Macrocyclic urea and sulfamide derivatives as inhibitors of TAFIa

Abstract

The invention relates to compounds of the formula (I) which are inhibitors of activated thrombin-activable fibrinolysis inhibitor. The compounds of the formula I are suitable for producing medicaments for prophylaxis, secondary prevention and treatment of one or more disorders associated with thromboses, embolisms, hypercoagulability or fibrotic changes.

Claims

1. A compound of the formula (I) ##STR00039## or a stereoisomer thereof or a physiologically tolerated salt of any of the foregoing compounds, where X is C(O) or SO.sub.2; U is an oxygen atom, sulfur atom, or NH; A is (C.sub.0)-alkylene-; V is (C.sub.2-C.sub.4)-alkylene-, wherein said alkylene is unsubstituted or substituted independently of one another once, twice or three times by OH, NH.sub.2 or halogen; D is (C.sub.1-C.sub.2)-alkylene-; Y is 1) (C.sub.3-C.sub.12)-cycloalkyl, wherein said cycloalkyl is substituted independently of one another once, twice or three times by R15, 2) (C.sub.6-C.sub.14)-aryl, wherein said aryl is unsubstituted or substituted independently of one another once, twice or three times by R15, or 3) Het, wherein Het is a 4- to 15-membered heterocyclic ring system having 4 to 15 ring atoms which are present in one, two or three ring systems which are connected together, and which comprise, depending on the ring size, one, two, three or four identical or different heteroatoms selected from the-group consisting of oxygen, nitrogen or sulfur, and in which Het is unsubstituted or substituted independently of one another once, twice or three times by a (C.sub.1-C.sub.3)-alkyl, halogen, NH.sub.2, CF.sub.3 or OCF.sub.3; R1 is 1) a hydrogen atom, 2) (C.sub.1-C.sub.6)-alkyl, 3) (C.sub.1-C.sub.6)-alkyl-OH, 4) (C.sub.0-C.sub.4)-alkyl-(C.sub.3-C.sub.6)-cycloalkyl, 5) (C.sub.1-C.sub.10)-alkyl-OC(O)OR2, 6) (CH.sub.2).sub.r(C.sub.6-C.sub.14)-aryl, in which aryl is unsubstituted or substituted independently of one another once, twice or three times by R15, and r is the integer zero, 1, 2 or 3, or 7) (CH.sub.2).sub.sHet, wherein Het is a 4- to 15-membered heterocyclic ring system having 4 to 15 ring atoms which are present in one, two or three ring systems which are connected together, and which comprise, depending on the ring size, one, two, three or four identical or different heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur, and in which Het is unsubstituted or substituted independently of one another once, twice or three times by R15, and s is the integer zero, 1, 2 or 3; R2 is 1) (C.sub.1-C.sub.6)-alkyl, 2) (CH.sub.2).sub.r(C.sub.6-C.sub.14)-aryl, wherein said aryl is unsubstituted or substituted independently of one another once, twice or three times by R15, and r is the integer zero, 1, 2 or 3, or 3) (C.sub.0-C.sub.4)-alkyl-(C.sub.3-C.sub.6)-cycloalkyl; R3 is 1) (C.sub.2-C.sub.6)-alkylene-NH.sub.2, wherein said alkylene is unsubstituted or substituted once, twice, three or four times by halogen, 2) (C.sub.1-C.sub.4)-alkylene-O(C.sub.1-C.sub.4)-alkylene-NH.sub.2, 3) (C.sub.1-C.sub.4)-alkylene-SO.sub.2(C.sub.1-C.sub.4)-alkylene-NH.sub.2, 4) (C.sub.0-C.sub.4)-alkylene-Het, wherein said Het is as defined above and is substituted by NH.sub.2 and once, twice or three times by R15, 5) (C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.8)-cycloalkyl-NH.sub.2 or 6) (C.sub.0-C.sub.6)-alkylene-cyclic amine, wherein said cyclic amine is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepinyl, morpholinyl, and thiomorpholinyl; R6 is 1) a hydrogen atom, 2) (C.sub.1-C.sub.6)-alkyl, wherein said alkyl is unsubstituted or substituted independently of one another once, twice or three times by R16, 3) O(C.sub.1-C.sub.6)-alkyl, wherein said alkyl is unsubstituted or substituted independently of one another once, twice or three times by R16, 4) (C.sub.0-C.sub.4)-alkylene-Het, wherein said Het is as defined above, wherein said alkylene and Het are unsubstituted or substituted independently of one another once, twice or three times by R16, 5) (C.sub.0-C.sub.4)-alkylene-aryl, wherein said alkylene and aryl are unsubstituted or substituted independently of one another once, twice or three times by R16, or 6) (C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.8)-cycloalkyl, wherein said alkylene and cycloalkyl are unsubstituted or substituted independently of one another once, twice or three times by R16; R7 is a hydrogen atom, halogen or (C.sub.1-C.sub.6)-alkyl; R8 is a hydrogen atom, halogen or (C.sub.1-C.sub.6)-alkyl; R9 is a hydrogen atom, halogen or (C.sub.1-C.sub.6)-alkyl; R15 is a hydrogen atom, (C.sub.1-C.sub.4)-alkyl, OCF.sub.3, NH.sub.2, OH, CF.sub.3 or halogen; and R16 is OCF.sub.3, NH.sub.2, OH, CF.sub.3 or halogen.

2. A compound of the formula (I) as claimed in claim 1, or a stereoisomer thereof or a physiologically tolerated salt of any of the foregoing compounds, where X is C(O) or SO.sub.2; U is oxygen atom, sulfur atom, or NH; A is (C.sub.0)-alkylene-; V is (C.sub.2-C.sub.4)-alkylene-; D is (C.sub.1-C.sub.2)-alkylene-; Y is 1) (C.sub.3-C.sub.6)-cycloalkyl, wherein said cycloalkyl is substituted independently of one another once, twice or three times by R15, 2) (C.sub.6-C.sub.14)-aryl, wherein said aryl is selected from the group of phenyl, naphthyl, anthryl or fluorenyl, and in which aryl is unsubstituted or substituted independently of one another once, twice or three times by R15, or 3) Het, wherein Het is selected from the group consisting of acridinyl, azepinyl, azetidinyl, aziridinyl, benzimidazalinyl, benzimidazolyl, benzo[1,3]dioxolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, cinnolinyl, deca-hydroquinolinyl, dibenzofuranyl, dibenzothiophenyl, dihydrofuran[2,3-b]-tetrahydrofuranyl, dihydrofuranyl, dioxolyl, dioxanyl, 2H, 6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolidinyl, 2-isothiazolinyl, isothiazolyl, isoxazolyl, isoxazolidinyl, 2-isoxazolinyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, oxothiolanyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridothiophenyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrahydropyridinyl, 6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienoimidazolyl, thienooxazolyl, thienopyridine, thienothiazolyl, thiomorpholinyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl and xanthenyl, and in which Het is unsubstituted or substituted independently of one another once, twice or three times by a (C.sub.1-C.sub.3)-alkyl, halogen, NH.sub.2, CF.sub.3 or OCF.sub.3; R1 is 1) a hydrogen atom or 2) (C.sub.1-C.sub.4)-alkyl; R3 is 1) (C.sub.2-C.sub.6)-alkylene-NH.sub.2, wherein said alkylene is unsubstituted or substituted once, twice, three or four times by halogen, 2) (C.sub.1-C.sub.4)-alkylene-SO.sub.2(C.sub.1-C.sub.4)-alkylene-NH.sub.2 or 3) (C.sub.0-C.sub.4)-alkylene-Het, wherein said Het is as defined above and is substituted by NH.sub.2 and once, twice or three times by R15; R6 is 1) a hydrogen atom, 2) (C.sub.1-C.sub.6)-alkyl, wherein said alkyl is unsubstituted or substituted independently of one another once, twice or three times by R16, 3) O(C.sub.1-C.sub.6)-alkyl, wherein said alkyl is unsubstituted or substituted independently of one another once, twice or three times by R16, 4) (C.sub.0-C.sub.4)-alkylene-Het, wherein said Het is as defined above, wherein said alkylene and Het are unsubstituted or substituted independently of one another once, twice or three times by R16, 5) (C.sub.0-C.sub.4)-alkylene-aryl, wherein said alkylene and aryl are unsubstituted or substituted independently of one another once, twice or three times by R16, or 6) (C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl, wherein said alkylene and cycloalkyl are unsubstituted or substituted independently of one another once, twice or three times by R16; R7 is a hydrogen atom, F or (C.sub.1-C.sub.4)-alkyl; R8 is a hydrogen atom, F or (C.sub.1-C.sub.4)-alkyl; R9 is a hydrogen atom, F or (C.sub.1-C.sub.4)-alkyl; R15 is a hydrogen atom, (C.sub.1-C.sub.4)-alkyl, OCF.sub.3, NH.sub.2, OH, CF.sub.3 or halogen; and R16 is OCF.sub.3, OH, CF.sub.3 or F.

3. A compound of the formula (I) as claimed in claim 1, or a stereoisomer thereof or a physiologically tolerated salt of any of the foregoing compounds, where X is C(O); U is oxygen atom; A is (C.sub.0)-alkylene-; V is (C.sub.2-C.sub.4)-alkylene-, wherein said alkylene is unsubstituted or substituted independently of one another once or twice by OH, F or Cl; D is (C.sub.1-C.sub.2)-alkylene-; Y is phenyl, wherein said phenyl is unsubstituted or substituted independently of one another once, twice or three times by R15; R1 is 1) a hydrogen atom or 2) (C.sub.1-C.sub.4)-alkyl; R3 is 1) (C.sub.2-C.sub.6)-alkylene-NH.sub.2, 2) (C.sub.1-C.sub.4)-alkylene-SO.sub.2(C.sub.1-C.sub.4)-alkylene-NH.sub.2 or 3) (C.sub.0-C.sub.4)-alkylene-pyridyl, wherein said pyridyl is substituted by NH.sub.2 and once, twice or three times by R15; R6 is 1) a hydrogen atom, 2) (C.sub.1-C.sub.6)-alkyl, 3) CF.sub.3, 4) (C.sub.0-C.sub.4)-alkylene-phenyl or 5) (C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl; R7, R8 and R9 are each hydrogen atom; and R15 is a hydrogen atom, (C.sub.1-C.sub.4)-alkyl, CF.sub.3 or halogen.

