HUP0004644A2 - Neutrophil elastase inhibitory pyrrolo-pyrrolone derivatives and pharmaceutical preparations containing such compounds as active ingredients - Google Patents

Abstract

The subject of the invention is compounds of general formula (I) and their salts and solvates - in the formula, R1 is C1-6 alkyl, R2 is C2-4 alkyl or C2-4 alkenyl, X is CO or SO2, Het is optionally substituted 5-10-membered monocyclic or bicyclic aromatic system containing 1-4 heteroatoms from O, N and S atoms, n is a number from 0 to 4, R3 and R4 are independently hydrogen atoms, 1-8 carbon atom alkyl, -( CH2)1-4CONR5R6, CO-1-4 carbon atom alkyl, or (CH2)0-2Ph, where Ph is a phenyl group substituted with one or more carbon 1-4 alkyl groups or halogen atoms, or the NR3R4 group together is an azetidinyl, pyrrolidinyl- , represents a piperidinyl, azepinyl, morpholinyl, piperazinyl group, optionally substituted with a 1-6 carbon alkyl group, a phenyl (optionally substituted with a halogen or a 1-4 carbon alkyl group) or a benzyl group (optionally substituted on the benzene ring with a halogen atom or a 1-4 carbon alkyl group) N -substituted, or NR3R4 collectively means a ring as described above, which is further substituted on the carbon atom with one or more C1-C4 alkyl groups, CONR5R6 or COOR6, R5 and R6 are independently a hydrogen atom or a C1-4 alkyl group (the relative stereochemistry is indicated in the formula ). The invention also applies to pharmaceutical preparations containing the above compounds of general formula (I) as active ingredients and to the use of the compounds, especially for the production of pharmaceutical preparations suitable for the treatment of inflammatory diseases of the respiratory tract. HE

Description

DANUBIA Patent and Trademark Office Ltd.

^BUDAPEST PUBLICATION COPY

Pyrrole^pyrrolone derivatives with neutrophil elastase inhibitory activity and pharmaceutical preparations containing such compounds as active ingredients

The invention relates to therapeutically active bicyclic compounds, to a process for their preparation and to pharmaceutical compositions containing them as active ingredients. The compounds of the invention can be used in chemotherapy and the novel compounds of the invention are particularly effective in the treatment of inflammatory diseases.

Inflammation is the primary response to tissue injury or the spread of microbial infection and is characterized by circulating leukocytes that bind to and leak through the vascular endothelium. Circulating leukocytes include neutrophils, eosinophils, basophils, monocytes, and lymphocytes. Different forms of inflammation are caused by different types of infiltrating leukocytes.

The inflammatory process can be triggered by a number of factors, including infection, tissue damage, and autoimmune reactions. As part of the inflammatory process, neutrophils migrate from the bloodstream into the tissue at the site of tissue injury. Neutrophils contain a large number of different intracellular granules, and upon activation at the site of inflammation, the contents of these granules are released into the tissue. The various

91720-5194 OE/OEM

-2granulocytes contain various enzymes and other proteins, many of which have antibacterial properties.

One of the enzymes found in azurophilic granules is neutrophil elastase. Neutrophil elastase has a wide spectrum of effects in the body. For example, in the lungs, the enzyme increases saliva production and changes the cellular composition of the epithelium. The enzyme also causes changes in vascular permeability within the microvessels of many tissues and is an effective destructive agent against many connective tissue components.

Although there are endogenous inhibitors of elastase within the body, such as anti-trypsin and leukocyte protease inhibitor, elastase activity has a role in the pathogenesis of several diseases, such as inflammatory diseases of the respiratory tract, skin and joints. The enzyme is also responsible for some or most of the symptoms of acute respiratory distress syndrome (ARDS) and certain acute inflammatory conditions induced by trauma and/or sepsis.

We have identified a new class of compounds that inhibit neutrophil elastase. Thus, these compounds have potential therapeutic effects in treating or alleviating symptoms of diseases that are associated with elastase activity.

Based on the above, our invention relates to compounds of general formula (I), salts and solvates thereof - in the formula (with relative stereochemistry indicated) R1 is C1-6 alkyl,

-3- .:·· s ·· - *

R ² is C 2-4 alkyl or C 2-4 alkenyl,

X is CO or SO ₂ ,

Het means an optionally substituted 5-10 membered monocyclic or bicyclic aromatic system containing 1-4 heteroatoms from Ο, N and S atoms, n is a number from 0 to 4,

R ³ and R ⁴ are independently hydrogen, C1-8 alkyl, -(CH2)i-4CONR ⁵ R ⁶ , CO-C1-4 alkyl, or (CH ₂ )o-2Ph, where Ph is a phenyl group substituted with one or more C1-4 alkyl or halogen groups, or the NR ³ R ⁴ group together represents an azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, piperazinyl group, which is optionally N-substituted with C1-6 alkyl, phenyl (optionally substituted with halogen or C1-4 alkyl) or benzyl (optionally substituted on the benzene ring with halogen or C1-4 alkyl), or NR ³ R ⁴ together represents a group as described above. means a ring which is further substituted on the carbon atom one or more times with a C1-C4 alkyl, CONR ⁵ R ⁶ or COOR ⁶ group,

R ⁵ and R ⁶ are independently hydrogen or C 1-4 alkyl.

The above compounds, their salts and solvates are hereinafter referred to as compounds of the invention.

- 4 “ ** , * *** **

The compounds of formula (I) contain chiral centers, the stereochemistry of which is apparent from the formula. The invention includes the racemic forms of these compounds, as well as the individual enantiomers when they are present in a predominant or exclusive manner. In general, the compounds of formula (I) are preferably in enantiomeric pure form, especially the enantiomers in the absolute stereochemical form indicated in formula (I).

The salts of the compounds of the invention are physiologically acceptable salts, which may be salts with inorganic or organic acids, such as hydrochlorides or tartrates.

Alkyl means a straight or branched chain alkyl group, but also includes cycloalkyl when three or more carbon atoms are present. Preferred alkyl groups R ¹ are methyl, ethyl and propyl.

