WO2002034751A1

WO2002034751A1 - Hexahydro-4-oxoazepino[3,2,1-hi]indoles

Info

Publication number: WO2002034751A1
Application number: PCT/EP2001/012251
Authority: WO
Inventors: Silvio Roggo; Samuel Hintermann; Vittorio Rasetti; Ulrike Von Krosigk
Original assignee: Novartis Ag; Novartis Pharma Gmbh
Priority date: 2000-10-25
Filing date: 2001-10-23
Publication date: 2002-05-02
Also published as: AU2002212341A1; GB0026106D0

Abstract

The invention provides compounds of formula (I): wherein Q° and A are as defined in the description, and the preparation thereof. The compounds of formula (I) are useful as pharmaceuticals.

Description

HEXAHYDRO-4-OXOAZEPINθr3.2,1-hπiNDOLES

The present invention relates to novel 1 , 2, 4, 5, 6, 7-hexahydro-4-oxoazepino[3,2,1- h ndoles, their preparation, their use as pharmaceuticals and pharmaceutical compositions containing them.

More particularly the invention provides a compound of formula I

wherein

Q° is phenyl or (Cι_₄)alkylphenyl, wherein in each case the phenyl ring optionally bears one to five substituents selected from halogen, (Cι.₄)alkyl, (Cι.₄₎)alkoxy,

(Ci_ )alkylthio or trifluoromethyl, and A is a group -X- Q^ wherein -X- is -0-, -S-, -N[ (d.₄)alkyl]- ,-NH-CH₂- or -N(phenyl)- and Qι is propargyl or phenyl optionally bearing 1 to 5 substituents selected from halogen, (C^alkyl, (C₁.₄)alkoxy, (C₁. )alkylthio, trifluoromethoxy and benzyl, in free form or as a salt.

Halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

On account of the asymmetrical carbon atoms which are present in the compounds of formula I and their salts, the compounds may exist in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures. All optical isomers and their mixtures including the racemic mixtures are part of the present invention.

In a further aspect, the invention provides a process for the production of the compounds of formula I and their salts, comprising the steps of reacting a compound of formula II

wherein Zι is A-CO- , A being as defined above, or an amino-protecting group, with a compound of formula III

wherein Q° is as defined above and Z₂ is a carboxy-protecting group; if is an amino- protecting group, deprotecting the amino group and introducing the desired A-CO- group; oxidizing the hydroxy to an oxo-group and deprotecting the carboxy group; and recovering the resulting compound of formula I in free form or in form of a salt.

The reaction of the compound of formula II with the compound of formula III can be effected according to conventional methods in the presence of a standard peptide coupling agent, e.g. as described in Example 1 i.

Amino-protecting groups Zi and carboxy-protecting groups Z₂ refer to groups commonly employed to block or protect the amino or carboxylic acid groups and are well known in the art. Also deprotection of amino and carboxy groups is effected according to conventional methods, e.g. as described in Example 1j and 1 m.

The oxidation of the hydroxy group can be effected according to known methods, for example using Dess-Martin periodinane in methylene chloride (see Example 11).

The starting materials of formulae II and III are known and may be obtained from known compounds, using conventional procedures, e.g. as described in Example 1 , a to h and 36, a to b. Compounds of formula I and their pharmaceutically acceptable salts, hereinafter referred to as agents of the invention, exhibit valuable pharmacological properties when tested in vitro and in animals, and are therefore useful as pharmaceuticals.

In particular the agents of the invention are inhibitors of interleukin-1 β converting enzyme and related proteases ("ICE/ced-3 family of cysteine proteases").

Interleukin 1 ("IL-1 ") is a major pro-inflammatory and immunoregulatory protein that stimulates fibroblast differentiation and proliferation, the production of prostaglandins, collagenase and phospholipase by synovial cells and chondrocytes, basophil and eosinophil degranulation and neutrophil activation. J. H. Oppenheim et al., Immunology Today, 7:45-56 (1986). As such, it is involved in the pathogenesis of chronic and acute inflammatory and autoimmune diseases. IL-1 is predominantly produced by peripheral blood monocytes as part of the inflammatory response. B. S. osely et al., Proc. Nat. Acad. Sci. , 84:4572-4576 (1987); G. Lonnemann et al., Eur. J. Immunol. , 19:1531-1536 (1989).

