Macrocyclic urea derivatives as inhibitors of TAFIa, their preparation and their use as pharmaceuticals

Abstract

The present invention relates to macrocydic urea derivatives of the formula I (I) in which R1, R2, R3, V and Y are as defined below. The compounds of the formula I are inhibitors of the enzyme TAFIa (activated thrombin-activatable fibrinolysis inhibitor). The invention further relates to the process for the preparation of the compounds of formula I and to the use thereof as medicaments. ##STR00001##

Claims

1. A compound of the formula I, ##STR00048## in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, wherein V is —(CH.sub.2).sub.4; Y is a covalent bond or phenyl, optionally substituted by one, two or three R15 groups; R1 is —(C.sub.1-C.sub.6)-alkyl R2 is methyl; R3 is Het substituted by —NH.sub.2, or (C.sub.4-C.sub.8)-cycloalkyl substituted by —NH.sub.2, wherein Het is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl and thiophenyl, bonded via a ring carbon atom to the methylene group to which R3 is attached, and wherein Het and —(C.sub.4-C.sub.8)-cycloalkyl are optionally substituted by one, two or three R15 groups; and each R15 group is independently —(C.sub.1-C.sub.4)-alkyl, —O—CF.sub.3, —NH.sub.2, —OH, —CF.sub.3 or halogen.

2. The compound of claim 1, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, wherein V is —(CH.sub.2).sub.4; Y is a covalent bond or phenyl; R1 is isopropyl; R2 is methyl; and R3 is Het substituted by —NH.sub.2, or —(C.sub.4-C.sub.8)-cycloalkyl substituted by —NH.sub.2, wherein Het is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl and thiophenyl, bonded via a ring carbon atom to the methylene group to which R3 is attached.

3. The compound of claim 1, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, wherein V is —(CH.sub.2).sub.4—; Y is a covalent bond or phenyl; R1 is isopropyl; R2 is methyl; and R3 is pyridinyl substituted by —NH.sub.2, cyclobutyl substituted by —NH.sub.2, or cyclopentyl substituted by —NH.sub.2.

4. The compound of claim 1 having the structure of formula II, ##STR00049## in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is: (S)-3-(6-Amino-pyridin-3-yl)-2-[3-((9 S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid; (S)-3-(3-Amino-cyclobutyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid; (S)-3-((1R,3R)-3-Amino-cyclopentyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid; or (S)-3-(6-Amino-pyridin-3-yl)-2-[3-((3 S,6R)-3-isopropyl-5-oxo-1,8-dioxa-4-aza-cyclododec-6-yl)-ureido]-2-methyl-propionic acid.

6. A pharmaceutical composition, comprising a compound of claim 1, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. A method for preparing a compound of claim 1, the method comprising: reacting a compound of formula XVI: ##STR00050## with a compound of formula VII: ##STR00051## to provide a compound of claim 1, wherein V is —(CH.sub.2).sub.4—; Y is a covalent bond or phenyl, optionally substituted by one, two or three R15 groups; R1 is —(C.sub.1-C.sub.6)-alkyl; R2 is methyl; R3 is Het substituted by —NH.sub.2, or —(C.sub.4-C.sub.8)-cycloalkyl substituted by —NH.sub.2, wherein Het is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl and thiophenyl, wherein each group is bonded via a ring carbon atom to the methylene group to which R3 is attached, and wherein Het and —(C.sub.4-C.sub.8)-cycloalkyl are optionally substituted by one, two or three R15 groups; each R15 group is independently —(C.sub.1-C.sub.4)alkyl, —OCF.sub.3, —NH.sub.2, —OH, —CF.sub.3 or halogen; and PG is an ester protective group.

8. The method of claim 7, further comprising preparing the compound of formula XVI: ##STR00052## the method comprising: reacting a compound of formula XV: ##STR00053## with an azide source to provide a compound of formula XVI, wherein R2 is methyl; R3 is Het substituted by —NH.sub.2, or —(C.sub.4-C.sub.8)-cycloalkyl substituted by —NH.sub.2, wherein Het is selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl and thiophenyl, wherein each group is bonded via a ring carbon atom to the methylene group to which R3 is attached, and wherein Het and —(C.sub.4-C.sub.8)-cycloalkyl are optionally substituted by one, two or three R15 groups; each R15 group is independently —(C.sub.1-C.sub.4)alkyl, —OCF.sub.3, —NH.sub.2, —OH, —CF.sub.3 or halogen; and PG is an ester protective group.

9. A pharmaceutical composition comprising a compound of claim 1 and an antithrombotic, thrombolytic or other substance having profibrinolytic activity.

Description

EXPERIMENTAL PART

List of Abbreviations

(1) DIPEA N,N-diisopropylethylamine

(2) DMF Dimethylformamide

(3) LiHMDS Lithium bis(trimethylsilyl)amide

(4) min Minute(s)

(5) R.sub.t Retention time

(6) RT Room temperature

(7) TFA Trifluoroacetic acid

(8) THF Tetrahydrofuran

(9) Final products were normally determined by mass spectroscopic methods (FAB-, ESI-MS) and .sup.1H-NMR; the main peak or two main peaks were indicated in each case. Temperatures are stated in degrees Celsius, RT means room temperature (21° C. to 24° C.). Abbreviations used are either explained or correspond to usual conventions.

(10) Unless stated otherwise, the LC-MS analyses were carried under the following conditions:

(11) Method A: column: YMC Jsphere ODS H80 20×2.1 mm, packing material 4 μm, mobile phase: CH.sub.3CN+0.05% trifluoroacetic acid (TFA): H.sub.2O+0.05% TFA, gradient: 4:96 (0 min) to 95:5 (2.0 min), flow rate: 1 ml/min, temperature: 30° C.