The group Het can be, for example, a furanyl, imidazolyl, thiophenyl, pyrrolyl, thiazolyl, isoxazolyl, pyrazolyl, pyridinyl or pyrazinyl group.

The Het can be attached to the pyrrolidine ring at any position through the group X. The attachment can be, for example, furan-2-yl, furan-3-yl, imidazol-2-yl, imidazol-4-yl, thiophen-2-yl, pyrrol-2-yl, thiazol-4-yl, isoxazol-3-yl, pyrazol-3-yl, pyrazol-5-yl, pyridin-3-yl, 1-methylpyrrol-2-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-5-yl, or pyrazin-2-yl.

The substituent of the group Het can be, for example, a C1-C4 alkyl group, for example a methyl or ethyl group, a C1-C6 alkoxy group, for example a methoxy group, and also a nitro group or a halogen atom, for example a

as well as chlorine, bromine, fluorine, iodine atoms. The substituents can be on the carbon atom or the nitrogen atom.

The substituted Het group may be, for example, 1-methylpyrrolyl, 1-methylpyrazolyl.

In the general formula (I), the side chains may be, for example, in the following positions: furan-2-yl in the 5-position, furan-3-yl in the 2-position, thiophen-2-yl in the 5-position, pyrrol-2-yl in the 4- or 5-position, 1-methylpyrrol-2-yl in the 5-position, thiazol-4-yl in the 2-position, isoxazol-3-yl in the 5-position, 1-methylpyrazole in the 5-position, 1-methylpyrazol-3-yl in the 5-position, pyridin-3-yl in the 6-position and pyrazin-2-yl in the 5-position.

The C1-8 alkyl group in the meaning of R ³ and R ⁴ can be, for example, methyl, ethyl, cyclopropyl, η-propyl, isopropyl, n-butyl, CH(iPr) 2 or cyclohexyl.

When R ³ and R ⁴ independently represent (CH ₂ ) _0.2 Ph, it may be _, for example, a phenyl, benzyl or (4-F-phenyl)methyl group.

When ^NR3R4 together represent an N-substituted piperazinyl group, this may be ^an N-phenylpiperazinyl or N-methylpiperazinyl group.

When NR ³ R ⁴ together represent a ring substituted on carbon, the substituent may be a methyl, CONH ₂ or COOMe group, such NR ³ R ⁴ group may be, for example, a 4-methylpiperidin-1-yl group.

R ¹ is preferably a methyl or ethyl group, preferably a methyl group.

R is preferably isopropyl or propyl, particularly preferably isopropyl.

- 6 - .*n* * <· ·*

X is preferably a CO group.

Het is preferably a 5- or 6-membered monocyclic aromatic ring containing one or two heteroatoms from O, N and S atoms, which are particularly preferably thiazolyl, oxazolyl, pyrazolyl or pyrazinyl, especially thiazolyl (more particularly thiazolyl-4-yl) or pyrazinyl.

Seven can also mean a pyridinyl group, especially a 3-pyridinyl group.

Particularly preferably, Het is a pyrazinyl group, ideally Het is a pyrazinyl-2-yl group in which the side chain is in the 5-position.

Another preferred meaning is oxazolyl, especially oxazolyl-4-yl.

n is preferably 1-3, especially 1 or 2, more especially 1.

R ³ and R ⁴ are preferably hydrogen or C 1-8 alkyl or NR ³ R ⁴ is pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl optionally N-substituted with C 1-8 alkyl or phenyl (optionally substituted with halogen or C 1-4 alkyl). When R ³ and R ⁴ are independently hydrogen or C 1-8 alkyl, NR ³ R ⁴ is preferably NMe ₂ , N(n-butyl) ₂ , NHMe, NH(cyclopropyl), NHCH(iPr) ₂ or N(cyclohexyl) ₂ .

Of particular interest among the compounds of general formula (I) are the compounds of general formula (IA), in which Het represents an oxazol-4-yl group and ol-

The chain is in the 2-position, the stereochemistry is indicated in the formula, and R ⁴ , R ³ , η, X, R ² and R ¹ have the meanings above.

X is preferably CO, R is preferably isopropyl or propyl, especially isopropyl, R ¹ is preferably methyl or ethyl, especially methyl, n is preferably 1-3, especially 1 or 2, especially 1. R ³ and R ⁴ are preferably independently hydrogen or C 1-8 alkyl or the group NR ³ R ⁴ is pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, which is optionally N-substituted with C 1-8 alkyl or phenyl (optionally substituted with halogen or C 1-4 alkyl). The group NR ³ R ⁴ is particularly preferably pyrrolidinyl, piperidinyl, N-phenylpiperazinyl, N(butyl) ₂ , NMe(cyclopropyl) or N(cyclohexyl) ₂ , most especially pyrrolidinyl.

The neutrophil elastase inhibitory effect of the compounds of the invention was demonstrated, for example, by the following in vitro and in vivo tests.

In vitro assay of human neutrophil elastase

The following composition was used for the study:

mM Tris/HCl (pH 8.6)

150 mM NaCl

11.8 nM purified human neutrophil elastase

The appropriate concentrations of the test compounds were adjusted by aqueous dilution starting from a 10 mM stock solution in dimethyl sulfoxide. The above value represents the final concentration after addition of the substrate solution (see below).

-8The above mixture was incubated for 15 minutes at 30°C, and the residual elastase activity was measured for 10 minutes using a BioTek 340i plate reader after the addition of 0.6 mM MeO-succinylalanylalanylpropylvalyl-p-nitroanilide. The rate of increase in absorbance at 405 nm was proportional to the elastase activity. The enzyme activity was plotted against the inhibitor concentration and IC50 values were determined using curve-fitting software.