4. A compound of the formula (I) as claimed in claim 1, or a stereoisomer thereof or a physiologically tolerated salt of any of the foregoing compounds, where X is C(O); U is oxygen atom; A is (C.sub.0)-alkylene-; V is (C.sub.2-C.sub.4)-alkylene-; D is (C.sub.1-C.sub.2)-alkylene-; Y is phenyl, wherein said phenyl is unsubstituted or substituted independently of one another once, twice or three times by R15; R1 is 1) a hydrogen atom or 2) (C.sub.1-C.sub.4)-alkyl; R3 is 1) (C.sub.2-C.sub.6)-alkylene-NH.sub.2, 2) (C.sub.1-C.sub.4)-alkylene-SO.sub.2(C.sub.1-C.sub.4)-alkylene-NH.sub.2 or 3) (C.sub.0-C.sub.4)-alkylene-pyridyl, wherein said pyridyl is substituted by NH.sub.2 or once, twice or three times by R15; R6 is 1) a hydrogen atom, 2) (C.sub.1-C.sub.6)-alkyl, 3) CF.sub.3, 4) (C.sub.0-C.sub.4)-alkylene-phenyl or 5) (C.sub.0-C.sub.4)-alkylene-(C.sub.3-C.sub.6)-cycloalkyl; R7, R8 and R9 are each hydrogen atom; and R15 is a hydrogen atom, (C.sub.1-C.sub.4)-alkyl, CF.sub.3 or halogen.

5. A compound of the formula (I), or a physiologically tolerated salt of any of the foregoing, as claimed in claim 1, wherein the compound of the formula (I) is, wherein the compound of the formula (I) is (S)-3-(6-aminopyridin-3-yl)-2-[3-((8S,11R)-8-isopropyl-10-oxo-6-oxa-1,9,14-triazabicyclo[11.2.1]hexadeca-13(16),14-dien-11-yl)ureido]propionic acid, or (S)-3-(6-aminopyridin-3-yl)-2-[3-((3R,6S)-6-isopropyl-4-oxo-8-oxa-5-azabicyclo[11.2.2]heptadeca-1(16),13(17),14-trien-3-yl)ureido]propionic acid.

6. A process for preparing the compound of the formula (I) as claimed in claim 1, or a stereoisomer thereof or a physiologically tolerated salt of any of the foregoing compounds, which comprises a) reacting a compound of the formula (II) ##STR00040## wherein U, R6 and R8 have the meanings mentioned in the compound of the formula (I), with an amino acid of the formula (III) ##STR00041## wherein R9, A, Y and D have the meanings mentioned in the compound of the formula (I), resulting in a compound of the formula (IV) ##STR00042## which is converted under the conditions of ring-closure metathesis and subsequent hydrogenation of the resulting double bond into a compound of the formula (V) ##STR00043## wherein V is (C.sub.2-C.sub.4)-alkylene-, subsequently eliminating the protective group PG, and obtaining the compound of the formula (VI), ##STR00044## and reacting the compound of formula (VI), a compound of the formula (VII) ##STR00045## wherein R3 and R7 have the meanings mentioned in formula (I), PG is a suitable ester protective group radical, and the nitrogen in R3 is protected where appropriate by a suitable amino protective group, and phosgene or a phosgene equivalent to give a compound of the formula (VIII) ##STR00046## subsequently the protective group PG and the protective group which is present where appropriate on the nitrogen in R3 are eliminated, resulting in the compound of the formula (I); or b) reacting a compound of the formula (IX) ##STR00047## wherein U, V, R6 and R8 have the meanings mentioned in the compound of the formula (I), and PG.sub.a is a suitable carboxyl protective group, with an amino acid of the formula (X) ##STR00048## wherein R9, Y and D have the meanings mentioned in the compound of the formula (I), and PG.sub.b and PG.sub.c are suitable amino protective groups, resulting in a compound of the formula (XI) ##STR00049## which, after elimination of the protective groups PG.sub.a and PG.sub.b, is converted into the compound of the formula (XII) ##STR00050## which is converted by means of an amide coupling into a compound of the formula (V), wherein A has the meanings mentioned in the compound of the formula (I), subsequently the protective group is eliminated and the compound of the formula (VI) is obtained, and reacting the compound of formula (VI), a compound of the formula (VII) wherein R3 and R7 have the meanings mentioned in formula (I), PG is a suitable ester protective group radical, and the nitrogen in R3 is protected where appropriate by a suitable amino protective group, and phosgene or a phosgene equivalent to give a compound of the formula (VIII), subsequently the protective group PG and the protective group which is present where appropriate on the nitrogen in R3 are eliminated, resulting in the compound of the formula (I); or c) reacting a compound of the formula (XIII) ##STR00051## wherein U, V, R6 and R8 have the meanings mentioned in the compound of the formula (I), and PG.sub.d is a suitable amino protective group, with an amino acid of the formula (XIV) ##STR00052## wherein R9, Y and D have the meanings mentioned in the compound of the formula (I), and PG.sub.c is a suitable amino protective group and PG.sub.e is a suitable carboxyl protective group, resulting in a compound of the formula (XV) ##STR00053## which, after elimination of the protective groups PG.sub.d and PG.sub.e, is converted into the compound of the formula (XVI) ##STR00054## which is reacted to give a compound of the formula (V), wherein A has the meanings mentioned in the compound of the formula (I), subsequently the protective group is eliminated and the compound of the formula (VI) is obtained, and reacting a compound of formula (VI), a compound of the formula (VII), wherein R3 and R7 have the meanings mentioned in formula (I), PG is a suitable ester protective group radical, and the nitrogen in R3 is protected where appropriate by a suitable amino protective group, and phosgene or a phosgene equivalent to give a compound of the formula (VIII), and subsequently the protective group PG and the protective group which is present where appropriate on the nitrogen in R3 are eliminated, resulting in the compound of the formula (I); or d) reacting a compound of the formula (XVII) ##STR00055## wherein U, V, A, Y, D, R.sub.6, R.sub.8 and R.sub.9 have the meanings mentioned in the compound of the formula (I), with a compound of the formula (V), subsequently the protective groups are eliminated, and a compound of the formula (VI) is obtained, and reacting a compound of formula (VI), a compound of the formula (VII), wherein R3 and R7 have the meanings mentioned in formula (I), PG is a suitable ester protective group radical, and the nitrogen in R3 is protected where appropriate by a suitable amino protective group, and phosgene or a phosgene equivalent to give a compound of the formula (VIII), and subsequently the protective groups PG and, where appropriate, the protective group on the nitrogen in R3 are eliminated, resulting in the compound of the formula (I); or e) converting a compound of the formula (VIIIa) ##STR00056## wherein V is (C.sub.3-C.sub.4)-alkenylene-, into the compound of the formula (VIIIb) ##STR00057## wherein V is (C.sub.3-C.sub.4)-alkylene-, wherein said alkylene is substituted independently of one another once, twice or three times by OH, NH.sub.2 or halogen, subsequently the compound of the formula (VIIIb) is converted in analogy to process a) into the compound of the formula (I); or f) reacting a compound of the formula (XVIII) ##STR00058## wherein V is as defined in the compound of the formula (I), successively with the compounds of the formula (XIX) and (XX) ##STR00059## employing bases in polar, aprotic solvents, and converting the resulting compounds of the formula (XXI) ##STR00060## by removing the protective group PGa and subsequent formation of a peptide linkage into a compound of the formula (V), and reacting the latter as in process a) to give compounds of the formula (I), wherein R6, R8, R9, and A, D, U, V and Y have the meanings mentioned in formula (I), and PG is suitable protective groups, and LG is a leaving group selected from the group consisting of chlorine, bromine, iodine and sulfonic ester; or g) reacting a compound of the formula (VI) with a compound of the formula (XXII) ##STR00061## wherein R3 and R7 have the meanings mentioned in the compound of the formula (I), and PG is a suitable protective group radical, to give a compound of the formula (XXIII) ##STR00062## and then converting into a compound of the formula (I); or h) fractionating a compound of the formula (I) prepared by processes a), b), c), d), e), f) or g), or a suitable precursor of the formula (I) which occurs in enantiomeric forms owing to its chemical structure, by salt formation with enantiopure acids or bases, chromatography on chiral stationary phases or derivatization by means of chiral enantiopure compounds, separation of the diastereomers obtained in this way, and elimination of the chiral auxiliary groups into the pure enantiomers; or i) either isolating in free form the compound of the formula (I) prepared by processes a), b), c), d), e), f) or g), or converting into physiologically tolerated salts in the case where acidic or basic groups are present.

7. A medicament comprising an effective content of at least one compound of the formula (I) as claimed in claim 1, a stereoisomer thereof, mixtures of these forms in any ratio, or a physiologically tolerated salt of any of the foregoing compounds, together with a pharmaceutically suitable and physiologically tolerated carrier, additive and/or other active ingredients and excipients.

8. A method for the prophylaxis, secondary prevention and therapy of one or more disorders which are associated with thromboses, embolisms, hypercoagulability or fibrotic changes, comprising administering a therapeutically effective amount of a compound of the formula (I) according to claim 1, a stereoisomer thereof, mixtures of these forms in any ratio, or a physiologically tolerated salt of any of the foregoing compounds, to a patient in need of such treatment.

9. The method according to claim 8, wherein the one or more disorders are selected from the group consisting of myocardial infarction, angina pectoris, acute coronary syndrome, stroke, peripheral vascular disorders, deep vein thrombosis, pulmonary embolism, embolic or thrombotic events caused by cardiac arrhythmias, and restenosis following revascularization, angioplasty, stent implantation, or bypass operations.

10. A method for reducing the risk of thrombosis formation following surgical procedures comprising administering a therapeutically effective amount of a compound according to claim 1, a stereoisomer thereof, mixtures of these forms in any ratio, or a physiologically tolerated salt of any of the foregoing, to a patient in need of such treatment.

11. The method according to claim 10, wherein the surgical procedure is selected from the group consisting of knee replacement surgery and hip replacement surgery.

12. A method for the prophylaxis, secondary prevention or therapy of disseminated intravascular coagulation, sepsis or intravascular events associated with inflammation comprising administering a therapeutically effective amount of a compound according to claim 1, a stereoisomer thereof, mixtures of these forms in any ratio, or a physiologically tolerated salt of any of the foregoing, to a patient in need of such treatment.

13. A method for the prophylaxis, secondary prevention or therapy of atherosclerosis, tumor growth and metastasis, inflammatory and degenerative articular disorders, diabetes or metabolic syndrome and the sequelae thereof comprising administering a therapeutically effective amount of a compound according to claim 1, a stereoisomer thereof, mixtures of these forms in any ratio, or a physiologically tolerated salt of any of the foregoing, to a patient in need of such treatment.

14. The method according to claim 13, wherein the articular disorder is chosen from the group consisting of rheumatoid arthritis and arthrosis.