(12) Method B: column: Luna C18 10×2 mm, packing material 3 μm, mobile phase: CH.sub.3CN+0.05% trifluoroacetic acid (TFA): H.sub.2O+0.05% TFA, gradient: 7:93 (0 min) to 95:5 (1.2 min), flow rate: 1.1 ml/min, temperature: 30° C.

(13) Method C: column: Waters UPLC BEH C18 50×2.1 mm, packing material 1.7 μm, mobile phase: CH.sub.3CN+0.08% formic acid (FA): H.sub.2O+0.1% FA, gradient: 5:95 (0 min) to 95:5 (1.1 min), flow rate: 0.9 ml/min, temperature: 55° C.

(14) Unless indicated otherwise, chromatographic separations were carried out on silica gel with ethyl acetate/heptane mixtures as mobile phase, and preparative separations on reversed phase (RP) silica gel (HPLC) with trifluoroacetic acid-containing water/acetonitrile mixtures as mobile phase.

(15) Solvents were evaporated off usually under reduced pressure at 35° C. to 45° C.

Example 1

(S)-3-(6-Amino-pyridin-3-yl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid

(16) ##STR00014##

A. (R)-2-(6-tert-Butoxycarbonylamino-pyridin-3-ylmethyl)-2-methyl-malonic acid tert-butyl ester ethyl ester (A compound of formula XIV)

(17) ##STR00015##

(18) 60.0 g (297 mmol) 2-Methyl-malonic acid tert-butyl ester ethyl ester (compound of formula XIII) were dissolved in 800 ml THF. To this solution were added 297 ml (297 mmol) LiHMDS (1 M solution in methyl tert-butyl ether) with water bath cooling. After 30 minutes 66.6 g (275 mmol) (5-Chloromethyl-pyridin-2-yl)-carbamic acid tert-butyl ester were added in portions and the mixture was stirred for 90 minutes at RT. The mixture was added to 800 ml water and aqueous NH.sub.4Cl-solution. The solvents were removed and the resulting solid was filtered and air-dried to yield the crude product in quantitative yield.

(19) LC/MS (method A): R.sub.t=1.74 min, m/z: 409.20 [Mh.sup.+].

(20) The crude product was submitted to chiral preparative HPLC (AD-H-30, 250×30 mm, EtOH/MeOH 1:1, 24 ml/min) to yield 40 g (33% yield) of the chiral diester.

(21) Chiral HPLC: (Chiralpak AD-H/39 (250×4.6 mm), EtOH/MeOH 1:1, 30° C., 1 ml/min): R.sub.t=4.31 min.

B. (R)-2-(6-tert-Butoxycarbonylamino-pyridin-3-ylmethyl)-2-methyl-malonic acid mono tert-butyl (A compound of formula XV)

(22) ##STR00016##

(23) 40 g (98 mmol) (R)-2-(6-tert-Butoxycarbonylamino-pyridin-3-ylmethyl)-2-methyl-malonic acid tert-butyl ester ethyl ester (compound from step A) were dissolved in 560 ml THF and 200 ml MeOH. To this solution were added 25 g (0.59 mol) LiOH×H.sub.2O in 210 ml water and the mixture was stirred for 14 hours at 30° C. The pH was adjusted to 3 by addition of aqueous NaHSO.sub.4, the organic solvents were removed and the solid was filtered and air-dried to yield the acid in quantitative yield.

(24) LC/MS (method A): R.sub.t=1.39 min, m/z: 381.20 [MH.sup.+], 325.10 [MH.sup.+-tBu].

C. (S)-3-(6-tert-Butoxycarbonylamino-pyridin-3-yl)-2-isocyanato-2-methyl-propionic acid tert-butyl ester (A compound of formula XVI)

(25) ##STR00017##

(26) 30.3 g (79.7 mmol) of the acid from step B and 17.1 ml (95.7 mmol) N,N-diisopropyl ethyl amine were dissolved in 300 ml MeCN and heated to 70° C. 17.3 ml (79.7 mmol) diphenylphosphoryl azide were slowly added and the mixture was stirred for 4 hours at 70° C. The obtained isocyanate-solution was directly used in the next step.

(27) LC/MS (method A): R.sub.t=1.76 min, m/z: 378.20 [MH.sup.+], 322.10 [MH.sup.+-tBu].

D. (S)-3-(6-tert-Butoxycarbonylamino-pyridin-3-yl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid tert-butyl ester (A compound of formula XII)

(28) ##STR00018##

(29) To the isocyanate-solution (from step C) were added 25.6 g (79.7 mmol) of (9S,12R)-12-Amino-9-isopropyl-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-11-one (A compound of formula VII) at 45° C. and the mixture was stirred for 18 hours at 45° C. After cooling to RT, 150 ml phosphate buffer (pH 7) were added and the solvent was removed. The product was extracted twice with ethylacetate. The combined organic layers were successively washed with aqueous NaHSO.sub.4, aqueous NaHCO.sub.3 and brine, dried with MgSO.sub.4 and concentrated. 47.6 g (86% yield) of the urea were obtained after crystallisation from methyl tert-butyl ether.

(30) LC/MS (method A): R.sub.t=1.66 min, m/z: 698.40 [MH.sup.+].