In vivo activity of human neutrophil elastase inhibitors Oral in vivo model using IL-8 induced lung infiltrates to determine intracellular elastase inhibition

Adult guinea pigs (100-150 g) were randomly divided into groups (n=4) and fasted overnight. Under gas anesthesia (3% isofluorane), the animals were orally administered compounds pre-dissolved in 1 ml/100 g of water vehicle. Either at the same time or subsequently under anesthesia, the animals were intratracheally administered 1 pg of recombinant IL-8 in 100 µl of sterile saline. Six hours after IL-8 administration, the animals were sacrificed by intraperitoneal pentobarbital administration, the lungs were lavaged twice with 2.5 ml of sterile saline, and the femurs were dissected out.

Intracellular elastase was prepared from neutrophils obtained from the lavage and femoral bone marrow. This was done by ultrasonicating the neutrophils and then centrifuging them to obtain intracellular granules. These were disrupted by freeze-thawing and ultrasonication, and the resulting samples were subjected to elastase and

-9myeloperoxidase assays to determine the efficacy of the compounds and normalize neutrophil recovery.

Human whole blood elastase inhibition assay

Fresh, heparinized human whole blood (200 μΐ) was added in triplicate to the appropriately diluted compounds of the invention (10 μΐ). Control samples (6 replicates) contained water instead of the compound. The samples were mixed well using a pipette and incubated at 37°C for 30 minutes. Cold, red cell lysis buffer (750 μΐ, 150 mM ammonium chloride, 0.12 mM EDTA, 10 mM potassium bicarbonate, pH=7.4) was then added. The tubes were sealed, inverted several times, and stored at 4°C for 15 minutes, inverted every 5 minutes. The samples were then centrifuged at 250 G for 10 minutes at 4°C, and the resulting pelleted cells were washed. Washing was performed with 300 μΐ saline, followed by centrifugation at 100 G for 10 min at 4°C. The pellets were washed twice, and the final cell pellet was resuspended in buffer (200 μΐ, 100 mM Tris, 300 mM NaCl, 1 v/v% HTAB, pH=8.6). The samples were stored at -20°C. The samples were then freeze-thawed four times and elastase activity was determined by colorimetric assay in 50 mM Tris, 150 mM NaCl, 0.6 mM MeO-Succ-Ala-Ala-Pro-Val-pNA, pH=8.6 buffer based on the rate of increase in absorbance at 405 nm.

Studies have shown that the compounds of the invention are effective in treating and alleviating the symptoms of diseases which are based on elastase activity. Such diseases include, in particular, bronchitis, including chronic bronchitis, and

- 10 any chronic obstructive pulmonary disease (COPD).

Diseases in which the compounds of the invention may be effective include, for example, inflammatory diseases of the respiratory tract, such as bronchitis (including chronic bronchitis), bronchiectasis, asthma, and hyperreactive lung conditions, acute respiratory distress syndrome, and septic shock, inflammatory or destructive conditions of the lungs, such as emphysema and cystic fibrosis, and inflammatory or destructive diseases of the external tissues, such as skin diseases (lupus and psoriasis), periodontal diseases, such as gingivitis.

Other diseases and conditions in which the compounds of the invention may be advantageously used include, for example, the following: wound healing and treatment of burns, cardiovascular diseases such as myocardial infarction and stroke, peripheral vascular diseases such as intermittent claudication, atherosclerosis, reperfusion injury, cardiovascular changes occurring in cardiopulmonary bypass surgery, and sepsis.

The compounds of the invention can also be used for the treatment of connective tissue disorders, such as rheumatoid arthritis, arthritis, osteoarthritis and spondylitis, and inflammatory diseases of the kidney, such as glomerulonephritis.

The compounds of the invention can also be used to treat certain leukemic diseases, such as bone marrow leukemia, acute myelomonocytic leukemia and chronic monocytic leukemia, as well as solid tumors, such as

- 11 doses to inhibit the metastasis of lung, breast, prostate and stomach tumors and melanomas.

The compounds of the invention are particularly useful in the treatment of chronic bronchitis. Chronic bronchitis is caused, for example, by exposure of the airway surface to harmful chemicals or agents, or by other diseases. The symptoms are caused by excessive mucus secretion on the airway surface. This excess mucus cannot be cleared and causes reduced gas exchange in the lungs, resulting in dyspnea and hypoxemia, recurrent microbial infections, and a persistent cough with expectoration of mucus. The presumed mechanism of excessive mucus secretion is that neutrophils accumulate in the airways after irritants have come into contact with the epithelium; the neutrophils secrete elastase onto the airway surface, and this enzyme increases the amount of mucus secreted on the airway surface and causes dramatic changes in the cellular composition of the airway epithelium. Thus, the use of compounds of the invention, which inhibit elastase activity, is a potential treatment for chronic bronchitis. The reduced lung function that occurs in COPD (e.g., chronic bronchitis with airway obstruction) is also due to elastase-mediated lung damage, which leads to airway narrowing and inflammation. Thus, an elastase inhibitor improves lung function.

As is apparent from the above, the compounds of the invention can be used in human or veterinary medicine, in particular as inhibitors of the enzyme neutrophil elastase.

- 12More specifically, the compounds of general formula (I) according to the invention or their physiologically acceptable salts or solvates can be used in human or veterinary medicine, in particular for the treatment of diseases associated with elastase activity, such as for example chronic bronchitis.

It is clear that the term treatment includes both prevention and treatment of an already established disease.

The invention also provides the use of compounds of formula (I) or physiologically acceptable salts or solvates thereof in the preparation of pharmaceutical compositions for the treatment of diseases associated with elastase activity, in particular chronic bronchitis.

The compounds of formula (I) according to the invention or their physiologically acceptable salts or solvates are used in an effective amount in human or veterinary medicine for the treatment of diseases mediated by elastase activity.

The compositions of the invention may be formulated in any suitable form for administration, and thus these pharmaceutical compositions are also within the scope of the invention, comprising the compounds of formula (I) or physiologically acceptable salts or solvates thereof in admixture with one or more physiologically acceptable diluents or carriers.

The invention also includes a process for preparing such pharmaceutical compositions, in which the ingredients are mixed together.

- 13 The compositions of the invention may be formulated, for example, into compositions suitable for oral, buccal, parenteral, topical or rectal administration.

