyl-4-yl)quinuclidine-3-carboxamide hydrochloride

(15) ##STR00014##

(16) 480 mg (3.50 mmol) of potassium carbonate are added to a mixture, prepared under argon, of 490 mg (2.33 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 250 mg (1.17 mmol) of 4-amino-4-nitrobiphenyl in 11 ml of a 10:1 mixture of dioxane and DMF. The reaction mixture is stirred at 100 C. for 18 h and then concentrated. The residue is suspended in methanol and filtered. The filtration residue is washed with water, mixed with 20 ml of a 3:1 mixture of acetonitrile and 1 N hydrochloric acid, again concentrated and dried under high vacuum. The above filtrate is purified by preparative HPLC. The product fractions are concentrated, taken up in 5 ml of a 3:1 mixture of acetonitrile and 1 N hydrochloric acid, again concentrated and dried under high vacuum. 291 mg (61.7% of theory) of the title compound are obtained from the filtration residue, and a further 65 mg (12.4% of theory) are obtained from the filtrate, in this way.

(17) HPLC (Method 1): R.sub.t=4.13 min.

(18) MS (ESIpos): m/z=352 (M+H).sup.+.

EXAMPLE 7A

(3R)N-(4-Aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride

(19) ##STR00015##

(20) A solution of 739 mg (2.10 mmol) of (3R)N-(4-nitrobiphenyl-4-yl)quinuclidine-3-carboxamide (Example 6A) in 10 ml of methanol and 5 ml of 2 N hydrochloric acid is hydrogenated under atmospheric pressure in the presence of 448 mg (0.21 mmol) of 5% palladium on carbon for 2 h. Filtration through kieselgur is followed by washing with methanol and concentration of the filtrate and drying under high vacuum. 755 mg (89.2% of theory) of the title compound are obtained.

(21) HPLC (Method 1): R.sub.t=3.04 Train.

(22) MS (ESIpos): m/z=322 (M+H).sup.+.

EXAMPLE 8A

(3R)N-(3-Aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride

(23) ##STR00016##

(24) A degassed mixture of 200 mg (0.58 mmol) of (3R)N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide (Example 4A), 215.2 mg (0.58 mmol) of 3-aminophenylboronic acid hemisulfate, 579 l (1.74 mmol) of 3 N sodium hydroxide solution and 21.2 mg (0.03 mmol) of PdCl.sub.2(dppf) in 3 ml of DMF is heated at 90 C. for 18 h. Cooling to RT is followed by purification by preparative HPLC. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid and again concentrated. Drying under high vacuum results in 146 mg (39.4% of theory) of the title compound, which is reacted further without further purification.

EXAMPLE 9A

N-Benzyl-4-nitrobiphenyl-4-sulfonamide

(25) ##STR00017##

(26) 0.28 ml (2.52 mmol) of benzylamine is added to a solution of 150 mg (0.50 mmol) of 4-nitrobiphenyl-4-sulfonyl chloride in 2.0 ml of DMF. After 18 h at room temperature, 2.5 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction and dried under high vacuum. 159 mg (74.4% of theory) of the title compound are obtained and reacted further without further purification:

(27) LC-MS (Method 3): R.sub.t=3.83 min.; m/z 369 (M+H).sup.+.

EXAMPLE 10A

4-Amino-N-benzylbiphenyl-4-sulfonamide

(28) ##STR00018##

(29) 416.5 mg (1.85 mmol) of tin(II) chloride dihydrate are added to a solution of 136 mg (0.37 mmol) of N-benzyl-4-nitrobiphenyl-4-sulfonamide (Example 9A) in 2.0 ml of DMF. After 18 h at room temperature, the reaction mixture is purified by preparative HPLC. The product fractions are concentrated in vacuo and dried under high vacuum. 117 mg (84.3% of theory) of the title compound are obtained.

(30) HPLC (Method 1): R.sub.t=3.91 min.

(31) MS (ESIpos): m/z=339 (M+H).sup.+.