E (S)-3-(6-Amino-pyridin-3-yl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid (A compound of formula II)

(31) ##STR00019##

(32) 47.6 g (68.2 mmol) of (S)-3-(6-tert-Butoxycarbonylamino-pyridin-3-yl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid tert-butyl ester (Compound from step D) were dissolved in 250 ml THF and treated with 350 ml half concentrated aqueous HCl. The mixture was stirred for 6 hours at 45° C. After stirring the mixture was concentrated and the residue was distilled twice with 400 ml water. The crude product was dissolved in acetone/water and 68.2 ml (136 mmol) of aqueous sodium hydroxide were added. The solvent was removed and the residue was filtered over 540 g SPE-column (Supelco Dianion HP-20SS, water, water/acetone). The product was concentrated and crystallised from acetone/water to yield 18.5 g (48% yield) of the title compound as a sodium salt.

(33) LC/MS (method A): R.sub.t=1.14 min, m/z: 542.30 [MH.sup.+].

(34) .sup.1H-NMR (DMSO-d6, 400 MHz) δ[ppm]=0.68 (d, 3H), 0.73 (d, 3H), 1.36 (s, 3H), 1.38-1.71 (m, 5H), 2.62-2.71 (m, 2H), 2.79 (dd, 1H), 2.86 (d, 1H), 3.01 (dd, 1H), 3.15 (d, 1H); 3.19-3.35 (m, 3H, signal overlaid by water), 4.14-4.29 (m, 3H), 5.52 (bs, 2H), 6.13 (d, 1H), 6.28 (d, 1H), 6.47 (d, 1H), 6.66 (s, 3H), 6.81-6.89 (m, 3H), 7.13-7.20 (m, 2H), 7.65 (d, 1H).

Example 2

(35) (S)-3-trans-(3-Amino-cyclobutyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid

(36) ##STR00020##

A. (S)-2-(Benzhydrylidene-amino)-propionic acid tert-butyl ester

(37) ##STR00021##

(38) 13.81 g (76 mmol) L-Alanine-tert-butyl ester hydrochloride were dissolved in 50 ml dichloromethane. 13.78 g (76 mmol) Benzophenon imine were added. The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and dichloromethane. The organic phase was washed with brine, dried over anhydrous MgSO.sub.4 and concentrated under vacuum to give crude (S)-2-(benzhydrylidene-amino)-propionic acid tert-butyl ester in quantitative yield.

(39) LC/MS (method B): R.sub.t=0.75 min, m/z: 310.3 [MH.sup.+].

B. Tert-Butyl trans-3-iodomethyl-cyclobutyl-carbamate

(40) ##STR00022##

(41) To a solution of 8.0 g (39.8 mmol) tert-Butyl trans-3-hydroxymethyl-cyclobutyl-carbamate in 150 ml dichloromethane were added at 0° C. 2.98 g (43.7 mmol) imidazole, 11.47 g (43.7 mmol) triphenylphosphine and 11.1 g (43.7 mmol) iodine. After stirring for 1 hour at 0° C. the reaction mixture was concentrated under vacuum. The resulting residue was purified by flash chromatography using a n-heptane/ethylacetate eluent to give 10.3 g pure tert-Butyl trans-3-iodomethyl-cyclobutyl-carbamate (84% yield).

(42) The material was used in the next step without further characterization.

C. (S)-2-(Benzhydrylidene-amino)-3-trans-(3-tert-butoxycarbonylamino-cyclobutyl)-2-methyl-propionic acid tert-butyl ester (A compound of formula XI)

(43) ##STR00023##

(44) 5.7 g (18.4 mmol) (S)-2-(Benzhydrylidene-amino)-propionic acid tert-butyl ester (compound of step A) were dissolved in 45 ml THF. At 0° C. under argon atmosphere 13.8 ml of a 2 M NaHMDS-solution (27.6 mmol) in THF were added dropwise. After 30 minutes a solution of 6.01 g (19.3 mmol) tert-butyl-trans-3-iodomethyl-cyclobutyl-carbamate (compound of step B) in 20 ml THF were added within 10 minutes. The reaction mixture was stirred for 3 hours at room temperature and then quenched with 50 ml of a saturated NH.sub.4Cl solution. The resulting mixture was extracted twice with 200 ml ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purification by flash chromatography using a n-heptane/ethyl acetate eluent gave 1.7 g pure 2-(benzhydrylidene-amino)-3-trans-(3-tert-butoxycarbonylamino-cyclobutyl)-2-methyl-propionic acid tert-butyl ester as racemate. Further chromatography using a chiral stationary phase (Chiralpak IC 250×30 mm 5μ) and CO.sub.2/Isopropanol as a mobile phase gave 450 mg of pure (S)-2-(benzhydrylidene-amino)-3-trans-(3-tert-butoxycarbonylamino-cyclobutyl)-2-methyl-propionic acid tert-butyl ester.

(45) LC/MS (method B): R.sub.t=0.93 min, m/z: 493.2 [MH.sup.+].

D. (S)-2-Amino-3-trans-(3-tert-butoxycarbonylamino-cyclobutyl)-2-methyl-propionic acid tert-butyl ester (A compound of formula VIII)

(46) ##STR00024##

(47) 380 mg (0.77 mmol) (S)-2-(benzhydrylidene-amino)-3-trans-(3-tert-butoxycarbonylamino-cyclobutyl)-2-methyl-propionic acid tert-butyl ester (Compound of step C) were dissolved in 30 ml methanol. Under Argon 125 mg palladium on charcoal (10%) were added. The argon atmosphere was replaced by hydrogen and the resulting mixture was stirred for 4 hours at room temperature. The reaction mixture was filtered over celite and concentrated under reduced pressure to give 250 mg of crude (S)-2-amino-3-trans-(3-tert-butoxycarbonylamino-cyclobutyl)-2-methyl-propionic acid tert-butyl ester ester as yellow oil (99% yield).