Tablets or capsules suitable for oral administration may contain conventional excipients such as binders, such as syrup, acacia, gelatin, sorbitol, tragacanth, starch mucilages or polyvinylpyrrolidone; fillers, such as lactose, microcrystalline cellulose, sugar, corn starch, calcium phosphate or sorbitol; lubricants, such as magnesium stearate, stearic acid, talc, polyethylene glycol or silica gel; disintegrating agents, such as potato starch, croscarmellose sodium or sodium starch glycolate; and wetting agents, such as sodium lauryl sulfate. The tablets may also be coated in a known manner. Liquid preparations for oral administration may be, for example, oily suspensions, solutions, emulsions, syrups or elixirs, or they may be products which are reconstituted with water or other suitable vehicle immediately before use into a preparation suitable for administration. Such liquid preparations may contain conventional additives, which may be suspending agents, such as sorbitol syrup, methylcellulose, glucose/sugar syrup, gelatin, hydroxymethylcellulose, carboxymethylcellulose, aluminum stearate, gelling agents or hydrogenated edible fats; emulsifying agents, such as lecithin, sorbitan, monooleate or acacia; non-aqueous vehicles (including edible oils), such as almond oil, fractionated coconut oil, oily esters,

-14-propylene glycol or ethyl alcohol; or preservatives, such as methyl or propyl p-hydroxybenzoates or sorbic acid. The compositions may also contain buffer salts, flavoring, coloring and/or sweetening agents (e.g. mannitol), if desired.

Buccal administration compositions may be tablets or sublingual compositions prepared in a manner known in the art.

The compounds can also be formulated into suppositories, for example, containing conventional suppository ingredients such as cocoa butter or other glycerides.

The compounds of the invention may also be formulated for parenteral administration, such as bolus injections or continuous infusions, in unit doses such as ampoules, vials, small volume infusions or prefilled syringes, or in multi-dose containers to which a preservative is added. The formulations may be solutions, suspensions or emulsions in aqueous or non-aqueous vehicles and may contain various additives such as antioxidants, buffers, antimicrobials and/or toxicity-adjusting agents. The formulation may also be in powder form or a powder which can be reconstituted with a suitable vehicle such as sterile, non-pyrogenic water before use. Dry powder formulations may be aseptically filled into individual sterile containers as a sterile powder, or the sterile solution may be aseptically filled into the containers and freeze-dried.

Compositions suitable for topical administration may include, for example, insufflation or inhalation compositions.

- 15 other topical dosage forms include creams, ointments, washes, powders, pessaries, sprays, aerosols, capsules or cartridges suitable for inhalation or suction, or may be drops (e.g. eye or nose drops).

Ointments and creams are prepared, for example, on an aqueous or oily basis, with the addition of suitable thickening and/or gelling agents and/or solvents. Such a base may be, for example, water and/or an oil, such as liquid paraffin or a vegetable oil, such as arachis oil or castor oil, or a solvent, such as polyethylene glycol. The thickening agent may be, for example, soft paraffin, aluminum stearate, ketostearyl alcohol, polyethylene glycol, microcrystalline wax or beeswax.

The solutions may be aqueous or oily based and generally also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.

Powders suitable for topical administration are prepared with a suitable powder base, for example talc, lactose or starch. Drops are prepared with an aqueous or non-aqueous base and may further contain one or more dispersing agents, solubilizing agents or suspending agents.

Spray compositions may be, for example, aqueous solutions or suspensions or aerosols delivered from a pressurized container, containing a suitable carrier such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,2-tetrafluoroethane, carbon dioxide or other suitable gas.

- 16 The fillings used in capsules, e.g. gelatin capsules, or in inhalers or snuffers, are obtained from a mixture containing the compound of the invention and a suitable powder base, such as lactose or starch.

Other therapeutic agents may also be used in the pharmaceutical compositions of the invention, such as anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2-adrenergic agonists and xanthines (e.g. theophylline), mucolytic agents, anti-muscarinics, anti-leukotrienes, cell adhesion inhibitors (e.g. ICAM antagonists), antioxidants (e.g. N-acetylcysteine), pulmonary surfactants and/or antimicrobial and antiviral agents. The compositions of the invention may also be used in combination with gene replacement therapy.

The invention therefore also includes pharmaceutical compositions comprising the compound of general formula (I) or a physiologically acceptable salt or solvate thereof in combination with another therapeutically active agent.

The above combination is preferably used in the form of pharmaceutical compositions, which compositions comprise the above combination together with a pharmaceutically acceptable carrier.

The individual components of such combinations may be administered sequentially or together, in the form of separate or combined pharmaceutical compositions. Appropriate dosages of known therapeutic agents can be readily determined by one skilled in the art.

- 17 The compounds of the invention are preferably administered orally, for example, in a dose of 0.01-50 mg/kg body weight, in particular 0.05-25 mg/kg body weight, once or more times a day. The exact dosage will of course depend on the age and condition of the patient, the route of administration and the disease to be treated. In the treatment of bronchitis, the compounds of the invention are preferably administered orally. Other dosages may be necessary for other indications, for example, iv administration is preferred in the case of ARDS.

The compounds of the invention have a suitable duration of action.

The compounds of formula (I) according to the invention and their salts and solvates can be prepared as described below, which also fall within the scope of the invention.