IL-1 β is synthesized as a biologically inactive precursor, prolL-1 β. ProlL-1 β is cleaved by a cysteine protease called interleukin-1 β converting enzyme ("ICE") between Asp-116 and Ala- 117 to produce the biologically active C-terminal fragment found in human serum and synovial fluid. P. R. Sleath et al., J. Biol. Chem. , 265:14526-14528 (1992); A. D. Howard et al., J. Immunol. , 147:2964-2969 (1991 ).

ICE is a cysteine protease localized primarily in monocytes. In addition to promoting the pro- inflammatory and immunoregulatory properties of IL-1 β, ICE, and particulary its homologues, also appear to be involved in the regulation of cell death or apoptosis. J. Yuan et al., Cell, 75:641-652 (1993); M. Miura et al., Cell, 75:653-660 (1993); M. A. Nett-Giordalisi et al., J. Cell Biochem., 17B:117 (1993). In particular, ICE or ICE/ced-3 homologues are thought to be associated with the regulation of apoptosis in neurogenerative diseases, such as Alzheimer's and Parkinson's disease. J. Marx and M. Baringa, Science, 259:760-762 (1993); V. Gagliardini et al., Science, 263:826-828 (1994).

Thus, disease states in which inhibitors of the ICE/ced-3 family of cysteine proteases may be useful as therapeutic agents include: infectious diseases, such as meningitis and salpingitis; septic shock, respiratory diseases; inflammatory conditions, such as arthritis, cholangitis, colitis, encephalitis, endocerolitis, hepatitis, pancreatitis and reperfusion injury, ischemic diseases such as myocardial infarction, stroke and ischemic kidney disease; immune-based diseases, such as hypersensitivity; auto-immune diseases, such as multiple sclerosis; bone diseases; certain neurodegenerative diseases such as Alzheimer's and Parkinson's disease; and ophthalmic diseases such as glaucoma and myopia.

The agents of the invention inhibit the ICE/ced-3 family of cysteine proteases, as determined in the assay according to J.C. Wu and L.C. Fritz [Methods, 17(4): 320-8 (1999)] or in the assay according to M. Garcia - Calvo et al. [J. Biol. Chem., 273(49): 32608-13 (1998)] in which the agents of the invention exhibit Ki values of from about 0.1 to about 5000 nanoMolar.

The agents of the invention are therefore Useful in the treatment of the above-listed disease states, more particularly in the treatment of inflammatory diseases, autoimmune diseases and neurodegenerative diseases, and for inhibiting unwanted apoptosis involved in ischemic injury, such as ischemic injury to the heart (e.g. .myocardial infraction), brain (e.g. , stroke), and kidney (e.g. , ischemic kidney disease).

The utility of the agents of the invention in the above-indicated diseases could be confirmed in a range of standard tests, for example they reduce ischaemia-induced neuronal damage and ensuing symptoms in the middle cerebral artery (MCA) occlusion model in rats at a dosage of 3-100 mg/kg i.p., i.v. and p.o. [cf. A. Tamura et al., J. Cereb. Blood Flow Metabol. 1 , 53-60 (1981 ), A. Sauter, M. Rudin, Stroke 17, 1228-1234 (1986)].

For the above-mentioned indications, the appropriate dosage will of course vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.05 to about 150, preferably from about 0.1 to about 100 mg/kg animal body weight. In larger mammals, for example humans, an indicated daily dosage is in the range from about 0.5 to about 5000, preferably from about 1 to about 500mg of an agent of the invention, conveniently administered, for example, in divided doses up to four times a day or in sustained release form. The agent of the invention may be administered by any conventional route, in particular enterally, preferably orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions.

In accordance with the foregoing, the present invention also provides an agent of the invention, for use as pharmaceutical, e.g. for the treatment of any condition indicated above.

The present invention furthermore provides a pharmaceutical composition comprising an agent of the invention in association with at least one pharmaceutical carrier or diluent. Such compositions may be manufactured in conventional manner. Unit dosage forms contain, for example, from about 0.1 to about 2500, preferably from 0.1 to about 250 mg of a compound according to the invention.

Moreover the present invention provides the Use of an agent of the invention, for the manufacture of a medicament for the treatment of any condition mentioned above.

In still a further aspect the present invention provides a method for the treatment of any condition mentioned above, in a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of an agent of the invention.

The following examples illustrate the invention. The temperatures are given in degrees Celsius and are uncorrected.