(48) LC/MS (method B): R.sub.t=0.68 min, m/z: 329.2 [MH.sup.+].

E (S)-3-trans-(3-tert-Butoxycarbonylamino-cyclobutyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid tert-butyl ester (A compound of formula XII)

(49) ##STR00025##

(50) 250 mg (0.76 mmol) crude (S)-2-amino-3-trans-(3-tert-butoxycarbonylamino-cyclobutyl)-2-methyl-propionic acid tert-butyl ester ester (Compound of step D) were dissolved in 6 ml DMF. 129 μl (0.76 mmol) N,N-diisopropylethylamine (DIPEA) were added. At 0° C. 123 mg (0.76 mmol) 1,1′-carbonyldiimidazole (CU) were added and the resulting mixture was stirred for 30 min. Then a solution of 244 mg (0.76 mmol) (9S,12R)-12-Amino-9-isopropyl-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-11-one (A compound of formula VII) in 2 ml DMF were added dropwise. After stirring for 1 hour at 0° C. and 10 hours at room temperature the mixture was concentrated under reduced pressure and purified by preparative RP-HPLC (CH.sub.3CN/H.sub.2O gradient+0.1% TFA). 115 mg (S)-3-trans-(3-tert-butoxycarbonylamino-cyclobutyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid tert-butyl ester (22% yield) were obtained.

(51) LC/MS (method B): R.sub.t=1.07 min, m/z: 675.3 [MH.sup.+].

F (S)-3-trans-(3-Amino-cyclobutyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid (A compound of formula II)

(52) ##STR00026##

(53) 115 mg (170 μmol) (S)-3-trans-(3-tert-butoxycarbonylamino-cyclobutyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid tert-butyl ester (Compound of step E) were dissolved in a mixture of 9.5 ml TFA, 0.25 ml H.sub.2O and 0.25 ml triisopropyl-silane and stirred for 2 hours at room temperature. The mixture was concentrated under reduced pressure and purified by preparative RP-HPLC (CH.sub.3CN/H.sub.2O gradient+0.1% TFA) to give 86 mg pure (S)-3-trans-(3-amino-cyclobutyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid as trifluoroacetate in form of a colorless amorphous material (80% yield).

(54) LC/MS (method B): R.sub.t=0.62 min, m/z: 519.3 [MH.sup.+].

(55) .sup.1H-NMR (DMSO-d6, 400 MHz) δ[ppm]=12.80 (1H, s, br), 7.90 (3H, s, br), 7.22 (1H, d), 6.91 (3H, m), 6.61 (1H, s), 6.39 (1H, d), 5.87 (1H, d), 4.29 (1H, m), 4.20 (2H, m), 3.69 (1H, m), 3.25 (4H, t), 3.08-3.15 (1H, dd), 2.80-2.91 (2H, dd), 2.60 (1H, dd), 2.18-2.28 (1H, m), 1.95-2.19 (4H, m), 1.92 (1H, m), 1.69 (1H, m), 1.49-1.62 (3H, m) 1.38 (3H, s), 0.73 (3H, d), 0.70 (3H, d).

Example 3

(S)-3-((1R,3R)-3-Amino-cyclopentyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid

(56) ##STR00027##

A. ((1S,3S)-3-Hydroxymethyl-cyclopentyl)-carbamic acid tert-butyl ester

(57) ##STR00028##

(58) 5.0 g (20.55 mmol) (1S,3S)-3-tert-Butoxycarbonylamino-cyclopentanecarboxylic acid methyl ester were dissolved in 15 ml THF. Under argon atmosphere 3.3 g (82.2 mmol) LiAIH.sub.4 were added portionwise at 0° C. The resulting mixture was stirred for 2 hours and then carefully quenched with water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and concentrated under reduced pressure to give crude 4.25 g ((1S,3S)-3-Hydroxymethyl-cyclopentyl)-carbamic acid tert-butyl ester (97% yield).

(59) The material was used in the next step without further characterization.

B. ((1S,3S)-3-Iodomethyl-cyclopentyl)-carbamic acid tert-butyl ester

(60) ##STR00029##

(61) To a solution of 2.1 g (9.7 mmol) tert((1S,3S)-3-Hydroxymethyl-cyclopentyl)-carbamic acid tert-butyl ester (Compound from step A) in 40 ml dichloromethane were added at 0° C. 724 mg (10.6 mmol) imidazole, 2.8 g (10.6 mmol) triphenylphosphine and 2.7 g (10.6 mmol) iodine. After stirring for 1 hour at 0° C. the reaction mixture was concentrated under vacuum. The resulting residue was purified by flash chromatography using a n-heptane/ethylacetate eluent to give 2.4 g pure ((1S,3S)-3-Iodomethyl-cyclopentyl)-carbamic acid tert-butyl ester (75% yield).

(62) The material was used in the next step without further characterization.

C. (RS)-2-(Benzhydrylidene-amino)-3-((1R,3R)-3-tert-butoxycarbonylaminocyclopentyl)-2-methyl-propionic acid tert-butyl ester (A compound of formula XI)

(63) ##STR00030##

(64) 1.0 g (3.2 mmol) (S)-2-(Benzhydrylidene-amino)-propionic acid tert-butyl ester (Compound from example 2, step A) were dissolved in 20 ml THF. At 0° C. under argon atmosphere 2.4 ml of 2 M NaHMDS-solution (4.8 mmol) in THF were added within 10 minutes. After 30 minutes 1.1 g (3.4 mmol) ((1S,3S)-3-Iodomethyl-cyclopentyl)-carbamic acid tert-butyl ester (Compound from step B) in 5 ml THF were added slowly. The reaction mixture was stirred for 4 hours at room temperature and then quenched with 10 ml of a saturated NH.sub.4Cl solution. The resulting mixture was extracted twice with 50 ml ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purification by flash chromatography using a n-heptane/ethyl acetate eluent gave 1.3 g 2-(benzhydrylidene-amino)-3-((1R,3R)-3-tert-butoxycarbonylaminocyclopentyl)-2-methyl-propionic acid tert-butyl ester as racemate (80% yield).