In the process of the invention, the compounds of general formula (I) are obtained by (i) condensing a compound of general formula (II) with a compound of general formula R ⁴ R ³ N(CH2)nHetCOOH or an acid derivative thereof, such as an acid chloride, an activated ester, an acid anhydride or a mixed anhydride thereof, or with a compound of general formula R ⁴ R ³ N(CH2) _nHetXY , where Y is a reactive group, such as a halogen atom, for example a chlorine atom, or a protected derivative thereof, or (ii) sulfonating a compound of general formula (III) or a protected derivative thereof with a group of general formula YC^SR ¹ - where Y is a reactive group, such as a halogen atom, for example a chlorine atom - or a protected derivative thereof; or (iii) cyclizing a compound of general formula (IV) or a carboxylic acid ester thereof; or (iv) a compound of formula (V) - in which X a represents _a sulfur atom or a SO group - is oxidized; or (v) a compound of formula (VI) - in which L represents a leaving group - is reacted with a compound of formula R ⁴ R ³ NH; or (vi) to prepare compounds of formula (I) in which n is 1-4, a compound of formula (VII) and a compound of formula R ⁴ R ³ NH are reduced; or (vii) to prepare compounds of formula (I) in which n is 1, a compound of formula (VIII) is reacted with formaldehyde or paraformaldehyde and a compound of formula R ⁴ R ³ NH under acidic conditions; or (viii) optionally removing the protecting groups from the compound of formula (I); or (ix) separating one enantiomer of the compound of formula (I) from a mixture of enantiomers;

and optionally converting the resulting free base into a physiologically acceptable salt or converting the salt form into another physiologically acceptable salt.

The relative stereochemistry is indicated in the formula of the aforementioned starting compounds.

(i) procedure

The condensation with the compound of general formula R ⁴ R ³ N(CH2) _n HetCOOH is preferably carried out using a coupling agent, such as

- 19l-(3-N,N-dimethylaminopropyl)-3-ethylcarbodiimide and preferably also HOBT in a solvent such as dichloromethane, DMF, MeCN or tetrahydrofuran, in particular between 0°C and ambient temperature. If an acid derivative such as an acid chloride, an activated ester, an acid anhydride or a mixed acid anhydride is used, the reaction conditions must be modified accordingly, for example by using a base. If one or both of R ³ , R ⁴ represent a hydrogen atom, the group is preferably protected by introducing a protecting group, for example by introducing a BOC group.

The reaction with the compound of general formula R ⁴ R ³ N(CH ₂ ) _n HetSO 2 Y is preferably carried out in the presence of a base, such as triethylamine, and a solvent, such as DCM, preferably at a temperature between 0°C and ambient.

(ii) procedure

The sulfonylation reaction is preferably carried out in the presence of LHMDS or NaH in a solvent (e.g. tetrahydrofuran) at a temperature between -78°C and 0°C.

If one or both of R ³ and R ⁴ represent a hydrogen atom, it may be necessary to protect the group, for example with a BOC group.

(iii) procedure

The cyclization reaction is carried out in particular in the presence of 2-chloro-1-methylpyridinium iodide or EDC in a solvent such as dichloromethane, in particular at a temperature between 0°C and reflux. This reaction can also be carried out with a carboxylic acid thioester derivative of the compound of general formula (IV). Other acid-20• ^J «. J ·♦*·»*·

-derivatives (e.g. acid halides, such as acid chlorides) may also be used.

(iv) procedure

The oxidation reaction is carried out in the usual manner, for example by peracid oxidation.

(v) procedure

The preferred leaving group is a halogen atom (e.g. chlorine, bromine or iodine), a mesylate or tosylate group. The reaction can be carried out by reacting the reagents optionally in the presence of a base such as triethylamine or potassium carbonate in an inert solvent such as DMF or MeCN.

(vi) procedure

The reaction is carried out by reacting the reactants in an inert solvent, such as DCM, at ambient or elevated temperature. The reduction can also be carried out in situ using commonly known mild reducing agents, such as NaBH3CN or NaBH(OAc)3.

(vii) procedure

The reaction of the heterocyclic compound of formula (VIII) with formaldehyde or para-formaldehyde and an amine is carried out under conditions corresponding to the standard Mannich reaction, for example using reflux under acidic conditions, usually working in an acetic acid/ethanol mixture. If the amine is used in the form of an acid salt (e.g. hydrochloride), the acetic acid can be omitted.

(viii) procedure

Protecting groups, especially nitrogen protecting groups, and deprotection are described, for example, in the following literature references:

-21 described in: TW Green, Protective Groups in Organic Synthesis, 2nd edition (1991) J. Wiley & Sons.

(ix) procedure

The separation of enantiomers can be carried out by conventional methods, such as by chiral chromatography (e.g. chiral HPLC) or crystallization with a homochiral acid (e.g. tartaric acid).

Physiologically acceptable salts of the compounds of formula (I), for example hydrochlorides or tartrates, can be prepared by reacting the base compound of formula (I) with the desired acid.

The intermediate compounds of general formula (II) can be prepared, for example, by the process shown in Scheme 1:

Step (a)

This conventional protecting group introduction reaction, when P ₂ is BOC, is carried out, for example, by reacting the compound (BOC) ₂ with O in the presence of a base (e.g. NaOH) in a polar solvent system, e.g. a dioxane/water mixture.

Step (b)

The conversion reaction is carried out by treatment with ammonium bicarbonate in a suitable solvent, for example a pyridine/DMF system, in the presence of (BOC) ₂ O or a suitable equivalent thereof.

Step (c)

This conventional protecting group introduction reaction is carried out when Pi is CBZ by reacting the compound with nBuLi followed by CBZ-C1 in an inert solvent such as THF at below -50°C.

Step (d)

The reaction is carried out by treatment with a compound of the general formula (RX), (RX) being a compound (e.g. Mel, benzyl iodide or Me2SO4) capable of partially converting the sulfur of SMe to the sulfonium in a suitable solvent, e.g. propanone or acetonitrile. Generally, R is an alkyl or aralkyl group and X is a halide, especially iodide or sulfate. The amide group may also be protected, although this is not always essential for the reaction.

Step (e)

The ring closure reaction is carried out by treatment with Dowex 2x8 400 mesh OH' resin in a suitable solvent, for example MeCN. The ring closure can also be carried out by treatment with potassium carbonate in a suitable solvent, for example MeCN.

Step (f)

The deprotection is carried out in a known manner, for example the BOC protecting group can be removed by treatment with hydrochloric acid, for example in dioxane.

Step (g)

The reaction is carried out by treatment with trifluoroacetic acid alkyl esters (e.g. methyl ester) or trifluoroacetic anhydride in the presence of a suitable base, e.g. N-methylmorpholine.