Example 1

4-Oxo-3-[(4-oxo-5-phenoxycarbonylamino-1 ,2,4,5,6,7-hexahydro-azepino[3,2,1 - hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

a) 3-Benzyloxycarbonylamino-N-methoxy-N-methyl-succinamic acid tert-butyl ester

A solution of 50.0 g (154.6 mmol) 2-benzyloxycarbonylamino-succinic acid 4-tert-butyl ester, 24.7 g (162.4 mmol, 1.05 eq.) 1-hydroxy-benztriazole hydrate (HOBt.H₂0) and 32.6 g (170.1 mmol, 1.1 eq.) N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimid- hydrochloride (EDC.HCI) in 500 ml of methylene chloride is stirred at 0 ° for 15 min. Then, 17.4 g (178.5 mmol, 1.15 eq.) of N.O-dimethyl hydroxylamine hydrochloride and 20 ml (181 mmol, 1.17 eq.) of N-methyl morpholine are added and stirring is continued for 16 hours under warming to room temperature. The solvent is evaporated, the residue dissolved in ethyl acetate, washed with 5% KHS0 solution, saturated NaHCO₃ solution and brine, dried (Na₂S0 ) and concentrated. Crystallization from methylene chloride/hexane yields 108.22 g (96%) of the desired product. Mp. 72-74°

b) 3-Benzyloxycarbonylamino-4-oxo-butyric acid tert-butyl ester

A solution of 40.3 g (110 mmol) of 3-benzyloxycarbonylamino-N-methoxy-N-methyl- succinamic acid tert-butyl ester is dissolved in 1100 ml of diethyl ether and cooled to - 5 °. At this temperature 66 ml (66 mmol, 0.6 eq.) of a 1 M lithium aluminum hydride solution in diethyl ether are carefully added and the mixture is stirred for 2 hours. The reaction is quenched by careful addition of 260 ml of 0.3M KHSO solution, the phases separated, and the aqueous phase extracted with diethyl ether. The combined organic fractions are then washed with 5% KHS0₄ solution and brine, dried (Na₂S0₄) and concentrated. This yields 34.9 g (quant.) of the title compound as a pale yellow oil which is used without further purification.

c) 3-Benzyloxycarbonylamino-pent-4-enoic acid tert-butyl ester

To a solution of 1.03 g (2.88 mmol, 1.6 eq.) of methyl triphenylphosphonium bromide in 25 ml of THF is added 3.7 ml (2.75 mmol, 1.7 eq.) of a 15% potassium bis(trimethylsilyl)amide solution in toluene and stirring is continued at room temperature for 1 hour. Then, the reaction mixture is cooled to -75 ° and 0.5 g (1.6 mmol) of 3-benzyloxycarbonylamino-4-oxo-butyhc acid tert-butyl ester are added dropwise. After 2 hours the reaction mixture is warmed to room temperature, quenched with 2.5 ml of MeOH and poured onto potassium sodium tartrate solution and extracted with ethyl acetate. The organic fractions are washed with brine, dried (Na₂SO₄) and concentrated. Purification by silica gel chro atography (2.5-5% ethyl acetate/hexane) yields 0.311 g (63%) of 3-benzyloxycarbonylamino-pent-4-enoic acid tert-butyl ester. Mass spectrum: m/z 306.2 (M+H).

d) 3-Benzyloxycarbonylamino-4,5-dihydroxy-pentanoic acid tert-butyl ester

A solution of 0.229 g (0.75 mmol) 3-benzyloxycarbonylamino-pent-4-enoic acid tert- butyl ester in 1.2 ml of acetone and 0.75 ml of water is treated with N-methyl morpholine-N-oxide monohydrate (0.1 12 g, 1.1 eq.) and 0.2 ml of a 2.5% solution of Os0 in t-butanol. After 16 hours stirring at room temperature, the black solution is dissolved in ethyl acetate and washed three times with brine. The organic fractions are dried (Na₂S0₄) and concentrated. Filtration over silica gel (70% ethyl acetate/hexane) yields 0.23 g (90%) of the desired product as an oil. Mass spectrum: m/z 340.3 (M+H).

e) 3-Benzyloxycarbonylamino-5-(tert-butyl-dimethyl-silanyloxy)-4-hydroxy- pentanoic acid tert-butyl ester

To a solution of 16.7 g (49.2 mmol) of 3-benzyloxycarbonylamino-4,5-dihydroxy- pentanoic acid tert-butyl ester in 150 ml of DMF at 0 ° are added 4.02 g (59.0 mmol, 1.2 eq.) of imidazole and dropwise 8.15 g (54.1 mmol, 1.1 eq.) of tert-butyl-chloro- dimethyl-silane dissolved in 15 ml of DMF. After 6 hours at room temperature, the solvent is removed and the residue dissolved in 150 ml of ethyl acetate. The organic fractions are washed with NaHS0₄ (5%, 200 ml), water (100 ml), brine (100 ml), dried (Na₂S0₄) and concentrated which yields 23.0 g of an oil that is used for the next step without further purification. Mass spectrum: m/z 454 (M+H).