(65) LC/MS (method B): R.sub.t=0.93 min, m/z: 507.20 [MH.sup.+].

D (RS)-2-Amino-3-((1R,3R)-3-tert-butoxycarbonylamino-cyclopentyl)-2-methyl-propionic acid tert-butyl ester (A compound of formula VIII)

(66) ##STR00031##

(67) 1.28 g (2.5 mmol) racemic 2-(benzhydrylidene-amino)-3-((1R,3R)-3-tert-butoxycarbonylaminocyclopentyl)-2-methyl-propionic acid tert-butyl ester (Compound of step C) were dissolved in 100 ml methanol. Under Argon 670 mg palladium on charcoal (10%) were added. The argon atmosphere was replaced by hydrogen and the resulting mixture was stirred for 24 hours at room temperature. After filtration of the catalyst 670 mg fresh palladium on charcoal were added and the reaction mixture was stirred for another 4 hours under a hydrogen atmosphere. The reaction mixture was filtered over celite and concentrated under reduced pressure. The resulting residue was purified by flash chromatography using a n-heptane/ethyl acetate eluent (addition of 1% triethyl amine) to give 312 mg of racemic 2-amino-3-((1R,3R)-3-tert-butoxycarbonylamino-cyclopentyl)-2-methyl-propionic acid tert-butyl ester (36% yield).

(68) LC/MS (method B): R.sub.t=0.68 min, m/z: 343.2 [MH.sup.+].

E (RS)-3-((1R,3R)-3-tert-Butoxycarbonylamino-cyclopentyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid tert-butyl ester (A compound of formula XII)

(69) ##STR00032##

(70) 100 mg (0.31 mmol) (9S,12R)-12-Amino-9-isopropyl-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-11-one (A compound of formula VII) were dissolved in 3 ml DMF. 53 μl (0.31 mmol) DIPEA were added. At 0° C. 50.6 mg (0.31 mmol) 1,1′-carbonyldiimidazole (CU) were added and the resulting mixture was stirred for 30 minutes. Then a solution of 107 mg (0.31 mmol) racemic 2-amino-3-((1R,3R)-3-tert-butoxycarbonylamino-cyclopentyl)-2-methyl-propionic acid tert-butyl ester (Compound from step D) 53 μl (0.31 mmol) N,N-diisopropylethylamine (DIPEA) in 1 ml DMF were added dropwise. After stirring for 1 hour at 0° C. and 1 hour at room temperature the mixture was concentrated under reduced pressure and purified by preparative HPLC (CH.sub.3CN/H.sub.2O gradient+0.1% TFA). 44 mg of racemic 3-((1R,3R)-3-tert-Butoxycarbonylamino-cyclopentyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid tert-butyl ester (20% yield) were obtained.

(71) LC/MS (method B): R.sub.t=1.10 min, m/z: 689.3 [MH.sup.+].

F (S)-3-((1R,3R)-3-Amino-cyclopentyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid (A compound of formula II)

(72) ##STR00033##

(73) 44 mg (63.1 μmol) of racemic 3-((1R,3R)-3-tert-butoxycarbonylamino-cyclopentyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid tert-butyl ester (Compound of step E) were dissolved in a mixture of 0.5 ml TFA, 15 μl H.sub.2O and 15 μl triisopropyl-silane and stirred for 1 hour at room temperature. The mixture was purified by preparative RP-HPLC (CH.sub.3CN/H.sub.2O gradient+0.1% TFA) to give 32 mg pure racemic (S)-3-((1R,3R)-3-Amino-cyclopentyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid. The diastereomers were separated by using a chiral stationary phase (Chiralpak IC 250×20 mm) and a mixture of heptane/ethanol/methanol (5:1:1, conditioned with N,N-diethylamine) as mobile phase. Accordingly, 8.5 mg of pure (S)-3-((1R,3R)-3-Amino-cyclopentyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-aza-bicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)-ureido]-2-methyl-propionic acid were obtained as colorless amorphous material (25% yield).

(74) LC/MS (method B): R.sub.t=0.64 min, m/z: 533.3 [MH.sup.+].

Example 4

(S)-3-(6-Amino-pyridin-3-yl)-2-[3-((3S,6R)-3-isopropyl-5-oxo-1,8-dioxa-4-aza-cyclododec-6-yl)-ureido]-2-methyl-propionic acid

(75) ##STR00034##

A. 2-(Benzhydrylidene-amino)-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-methyl-propionic acid tert-butyl ester ester (A compound of formula XI)

(76) ##STR00035##

(77) A solution of 3.35 g (10.83 mmol) (S)-2-(Benzhydrylidene-amino)-propionic acid tert-butyl ester (Compound from example 2, step A) in 25 mL DMF was cooled to 0° C. under Argon atmosphere, 8.13 mL NaHMDS (2M in THF, 16.25 mmol) were slowly added and the mixture was stirred for 30 min. A solution of 3.11 g (10.83 mmol) (5-Bromoethyl-pyridin-2-yl)-carbamic acid tert-butyl ester in 15 mL DMF was added dropwise and the mixture was allowed to warm to room temperature. After 5 hours the reaction was quenched with NH.sub.4Cl-solution, ethyl acetate was added and the layers were separated. The organic layer was washed with NaCl-solution, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using n-heptane/ethyl acetate as an eluent to give 1.09 g (19% yield) of the title compound.