Step (h)

The conversion is carried out, for example, by treating the compounds of formula (XV) with a reducing agent, such as lithium borohydride, followed by concentrated sulfuric acid in the presence of an alcohol solvent, such as ethanol.

Step (i)

-23 The reaction of compounds of formula (XVI) and (XVII) is carried out in the presence of a Lewis acid, such as boron trifluoroetherate, and an inert solvent, such as dichloromethane or MeCN. The alkyl group in the Oalkyl and OSi(alkyl) ₃ groups generally means an alkyl group having 1 to 6 carbon atoms. In formula (VII), the alkyl group in the silyl group may be, for example, a methyl, isopropyl or tert-butyl group. The preferred Oalkyl group is OEt and the preferred OSi(alkyl) 3 group is OSi(i-Pr) ₃ or OSi(Me) ₂ (tert-Bu). Other compounds of formula (XVII) in which the Oalkyl group is replaced by an OSi(alkyl) ₃ group may also be used.

For example, the compound of formula (XVII) is prepared by reacting the corresponding carboxylic acid ester (R ² CH ₂ COOEt or other alkyl ester, which compound is either known or can be prepared by known methods) with a strong base (e.g. LHMDS) followed by a trialkylsilyl chloride (e.g. trimethylsilyl chloride) or a trialkylsilyl triflate. The reaction is generally carried out at low temperature (below 0°C) and in an inert solvent (e.g. THF) in the presence of DMPU.

Step (j)

Removal of the protecting group is accomplished by treatment with a base, such as potassium carbonate.

Step (k)

The ring closure reaction is carried out, for example, by treatment with an alkyl Grignard reagent (e.g., tert-butylmagnesium chloride) in a solvent, such as THF, in the presence of tetramethylenediamine at a temperature between -20°C and 25°F.

Step (1)

-24A reaction is a lactam sulfonylation reaction, preferably carried out by reacting with a compound of the general formula R^Oj-Y, where Y is a reactive group, preferably a chlorine atom, in the presence of LHMDS, NaH or KH in a solvent (e.g. THF), the temperature being preferably between -78°C and 0°C.

(m) step

In the reaction, the N-protecting group is removed in a known manner. Thus, if Pi is a CBZ group, it is preferably removed by hydrogenation in the presence of a Pd(OH) ₂ catalyst in a solvent such as ethyl acetate or THF.

The compound of formula (XV) can be prepared according to reaction scheme 2.

Step (a)

The reaction is carried out under standard conditions known for the formation of alkyl esters, for example by treatment with an alcohol, such as methanol, in the presence of SOCl. _R13 is in particular an alkyl group having 1-6 carbon atoms, preferably methyl.

Step (b)

The cyclization reaction is carried out by treatment on Dowex 2X8 (preferably 400 mesh) aqueous resin.

Step (c)

The formation of the TFA protected amine is carried out by treating the compound of formula (XXIV) with methyl trifluoroacetate in a polar solvent, such as MeOH.

(d) spleen and

The preferred P] protecting group is CBZ. In this case, the compound of formula (XXV) is treated with a strong base, which

-25 can be LHMDS or nBuLi, in an inert solvent, for example THF, and then reacted with CBZ-C1.

The compound of formula (XX) according to Scheme 1 can be prepared, for example, according to Scheme 3:

Step (a)

The compound of formula (XXVI) is known or can be prepared in a known manner. P1 represents an N-protecting group, preferably CBZ. The reaction according to step (a) is further a reaction for introducing an N-protecting group. _P2 represents a different N-protecting group in formula (XXVII), preferably BOC. When _P2 represents BOC, the reaction is suitably carried out using _BOC2O .

The reaction is preferably carried out in the presence of a base, such as triethylamine or 4-dimethylaminopyridine, in a solvent, such as ethyl acetate, generally between 0-25°C.

Step (b)

The conversion is carried out in particular with pyridinium p-toluenesulfonate in a solvent (e.g. acetone/water) at a temperature between 25-75°C.

Step (c)

The condensation transformation reaction is generally carried out using 2-phenylsulfonylacetic acid ester (PhSOCH ₂ CO ₂ Ri 3 ) and piperidine in a solvent such as acetonitrile, preferably at ambient temperature. Ri ₃ is a C 1-6 alkyl group, preferably a methyl group.

Step (d)

This is a Mitsunobu substitution reaction involving phthalimide, PPh ₃ and a dialkylazodicarboxylate such as DEAD.

-26 is used, the reaction is carried out in a solvent, for example THF, especially at a temperature between 0°C and 40°C.

Step (e)

The removal of the protecting group is preferably carried out with a strong acid, such as TFA, in a solvent, such as DCM, at a temperature in particular between 0°C and 40°C, R _n is a C 1-6 alkyl, preferably ethyl, group.

Step (f)

The cyclization reaction is preferably carried out by an intramolecular Michael reaction. Preferably, NaH is used in a solvent such as THF, and the temperature is preferably between 0°C and 25°C.

Step (g)

In this step, two reactions take place: removal of the N-protecting group and reintroduction of the protecting group. The phthalimido group is removed in particular with hydrazine hydrate in a solvent, for example ethanol, between 0°C and reflux temperature. The protecting group P ₃ is introduced in a known manner. If P 3 is BOC, BOC ₂ O is preferably used as the reagent.

Step (h)

The R ₂ side chain is introduced, for example, by alkylation, for example using a compound of the formula R -Y, where Y is a reactive group, for example a bromine or iodine atom. The reaction is preferably carried out in the presence of a strong base, such as LHMDS. In the case of LHMDS, DMPU co-solvent is preferably used in THF. The reaction temperature is in particular between -78°C and 50°C.

-ΤΊ value, under such conditions the reaction usually proceeds with good stereochemical control.

Step (i)

Ester hydrolysis is carried out, followed by removal of the N-protecting group. The reaction is carried out in a known manner, for example using KOH/aqueous ethanol at 25°C to 80°C. The latter reaction is also carried out in a known manner, for example using HCl/dixoane, generally at a temperature of 0°C to 50°C or, if the protecting group is trifluoroacetate, by treatment with a base.