f) [3-Benzylcarbamoyl-2,2-dimethyl-5-(tert-butyl-dimethyl-silanyloxymethyl)- oxazolidin-4-yl] acetic acid tert-butyl ester

A solution of 23.0 g (49.2 mmol, crude) of 3-benzyloxycarbonylamino-5-(tert-butyl- dimethyl-silanyloxy)-4-hydroxy-pentanoic acid tert-butyl ester and 1.23 g (4.9 mmol, 0.1 eq.) of pyridinium 4-toluenesulfonate in 100 ml of dimethoxy propane is stirred at 80 ° for 3 hours. The reaction mixture is cooled to room temperature, filtered and concentrated in vacuo to give 24.5 g of the title compound as a pale oil which is used without further purification for the next step.

g) [3-Benzylcarbamoyl-2,2-dimethyl-5-hydroxymethyl-oxazolidin-4-yl]-acetic acid tert-butyl ester

Crude [3-Benzylcarbamoyl-2,2-dimethyl-5-(tert-butyl-dimethyl-silanyloxymethyl)- oxazolidin-4-yl] acetic acid tert-butyl ester (24.5 g, <49.2 mmol) is dissolved in 200 ml of THF. To this solution 17.1 g (54.2 mmol) of tetrabutylammonium fluoride trihydrate (TBAF.3H₂0) are added and the mixture is stirred at room temperature for 30 minutes. The solution is poured onto 400 ml of ethyl acetate, the organic fractions are washed with water (100 ml), brine (100 ml), dried (Na₂S0₄) and concentrated. Flash chromatography (10 to 33% ethyl acetate/hexane) of the residue affords 10.3 g (55% over 3 steps) of the pure product as a clear oil. Mass spectrum: m/z 380.3 (M+H).

h) [3-Benzylcarbamoyl-2,2-dimethyl-5-(2,3,5,6-tetrafluoro-phenoxymethyl)- oxazolidin-4-yl]-acetic acid tert-butyl ester

To a solution of 12.8 g (48.8 mmol, 2.5 eq.) of triphenyl phosphine, 4.1 g (24.7 mmol, 1.25 eq.) of 2,3,5, 6-tetrafluoro phenol and 7.4 g (19.5 mmol) of [3-Benzylcarbamoyl- 2,2-dimethyl-5-hydroxymethyl-oxazolidin-4-yl]-acetic acid tert-butyl ester in 15 ml of THF is carefully added 7.6 ml (48.8 mmol, 2.5 eq.) of diethyl azodicarboxylate (DEAD) at rt. After 4 hours stirring the mixture is poured onto ethyl acetate and washed with sat. NaHC0₃ solution and brine, dried (Na₂S0₄) and concentrated. Column chromatography (5-10% ethyl acetate/hexane) yields 8.5 g (83%) of the desired ester as a white solid. Mass spectrum: m/z 528.2 (M+H).

i) 4-Hydroxy-3-[(4-oxo-5-benzyloxycarbonylamino-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)- pentanoic acid tert-butyl ester

To a solution of 16.5 g (31.3 mmol) [3-benzylcarbamoyl-2,2-dimethyl-5-(2, 3,5,6- tetrafluoro-phenoxymethyl)-oxazolidin-4-yl]-acetic acid tert-butyl ester in 0.5 I ethyl alcohol 1.65 g of 10% Pd/C are added. The reaction mixture is kept at room temperature under hydrogen gas for 4 hours and is then filtered over Hyflo. The residue is washed again with ethanol and the combined fractions are evaporated and dried at high vacuum to yield 12.16 g crude product. 5.81 g (16.5 mmol) of the product and 5.7 g (15.0 mmol) 5-benzyloxycarbonylamino-4-oxo-1 ,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carboxylic acid are dissolved in 80 ml DMF, subsequently 6.25 g (16.5 mmol) 2-(1 H-benzotriazolyl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (HBTU) and 5.21 ml (37.5 mmol) triethylamine are added. The reaction mixture is stirred for 1.5 hours at room temperature, then diluted with ethyl acetate and washed successively with 5% potassium hydrogensulfate, saturated sodium chloride, saturated sodium bicarbonate and again with saturated sodium chloride. The combined organic fractions are dried over sodium sulfate and evaporated in vacuo. Flash cromatography on silica gel with hexane/ethyl acetate 7:3 gives 8.29 g (77%) of the title compound.