15. A method for the prophylaxis, secondary prevention or therapy for impairments to the hemostatic system comprising administering a therapeutically effective amount of a compound according to claim 1, a stereoisomer thereof, mixtures of these forms in any ratio, or a physiologically tolerated salt of any of the foregoing, to a patient in need of such treatment.

16. The method according to claim 15, wherein said impairment to the hemostatic system is fibrin deposition.

17. A method for the prophylaxis, secondary prevention or therapy of chronic obstructive pulmonary disease, adult respiratory distress syndrome, fibrin deposits in the eye following eye operations or the prevention or treatment of scarring of the eye comprising administering a therapeutically effective amount of a compound according to claim 1, a stereoisomer thereof, mixtures of these forms in any ratio, or a physiologically tolerated salt of any of the foregoing, to a patient in need of such treatment.

Description

EXAMPLES

(1) Final products are normally determined by mass spectroscopic methods (FAB-, ESI-MS) and .sup.1H-NMR; the main peak or two main peaks are indicated in each case. Temperatures are stated in degrees Celsius, RT means room temperature (21 C. to 24 C.). TFA means trifluoroacetic acid, THF means tetrahydrofuran, DMF means dimethylformamide, HATU means 2-(7-aza-1H-benzotriazol-1-yl)-1, 1,3,3-tetramethyluronium hexafluorophosphate, HOAt means 1-hydroxy-7-azabenzotriazole. Abbreviations used are either explained or correspond to usual conventions.

(2) Unless stated otherwise, the LC/MS analyses were carried out under the following conditions:

(3) Method A:=method column: YMC Jsphere H80 202 mm, packing material 4 m, mobile phase: CH.sub.3CN:H.sub.2O+0.05% trifluoroacetic acid (TFA), gradient: 4:96 (0 min.) to 95:5 (2.0 min.) to 95:5 (2.4 min.) to 4:96 (2.45 min.) flow rate: 1.0 ml/min., temperature: 30 C.

(4) Method B: column: Phenomenex LunaC.sub.18 102.0 mm, packing material 3 m, mobile phase: CH.sub.3CN:H.sub.2O+0.05% TFA, gradient: 7:93 (0 min) to 95:5 (1.2 min) to 95:5 (1.4 min) to 7:93 (1.45 min), flow rate: 1.1 ml/min, temperature: 30 C.

(5) Method C: column: WatersXBridgeC.sub.18, 4.6*50 mm, 2.5 m, gradient: H.sub.2O+0.05% TFA:CH.sub.3CN+0.05% TFA 95:5 (0 min) to 95:5 (0.3 min) to 5:95 (3.5 min) to 5:95 (4 min), flow rate: 1.3 ml/min, temperature: 40 C.

(6) Method D: column: Waters XBridge C.sub.18 4.6*50 mm; 2.5 m gradient: H.sub.2O+0.1% formic acid:CH.sub.3CN+0.08% formic acid 97:3 (0 min) to 40:60 (3.5 min) to 2:98 (4 min) to 2:98 (5 min) to 97:3 (5.2 min) to 97:3 (6.5 min), flow rate: 1.4 ml/min, temperature: RT.

(7) Method E: column: YMC Jsphere 33*2 mm, 4 m, H80, gradient: H.sub.2O+0.05% TFA:CH.sub.3CN+0.05% TFA 98:2 (1 min) to 5:95 (5.0 min) to 5:95 (6.25 min), flow rate: 1 ml/min, temperature: RT.

(8) Method F: column: WatersXBridgeC.sub.18, 4.6*50 mm, 2.5 m, gradient: H.sub.2O+0.1% formic acid:CH.sub.3CN+0.1% formic acid 97:3 (0 min) to 40:60 (3.5 min) to 2:98 (4 min) to 2:98 (5 min) to 97:3 (5.2 min) to 97:3 (6.5 min), temperature: RT.

(9) Method G: column: WatersXBridgeC.sub.18, 4.6*50 mm, 2.5 m; gradient: H.sub.2O+0.05% TFA:CH.sub.3CN+0.05% TFA 95:5 (0 min) to 95:5 (0.2 min) to 5:95 (2.4 min) to 5:95 (3.5 min) to 95:5 (3.6 min) to 95:5 (4.5 min), flow rate: 1.7 ml/min, temperature: 50 C.

(10) Method H: column WatersXBridgeC.sub.18, 4.6*50 mm, 2.5 m; gradient: H.sub.2O+0.05% TFA:CH.sub.3CN+0.05% TFA 95:5 (0 min) to 95:5 (0.2 min) to 5:95 (2.4 min) to 5:95 (3.2 min) to 95:5 (3.3 min) to 95:5 (4.0 min), flow rate: 1.7 ml/min, temperature: 40 C.

(11) Method I: column Merck Chromolith FastGrad RP-18e, 502 mm; gradient: H.sub.2O+0.05% TFA:CH.sub.3CN+0.05% TFA 98:2 (0.2 min) to 2:98 (2.4 min) to 2:98 (3.2 min) to 98:2 (3.3 min) to 98:2 (4 min), flow rate: 2.0 ml/min, temperature: RT.

(12) Method J: column: YMC Jsphere 33*2 mm, 4 m, gradient: H.sub.2O+0.05% TFA:CH.sub.3CN+0.05% TFA 98:2 (1 min) to 5:95 (5.0 min) to 5:95 (6.25 min), flow rate: 1 ml/min, temperature: RT.

(13) Method K: column YMC Jsphere 33*2 mm, 4 m, H80, gradient: H.sub.2O+0.05% TFA:CH.sub.3CN+0.05% TFA 96:4 (0 min) to 5:95 (2.0 min) to 5:95 (2.4 min) to 96:4 (2.45 min).

(14) Method L: column YMC Jsphere 33*2 mm, 4 m, gradient: CH.sub.3OH+0.05% TFA: H.sub.2O+0.05% TFA 2:98 (1 min) to 95:5 (5 min) to 95:5 (6.25 min), flow rate: 1 ml/min, temperature: RT.

(15) Unless indicated otherwise, chromatographic separations were carried out on silica gel with ethyl acetate/heptane mixtures as mobile phase. Preparative separations on reversed phase (RP) silica gel (HPLC) were carried out, unless indicated otherwise, on C.sub.18-RP phases as stationary phase and H.sub.2O-TFA-acetonitrile mixtures as mobile phase.

(16) Evaporation of solvents normally took place under reduced pressure in a rotary evaporator at 35 C. to 45 C.

Example 1-1

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

(17) ##STR00033##

A. (S)-3-Methyl-2-{[1-phenylmethylidene]amino}butan-1-ol

(18) 2.64 ml (2.78 g, 26.16 mmol) of benzaldehyde were added to a stirred solution of 2.57 g (24.91 mmol) of L-valinol in 28 ml of toluene, and the mixture was heated under reflux with a water trap for one hour. Cooling was followed by concentration and recrystallization from heptane. The colorless solid was filtered off with suction and dried under reduced pressure (3.74 g).

(19) .sup.1H-NMR (DMSO-d6, 400 MHz) [ppm]=8.23 (s, 1H), 7.77 (d, 2H), 7.45-7.40 (m, 3H), 4.49 (t, 1H), 3.68-3.31 (m, 1H), 3.48-3.40 (m, 1H), 2.96 (ddd, 1H), 1.94-1.81 (m, 1H), 0.88 (s, 5H).

B. (S)-1-Allyloxymethyl-2-methylpropylamine

(20) 1.25 g (60%, 31.36 mmol) of sodium hydride were added to a solution of 3.00 g (15.68 mmol) of (S)-3-methyl-2-{[1-phenylmethylidene]amino}butan-1-ol in 28 ml of dry THF, and the mixture was stirred at RT for 45 min. Then 1.43 ml (16.46 mmol) of allyl bromide were added, and the mixture was stirred further at RT overnight. 20 ml of methanol were added to quench, and the mixture was acidified (pH 1) with 1N hydrochoric acid and stirred further. After 3 h, the reaction mixture was washed twice with dichloromethane, and the combined dichloromethane phases were extracted with 1N hydrochloric acid. The combined aqueous phases were basified with 1N sodium hydroxide solution (pH 14), saturated with sodium chloride and extracted three times with ethyl acetate, readjusting the pH after each extraction step. The combined organic phases were dried over sodium sulfate, filtered and concentrated, and taken up once in dichloromethane and again concentrated. 1.56 g of the title compound were obtained as a pale yellow liquid.

(21) LC/MS (method A): R.sub.t=0.68 min, m/z: 144.2 [MH.sup.+].

C. 9H-Fluoren-9-ylmethyl [(R)-1-((S)-1-allyloxymethyl-2-methylpropylcarbamoyl)-2-(4-allyloxyphenyl)ethyl]carbamate

(22) 25.74 g (58.04 mmol) of (R)-3-(4-allyloxyphenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propionic acid were introduced into 400 ml of THF and, after successive addition of 8.88 g (58.04 mmol) of N-hydroxybenzotriazole and 11.98 g (58.04 mmol) of N,N-dicyclohexylcarbodiimide, stirred at RT. After leaving the mixture to stand overnight it was filtered and concentrated. The residue was taken up in ethyl acetate and washed successively with saturated sodium bicarbonate solution and dilute hydrochloric acid. The organic phase was dried over sodium sulfate and concentrated, and the residue was separated by chromatography on silica gel. 13.55 g of the desired compound were obtained.

(23) LC/MS (method A): R.sub.t=1.95 min, m/z: 569.3 [MH.sup.+].

D. 9H-Fluoren-9-ylmethyl ((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),4,14(18), 15-tetraen-12-yl)carbamate

(24) A solution of 1.25 g (2.20 mmol) of 9H-fluoren-9-ylmethyl [(R)-1-((S)-1-allyloxymethyl-2-methylpropylcarbamoyl)-2-(4-allyloxyphenyl)ethyl]carbamate and 0.40 g (0.659 mmol) of dichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium (Hoyveda-Grubbs catalyst) in 610 ml of dichloromethane was stirred at 40 C. for 24 h. The reaction mixture was then concentrated, and the residue was purified by chromatography on silica gel. 1.03 g of the desired compound were obtained as a colorless solid.

(25) LC/MS (method A): R.sub.t=1.75 min, m/z: 541.3 [MH.sup.+].

E. (9S,12R)-12-Amino-9-isopropyl-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-11-one

(26) A mixture of 6.82 g (12.62 mmol) of 9H-fluoren-9-ylmethyl ((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),4,14(18), 15-tetraen-12-yl)-carbamate and 4.4 g of 10% Pd/C in 880 ml of methanol was stirred under a hydrogen atmosphere at RT. After 6 h, it was filtered and freed of solvent. The residue was separated by preparative HPLC. The required fractions were combined, acetonitrile was evaporated off, and the resulting aqueous solution was made slightly alkaline with sodium bicarbonate. The aqueous phase was extracted several times with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. Chromatography on silica gel with ethyl acetate/methanol mixtures afforded the title compound (2.90 g).