EXAMPLE 11A

N-Isopropyl-4-nitrobiphenyl-4-sulfonamide

(32) ##STR00019##

(33) 0.22 ml (2.52 mmol) of isopropylamine is added to a solution of 150 mg (0.50 mmol) of 4-nitrobiphenyl-4-sulfonyl chloride in 2.0 ml of DMF. After 18 h at room temperature, 2.5 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction and dried under high vacuum. 126 mg (64.4% of theory) of the title compound are obtained and reacted further without further purification.

(34) LC-MS (Method 3): R.sub.t=3.66 min.; m/z=321 (M+H).sup.+.

EXAMPLE 12A

4-Amino-N-isopropylbiphenyl-4-sulfonamide

(35) ##STR00020##

(36) 288.8 mg (1.28 mmol) of tin(II) chloride dihydrate are added to a solution of 100 mg (0.26 mmol) of N-isopropyl-4-nitrobiphenyl-4-sulfonamide (Example 11A) in 2.0 ml of DMF. After 18 h at room temperature, the reaction mixture is purified by preparative HPLC. The product fractions are concentrated in vacuo and dried under high vacuum. 47 mg (63.2% of theory) of the title compound are obtained.

(37) HPLC (Method 1): R.sub.t=3.57 min.

(38) MS (DCI): m/z=291 (M+H).sup.+.

Exemplary Embodiment

EXAMPLE 1

[(4-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylcarbonyl]amino}biphenyl-4-yl)amino](oxo)acetic acid hydrochloride

(39) ##STR00021##

(40) 300 mg (2.14 mmol) of potassium carbonate are added to a mixture, prepared under argon, of 300 mg (1.43 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 180 mg (0.71 mmol) of [(4-aminobiphenyl-4-yl)amino](oxo)acetic acid [CAS Registry No. 100872-66-0] in 11 ml of a 10:1 mixture of dioxane and DMF. After 18 h at 100 C., the reaction mixture is concentrated in vacuo, and the residue is dissolved in water and acetonitrile and purified by preparative HPLC. The concentrated product fractions are mixed with 5 ml of a 2:1 mixture of acetonitrile and 1 N hydrochloric acid and again concentrated. Drying under high vacuum results in 64 mg (20.3% of theory) of the title compound.

(41) HPLC (Method 1): R.sub.t=3.40 min.

(42) MS (ESIpos): m/z=350 (M+H).sup.+.

EXAMPLE 2

(3R)N-{4-[(Methylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride

(43) ##STR00022##

(44) 300 mg (2.14 mmol) of potassium carbonate are added to a mixture, prepared under argon, of 300 mg (1.43 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 187 mg (0.71 mmol) of N-(4-aminobiphenyl-4-yl)methylsulfonamide [CAS Registry No. 82315-47-7] in 11 ml of a 10:1 mixture of dioxane and DMF. After 18 h at 100 C., the reaction mixture is concentrated in vacuo, and the residue is dissolved in water and acetonitrile and purified by preparative HPLC. The concentrated product fractions are mixed with 5 ml of a 2:1 mixture of acetonitrile and 1 N hydrochloric acid and again concentrated. Drying under high vacuum results in 186 mg (58.3% of theory) of the title compound.

(45) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =10.45 (s, 1H), 10.19 (br. s, 1H), 9.80 (s, 1H), 7.71 (m, 2H), 7.61 (m, 4H), 7.28 (m, 2H), 3.60 (dd, 1H), 3.42-3.10 (m, 6H), 3.01 (s, 3H), 2.45 (m, 1H), 1.93 (m, 2H), 1.76 (m, 2H).

(46) HPLC (Method 1): R.sub.t=3.59 min.

(47) MS (ESIpos): m/z=400 (M+H).sup.+.

EXAMPLE 3

(3R)N-{3-[(Methylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride

(48) ##STR00023##

(49) 63.6 l (0.46 mmol) of triethylamine and 21.2 l (0.27 mmol) of methanesulfonyl chloride are added to a solution of 60 mg (0.09 mmol) of (3R)N-(3-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 8A) in 1 ml of DMF at room temperature. After 18 h at room temperature, the reaction mixture is diluted with a 1:1 mixture of acetonitrile and water and purified by preparative HPLC. The product fractions are concentrated, taken up in 1 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 14 mg (35.2% of theory) of the title compound are obtained.

(50) HPLC (Method 1): R.sub.t=3.70 ruin.