j) S-^S-Amino^-oxo-I^^.S.β.Z-hexahydro-azepinotS^ -hilindole^-carbonyl)- amino]-4-hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester

To a solution of 16.85 g (23.5 mmol) 4-hydroxy-3-[(4-oxo-5-benzyloxycarbonylamino- 1 ,2,4,5,6,7-hexahydro-azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2, 3,5,6- tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester in one liter ethyl alcohol 1.68 g of 10% Pd/C are added. The reaction mixture is kept at room temperature under hydrogen gas for three hours and is diluted with ethyl acetate due to precipitation of the product and then filtered over Hyflo. The combined organic fractions are evaporated and dried in vacuo. Recrystallization from methylene chloride-ether yields 15.5 g (84%) of the title compound.

k) 4-Hydroxy-3-[(4-oxo-5-phenoxycarbonylamino-1 ,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafϊuoro-phenoxy)- pentanoic acid tert-butyl ester

A solution of 0.06 ml (0.473 mmol) phenyl chloroformate, 0.25 g (0,430 mmol) 3-[(5- amino-4-oxo-1 ,2,4,5,6,7-hexahydro-azepino[3,2,1-hi]indole-2-carbonyl)-amino]-4- hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester and 0.066 ml (0.473 mmol) triethylamine in 10 ml methylene chloride is stirred for one hour at room temperature under argon. The reaction mixture is diluted with ethyl acetate and washed successively with 0,1 N hydrochloride, saturated bicarbonate and saturated sodium chloride solutions. The organic fractions are evaporated in vacuo to yield 0.315 g of crude product which is used in the next step without further purification.

I) 4-Oxo-3-[(4-oxo-5-phenoxycarbonylamino-1 ,2,4,5,6,7-hexahydro-azepino[3,2,1 - hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert- butyl ester

A solution of 0.315 g (0,45 mmol) 4-hydroxy-3-[(4-oxo-5-phenoxycarbonylamino- 1 , 2,4,5,6, 7-hexahydro-azepino[3, 2,1 -hi]indole-2-carbonyl)-amino]-5-(2, 3,5,6- tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester and 0.38 g (0,9 mmol) Dess-Martin periodinane is stirred at room temperature in 20 ml methylene chloride under argon for one hour. The reaction mixture is diluted with ethyl acetate and washed successively with saturated sodium thiosulfate/sodium bicarbonate (1 :1 ), saturated sodium bicarbonate and saturated sodium chloride solutions. The organic fractions are dried with sodium sulfate and evaporated. The residue is recrystallized from ethylether to give 0.21 g (49%) pure product.

m) 4-Oxo-3-[(4-oxo-5-phenoxycarbonylamino-1 ,2,4,5,6,7-hexahydro-azepino[3,2,1 - hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

To a solution of 0.150 g (0,214 mmol) 4-oxo-3-[(4-oxo-5-phenoxycarbonylamino- 1 ,2,4,5,6,7-hexahydro-azepino[3,2, 1 -hi]indole-2-carbonyl)-amino]-5-(2, 3,5,6- tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester in 14 ml methylene chloride 3.5 ml trifluoroacetic acid are added and the reaction mixture is stirred for one hour at room temperature under argon. The solution is evaporated, ethyl ether is added and brought to dryness two times. The crude product is dissolved in methylene chloride and recrystallized from ethylether to yield 0.107 g (78%) of the desired product. Mp. 156-157°.

The following compounds of formula I are prepared in analogy to Example 1. Example 2

4-Oxo-3-[(4-oxo-5-(4-methoxy-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mp. 157-158°.

Example 3

4-Oxo-3-[(4-oxo-5-pentafluorophenylmethoxycarbonylamino-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mp. 142-144°.

Example 4

4-Oxo-3-[(4-oxo-5-p-tolyloxycarbonylamino-1 ,2,4,5,6,7-hexahydro-azepino[3,2,1- hi]indoIe-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mp. 144-145°.

Example 5

3-{[5-(4-Chloro-phenoxycarbonylamino)-4-oxo-1, 2,4,5, 6,7-hexahydro-azepino[3,2, 1 - hi]indoie-2-carbonyl]-amino}-4-oxo-5-(2,3,5,6-tetrafIuoro-phenoxy)-pentanoic acid

Mp. 165-166°.