(27) LC/MS (method A): R.sub.t=1.02 min, m/z: 321.2 [MH.sup.+].

F. tert-Butyl (S)-6-tert-butoxycarbonylamino-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)ureido]hexanoate

(28) A solution of 1.59 g (4.68 mmol) of tert-butyl (S)-2-amino-6-tert-butoxycarbonylaminohexanoate hydrochloride, 1.43 ml (1.04 g, 10.30 mmol) of triethylamine and 0.76 g (4.68 mmol) of carbonyldiimidazole in 25 ml of dimethylformamide (DMF) was stirred at RT for 1 h and then a solution of 1.5 g in 20 ml of DMF was added. The mixture was stirred at RT and left to stand overnight. Evaporation of the solvent was followed by partition between ethyl acetate and water, and the organic phase was dried over sodium sulfate, filtered and concentrated. The residue was separated by preparative HPLC, and the required fractions were combined and freed of acetonitrile. Sodium bicarbonate was used to make slightly alkaline, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 0.73 g of the title compound was obtained.

(29) LC/MS (method A): R.sub.t=1.68 min, m/z: 649.4 [MH.sup.+].

G. (S)-6-Amino-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-yl)ureido]hexanoic acid

(30) 0.71 g (1.10 mmol) of tert-butyl (S)-6-tert-butoxycarbonylamino-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-yl)ureido]hexanoate was dissolved in 11 ml of dichloromethane, and the same volume of trifluoroacetic acid was added. Stirring at RT for 4 h was followed by concentration and fractionation of the residue by preparative HPLC. The required fractions were combined and, after evaporation of acetonitrile, mixed with dilute hydrochloric acid, concentrated further and finally freeze dried. 0.42 g of the title compound was obtained as hydrochloride.

(31) .sup.1H-NMR (DMSO-d6, 400 MHz) [ppm]=7.79 (3H, s, br), 7.22 (1H, d), 6.99-6.90 (m, 3H), 6.87 (d, 1H), 6.29 (d, 1H), 5.79 (d, 1H), 4.32-4.17 (m, 3H), 4.10 (dd, 1H), 3.29-3.18 (m, 3H), 3.12 (dd, 1H), 2.96-2.87 (m, 2H), 2.83-2.72 (m, 2H), 2.65 (dd, 1H), 1.78-1.2 (m, 11H), 0.72 (d, 3H), 0.67 (d, 2H);

(32) LC/MS (method A): R.sub.t=0.94 min, m/z: 493.4 [MH.sup.+].

(33) The following examples were obtained in an analogous manner by employing the appropriate amino alcohols instead of valinol:

(34) TABLE-US-00001 R.sub.t m/z Example Name (min) [MH.sup.+] Method 1-2 (S)-6-Amino-2-[3-((R)-11-oxo-2,7- 0.77 451.4 A dioxa-10- azabicyclo[12.2.2]octadeca- 1(17),14(18),15-trien12- yl)ureido]hexanoic acid 1-3 (S)-6-Amino-2-[3-((R)-9,9- 0.93 479.2 A dimethyl-11-oxo-2,7-dioxa-10- azabicyclo[12.2.2]octadeca- 1(17),14(18),15-trien-12- yl)ureido]hexanoic acid 1-4 (S)-6-Amino-2-[3-((9S,12R)-11- 0.96 527.5 A oxo-9-phenyl-2,7-dioxa-10- azabicyclo[12.2.2]octadeca- 1(17),14(18),15-trien-12- yl)ureido]hexanoic acid 1-5 (S)-6-Amino-2-[3-((9S,12R)-9- 1.03 541.3 A benzyl-11-oxo-2,7-dioxa-10- azabicyclo[12.2.2]octadeca- 1(17),14(18),15-trien-12- yl)ureido]hexanoic acid 1-6 (S)-6-Amino-2-[3-((9S,12R)-9- 1.02 533.3 A cyclohexyl-11-oxo-2,7-dioxa-10- azabicyclo[12.2.2]octadeca- 1(17),14(18),15-trien-12- yl)ureido]hexanoic acid 1-7 (S)-6-Amino-2-[3-((9S,12R)-9- 2.26 479.26 C ethyl-11-oxo-2,7-dioxa-10- azabicyclo[12.2.2]octadeca- 1(17),14(18),15-trien-12- yl)ureido]hexanoic acid 1-8 (S)-6-Amino-2-[3-((9S,12R)-9- 2.21 465.25 C methyl-11-oxo-2,7-dioxa-10- azabicyclo[12.2.2]octadeca- 1(17),14(18),15-trien-12- yl)ureido]hexanoic acid 1-9 (S)-6-Amino-2-[3-((9S,12R)-9-tert- 2.39 507.33 E butyl-11-oxo-2,7-dioxa-10- azabicyclo[12.2.2]octadeca- 1(17),14(18),15-trien-12- yl)ureido]hexanoic acid 1-10 (S)-6-Amino-2-{3-[(9S,12R)-9- 2.41 507.24 C ((S)-sec-butyl)-11-oxo-2,7-dioxa- 10-azabicyclo[12.2.2]octadeca- 1(17),14(18),15-trien-12- yl]ureido}hexanoic acid

Example 2-1

(S)-6-Amino-2-[3-((13S,16R)-13-isopropyl-15-oxo-2,11-dioxa-14-azabicyclo[16.2.2]docosa-1(21), 18(22), 19-trien-16-yl)ureido]hexanoic acid

A. (R)-1-(2-Hept-6-enyloxyethyl)-2-methylpropylamine

(35) A solution of 3.00 g (15.68 mmol) of (S)-3-methyl-2-{[1-phenylmethylidene]amino}butan-1-ol (1-1A) was prepared in 28 ml of dry THF under argon, 1.50 g (60%, 37.51 mmol) of sodium hydride were added, and the mixture was stirred for 45 min. Addition of 2.83 g (15.68 mmol) of 7-bromohept-1-ene was followed by stirring further overnight, cautious quenching with 20 ml of methanol, subsequent addition of 300 ml of 1N hydrochloric acid (pH=1) and stirring at 40 C. for 2 h. The mixture was washed with dichloromethane, and the aqueous phase was adjusted to pH 14 with 1N sodium hydroxide solution and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 0.91 g of the crude product was obtained. The crude product was reacted further without further purification.

(36) LC/MS (method B): R.sub.t=0.72 min, m/z: 200.2 [MH.sup.+].

B. 9H-Fluoren-9-yl-methyl [(R)-2-(4-allyloxyphenyl)-1-((S)-1-hept-6-enyloxymethyl-2-methylpropylcarbamoyl)ethyl]carbamate

(37) A solution of 2.02 g (4.57 mmol) of N--(9-fluorenylmethyloxycarbonyl)-O-allyl-D-tyrosine in 46 ml of DMF was mixed with 0.77 g (5.02 mmol) of 1-hydroxybenzotriazole and 1.04 g (5.02 mmol) of N,N-dicyclohexylcarbodiimide and stirred at RT for 2 h. Then 0.91 g (4.57 mmol) of (R)-1-(2-hept-6-enyloxyethyl)-2-methylpropylamine was added, and the mixture was stirred further at RT and left to stand overnight. The precipitate was then filtered off, the filtrate was concentrated, the residue was taken up in ethyl acetate and washed successively with saturated sodium bicarbonate solution and dilute hydrochloric acid, and the organic phase was dried over sodium sulfate, filtered and concentrated. The residue was separated by preparative HPLC, and the required fractions were combined, freed of acetonitrile and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. 1.02 g of the title compound were obtained (method D): R.sub.t=5.49 min, m/z: 669 [M-H+HCOOH.sup.].

C. 9H-Fluoren-9-yl-methyl ((13S,16R)-13-isopropyl-15-oxo-2,11-dioxa-14-azabicyclo[16.2.2]docosa-1(21),4,18(22), 19-tetraen-16-yl)carbamate

(38) A solution of 1.01 g (1.61 mmol) of 9H-fluoren-9-yl-methyl [(R)-2-(4-allyloxyphenyl)-1-((S)-1-hept-6-enyloxymethyl-2-methylpropylcarbamoyl)ethyl]carbamate and 0.15 g (0.24 mmol) of dichloro(o-isopropoxyphenylmethylene)(tricyclohexylphosphine)ruthenium (Hoyveda-Grubbs catalyst) in 460 ml of dichloromethane was stirred at 40 C. for 24 h. The reaction mixture was then concentrated, and the residue was purified by chromatography on silica gel. 0.87 g of the desired compound was obtained as a colorless solid.

(39) LC/MS (method C): R.sub.t=4.30 min, m/z: 597.39 [MH.sup.+].

D. (13S,16R)-16-Amino-13-isopropyl-2,11-dioxa-14-azabicyclo[16.2.2]docosa-1(21),18(22), 19-trien-15-one

(40) A mixture of 0.87 (1.46 mmol) of 9H-fluoren-9-yl-methyl ((13S,16R)-13-isopropyl-15-oxo-2,11-dioxa-14-azabicyclo[16.2.2]docosa-1(21),4,18(22), 19-tetraen-16-yl)-carbamate and 0.16 g of 10% Pd/C in 100 ml of methanol was stirred under a hydrogen atmosphere at RT. After stirring overnight and addition of 0.5 ml of piperidine, stirring was continued for 2 h, and the mixture was filtered and freed of solvent. The residue was separated by preparative HPLC. The required fractions were combined and freeze dried. 0.18 g of the title compound was obtained as trifluoroacetate.

(41) LC/MS (method C): R.sub.t=3.07 min, m/z: 377.22 [MH.sup.+].

E. (S)-6-Amino-2-[3-((13S,16R)-13-isopropyl-15-oxo-2,11-dioxa-14-azabicyclo[16.2.2]docosa-1(21), 18(22),19-trien-16-yl)ureido]hexanoic acid

(42) A solution of 0.18 g (0.37 mmol) of (13S,16R)-16-amino-13-isopropyl-2,11-dioxa-14-azabicyclo[16.2.2]docosa-1(21), 18(22), 19-trien-15-one in 3.8 ml of DMF was added to 60 mg (0.37 mmol) of 1,1-carbonyldiimidazole and, after addition of 0.2 ml (0.15 g, 1.47 mmol) of triethylamine, stirred under argon. After 10 min, 124 mg (0.37 mmol) of tert-butyl (S)-2-amino-6-tert-butoxycarbonylaminohexanoate hydrochloride were added, and the mixture was stirred for 3 h. It was concentrated and partitioned between water and ethyl acetate, and the organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. The required fractions were combined and concentrated. The residue was taken up in 20 ml of dichloromethane/TFA (1:1, v/v) and left to stand for 2 h. The mixture was concentrated, dissolved in 1N hydrochloric acid with a little acetonitrile and freeze dried. An amorphous solid (0.12 g) was obtained as hydrochloride.