(51) LC-MS (Method 2): R.sub.t=2.45 min.; m/z=400 (M+H).sup.+.

EXAMPLE 4

(3R)N-{4-[(Ethylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride

(52) ##STR00024##

(53) 39.1 mg (0.30 mmol) of ethanesulfonyl chloride and 84.8 l (0.61 mmol) of triethylamine are added to a solution of 60 mg (0.15 mmol) of ((3R)N-(4-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at room temperature, the reaction mixture is purified by preparative HPLC. The product fractions are concentrated, mixed with 2 ml of a 1:1 mixture of acetonitrile and 1 N hydrochloric acid, again concentrated and dried under high vacuum. 26 mg (35.2% of theory) of the title compound are obtained.

(54) HPLC (Method 1): R.sub.t=3.71 min.

(55) MS (ESIpos): m/z=414 (M+H).sup.+.

EXAMPLE 5

(3R)N-{4-[(Phenylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride

(56) ##STR00025##

(57) A solution of 80 mg (0.20 mmol) of ((3R)N-(4-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 71.7 mg (0.41 mmol) of phenylsulfonyl chloride in 1.0 ml of pyridine is stirred at room temperature for 18 h. The reaction mixture is concentrated in vacuo and the residue is purified by preparative HPLC. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 52 mg (51.5% of theory) of the title compound are obtained.

(58) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =10.40 (s, 1H), 10.37 (s, 1H), 9.85 (br, s, 1H), 7.80 (m, 2H), 7.66 (m, 2H), 7.63-7.49 (m, 7H), 7.17 (m, 2H), 3.61 (dd, 1H), 3.43-3.17 (m, 5H), 3.11 (m, 1H), 2.41 (m, 1H), 1.92 (m, 2H), 1.73 (m, 2H).

(59) HPLC (Method 1): R.sub.t=4.05 min.

(60) MS (ESIpos): m/z=462 (M+H).sup.+.

EXAMPLE 6

(3R)N-{4-[(Benzylsulfonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride

(61) ##STR00026##

(62) A solution of 80 ing (0.20 mmol) of ((3R)N-(4-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 77.4 mg (0.41 mmol) of phenylmethanesulfonyl chloride in 1.0 ml of pyridine is stirred at room temperature for 18 h. The reaction mixture is concentrated in vacuo and the residue is purified by preparative HPLC. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 34 mg (32.7% of theory) of the title compound are obtained.

(63) HPLC (Method 1): R.sub.t=4.12 min.

(64) MS (ESIpos): m/z=476 (M+H).sup.+.

EXAMPLE 7

(3R)N-[4-(Aminosulfonyl)biphenyl-4-yl]quinuclidine-3-carboxamide hydrochloride

(65) ##STR00027##

(66) 213.5 mg (1.54 mmol) of potassium carbonate are added to a mixture, prepared under argon, of 216.3 mg (1.03 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 127.8 mg (0.51 mmol) of (4-amino-4-biphenyl)sulfonamide in 5.5 ml of a 10:1 mixture of dioxane and DMF. After 18 h at 100 C., a further 216.3 mg (1.03 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride are added. After a further 18 h at 100 C., the product is precipitated by adding acetonitrile/water (2:1). Drying under high vacuum results in 148 mg (71.9% of theory) of the title compound.

(67) .sup.1H-NMR (200 MHz, DMSO-d.sub.6): =10.06 (s, 1H), 7.92-7.80 (m, 4H), 7.79-7.68 (m, 4H), 7.39 (s, 2H), 3.22 (dd, 1H), 2.93-2.58 (m, 6H), 2.09 (m, 1H), 1.60 (m, 3H), 1.33 (m, 1H).

(68) HPLC (Method 1): R.sub.t=3.40 min.

(69) MS (ESIpos): m/z=386 (M+H).sup.+.