Example 6

4-Oxo-3-[(4-oxo-5-(3-Methyl-3-phenyl-ureido)-1 ,2,4,5,6,7-hexahydro-azepino[3,2,1 - hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mp. 174-175°.

Example 7

4-Oxo-3-[(4-oxo-5-(3-[4-methoxy-benzyl]-ureido)-1,2,4,5,6,7-hexahydro-azepino[3,2,1- hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mass spectrum: m / z 686 (M+H). Example 8

4-Oxo-3-[(4-oxo-5-(3-benzyl-ureido)-1,2,4,5,6,7-hexahydro-azepino[3,2,1-hi]indole-2- carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mp. 172-174°.

Example 9

4-Oxo-3-[(4-oxo-5-(3,3-diphenyl-ureido)-1,2,4,5,6,7-hexahydro-azepino[3,2,1-hi]indole- 2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mass spectrum: m / z 718.7 (M+H)

Example 10

4-Oxo-3-[(4-oxo-5-(3,3-dimethyl-ureido)-1,2,4,5,6,7-hexahydro-azepino[3,2,1-hi]indole- 2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mass spectrum: m / z 594.5 (M+H).

Example 11

4-Oxo-3-[(4-oxo-5-(morpholine-4-carbonylamino)-1,2,4,5,6,7-hexahydro-azepino[3,2,1- hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mass spectrum: m / z 636.6 (M+H).

Example 12

4-Oxo-3-[(4-oxo-5-(3-methoxy-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mass spectrum: m / z 673.6 (M+H).

Example 13

4-Oxo-3-[(4-oxo-5-(2-methoxy-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mp. 108-1 10°. Example 14

4-Oxo-3-[(4-oxo-5-(2,3-dimethoxy-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mp. 103-105°.

Example 15

4-Oxo-3-[(4-oxo-5-(3,4-dimethoxy-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mp. 162-163°.

Example 16

4-Oxo-3-[(4-oxo-5-(3,5-dimethoxy-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Dec. at 155°; mass spectrum: m / z 703.6 (M+H).

Example 17

4-Oxo-3-[(4-oxo-5-(4-fluoro-phenoxycarbonylamino)-1 , 2,4,5, 6,7- exahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mp. 162-163°.

Example 18

4-Oxo-3-[(4-oxo-5-(3,4,5-trimethoxy-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Dec. at 135°; mass spectrum: m / z 733.6 (M+H). Example 19

4-Oxo-3-[(4-oxo-5-(benzo[1,3]dioxol-5-yloxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Dec. at 140°; mass spectrum: m / z 687.6 (M+H).

Example 20

4-Oxo-3-[(4-oxo-5-prop-2-ynyloxycarbonylamino-1, 2,4,5, 6,7-hexahydro-azepino[3,2, 1 - hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Dec. at 115°, Mass spectrum: m/z 605 (M+H).

Example 21

4-Oxo-3-[(4-oxo-5-(3-methoxy-5-methyl-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Dec at 160°; mass spectrum: m / z 687.6 (M+H).

Example 22

4-Oxo-3-[(4-oxo-5-(2,5-dimethoxy-phenoxycarbonylamino)-1 ,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mp. 144-145°.

Example 23

4-Oxo-3-[(4-oxo-5-(2-benzyl-5-methoxy-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mp. 169-170°.

Example 24

4-Oxo-3-[(4-oxo-5-(4-methylsulfanyl-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mp. 159-160°. Example 25

4-Oxo-3-[(4-oxo-5-(4-propoxy-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mp. 118-1 19°.

Example 26

4-Oxo-3-[(4-oxo-5-phenylsulfanylcarbonylamino-1,2,4,5,6,7-hexahydro-azepino[3,2,1- hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mp. 164-165°.

Example 27

4-Oxo-3-[(4-oxo-5-(4-trifluoromethoxy-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mp. 165-166°.

Example 28

4-Oxo-3-[(4-oxo-5-(4-chloro-phenylsulfanylcarbonylamino)-1 , 2,4,5, 6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid

Mp. 171-172°.

Example 29

4-Oxo-3-[(4-oxo-5-(4-methoxy-phenoxycarbonylamino)-1 ,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyI)-amino]-5-(2-fluoro-phenoxy)-pentanoic acid

Mass spectrum: m/z 619.8 (M+H).