(43) LC/MS (method C): R.sub.t=2.88 min, m/z: 549.21 [MH.sup.+].

Example 3-1 (S)-6-Amino-2-[3-((E)-(9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),4,14(18), 15-tetraen-12-yl)ureido]hexanoic acid

(44) The title compound was obtained in analogy to Example 1-1 with omission of the hydrogenation step and without final freeze drying with hydrochloric acid directly as trifluoroacetate.

(45) LC/MS (method A): R.sub.t=0.89 min, m/z: 491.2 [MH.sup.+].

Example 4-1 (S)-6-Amino-2-[3-((3S,6R)-3-isopropyl-5-oxo-1-oxa-4-azacyclotetradec-6-yl)ureido]hexanoic acid

(46) The title compound was obtained in analogy to Example 2-1 using Fmoc-D-allylglycine instead of Fmoc-D-O-allyltyrosine.

(47) LC/MS (method C): R.sub.t=2.35 min, m/z: 443.34 [MH.sup.+].

(48) The following were obtained in the same way using other amino alcohols and, where appropriate, using or introducing an ester protective group:

(49) TABLE-US-00002 R.sub.t m/z Example Name (min) [MH.sup.+] Method 4-2 (S)-3-(6-Aminopyridin-3-yl)-2-[3- 2.52 478.27 H ((3S,6R)-3-isopropyl-5-oxo-1- oxa-4-azacyclotetradec-6- yl)ureido]propionic acid 4-3 (S)-3-(6-Aminopyridin-3-yl)-2-[3- 1.66 450.26 G ((3S,6R)-3-methyl-5-oxo-1-oxa-4- azacyclotetradec-6- yl)ureido]propionic acid 4-4 Ethyl (S)-3-(6-aminopyridin-3-yl)- 0.66 506.4 B 2-[3-((3S,6R)-3-isopropyl-5-oxo- 1-oxa-4-azacyclotetradec-6- yl)ureido]propionate 4-5 Ethyl (S)-3-(6-amino-pyridin-3-yl)- 1.81 478.37 G 2-[3-((3S,6R)-3-methyl-5-oxo-1- oxa-4-azacyclotetradec-6- yl)ureido]propionate

Example 5-1

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

(50) ##STR00034##

A. Benzyl (R)-3-(2-benzyloxycarbonylaminoethylsulfanyl)-2-tert-butoxycarbonylaminopropionate

(51) A solution of 2.30 g (5.77 mmol) of (R)-3-(2-benzyloxycarbonylaminoethylsulfanyl)-2-tert-butoxycarbonylaminopropionic acid, 0.60 ml (0.62 g, 5.77 mmol) of benzyl alcohol, 0.07 g (0.58 mmol) of 4-dimethylaminopyridine and 1.33 g (6.93 mmol) of N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride in 30 ml of dichloromethane was stirred at RT overnight. The reaction mixture was washed successively with 1N hydrochloric acid, 1N sodium bicarbonate solution and with water. After drying over sodium sulfate, filtering and concentrating, the residue was chromatographed on silica gel. 2.09 g of the title compound were obtained as a colorless oil.

(52) LC/MS (method C): R.sub.t=3.63 min, m/z: 389.17 [M-Boc+H.sup.+].

B. Benzyl (R)-2-amino-3-(2-benzyloxycarbonylaminoethylsulfanyl)propionate

(53) A solution of 0.50 g (1.023 mmol) of benzyl (R)-3-(2-benzyloxycarbonylaminoethylsulfanyl)-2-tert-butoxycarbonylaminopropionate in 5 ml of dichloromethane was mixed with the same volume of trifluoroacetic acid and left to stand at RT for 1 h. It was then concentrated and directly reacted further.

(54) LC/MS (method A): R.sub.t=1.06 min, m/z: 389.1 [MH.sup.+].

C. Benzyl (R)-3-(2-benzyloxycarbonylaminoethylsulfanyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17), 14(18),15-trien-12-yl)ureido]propionate

(55) A solution of 166 mg (1.02 mmol) of 1,1-carbonyldiimidazole in 8 ml of DMF was mixed with 515 mg (1.02 mmol) of the trifluoroacetate from step B and 0.57 ml (415 mg, 4.10 mmol) of triethylamine. A solution of 328 mg (1.02 mmol) of (9S,12R)-12-amino-9-isopropyl-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-11-one (1-1E) in 8 ml of DMF was added to this mixture under argon, and the mixture was stirred at RT overnight. The reaction mixture was then concentrated and separated by preparative HPLC. The required fractions were combined and freed of acetonitrile. The resulting aqueous solution was extracted with ethyl acetate, and the organic phase was dried over sodium sulfate, filtered and concentrated. 222 mg of the title compound were obtained.

(56) LC/MS (method A): R.sub.t=1.72 min, m/z: 735.3 [MH.sup.+].

D. Benzyl (R)-3-(2-benzyloxycarbonylaminoethanesulfonyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)ureido]propionate

(57) A mixture of 222 mg (0.30 mmol) of benzyl (R)-3-(2-benzyloxycarbonylaminoethylsulfanyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-yl)ureido]propionate in 5 ml of methanol and 5 ml of water was cooled to 0 C and 742 mg (1.21 mmol) of Oxone were added in portions. After 2 h, the mixture is diluted with ethyl acetate, and the organic phase is separated off and extracted twice more with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 198 mg were obtained and were reacted further without further purification.

(58) LC/MS (method A): R.sub.t=1.54 min, m/z: 767.3 [MH.sup.+].

E. (R)-3-(2-Aminoethanesulfonyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-yl)ureido]propionic acid

(59) 83 mg of 5% palladium/C were added to a solution of 198 mg (0.26 mmol) of benzyl (R)-3-(2-benzyloxycarbonylaminoethanesulfonyl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-yl)ureido]propionate in 10 ml of methanol, and the mixture was hydrogenated under a hydrogen atmosphere (balloon pressure). After leaving to stand for 2 days, the mixture was filtered, concentrated and purified by preparative HPLC. The required fractions were combined and freeze dried after addition of 1N hydrochloric acid. 23 mg of the title compound were obtained as hydrochloride.

(60) LC/MS (method C): R.sub.t=2.35 min, m/z: 543.26 [MH.sup.+].

Example 5-2 (S)-3-(6-Aminopyridin-3-yl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-yl)ureido]propionic acid

(61) ##STR00035##

A. tert-Butyl 2-(benzhydrylideneamino)-3-(6-tert-butoxycarbonylaminopyridin-3-yl)propionate

(62) 84.64 ml (84.64 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide in THF were added dropwise to a solution of 25.00 g (84.64 mmol) of N-(diphenylmethylene)glycine tert-butyl ester in 185 ml of THF under argon at 0 C. After stirring at this temperature for 15 min, 24.31 g (84.64 mmol) of tert-butyl (5-bromomethylpyridin-2-yl)carbamate were added as solid, and stirring was continued for 1 h. The reaction mixture was cautiously diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. 44.08 g of the crude product were obtained and were reacted further without further purification.

(63) LC/MS (method A): R.sub.t=1.68 min, m/z: 502.2 [MH.sup.+].

B. tert-Butyl (S)-2-amino-3-(6-tert-butoxycarbonylaminopyridin-3-yl)propionate

(64) After addition of 4.14 g of 10% palladium/carbon to a solution of 19.50 g (38.87 mmol) of the crude product from step A in 1.8 I of methanol it was hydrogenated under autogenous pressure. After the reaction was complete, the mixture was filtered and concentrated. The crude mixture was taken up in heptane and mixed with 45 ml of 1N hydrochloric acid and 90 ml of water, and the aqueous phase was added to 90 ml of 1N sodium hydroxide solution and extracted four times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The racemate was separated by chiral chromatography.

(65) LC/MS (method A): R.sub.t=0.89 min, m/z: 338.1 [MH.sup.+]. Chiral chromatography (Chiralpak AD-H/44, 2504.6 mm, ethanol:methanol 1:1+0.1% diethylamine, 40 min): R.sub.t=17.48 min.

C. tert-Butyl (S)-3-(6-tert-butoxycarbonylaminopyridin-3-yl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-yl)ureido]propionate

(66) 112 mg (0.69 mmol) of 1,1-carbonyldiimidazole were added to a mixture of 234 mg (0.69 mmol) of tert-butyl (S)-2-amino-3-(6-tert-butoxycarbonylaminopyridin-3-yl)-propionate and 106 l (77 mg, 0.76 mmol) of triethylamine in 2.5 ml of DMF. The solution was stirred at RT for 1 h, before a solution of 222 mg (0.69 mmol) of (9S,12R)-12-amino-9-isopropyl-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-11-one (1-1E) in 2.5 ml of DMF was added. The mixture was left to stand overnight and then concentrated and partitioned between water and ethyl acetate. The organic phase was separated off, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. The required fractions were combined, freed of acetonitrile, made slightly alkaline with sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated.

(67) LC/MS (method A): R.sub.t=1.47 min, m/z: 684.3 [MH.sup.+].

D. (S)-3-(6-Aminopyridin-3-yl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-yl)ureido]propionic acid

(68) 160 mg (0.23 mmol) of tert-butyl (S)-3-(6-tert-butoxycarbonylaminopyridin-3-yl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)ureido]propionate were dissolved in 6 ml of dichloromethane and, after addition of the same volume of TFA, stirred at RT. After 5 h, the mixture was concentrated and purified by preparative HPLC. The required fractions were combined, freed of acetonitrile, mixed with 1N hydrochloric acid, concentrated further and finally freeze dried. 108 mg of the title compound were obtained as hydrochloride.

(69) LC/MS (method A): R.sub.t=0.92 min, m/z: 528.3 [MH.sup.+].

Example 5-3

(S)-3-(6-Aminopyridin-3-yl)-2-[3-((9S,12R)-9-cyclopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-yl)ureido]propionic acid

(70) The title compound was prepared in analogy to Example 5-2 from (S)-2-amino-2-cyclopropylethanol (U.S. Pat. No. 6,191,306) instead of 1-1E using (9S,12R)-12-amino-9-cyclopropyl-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-11-one.

(71) LC/MS (method J): R.sub.t=2.39 min, m/z: 526.41 [MH.sup.+].

Example 5-4

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

(72) The title compound is obtained in analogy to Example 5-2 by using ethyl (S)-2,6-diamino-6-methylheptanoate hydrochloride with the addition of triethylamine as auxiliary base.