EXAMPLE 8

(3R)N-{4-[(Isopropylamino)sulfonyl]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride

(70) ##STR00028##

(71) 64.3 mg (0.46 mmol) of potassium carbonate are added to a mixture, prepared under argon, of 65.1 mg (0.31 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 45.0 ing (0.15 mmol) of 4-amino-N-isopropylbiphenyl-4-sulfonamide (Example 12A) in 2.2 ml of a 10:1 mixture of dioxane and DMF. After 18 h at 100 C., the reaction mixture is concentrated in vacua. The residue is dissolved in water and acetonitrile and purified by preparative HPLC. The product fractions are concentrated, mixed with 5 ml of a 2:1 mixture of acetonitrile and 1 N hydrochloric acid, again concentrated and dried under high vacuum. 21 mg (29.2% of theory) of the title compound are obtained.

(72) HPLC (Method 1): R.sub.t=3.93 min.

(73) MS (ESIpos): m/z=428 (M+H).sup.+.

EXAMPLE 9

(3R)N-{4-[(Benzylamino)sulfonyl]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride

(74) ##STR00029##

(75) 73.5 mg (0.60 mmol) of potassium carbonate are added to a mixture, prepared under argon, of 74.5 mg (0.35 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 60 mg (0.18 mmol) of 4-amino-N-benzylbiphenyl-4-sulfonamide (Example 10A) in 2.2 ml of a 10:1 mixture of dioxane and DMF. After 18 h at 100 C., a further 74.5 mg (0.35 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride are added. After a further 24 h at 100 C., the reaction mixture is concentrated in vacuo. The residue is dissolved in water and acetonitrile and purified by preparative HPLC. The product fractions are concentrated, mixed with 5 ml of a 2:1 mixture of acetonitrile and 1 N hydrochloric acid, again concentrated and dried under high vacuum. 64 mg (70.5% of theory) of the title compound are obtained.

(76) HPLC (Method 1): R.sub.t=4.17 min.

(77) MS (ESIpos): m/z=476 (M+H).sup.+.

EXAMPLE 10

(3R)N-(4-{[(Methylamino)carbonyl]amino}biphenyl-4-yl)quinuclidine-3-carboxamide

(78) ##STR00030##

(79) 17.4 mg (030 mmol) of methyl isocyanate and 84.8 l (0.61 mmol) of triethylamine are added to a solution of 60 mg (0.15 mmol) of ((3R)N-(4-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at room temperature, 5 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction, washed with water and dried under high vacuum. 47 mg (73.5% of theory) of the title compound are obtained.

(80) HPLC (Method 1): R.sub.t=3.44 min.

(81) MS (ESIpos): m/z=379 (M+H).sup.+.

EXAMPLE 11

(3R)N-(4-{[(Cyclopentylamino)carbonyl]amino}biphenyl-4-yl)quinuclidine-3-carboxamide hydrochloride

(82) ##STR00031##

(83) 33.8 mg (0.30 mmol) of cyclopentyl isocyanate and 84.8 l (0.61 mmol) of triethylamine are added to a solution of 60 mg (0.15 mmol) of ((3R)N-(4% aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at room temperature, 5 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction, washed with water and dried under high vacuum. A preparative HPLC is carried out for further purification. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 28 mg (39.2% of theory) of the title compound are obtained.

(84) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): =10.33 (s, 1H), 9.95 (s, 1H), 8.51 (s, 1H), 7.67 (m, 2H), 7.58 (m, 2H), 7.50 (m, 2H), 7.44 (m, 2H), 6.29 (br. S, 1H), 3.96 (m, 1H), 3.60 (m, 1H), 3.37 (m, 1H), 3.29-3.08 (m, 5H), 2.43 (m, 1H), 1.92 (m, 2H), 1.84 (m, 2H), 1.77 (m, 2H), 1.64 (m, 2H), 1.55 (m, 2H), 1.38 (m, 2H).

(85) HPLC (Method 1): R.sub.t=4.05 min.

(86) MS (ESIpos): m/z=433 (M+H).sup.+.

EXAMPLE 12

(3R)N-(4-{[(Ethylamino)carbonyl]amino}biphenyl-4-yl)quinuclidine-3-carboxamide

(87) ##STR00032##

(88) 21.6 mg (0.30 mmol) of ethyl isocyanate and 84.8 l (0.61 mmol) of triethylamine are added to a solution of 60 mg (0.15 mmol) of ((3R)N-(4-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at room temperature, 5 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction, washed with water and dried under high vacuum. 57 mg (88.0% of theory) of the title compound are obtained.