(78) LC/MS (method B): R.sub.t=1.01 min, m/z: 516.3 [MH.sup.+].

B. 2-Amino-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-methyl-propionic acid tert-butyl ester ester (A compound of formula VIII)

(79) ##STR00036##

(80) To a solution of 680 mg (1.32 mmol) 2-(Benzhydrylidene-amino)-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-methyl-propionic acid tert-butyl ester (Compound from step A) in 120 mL ethyl acetate were added 67 mg Pd/C (10%) and the mixture was hydrogenated at 2 bar H.sub.2 at room temperature. After stirring overnight, 100 mL MeOH were added together with another portion of 67 mg 10% Pd/C and the was hydrogenation repeated. After one day, the catalyst was filtered off and the solution concentrated under reduced pressure. The residue was purified by prep. HPLC to give 358 mg (58% yield) of the desired compound.

(81) LC/MS (method B): R.sub.t=0.65 min, m/z: 352.3 [MH.sup.+].

C. (S)-2-Amino-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-methyl-propionic acid tert-butyl ester (A compound of formula VIII)

(82) ##STR00037##

(83) 12.5 g of racemic 2-Amino-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-methyl-propionic acid tert-butyl ester were separated into its enantiomers using Chiralcel OD-H as a stationary phase and n-heptane/ethanol with 0.1% diethylamine as mobile phase to give 5.5 g (44% yield) of the desired material.

D. (S)-3-(6-tert-Butoxycarbonylamino-pyridin-3-yl)-2-[3-((3S,6R)-3-isopropyl-5-oxo-1,8-dioxa-4-aza-cyclododec-6-yl)-ureido]-2-methyl-propionic acid tert-butyl ester (A compound of formula XII)

(84) ##STR00038##

(85) 0.358 g (1.018 mmol) (S)-2-Amino-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-2-methyl-propionic acid tert-butyl ester (Compound form step C) were added to a solution of 0.165 g (1.018 mmol) 1,1′-Carbonyldiimidazole in 16 mL DMF and stirred at RT under Argon. A solution of 0.481 g (1.018 mmol) (3R,6R)-6-Amino-3-isopropyl-1,8-dioxa-4-aza-cyclododecan-5-one-trifluoroacetate and 0.376 mL (2.036 mmol) N,N-diisopropyl ethyl amine in 16 mL DMF was added and stirred overnight at RT under Argon. The solvent was evaporated and the residue purified by prep. HPLC to yield 0.218 g (35% yield) of the desired product.

(86) LC/MS (method B): R.sub.t=0.84 min, m/z: 622.45 [MH.sup.+].

E. (S)-3-(6-Amino-pyridin-3-yl)-2-[3-((3S,6R)-3-isopropyl-5-oxo-1,8-dioxa-4-aza-cyclododec-6-yl)-ureido]-2-methyl-propionic acid (A compound of formula II)

(87) ##STR00039##

(88) A solution of 0.218 g (0.3 mmol) (S)-3-(6-tert-Butoxycarbonylamino-pyridin-3-yl)-2-[3-((3S,6R)-3-isopropyl-5-oxo-1,8-dioxa-4-aza-cyclododec-6-yl)-ureido]-2-methyl-propionic acid tert-butyl ester (Compound from step D) was dissolved in 6 mL DCM/TFA (1:1, v/v) and stirred for 3 hours at RT. Upon evaporation, the residue was taken up in 1N HCl and freeze dried to give 0.148 g of the title compound as hydrochloride salt (99% yield).

(89) LC/MS (method C): R.sub.t=0.73 min, m/z: 465.3 [MH.sup.+]

(90) .sup.1H-NMR (DMSO-d6, 400 MHz) δ[ppm]=8.00 (2H, s, br), 7.70-7.58 (2H, m), 7.18 (d, 1H), 6.91 (d, 1H), 6.60-6.56 (m, 2H), 4.07 (t, 1H), 3.72-3.29 (m, 10H), 3.11 (dd, 2H), 1.78 (m, 1H), 1.67 (m, 2H), 1.51 (m, 1H), 1.28 (s, 3H), 0.86 (d, 3H), 0.80 (d, 3H).

(91) The table below illustrates the chemical structures of some examples of the compounds of formula I according to the invention.

(92) TABLE-US-00001 TABLE 1 Example Chemical name Formula 1 (S)-3-(6-Amino-pyridin-3-yl)- 2-[3-((9S,12R)-9-isopropyl- 11-oxo-2,7-dioxa-10-aza- bicyclo[12.2.2]octadeca- 1(17),14(18),15-trien-12-yl)- ureido]-2-methyl-propionic acid 0 2 (S)-3-(3-Amino-cyclobutyl)- 2-[3-((9S,12R)-9-isopropyl- 11-oxo-2,7-dioxa-10-aza bicyclo[12.2.2]octadeca- 1(17),14(18),15-trien-12-yl)- ureido]-2-methyl-propionic acid 3 (S)-3-((1R,3R)-3-Amino- cyclopentyl)-2-[3-((9S,12R)- 9-isopropyl-11-oxo-2,7- dioxa-10-aza- bicyclo[12.2.2]octadeca- 1(17),14(18),15-trien-12-yl)- ureido]-2-methyl-propionic acid 4 (S)-3-(6-Amino-pyridin-3-yl)- 2-[3-((3S,6R)-3-isopropyl-5- oxo-1,8-dioxa-4-aza- cyclododec-6-yl)-ureido]-2- methyl-propionic acid