(73) LC/MS (method C): R.sub.t=2.34 min, m/z: 521.26 [MH.sup.+].

Example 5-5

Ethyl (S)-3-(6-aminopyridin-3-yl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1-(17),14(18), 15-trien-12-yl)ureido]propionate

(74) The title compound is obtained in analogy to Example 5-2 by using N-(diphenylmethylene)glycine ethyl ester instead of N-(diphenylmethylene)glycine tert-butyl ester.

(75) LC/MS (method C): R.sub.t=2.53 min, m/z: 556.2 [MH.sup.+].

(76) The following compound was prepared in an analogous manner:

Example 5-6

(S)-2-[3-((9S,12R)-9-Isoproyl-11-oxo-2,7-dioxa-10-azabicylo[12.2.2]octadeca-1(17),14(18), 15-trien-12-yl)ureido]-3-piperidin-3-ylpropionic acid

(77) LC/MS (method I): R.sub.t=1.20 min, m/z: 519.38 [MH.sup.+].

Example 5-7

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

(78) LC/MS (method B): R.sub.t=0.54 min, m/z: 500.3 [MH.sup.+].

Example 6-1

(S)-3-(6-Aminopyridin-3-yl)-2-[3-((8S,11R)-8-isopropyl-10-oxo-6-oxa-1,9,14-triazabicyclo[11.2.1]hexadeca-13(16),14-dien-11-yl)ureido]propionic acid

A. (R)-3-(1-Allyl-1H-imidazol-4-yl)-2-benzyloxycarbonylaminopropionic acid

(79) 3.53 ml (4.24 g, 24.84 mmol) of benzyl chloroformate were added to a solution of 4.85 g (24.84 mmol) of (R)-3-(1-allyl-1H-imidazol-4-yl)-2-aminopropionic acid (as described for the (S)-enantiomer in Bioorg. Med. Chem. 2006, 14, 5981-5988) in 13 ml of 2N sodium hydroxide solution while stirring at 0 C., and stirring was continued at this temperature with addition of a further 13 ml of 2N sodium hydroxide solution for 2 h, and the mixture was them warmed to RT. The reaction mixture was covered with a layer of ethyl acetate, and the pH was adjusted to 3 to 4 with 6N hydrochloric acid. The organic phase was separated off, and the aqueous phase was washed again with ethyl acetate and then freeze dried. The residue was mixed with THF and DMF until stirrable and was thoroughly stirred, and the suspension was filtered. The resulting solution was concentrated and reacted without further purification in the next step.

(80) LC/MS (method B): R.sub.t=0.52 min, m/z: 330.2 [MH.sup.+].

B. Benzyl [(R)-2-(1-allyl-1H-imidazol-4-yl)-1-((S)-1-allyloxymethyl-2-methylpropylcarbamoyl)ethyl]carbamate

(81) A solution of the material from step A in 180 ml of DMF was mixed with 4.18 g (27.32 mmol) of N-hydroxybenzotriazole and 5.64 g (27.32 mmol) of N,N-dicyclohexylcarbodiimide and stirred at RT for 2 h. Addition of 3.56 g (24.84 mmol) of (S)-1-allyloxymethyl-2-methylpropylamine (1-1B) was followed by stirring at RT for a further 24 h and then concentration, and the residue was partitioned between ethyl acetate and saturated NaHCO.sub.3 solution. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by preparative HPLC. After washing with saturated NaHCO.sub.3 solution, 5.02 g of the title compound are obtained.

(82) LC/MS (method B): R.sub.t=0.75 min, m/z: 454.9 [MH.sup.+].

C. Benzyl ((8S,11R)-8-isopropyl-10-oxo-6-oxa-1,9,14-triazabicyclo[11.2.1]hexadeca-3,13(16),14-trien-11-yl)carbamate

(83) A solution of 0.735 g (1.62 mmol) of benzyl [(R)-2-(1-allyl-1H-imidazol-4-yl)-1-((S)-1-allyloxymethyl-2-methylpropylcarbamoyl)ethyl]carbamate in 370 ml of dichloromethane was mixed with 0.210 g (0.24 mmol) of benzylidene[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]dichloro(tricyclohexylphosphine)ruthenium (Grubbs II catalyst) and stirred at RT. The mixture was stirred at RT for several days with repeated addition of Grubbs II catalyst until starting material was no longer present (LC/MS). The mixture was concentrated and the residue was chromatographed on silica gel (dichloromethane/methanol 99:1.fwdarw.9:1). 0.506 g of the title compound was obtained.

(84) LC/MS (method B): R.sub.t=0.64 min, m/z: 427.3 [MH.sup.+].

D. (8S,11R)-11-Amino-8-isopropyl-6-oxa-1,9,14-triazabicyclo[11.2.1]hexadeca-13(16),14-dien-10-one

(85) A solution of 0.49 g (1.14 mmol) of benzyl ((8S,11R)-8-isopropyl-10-oxo-6-oxa-1,9,14-triazabicyclo[11.2.1]hexadeca-3,13(16),14-trien-11-yl)carbamate from step C in 80 ml of methanol was hydrogenated over 0.12 g of palladium on carbon (10%) under a hydrogen atmosphere under autogenous pressure at RT. After the starting material had completely reacted, the mixture was filtered and concentrated. The residue was purified by preparative HPLC. 0.06 g of the title compound was obtained.

(86) LC/MS (method B): R.sub.t=0.22 min, m/z: 295 [MH.sup.+].

E. tert-Butyl (S)-3-(6-tert-butoxycarbonylaminopyridin-3-yl)-2-[3-((8S,11R)-8-isopropyl-10-oxo-6-oxa-1,9,14-triazabicyclo[11.2.1]hexadeca-13(16),14-dien-11-yl)ureido]propionate

(87) A solution of 56 mg (190 mol) of (8S,11R)-11-amino-8-isopropyl-6-oxa-1,9,14-triazabicyclo[11.2.1]hexadeca-13(16),14-dien-10-one from step D in 5 ml of DMF was cooled to 0 C. and, while stirring, 32 mg (194 mol) of 1,1-carbonyldiimidazole were added. The mixture was stirred for 30 min, and then 64 mg (190 mol) of tert-butyl (S)-2-amino-3-(6-tert-butoxycarbonylaminopyridin-3-yl)propionate were added, and the mixture was warmed to RT. After standing overnight, the same amount of 1,1-carbonyldiimidazole was again added, and the mixture was stirred for a further 24 h. It was then concentrated and purified by preparative HPLC. 27 mg of the desired compound were obtained.

(88) LC/MS (method B): R.sub.t=0.58 min, m/z: 658.9 [MH.sup.+].

F. (S)-3-(6-Aminopyridin-3-yl)-2-[3-((8S,11R)-8-isopropyl-10-oxo-6-oxa-1,9,14-triazabicyclo[11.2.1]hexadeca-13(16),14-dien-11-yl)ureido]propionic acid

(89) A solution of 27 mg (41 mol) in 6 ml of TFA/dichloromethane (1:1, v/v) was stirred at RT for 4 h. It was then concentrated and taken up in 1N hydrochloric acid and subsequently freeze dried. 20 mg of the title compound were obtained as hydrochloride.

(90) LC/MS (method B): R.sub.t=0.36 min, m/z: 502.9 [MH.sup.+].

Example 6-2

(S)-3-(6-Aminopyridin-3-yl)-2-[3-((3R,6S)-6-isopropyl-4-oxo-8-oxa-5-azabicyclo[11.2.2]heptadeca-1(16),13(17), 14-trien-3-yl)ureido]propionic acid

A. (R)-3-(4-Allylphenyl)-2-tert-butoxycarbonylaminopropionic acid

(91) A solution of 2.03 g (6.36 mmol) of methyl (R)-3-(4-allylphenyl)-2-tert-butoxycarbonylaminopropionate (prepared as in Synlett, 2005, 12, 1877-1880) in 20 ml of dioxane/water (1:1, v/v) and 0.30 g (12.71 mmol) of lithium hydroxide was stirred at RT for 2 h and then neutralized with 1N hydrochloric acid. The reaction mixture was extracted with ethyl acetate, and the organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated. 1.90 g of the title compound were obtained.

(92) LC/MS (method B): R.sub.t=0.97 min, m/z: 206.0 [MH.sup.+].

(93) The compound was employed instead of (R)-3-(4-allyloxyphenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propionic acid in order to prepare Example 6-2 in analogy to Example 5-2. The Boc protective group used instead of the Fmoc protective group was eliminated in a known manner with dichloromethane/TFA mixtures.

(94) LC/MS (method I): R.sub.t=1.29 min, m/z: 512.3 [MH.sup.+].

Example 6-3

(S)-3-(6-Aminopyridin-3-yl)-2-[3-((9S,12R)-16-fluoro-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-yl)ureido]propionic acid

A. (R)-3-(4-Allyloxy-3-fluorophenyl)-2-tert-butoxycarbonylaminopropionic acid

(95) 1.18 g (60%, 29.39 mmol) of sodium hydride were added to a solution of 4.0 g (13.36 mmol) of (R)-2-tert-butoxycarbonylamino-3-(3-fluoro-4-hydroxyphenyl)propionic acid in 23 ml of DMF while stirring at 0 C., and the mixture was stirred at this temperature. After 15 min, 1.27 ml (1.78 g, 14.7 mmol) of allyl bromide were added, and stirring was continued for 1 h while the mixture reached RT. It was quenched with methanol and, after cooling, excess methanol was removed in a rotary evaporator. Dilution with diethyl ether was followed by acidification with 1N hydrochloric acid, and the aqueous phase was extracted twice more with diethyl ether, and the combined organic phases were washed with saturated sodium chloride solution, dried over NaSO.sub.4, filtered and concentrated. 4.50 g of a yellowish oil were obtained.

(96) LC/MS (method B): R.sub.t=0.94 min, m/z: 239.9 [MH.sup.+].

(97) The compound was employed instead of (R)-3-(4-allyloxyphenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propionic acid in order to prepare Example 6-3 in analogy to Example 5-2. The Boc protective group used instead of the Fmoc protective group was eliminated in a known manner with dichloromethane/TFA mixtures.

(98) LC/MS (method E): R.sub.t=2.40 min, m/z: 546.43 [MH.sup.+].