Example 30

4-Oxo-3-[(4-oxo-5-(4-methoxy-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3-difluoro-phenoxy)-pentanoic acid

Mass spectrum: m/z 637.7 (M+H). Example 31

4-Oxo-3-[(4-oxo-5-(4-methoxy-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,6-difluoro-phenoxy)-pentanoic acid

Mass spectrum: m/z 637.7 (M+H).

Example 32

4-Oxo-3-[(4-oxo-5-(4-methoxy-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,4,6-trifluoro-phenoxy)-pentanoic acid

Mass spectrum: m/z 655.8 (M+H).

Example 33

4-Oxo-3-[(4-oxo-5-(4-methoxy-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(2,3,6-trifluoro-phenoxy)-pentanoic acid

Mass spectrum: m/z 655.8 (M+H).

Example 34

4-Oxo-3-[(4-oxo-5-(4-methoxy-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-pentafluorophenoxy-pentanoic acid

Mass spectrum: m/z 691.9 (M+H).

Example 35

4-Oxo-3-[(4-oxo-5-(4-methoxy-phenoxycarbonylamino)-1, 2,4,5, 6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(3-phenyl-propoxy)-pentanoic acid

a) 5-(4-Methoxy-phenoxycarbonylamino)-4-oxo-1 ,2,4,5,6,7-hexahydro-azepino[3,2,1 - hi]indole-2-carboxylic acid

In 18 ml of dioxane 10.0 g (33.1 mmol) 5-acetylamino-4-oxo-1 ,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carboxylic acid methyl ester are dissolved and 35 ml of 2M HCI solution is added. The mixture is heated to 100 ° and stirred for 5 hours. Then, the solvents are removed and the residue dried in vacuo. The resulting solid is suspended in 80 ml of THF, 70 ml of NaHC0₃ solution (10%) is added and the mixture cooled to 0 °. At this temperature 7.28 g (39.0 mmol, 1.10 eq.) of 4-Methoxyphenyl chloroformate are added dropwise and the mixture is stirred under warming to room temperature for 16 hours. The resulting solution is acidified with 4M HCI, poured onto 1 M HCI and three times extracted with methylene chloride. The combined organic phases are washed with brine, dried (Na₂S0₄) and concentrated. Column chromatography (2-10% MeOH/methylene chloride) yields 2.06 g (15%) of the desired carboxylic acid. Mass spectrum: m/z 397.1 (M+H).

b) 3-Amino-4-hydroxy-5-(3-phenyl-propoxy)-pentanoic acid tert-butyl ester

To a solution of 0.9 g (1.81 mmol) of 4-tert-butoxycarbonylmethyl-2,2-dimethyl-5-(3- phenyl-propoxymethyl)-oxazolidine-3-carboxylic acid benzyl ester in 30 ml of ethanol is added 0.25 g of 10% Pd/C and the mixture hydrogenated for 2 hours. Then, the mixture is filtered over a hyflo filter and concentrated. This yields 0.594 g (quant.) of the desired amino alcohol which is used for the next step without further purification. Mass spectrum: m/z 324.2 (M+H).

c) 4-Hydroxy-3-[(4-oxo-5-(4-methoxy-phenoxycarbonylamino)-1,2,4,5,6,7- hexahydro-azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(3-phenyl-propoxy)- pentanoic acid tert-butyl ester

To a solution of 0.2 g (0.51 mmol) 5-(4-methoxy-phenoxycarbonylamino)-4-oxo- 1 ,2,4,5,6,7-hexahydro-azepino[3,2,1-hi]indole-2-carboxylic acid and 0.196 g (0.61 mmol, 1.2 eq.) of 3-amino-4-hydroxy-5-(3-phenyl-propoxy)-pentanoic acid tert-butyl ester in 6 ml of CH₃CN is added N-ethyl diisopropylamine (0.197 g, 1.53 mmol, 3 eq.), 1-hydroxy-benzotriazole monohydrate (HOBt.H₂0) (0.086 g, 0.56 mmol, 1.1 eq.) and 0-(benzotriazole-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate (HBTU) (0.213 g, 0.56 mmol, 1.1 eq.). After stirring 16 hours at room temperature, the reaction mixture is poured onto ethyl acetate, washed with KHS0 (5%) and NaHC0₃ (5%), dried (Na₂SO₄) and concentrated. Flash chromatography (20-30% ethyl acetate/methylene chloride) of the residue yields 0.180 g (45%) of the desired product. Mass spectrum: m/z 701.9 (M+H).

d) 4-Oxo-3-[(4-oxo-5-(4-methoxy-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(3-phenyl-propoxy)-pentanoic acid tert-butyl ester