Pharmacological Examples

Pharmacological Example 1

TAFIa Inhibition

(93) The prepared substances were tested for TAFIa inhibition using the Actichrome plasma TAFI Activity Kit from American Diagnostica (Pr. No. 874). This entailed adding 28 μl of assay buffer (20 mM Hepes, 150 mM NaCl, pH 7.4) and 10 μl of TAFIa (American Diagnostica Pr. No. 874TAFIA; 2.5 μg/ml) to 2 μl of 2.5 mM DMSO solution of the substance and incubating in a 96 half-well microtiter plate at room temperature for 15 minutes. The enzyme reaction was started by adding 10 μl of TAFIa developer (prediluted 1:2 with assay buffer). The time course of the reaction was followed at 420 nm in a microtiter plate reader (SpectraMax plus 384; Molecular Devices) for 15 minutes.

(94) The IC.sub.50 values were calculated from the averaged values (duplicate determination) of serial dilutions of the substance with the aid of the Softmax Pro software (version 4.8; Molecular Devices).

(95) TABLE-US-00002 TABLE 2 IC.sub.50 values for the example compounds and comparision examples according to WO2009146802 IC.sub.50 of Comparison Example examples No. IC.sub.50 [μM] [μM] Structures of comparision examples 1 0.0003 0.009 (Example 5-2 of WO2009146802) 2 0.0003 0.004 3 0.001  — — 4 0.001  0.055

(96) The comparison examples can be prepared as described in WO2009146802 or via similar processes.

(97) It is apparent that the compounds of formula I according to the invention have a strong inhibitory activity for the enzyme TAFIa. Additionally, table 2 shows that the compounds of formula I according to the invention show surprisingly a significantly higher activity as TAFIa inhibitors than the compounds described in WO2009146802.

(98) Furthermore, it was surprisingly found that compounds of formula I show in contrast to TAFIa inhibitors described in WO2009146802 a time dependent IC.sub.50 and therefore a slow tight-binding mechanism (longer residence time) which can result in a favourable longer duration of action. Pharmacological example 2 and Table 3 exemplify this observation.

Pharmacological Example 2

TAFIa Inhibition at Variable Perincubation Times

(99) The prepared substances were tested for TAFIa inhibition using the Actichrome plasma TAFI Activity Kit from American Diagnostica (Pr. No. 874). This entailed adding 28 μl of assay buffer (20 mM Hepes, 150 mM NaCl, pH 7.4) and 10 μl of TAFIa (American Diagnostica Pr. No. 874TAFIA; 2.5 μg/ml) to 2 μl of 2.5 mM DMSO solution of the substance and incubating in a 96 half-well microtiter plate at room temperature for variable pre-incubation times (0, 5, 15 and 30 minutes). The enzyme reaction was started by adding 10 μl of TAFIa developer (prediluted 1:2 with assay buffer). The time course of the reaction was followed at 420 nm in a microtiter plate reader (SpectraMax plus 384; Molecular Devices) for 15 minutes.

(100) The IC.sub.50 values were calculated from the averaged values (duplicate determination) of serial dilutions of the substance with the aid of the Softmax Pro software (version 4.8; Molecular Devices). The coefficient of IC.sub.50 values was determined by IC.sub.50 value at 0 min over IC.sub.50 value at x minutes, wherein x can be 0, 5, 15 or 30 minutes of pre-incubation time.

(101) TABLE-US-00003 TABLE 3 Coefficient of IC.sub.50s (IC.sub.50 value at 0 min/IC.sub.50 value at x min preincubation time) for example 2 and its comparison example from WO2009146802.                         Pre-incubation                         Example 2 time [min] Coefficient Coefficient  0 1   1    5 2.9 0.5 15 5.8 1.3 30 7.7 1  

(102) At the pre-incubation time of 0 minutes the coefficient for example 2 and the comparison compound according to WO1009146802 are similar. With increasing pre-incubation time the two compounds show a different behaviour. For compound 2 the coefficient increases. For the comparison compound the coefficient stays nearly constant in time. This shows the time dependent inhibitor activity of the compounds of formula I in contrast to the compounds according to WO1009146802 and therefore a slow tight-binding mechanism (longer residence time) which can result in a favourable longer duration of action of the compounds according to the invention.

(103) The compounds of according to the invention can therefore be used as medicaments, especially medicaments which are inhibitors of TAFIa.

(104) Accordingly, in another of its aspects, the invention provides medicaments which comprise a compound of formula (I), in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof.

(105) The present invention further provides a compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof for use in the treatment of one or more disorders which are associated with thromboses, embolisms, hypercoagulability or fibrotic changes, more specifically of one or more disorders from the series of myocardial infarction, angina pectoris and other forms of acute coronary syndrome, stroke, peripheral vascular disorders, deep vein thrombosis, pulmonary embolism, embolic or thrombotic events caused by cardiac arrhythmias, cardiovascular events such as restenosis following revascularization and angioplasty and similar procedures such as stent implantations and bypass operations, or reducing the risk of thrombosis following surgical procedures such as operations on the knee and hip joints, or in the context of disseminated intravascular coagulation, sepsis, intravascular events associated with fibrin formation, atherosclerosis, diabetes and the metabolic syndrome and the sequelae thereof, tumor growth and tumor metastasis, inflammatory and degenerative articular disorders such as rheumatoid arthritis and osteoathritis, impairments of the hemostatic system such as fibrin deposits, fibrotic changes of the lung such as chronic obstructive pulmonary disease, adult respiratory distress syndrome or fibrin deposits in the eye following eye operations or scarring.