(99) The following examples were prepared in the same manner as above using (R)-3-allyloxy-2-tert-butoxycarbonylaminopropionic acid (prepared as described analogously in JACS, 129 (22), 6986-6987, 2007) instead of (R)-3-(4-allyloxyphenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)propionic acid:

(100) TABLE-US-00003 R.sub.t m/z Example Name (min) [MH.sup.+] Method 6-4 (S)-3-(6-Aminopyridin-3-yl)-2-[3- 1.42 452.29 G ((3S,6R)-3-isopropyl-5-oxo-1,8- dioxa-4-azacyclododec-6- yl)ureido]propionic acid 6-5 Methyl (S)-3-(6-aminopyridin-3- 2.40 466.33 D yl)-2-[3-((3S,6R)-3-isopropyl-5- oxo-1,8-dioxa-4-azacyclododec-6- yl)ureido]propionate 6-6 (S)-6-Amino-2-[3-((3S,6R)-3- 1.94 417.23 C isopropyl-5-oxo-1,8-dioxa-4- azacyclododec-6-yl)ureido]- hexanoic acid

Example 6-7

(S)-6-Amino-2-[3-((9S,12S)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo-[12.2.2]octadec-12-yl)ureido]hexanoic acid

A. (S)-2-tert-Butoxycarbonylamino-3-(4-hydroxycyclohexyl)propionic acid

(101) 0.74 g (7.17 mmol) of rhodium was added to a solution of 7.00 g (24.88 mmol) of (S)-2-tert-butoxycarbonylamino-3-(4-hydroxyphenyl)propionic acid in 50 ml of methanol, and hydrogenation was carried out at 50 C/6 bar pressure of hydrogen. After conversion was complete, the catalyst was filtered off and the filtrate was concentrated. The product was pure enough for further reactions.

(102) LC/MS (method K): R.sub.t=1.00 min, m/z: 188.2 [MH.sup.+].

B. (S)-3-(4-Allyloxycyclohexyl)-2-tert-butoxycarbonylaminopropionic acid

C. solution of 5.42 g (18.86 mmol) of (S)-2-tert-butoxycarbonylamino-3-(4-hydroxy-cyclohexyl)propionic acid

(103) In 20 ml of DMF was added dropwise over the course of 30 min to a suspension of 1.89 g (47.14 mmol) of 60% sodium hydride in 20 ml of DMF at 0 C. Then 2.28 g (18.86 mmol) of allyl bromide were added, and the mixture was warmed to RT and then stirred for 3 h. It was cautiously quenched with water and concentrated. The residue was dissolved in water and washed with ethyl acetate. The aqueous phase was adjusted to pH 2 with 6M HCl and extracted with ethyl acetate. The organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated. The title compound obtained in this way was reacted further without further purification.

(104) LC/MS (method K): R.sub.t=1.46 min, m/z: 228.1 [MH.sup.+-Boc].

(105) The further reactions to give Example 6-7 were carried out as described above by employing B. instead of D-Boc-O-allyltyrosine.

(106) LC/MS (method F): R.sub.t=2.8 min, m/z: 499.55 [MH.sup.+].

Example 7-1

(S)-6-Amino-2-[3-((8S,11R)-8-isopropyl-3,10-dioxo-6-oxa-2,9-diazabicyclo[11.2.2]heptadeca-1(16),13(17),14-trien-11-yl)ureido]hexanoic acid

(107) ##STR00036## ##STR00037##

A. Ethyl 3-((S)-2-tert-butoxycarbonylamino-3-methylbutoxy)propionate

(108) About 200 mg of sodium were added to a solution of 3.00 g (14.76 mmol) of Boc-L-valinol in 20 ml of absol. THF under argon. After 2 h, the solution was transferred by needle into an argon-flushed flaskleaving undissolved sodium behind. 2.25 ml (2.22 g, 22.14 mmol) of ethyl acrylate were added to the solution, and the mixture was stirred at room temp. for 2 h. 6 drops of glacial acetic acid were added to the reaction mixture, which was concentrated under reduced pressure. The residue obtained in this way (4.45 g of colorless oil) was employed crude in the next stage.

B. Ethyl 3-((S)-2-amino-3-methylbutoxy)propionate

(109) The crude product (4.45 g) obtained in 7-1 A was dissolved in a mixture of 10 ml of CH.sub.2Cl.sub.2 and 10 ml of TFA and stirred at room temp. for 2 h. After the reaction was complete, the mixture was concentrated in vacuo and codistilled with toluene several times. The crude product obtained in this way was purified by preparative HPLC (acetonitrile/water+addition of 0.5% TFA). 370 mg of ethyl 3-((S)-2-amino-3-methyl-butoxy)propionate were obtained in this way as trifluoroacetate in the form of a colorless oil (yield8%).

(110) LC/MS (method B): R.sub.t=0.52 min, m/z: 204.3 [MH.sup.+].

C. Ethyl 3-((S)-2-{(R)-2-tert-butoxycarbonylamino-3-[4-(9H-fluoren-9-ylmethoxy-carbonylamino)phenyl]propionylamino}-3-methylbutoxy)propionate

(111) 158.7 mg (1.17 mmol) of HOAt, 0.6 ml (3.5 mmol) of N,N-diisopropylethylamine and 443.3 mg (1.17 mmol) of HATU were successively added to a mixture of 586.0 mg (1.17 mmol) of R)-2-tert-butoxycarbonylamino-3-[4-(9H-fluoren-9-ylmethoxycarbonylamino)phenyl]propionic acid and 370.0 mg (1.17 mmol) of ethyl 3-((S)-2-amino-3-methylbutoxy)propionate in 10 ml of DMF, and the mixture was stirred at room temp. for 2 h. The reaction mixture was concentrated in vacuo. The remaining residue was taken up in dichloromethane, washed with sat. NaHCO.sub.3 solution, dried and freed of solvent under reduced pressure. The crude product obtained in this way was purified by flash chromatography on silica gel (heptane/ethyl acetate 1:1). 355.0 mg of pure ethyl 3-((S)-2-{(R)-2-tert-butoxycarbonylamino-3-[4-(9H-fluoren-9-ylmethoxy-carbonylamino)phenyl]propionylamino}-3-methylbutoxy)propionate are obtained in this way (yield 44%).

(112) LC/MS (method B): R.sub.t=1.23 min, m/z: 588.3 [M-Boc+H+].

D. 3-{(S)-2-[(R)-3-(4-Aminophenyl)-2-tert-butoxycarbonylaminopropionylamino]-3-methylbutoxy}propionic acid

(113) 355.0 mg (0.52 mmol) of ethyl 3-((S)-2-{(R)-2-tert-butoxycarbonylamino-3-[4-(9H-fluoren-9-ylmethoxycarbonylamino)phenyl]propionylamino}-3-methylbutoxy)propionate were dissolved in a mixture of 9 ml of THF and 3 ml of MeOH. 1.29 ml (1.29 mmol) of an aqueous 1M LiOH solution were added, and the resulting reaction mixture was stirred at room temp. for 1 h. After the reaction was complete, the mixture was neutralized by adding a little aqueous 1N HCl solution, concentrated under reduced pressure and codistilled with toluene. The product obtained in this way (225.0 mg) was employed crude in the next reaction.

(114) LC/MS (method B): R.sub.t=0.63 min, m/z: 438.3 [MH.sup.+].

E. tert-Butyl ((8S,11R)-8-isopropyl-3,10-dioxo-6-oxa-2,9-diazabicyclo[11.2.2]heptadeca-1(16),13(17),14-trien-11-yl)carbamate

(115) The 3-{(S)-2-[(R)-3-(4-aminophenyl)-2-tert-butoxycarbonylaminopropionylamino]-3-methylbutoxy}propionic acid (225 mg) obtained as crude product in 7-1 D was dissolved in 225 ml of DMF. 70.0 mg (0.51 mmol) of HOAt, 0.26 ml (1.5 mmol) of N,N-diisopropylethylamine and 195.4 mg (0.51 mmol) of HATU were successively added to this solution, and the mixture was stirred at room temp. for 1 h. The reaction mixture was concentrated in vacuo. The residue obtained in this way was taken up in CH.sub.2Cl.sub.2, washed with sat. NaHCO.sub.3 solution, dried over MgSO.sub.4 and freed of solvent in vacuo. The ring-closed compound obtained in this way was employed crude in the next stage. Yield: 215.0 mg.

(116) LC/MS (method B): R.sub.t=0.76 min, m/z: 364.3 [M-tBu+H.sup.+].

F. (8S,11R)-11-Amino-8-isopropyl-6-oxa-2,9-diazabicyclo[11.2.2]heptadeca-1(16),13(17), 14-triene-3,10-dione

(117) The crude product (215 mg) obtained in 7-1 E was stirred in a mixture of 4.75 ml of TFA, 0.13 ml of water and 0.13 ml of triisopropylsilane at room temp. for 2 h. After the reaction was complete, the mixture was concentrated in vacuo and codistilled with toluene several times. The crude product obtained in this way was purified by preparative HPLC (acetonitrile/water+addition of 0.1% TFA). 80 mg of (8S,11R)-11-amino-8-isopropyl-6-oxa-2,9-diazabicyclo[11.2.2]heptadeca-1(16),13(17),14-triene-3,10-dione were obtained in this way as trifluoroacetate in the form of a colorless amorphous material.

(118) LC/MS (method B): R.sub.t=0.44 min, m/z: 321.3 [MH.sup.+].

G. tert-Butyl (S)-6-tert-butoxycarbonylamino-2-[3-((8S,11R)-8-isopropyl-3,10-dioxo-6-oxa-2,9-diazabicyclo[11.2.2]heptadeca-1(16),13(17), 14-trien-11-yl)ureido]hexanoate

(119) 81.9 mg (0.41 mmol) of 4-nitrophenyl chloroformate were dissolved in 3 ml of CH.sub.2Cl.sub.2. While cooling in an ice bath, a solution of 80 mg (0.19 mmol) of the (8S,11R)-11-amino-8-isopropyl-6-oxa-2,9-diazabicyclo[11.2.2]heptadeca-1(16),13(17),14-triene-3,10-dione obtained in 7-1 F and 69 l (0.41 mmol) of N,N-diisopropylethylamine in 3 ml of CH.sub.2Cl.sub.2 were added. The mixture was then stirred at room temp. for 3 h. The reaction mixture was washed with sat. NaHCO.sub.3 solution, water and saturated NaCl solution, dried over MgSO.sub.4 and concentrated in vacuo. The residue obtained in this way was dissolved in 3 ml of DMF and mixed with a solution of 68.8 mg (0.2 mmol) of H-Lys(Boc)-OtBu hydrochloride and 65.9 l (0.39 mmol) of N,N-diisopropylethylamine in 3 ml of DMF. The reaction mixture was stirred at room temp. overnight and then concentrated in vacuo. The crude product obtained in this way was purified by flash chromatography on silica gel (heptane/ethyl acetate 1:1). Yield: 20 mg of tert-butyl (S)-6-tert-butoxycarbonylamino-2-[3-((8S,11R)-8-isopropyl-3,10-dioxo-6-oxa-2,9-diazabicyclo[11.2.2]heptadeca-1(16), 13(17),14-trien-11-yl)ureido]hexanoate.