Dess-Martin periodinane (0.091 g, 0.21 mmol, 1.5 eq.) is added to a solution of 0.1 g (0.14 mmol) of 4-Hydroxy-3-[(4-oxo-5-(4-methoxy-phenoxycarbonylamino)-1 , 2,4,5,6, 7- hexahydro-azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(3-phenyl-propoxy)-pentanoic acid tert-butyl ester in 5 ml of CH₂CI₂. After 1 hour the mixture is poured onto ethyl acetate, washed with sat. Na₂S₂0₃ solution and brine, dried (Na₂S0₄) and concetrated. Column chromatography (10% ethyl acetate/CH2CI2) gives 0.061 g (62%) of the desired product. Mass spectrum: m/z 700.0 (M+H).

e) 4-Oxo-3-[(4-oxo-5-(4-methoxy-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(3-phenyl-propoxy)-pentanoic acid

A solution of 0.06 g 0.09 mmol) of 4-Oxo-3-[(4-oxo~5-(4-methoxy- phenoxycarbonylamino)-1 , 2,4,5, 6,7-hexahydro-azepino[3, 2,1 -hi]indole-2-carbonyl)- amino]-5-(3-phenyl-propoxy)-pentanoic acid tert-butyl ester in 3 ml of 25% TFA/CH₂CI₂ is stirred at room temperature. After 1.5 hours the solvent is removed and the residue purified over MPLC (10-100% CH3CN/H20 over 35 min). After lyophilization, 0.039 g (71%) of the desired product is obtained as a white powder. Mass spectrum: m/z 644.0 (M+H).

The following compounds of formula I are prepared in analogy to Example 35:

Example 36

4-Oxo-3-[(4-oxo-5-(4-methoxy-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(3-(4-methoxy-phenyl)-propoxy)- pentanoic acid

Mass spectrum: m/z 674.2 (M+H).

Example 37

4-Oxo-3-[(4-oxo-5-(4-methoxy-phenoxycarbonylamino)-1,2,4,5,6,7-hexahydro- azepino[3,2,1-hi]indole-2-carbonyl)-amino]-5-(3-phenoxy-propoxy)-pentanoic acid

Mass spectrum: m/z 660.2 (M+H).

Claims

A compound of formula

wherein Q° is phenyl or (C-|.₄)alkylphenyl, wherein in each case the phenyl ring optionally bears one to five substituents selected from halogen, (C-ι. )alkyl,

(C₁.₄₎)alkoxy,

(C-|.₄)alkylthio or trifluoromethyl, and A is a group -X- Q-i wherein -X- is -0-, -S-, -N[ (C-|. )alkyl]- ,-NH-CH₂- or -

N(phenyl)- and C^ is propargyl or phenyl optionally bearing 1 to 5 substituents selected from halogen, (C₁.₄)alkyl, (C₁.₄)alkoxy,

(Cι.₄)alkylthio, trifluoromethoxy and benzyl, in free form or as a salt.

2. A process for the production of a compound of formula I as defined in claim 1 , in free form or as a salt, which comprises the steps of reacting a compound of formula II

wherein

is A-CO-, A being as defined in claim 1 , or an amino-protecting group, with a compound of formula III

wherein Q° is as defined in claim 1 and Z₂ is a carboxy-protecting group; if Zι is an amino-protecting group, deprotecting the amino group and introducing the desired A- CO- group; deprotecting the carboxy group and oxidizing the hydroxy to an oxo-group; and recovering the resulting compound of formula I in free form or in form of a salt.

3. A compound of formula I as defined in claim 1 , or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

4. A compound of formula I as defined in claim 1 , or a pharmaceutically acceptable salt thereof, for use in the treatment of any disease state responsive to a decrease of interleukin-1 β converting enzyme and related proteases.

5. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 , or a pharmaceutically acceptable salt thereof, in association with a pharmaceutical carrier or diluent.

6. The use of a compound of formula I as defined in claim 1 , or a pharmaceutically acceptable salt thereof, as a pharmaceutical for the treatment of any disease state responsive to a decrease of interleukin-1 β converting enzyme and related proteases.

7. The use of a compound of formula I as defined in claim 1 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of any disease state responsive to a decrease of interleukin-1 β converting enzyme and related proteases.

8. A method for the treatment of any disease state responsive to the decrease of interleukin-1 β converting enzyme and related proteases to a subject in need of such treatment, which comprises administering to such subject a therapeutically effective amount of a compound of formula I as defined in claim 1 , or a pharmaceutically acceptable salt thereof.