(106) The treatment of diseases is to be understood as meaning both the therapy of existing pathological changes or malfunctions of the organism or of existing symptoms with the aim of relief, alleviation or cure, and the prophylaxis or prevention of pathological changes or malfunctions of the organism or of symptoms in humans or animals which are susceptible thereto and are in need of such a prophylaxis or prevention, with the aim of a prevention or suppression of their occurrence or of an attenuation in the case of their occurrence.

(107) The present invention, according to another of its aspects, also provides a method of treatment of the disorders indicated above, which comprises administering to a patient an effective dose of compound of formula (I) according to the invention, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof.

(108) The compounds according to the invention can therefore be used for preparing medicaments, especially medicaments which are inhibitors of TAFIa.

(109) According to another of its aspects, the present invention relates to pharmaceutical compositions comprising as active principle a compound according to the invention. These pharmaceutical compositions comprise an effective dose of at least one compound according to the invention in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a pharmaceutically acceptable salt thereof and also at least one pharmaceutically acceptable excipient.

(110) The compounds of the formula I and their pharmaceutically acceptable salts, and pharmaceutical compositions and medicaments comprising them, can be administered enterally, for example by oral or rectal administration, parenterally, for example by intravenous, intramuscular or subcutaneous injection or infusion, or by another type of administration such as topical, percutaneous, transcutaneous, nasal, pharyngal or inhalative administration, the preferred form of administration depending on the particulars of the specific case. The compounds of the formula I and their pharmaceutically acceptable salts can also be used in combination with other pharmaceutically active compounds.

(111) The pharmaceutical compositions and medicaments according to the invention normally contain from about 0.01 to about 90 percent by weight of a compound or compounds of the formula I or pharmaceutically acceptable salt thereof, and an amount of active ingredient of the formula I and/or its pharmaceutically acceptable salt which in general is from about 0.01 mg to about 1 g, in particular from about 0.2 mg to about 500 mg, for example from about 1 mg to about 300 mg, per dose unit. Depending on the kind of the pharmaceutical composition and other particulars of the specific case, the amount may deviate from the indicated ones. The production of the pharmaceutical compositions and medicaments can be carried out in a manner known per se and familiar to the person skilled in the art. For this, the compounds of the formula I and/or their pharmaceutically acceptable salts can be mixed together with one or more solid or liquid vehicles and/or excipients, if desired also in combination with one or more other pharmaceutically active compounds, and brought into a suitable form for dosage and administration, which can then be used in human medicine or veterinary medicine. In the production of solid pharmaceutical compositions, for example, dry granules or wet granules can be prepared. The compounds of the formula I and their pharmaceutically acceptable salts can also be lyophilized and the resulting lyophilizates be used, for example for producing medicaments for injection or infusion.

(112) As vehicles, which may also be looked upon as diluents or solvents or bulking agents, and excipients suitable organic and inorganic substances can be used which do not react in an undesired manner with the compounds of the formula I. As examples of types of excipients, or additives, which can be contained in the pharmaceutical compositions and medicaments, lubricants, preservatives, gel formers, solubilizers, thickeners, stabilizers, disintegrants, wetting agents, emulsifiers, dispersants, antifoaming agents, salts, buffer substances, colorants, flavorings, antioxidants or agents for achieving a depot effect may be mentioned. The said vehicles, excipients or additives are selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art.

(113) For oral and rectal use, pharmaceutical forms such as, for example, tablets, coated tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, suppositories, solutions, including oily, alcoholic or aqueous solutions, or drops, furthermore suspensions or emulsions, can be used. For parenteral use, for example by injection or infusion, pharmaceutical forms such as solutions, suspensions or emulsions, for example aqueous solutions, can be used. For topical use, pharmaceutical forms such as ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions or powders can be used. Suitable as pharmaceutical compositions for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the active ingredient of the formula I or its pharmaceutically acceptable salt in a pharmaceutically acceptable solvent, such as ethanol or water or a mixture of such solvents, wherein the formulation may also comprise other pharmaceutical excipients such as surfactants, emulsifiers and stabilizers, and a propellant gas. Such a composition comprises the active ingredient normally in a concentration of about 0.01 percent to about 10 percent, in particular of about 0.3 percent to about 3 percent, by weight.

(114) As usual, the dosage of the compounds of the formula I and the frequency of administration depend on the circumstances of the specific case and are adjusted by the physician according to the customary rules and procedures. They depend, for example, on the compound of the formula I administered and its potency and duration of action, on the nature and severity of the individual syndrome, on the gender, age, weight and the individual responsiveness of the human or animal to be treated, on whether the treatment is acute or chronic or prophylactic, or on whether further pharmaceutically active compounds are administered in addition to a compound of the formula I. Normally, in the case of administration to an adult weighing about 75 kg, a dose from about 0.00013 mg to about 10 mg per kg per day, in particular from about 0.001 mg to about 5 mg per kg per day (in each case in mg per kg of body weight), is sufficient. The daily dose can be administered in the form of a single dose or divided into a number of individual doses, for example two, three or four individual doses. The administration can also be carried out continuously, for example by continuous injection or infusion. Depending on the individual behavior in a specific case, it may be necessary to deviate upward or downward from the indicated dosages, for example in acute episodes of a disease or in an intensive care unit.

(115) The TAFIa inhibitors according to the invention can be administered both as monotherapy and in combination or together with all antithrombotics (anticoagulants and platelet aggregation inhibitors), thrombolytics (plasminogen activators of every type, for example tissue-type plasminogen activator (t-PA)), or other substances having profibrinolytic activity, antihypertensives, regulators of blood glucose, lipid-lowering agents and antiarrhythmics.