(120) LC/MS (method B): R.sub.t=0.91 min, m/z: 648.5 [MH.sup.+].

H. (S)-6-Amino-2-[3-((8S,11R)-8-isopropyl-3,10-dioxo-6-oxa-2,9-diazabicyclo[11.2.2]heptadeca-1(16),13(17), 14-trien-11-yl)ureido]hexanoic acid

(121) 20.0 mg (0.03 mmol) of tert-butyl (S)-6-tert-butoxycarbonylamino-2-[3-((8S,11R)-8-isopropyl-3,10-dioxo-6-oxa-2,9-diazabicyclo[11.2.2]heptadeca-1 (16),13(17),14-trien-11-yl)ureido]hexanoate were stirred in a mixture of 0.95 ml of TFA, 25 l of water and 25 l of triisopropylsilane at room temp. for 2 h. After the reaction was complete, the mixture was concentrated in vacuo and codistilled with toluene several times. The crude product obtained in this way was purified by preparative HPLC (acetonitrile/water+addition of 0.1% TFA). 5 mg of the title compound were obtained in this way as trifluoroacetate in the form of a colorless amorphous material.

(122) LC/MS (method B): R.sub.t=0.47 min, m/z: 492.3 [MH.sup.+].

(123) The following examples were prepared in an analogous manner:

Example 7-2

(S)-3-(6-Aminopyridin-3-yl)-2-[3-((8S,11R)-8-methyl-3,10-dioxo-6-oxa-2,9-diazabicyclo[11.2.2]heptadeca-1(16),13(17), 14-trien-11-yl)ureido]propionic acid

(124) LC/MS (method B): R.sub.t=0.28 min, m/z: 499.25 [MH.sup.+]

Example 7-3

(S)-3-(6-Aminopyridin-3-yl)-2-[3-((3S,6R)-3-isopropyl-5, 9-dioxo-1-oxa-4,10-diazacyclotridec-6-yl)ureido]propionic acid

(125) LC/MS (method B): R.sub.t=0.42 min, m/z: 479.33 [MH.sup.+].

Example 7-4

(S)-3-(6-Aminopyridin-3-yl)-2-[3-((8S,11R)-8-isopropyl-2,10-dioxo-6-oxa-3,9-diazabicyclo[11.2.2]heptadeca-1(16),13(17), 14-trien-11-yl)ureido]propionic acid

(126) LC/MS (method A): R.sub.t=0.82 min, m/z: 527.20 [MH.sup.+].

Example 8-1

(S)-6-Amino-2-[3-((9S,12R)-4,5-dihydroxy-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)ureido]hexanoic acid

(127) ##STR00038##

A. (9S,12R)-12-Amino-9-isopropyl-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),4,14(18),15-tetraen-11-one

(128) A solution of 3.66 g (6.78 mmol) of 9H-fluoren-9-yl methyl ((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),4,14(18), 15-tetraen-12-yl)carbamate (1-1D) in 300 ml of dichloromethane was mixed with 75 ml of diethylamine and stirred at RT for 5 h. The mixture was concentrated and purified by preparative HPLC. Acetonitrile was removed from the combined product fractions in a rotary evaporator, saturated NaHCO.sub.3 solution was added, and the mixture was extracted twice with ethyl acetate, saturated with sodium chloride and again extracted with ethyl acetate. The combined ethyl acetate phases were dried over Na.sub.2SO.sub.4, filtered and concentrated. The resulting substance was pure enough for further reactions.

(129) LC/MS (method B): R.sub.t=0.58 min, m/z: 319.2 [MH.sup.+].

B. tert-Butyl (S)-6-tert-butoxycarbonylamino-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),4,14(18), 15-tetraen-12-yl)ureido]hexanoate

(130) The reaction took place as described in 1-1F. 1.13 g of the title compound were obtained.

(131) LC/MS (method B): R.sub.t=1.00 min, m/z: 647.3 [MH.sup.+].

C. tert-Butyl (S)-6-tert-butoxycarbonylamino-2-[3-((9S,12R)-4,5-dihydroxy-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-yl)ureido]hexanoate

(132) 8 mg (9.7 mol) of (DHQ)2PHAL (hydroquinine 1,4-phthalazinediyl diether) were added to a mixture of 541 mg (387 mmol) of AD-Mix-alpha and 3 mg (7.7 mol) of potassium osmate in tert-butanol/water (1:1, v/v). After a clear solution had formed, the reaction mixture was cooled to 0 C., 41 mg (425 mol) of methanesulfonamide were added, and the mixture was stirred at this temperature for 15 min. Then 250 mg (387 mol) of tert-butyl (S)-6-tert-butoxycarbonylamino-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),4,14(18), 15-tetraen-12-yl)ureido]hexanoate (step B) were added, and the mixture was warmed to RT and left to stand over the weekend. 195 mg (1.55 mmol) of sodium sulfite were then added, and the mixture was stirred at RT for 1 h. The reaction mixture was extracted with ethyl acetate, and the organic phase was dried over Na.sub.2SO.sub.4, filtered and concentrated in a rotary evaporator. The residue was purified by preparative HPLC. 164 mg of the title compound were obtained.

(133) LC/MS (method B): R.sub.t=0.84 min, m/z: 681.3 [MH.sup.+].

D. (S)-6-Amino-2-[3-((9S,12R)-4,5-dihydroxy-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-yl)ureido]hexanoic acid

(134) The protective groups were eliminated as described above in a TFA/dichloromethane mixture. A mixture of the diastereomers was obtained.

(135) LC/MS (method B): R.sub.t=0.42 min (double peak), m/z: 525.3 [MH.sup.+].

Example 8-2

(S)-6-Amino-2-[3-((9S,12R)-5-hydroxy-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-yl)ureido]hexanoic acid and (S)-6-amino-2-[3-((9S,12R)-4-hydroxy-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-yl)ureido]hexanoic acid

A. tert-Butyl (S)-6-tert-butoxycarbonylamino-2-[3-((9S,12R)-5-hydroxy-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-yl)ureido]-hexanoate

(136) 1.55 ml (773 mol) (0.5M in THF) of 9-borabicyclo[3.3.1]nonane were added to a solution of 50 mg (77 mol) of tert-butyl (S)-6-tert-butoxycarbonylamino-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),4,14(18),15-tetraen-12-yl)ureido]hexanoate (8-1B) in 1.5 ml of THF, and the mixture was stirred at RT overnight. Addition of 250 l (1.49 mmol) of 6N sodium hydroxide solution and 207 l (1.83 mmol) of hydrogen peroxide was followed by extraction with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was purified by preparative HPLC.

(137) LC/MS (method B): R.sub.t=0.86 min, m/z: 665.5 [MH.sup.+].

B. (S)-6-Amino-2-[3-((9S,12R)-5-hydroxy-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17), 14(18),15-trien-12-yl)ureido]hexanoic acid and (S)-6-amino-2-[3-((9S,12R)-4-hydroxy-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-yl)ureido]henanoic acid

(138) The protective groups were eliminated as described above in a TFA/dichloromethane mixture and subsequent stirring in 1 N HCl.

(139) LC/MS (method B): R.sub.t=0.48 min, m/z: 509.2 [MH.sup.+].

Example 8-3

3-(6-Aminopyridin-3-yl)-2-[3-((9S,12R)-4,5-dihydroxy-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-yl)ureido]propionic acid

(140) The title compound was obtained in analogy to the preceding examples.

(141) LC/MS (method L): R.sub.t=2.15 min, m/z: 560.26 [MH.sup.+].

Example 9-1

(S)-6-Amino-2-[((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-ylsulfamoyl)amino]hexanoic acid

A. tert-Butyl (S)-6-tert-butoxycarbonylamino-2-[((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-ylsulfamoyl)amino]hexanoate

(142) A solution of 387 mg (0.858 mmol) of tert-butyl (S)-6-tert-butoxycarbonylamino-2-(2-oxooxazolidine-3-sulfonylamino)hexanoate and 250 mg (0.780 mmol) of (9S,12R)-12-amino-9-isopropyl-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-11-one (compound 1-1E) in 15 ml of acetonitrile was stirred at 80 C. After 1 day (d), the same amount of the oxazolidine was again added, and the mixture was stirred for 1 d. The reaction mixture was then concentrated and the residue was purified by prep. HPLC. Product-containing fractions were combined, the acetonitrile was evaporated off, made slightly alkaline with sat. NaHCO.sub.3 solution and extracted several times with ethyl acetate. The combined organic phases were dried over Na.sub.2SO.sub.4, filtered and concentrated. 78 mg of the title compound were obtained.

(143) LC/MS (method B): R.sub.t=1.16 min, m/z: 585.9 [MH-Boc.sup.+].

B. (S)-6-Amino-2-[((9S,12R)-9-isopropyl-11-oxo-2,7-d ioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-ylsulfamoyl)amino]hexanoic acid

(144) A solution of 78 mg (0.114 mmol) of tert-butyl (S)-6-tert-butoxycarbonylamino-2-[((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-ylsulfamoyl)amino]hexanoate in 3 ml of dichloromethane/TFA (1:1, v/v) was left to stand at RT for 2 h and then concentrated. The crude product was purified by prep. HPLC. The required fractions were combined and freeze dried after addition of 1N hydrochloric acid. 34 mg of the title compound were obtained as hydrochloride. LC/MS (method F):

(145) R.sub.t=2.97 min, m/z: 529.23 [MH.sup.+].

Example 9-2

(S)-6-Amino-2-[((9S,12S)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18), 15-trien-12-ylsulfamoyl)amino]hexanoic acid

(146) The title compound was obtained in analogy to the preceding examples. LC/MS (method F): R.sub.t=2.81 min, m/z: 529.23 [MH.sup.+]

Pharmacological Examples

(147) 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 l of assay buffer (20 mM Hepes, 150 mM NaCl, pH 7.4) and 10 l of TAFIa (American Diagnostica Pr. No. 874TAFIA; 2.5 g/ml) to 2 l 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 l 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.

(148) 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).

(149) Table 1 shows the results.

(150) TABLE-US-00004 TABLE 1 Example IC.sub.50 No. [M] 1-1 0.006 1-2 9.044 1-3 0.269 1-4 0.071 1-5 0.105 1-6 0.811 1-7 0.049 1-8 0.029 1-9 0.019 2-1 0.0088 3-1 0.0077 4-1 0.017 5-1 0.649 5-2 0.009 5-3 0.032 6-1 0.052 6-2 0.021 6-3 0.012 6-4 0.055 6-6 0.053 7-1 0.022 7-4 0.040 8-1 0.023 8-2 0.033 8-3 0.059