(89) HPLC (Method 1): R.sub.t=3.62 min.

(90) MS (ESIpos): m/z=393 (M+H).sup.+.

EXAMPLE 13

(3R)N-[4-({[(3-Methoxyphenyl)amino]carbonyl}amino)biphenyl-4-yl]quinuclidine-3-carboxamide hydrochloride

(91) ##STR00033##

(92) 45.4 mg (0.30 mmol) of 3-methoxyphenyl isocyanate and 84.8 l (0.61 mmol) of triethylamine are added to a solution of 60 mg (0.15 mmol) of ((3R)N-(4-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) in 0.5 ml of DMF. After 18 h at room temperature, 5 ml of water are added to the reaction mixture. The resulting precipitate is filtered off with suction, washed with water and dried under high vacuum. A preparative HPLC is carried out for further purification. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum, 22 mg (27.6% of theory) of the title compound are obtained.

(93) HPLC (Method 1): R.sub.t=4.19 min.

(94) MS (ESIpos): m/z=471 (M+H).sup.+.

EXAMPLE 14

(3R)N-{4-[(3-Chlorobenzoyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride

(95) ##STR00034##

(96) A solution of 50 mg (0.13 mmol) of ((3R)N-(4-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 44.4 mg (0.25 mmol) of 3-chlorobenzoyl chloride in 1.0 nil of pyridine is stirred at room temperature for 3 h. The reaction mixture is concentrated in vacuo, and the residue is purified by preparative HPLC. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 62 mg (98.5% of theory) of the title compound are obtained.

(97) HPLC (Method 1): R.sub.t=4.41 min.

(98) MS (ESIpos): m/z=460 (M+H).sup.+.

EXAMPLE 15

(3R)N-{4-[(3-Fluorobenzoyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride

(99) ##STR00035##

(100) A solution of 50 mg (0.13 mmol) of ((3R)N-(4-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 40.2 mg (0.25 mmol) of 3-fluorobenzoyl chloride in 1.0 ml of pyridine is stirred at room temperature for 3 h. The reaction mixture is concentrated in vacuo, and the residue is purified by preparative HPLC. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 48 mg (73.4% of theory) of the title compound are obtained.

(101) .sup.1H-NMR (200 MHz, DMSO-d.sub.6): =10.48 (s, 1H), 10.43 (s, 1H), 10.21 (br. s, 1H), 7.92-7.80 (m, 3H), 7.79-7.57 (m, 8H), 7.49 (m, 1H), 3.61 (m, 1H), 3.44-3.08 (m, 611), 2.46 (m, 1H), 1.92 (m, 2H), 1.75 (m, 2H).

(102) HPLC (Method 1): R.sub.t=4.21 min.

(103) MS (ESIpos): m/z=444 (M+H).sup.+.

EXAMPLE 16

(3R)N-{4-[(2-Methoxyacetyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride

(104) ##STR00036##

(105) A solution of 50 mg (0.13 mmol) of ((3R)N-(4-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 27.5 mg (0.25 mmol) of methoxyacetyl chloride in 1.0 ml of pyridine is stirred at room temperature for 18 h. The reaction mixture is mixed with 3 ml of DMSO and purified by preparative HPLC. The product fractions are concentrated, mixed with 5 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 16 mg (29.4% of theory) of the title compound are obtained.

(106) HPLC (Method 1): R.sub.t=3.63 min.

(107) MS (ESIpos): m/z=394 (M+H).sup.+.

EXAMPLE 17

(3R)N-{4-[(Cyclopentylcarbonyl)amino]biphenyl-4-yl}quinuclidine-3-carboxamide hydrochloride

(108) ##STR00037##

(109) A solution of 50 mg (0.13 mmol) of ((3R)N-(4-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 38.5 l (0.32 mmol) of cyclopentanecarbonyl chloride in 1.0 ml of pyridine is stirred at room temperature for 18 h. The reaction mixture is mixed with 3 ml of DMSO and purified by preparative HPLC. The product fractions are concentrated, mixed with 5 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 22 mg (38.2% of theory) of the title compound are obtained.

(110) HPLC (Method 1): R.sub.t=4.18 min.

(111) MS (ESIpos): m/z=418 (M+H).sup.+.