Step (j)

This cyclocondensation reaction is preferably carried out using 2-chloro-1-methylpyridinium iodide and a suitable base, such as N,N-diisopropylethylamine, in a solvent, such as dichloromethane, at a temperature between 0°C and reflux. It has been found that a compound of formula (XXXV) can also be used as the carboxylic acid ester, in which case the ester hydrolysis step of step (i) is not required. In this case, the cyclocondensation reaction is preferably carried out using an alkyl Grignard reagent, such as t-BuMgCl, in THF at a temperature between -2°C and 25°C.

The compound of general formula (XXXIII) can be prepared, for example, according to reaction scheme 4:

Step (a)

The compounds of formula (XXXVI) are either novel or can be prepared in a known manner: P ₃ represents one of the protecting groups as defined above, in particular BOC. The reaction is carried out in particular in the presence of PIFA (phenyliodosylbis(trifluoroacetate)) and a base, such as pyridine, in an aqueous solvent, which may be, for example,

-28aqueous THF, dioxane or acetonitrile. Such a method is described in the following literature: Stansfield, CF Organic Preparations and Procedures Int., 1990, 22(5), 593-603.

Step (b)

Pi represents a protecting group, for example CBZ. The introduction of the protecting group can be carried out in a conventional manner, for example in the presence of a water-miscible solvent such as THF, DMF or dioxane using N-benzyloxysuccinamide, benzyloxycarbonyl chloride or other suitable source of benzyloxycarbonyl groups and adjusting the pH to alkaline with sodium carbonate.

Another suitable method is process (b ¹ ), in which the compound of general formula (XXXVIII) is prepared in a known manner using diaminobutyric acid.

Step (c)

This reaction is carried out in two steps. In the first step, the compound of formula (XXXVIII) is reacted at reduced temperature with N-methylmorpholine and then with an alkyl chloroformate, such as ethyl chloroformate, in an organic solvent, such as DCM, dioxane or THF. In a second step, the resulting product is reduced, in particular with sodium borohydride at reduced temperature, such as -20°C to 10°C, in a solvent, such as THF.

Step (d)

This oxidation step can be carried out in any manner, for example with oxalyl chloride in DMSO and methylene dichloride under a nitrogen atmosphere at reduced temperatures, such as between -30°C and -70°C, followed by reaction with triethylamine.

The intermediate of formula -29(XXXX) is isolated in a suitable manner.

Step (e)

This reaction is carried out in particular using a Witting reagent, in particular triphenylphosphorane _Ri3O2 CCH= _PPh3 , or a phosphonate can also be used in the Wadsworth-Emmons reaction.

Step (f)

The Michaels addition reaction is carried out using, for example, LHMDS or another strong base in an organic solvent, such as THF, ether or toluene, and preferably a complexing agent, such as TMEDA, is also present.

The intermediate of formula (III) can be prepared, for example, by reacting the deprotected compound of formula (XX) of reaction scheme 1 with a compound of formula R ⁴ R ³ N(CH 2 ) n HetCOOH or R ⁴ R ³ N(CH 2 ) _n HetXY, as described above in step (i) of the main process.

(The removal of the N-protecting group of the starting compound is carried out, for example, according to step (m) of Scheme 1).

The intermediate of general formula (IV) can be prepared starting from the compound of general formula (XIX) (with suitable protection of the primary amine) analogously to that described above for the preparation of the compound of general formula (III) from the compound of general formula (XX) together with step (ii) of the main process.

The compound of formula (V) in which X _a is S can be prepared from the corresponding compound of formula (III) by reacting it with a compound of formula R^SR ¹ in the following manner:

- 30 under standard conditions of nucleophilic displacement. A compound of formula (V) in which X _is SO can be prepared by peracid oxidation starting from the corresponding compound in which X _is S.

Compounds of formula (VI), (VII) and (VIII) can be prepared from compound of formula (II) by conventional methods. The mesylate and tosylate derivatives are obtained from the corresponding alcohol and then treated with MeSO ₂ Cl or para-methylbenzenesulfonyl chloride.

The compounds R ⁴ R ³ N(CH 2 ) n HetCOOH or their acid derivatives, as well as the compounds of the general formula R ⁴ R ³ N(CH 2 ) _n HetXY are known or can be prepared in a known manner.

It is apparent from Schemes 1, 2, 3 and 4 that they can be modified to produce homochiral compounds by using homochiral starting materials (e.g., S-methionine is used in Scheme 1 or S-diaminobutyric acid in Scheme 2) or by performing a subsequent chiral resolution step.

When the compound of formula (XIV) is prepared in racemic form from racemic methinone according to Scheme 1, it has been found that the isomers of the compound of formula (XIV) can be resolved by a dynamic resolution process. In this case, the racemic compound of formula (XIV) is treated with a homochiral di-p-toluene tartaric acid in the presence of 3,5-dichloro-2-hydroxybenzaldehyde as a catalyst in an inert solvent, such as THF. The homochiral salt of the compound of formula (XIV) is then obtained. The compound of formula (XV) is then

-31 is obtained by treatment with trifluoroacetic acid methyl ester in the presence of N-methylmorpholine.

Both enantiomers of the compound of formula (XIV) can also be prepared by synthesis starting from S-methionine or R-methionine in a similar manner.

It will be apparent to those skilled in the art that the above synthetic procedures can be modified by adding or removing protecting groups, or by using other protecting groups (such as those described in, for example, TW Green, Protective Groups in Organic Synthesis, 2nd ed. (1991), John Wiley & Sons) by routine optimization of experimental conditions.

The novel chiral intermediates as described above, which are used in the chiral and resolution steps, are also within the scope of the invention.

The process for preparing the intermediates also falls within the scope of the invention.

The compounds of the invention have the advantage of being more effective, exhibiting greater selectivity, having fewer side effects, having a longer duration of action, having better bioavailability at the preferred dosage, and exhibiting very favorable pharmacodynamic or pharmacokinetic properties, or having other advantageous properties, compared to similar, known compounds.

The invention is illustrated in more detail by the following non-limiting examples.

Abbreviations

BOG t-butyloxycarbonyl

CBZ Benzyloxycarbonyl (BOC) ₂ 0 Di-tert-butyl dicarbonate THF Tetrahydrofuran LHMDS Lithium bis(trimethylsilyl)amide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro 2(1H)-pyrimidinone DMAP 4-dimethylaminopyridine DMF Dimethylformamide EDC 1-(3-N,N-dimethylaminopropyl)-3-ethylcarbodiimide DEAD Diethyl azodicarboxylate DCM Dichloromethane TMEDA Tetramethylethylenediamine DMSO Dimethyl sulfoxide HOBT 1-hydroxybenzotriazole NaBH(OAc) ₃ sodium triacetoxyborohydride

In the following examples, TLC studies were performed on silica plates.

Starting compounds

Compound KI.

2,4-Diaminobutyric acid methyl ester dihydrochloride

350 g of D,L-diaminobutyric acid dihydrochloride were dissolved in 1.6 L of methanol and 200 ml of thionyl chloride were added at 0°C over 0.5 h. The mixture was heated under reflux for 3 h, then the solvent was removed in vacuo and the residue was mixed with 650 ml of toluene to give the title compound as a white solid (385 g).

-33 Mass spectrum for the free base MH ⁺ : (measured) 133 MH ⁺ (calculated) 133

Compound K2

3-Amino-pyrrolidin-2-one g KI. Compounds are mixed with 16.4 ml of Dowex 2x8-400 mesh resin in 70 ml of water, then the resin is filtered off, the filtrate is concentrated in vacuo to obtain the title compound as a white solid, amount 0.40 g.

Tlc (6/1 ethyl acetate/methanol) Rf 0.07

Compound K3

2,2,2-Trifluoro-N-(2-oxo-pyrrolidin-3-yl)-acetamide

Compound K2 (181 g) was suspended in methyl trifluoroacetate (218 ml) and ethanol (2.6 l) for 2 hours, and the solvent was removed in vacuo to give the title compound as a creamy solid (355 g).

Mass spectrum MNH ₄ ⁺ : (measured) 214 MNH ₄ ⁺ (calculated) 214

Compound K4

2-Oxo-3-(2,2,2-trifluoroacetylamino)pyrrolidine-1-carboxylic acid benzyl ester

To 3.5 g of compound K3 in 100 ml of tetrahydrofuran at -70°C was added 20 ml of LHMDS, then after % hour 2.8 ml of benzyl chloroformate was added. The resulting mixture was stirred at room temperature for 1 hour, then 25 ml of 1 M hydrochloric acid was added. The material was then extracted with 3x25 ml of ethyl acetate, the extracts were combined, washed with 2% ammonia solution, 2 M hydrochloric acid, then brine, dried over MgSO _4. Then the solvent was removed, the white solid was recrystallized

-34 from ethyl acetate/hexane=5/1 to give the title compound as white crystals, 4.2 g.

Tlc (9/1 ethyl acetate/methanol) Rf 0.7.

Compound K5

2-Ethoxy-3-(2,2,2-trifluoroacetylamino)-pyrrolidine-1-carboxylic acid benzyl ester g K4. To compound K4 in 1070 ml ethanol at -5°C, 9.86 g sodium borohydride are added, followed by the dropwise addition of 20 ml of 4 M hydrochloric acid/1,4-dioxane solution. Then, 4 M hydrochloric acid/1,4-dioxane is periodically added (2x5ml, 1x10ml), followed by the addition of 2 g sodium borohydride. After 3 hours, 11 ml of concentrated hydrochloric acid is added to the mixture and the mixture is heated at room temperature for 2 hours. Then, 300 ml of saturated aqueous sodium bicarbonate are added, and the ethanol and dioxane are removed in vacuo. The residue was diluted with 500 mL of water, extracted with 3 x 500 mL of ethyl acetate, the extracts were combined, washed with brine, and dried over MgSO4. The solvent was then removed in vacuo and the residue was purified by flash chromatography (silica gel 9385, ether) to give 21 g of the title compound.

Mass spectrum MNH4 ⁺ : (measured) 378 MNH4 ⁺ : (calculated) 378

Compound K6 trans-2-(1-Ethoxycarbonyl-2-methylpropyl)-3-(2,2,2trifluoroacetylamino)pyrrolidine-1-carboxylic acid benzyl ester g Compound K5, 11 ml ethyltrimethylsilylisopropylketene acetal and 250 ml dichloromethane are cooled to 5°C, % is added

-17 ml of boron trifluoride dietherate are added over 35 hours, then after 1 hour another 3.4 ml of boron trifluoride dietherate and 11 ml of ketene acetal are added. After another 1 hour, 200 ml of 1 M hydrochloric acid are added, the organic phase is separated, washed with brine, dried over MgSO _4. The solvent is removed in vacuo, thus obtaining 16.7 g of the title compound as an oil.

Tlc (2/1 ether/cyclohexane) Rf 0.18 and 0.27.

Compound K7 trans-3-Amino-2-(1-ethoxycarbonyl-2-methylpropyl)-pyrrolidine-1-carboxylic acid benzyl ester g Compound K6, 71 g potassium carbonate, 930 ml water and 930 ml ethanol are heated at 60°C for 3 hours, then the ethanol is removed in vacuo, the aqueous residue is extracted with 3x300 ml ethyl acetate, the organic extracts are combined, washed with brine, dried over MgSO ₄ and concentrated in vacuo. Thus, 17.5 g of the title compound are obtained in the form of a brown oil.

Mass spectrum MH ⁺ : (measured) 349 MH ⁺ : (calculated) 349

Compound K8. rel-(3R,3aR,6aS)-6-Isopropyl-5-oxo-hexahydropyrrolo[3,2-b]pyrrole-1-carboxylic acid benzyl ester. 5 g of compound K7. in 1800 ml of tetrahydrofuran were cooled to -5°C and 204 ml of 1 M tert-butylmagnesium chloride/tetrahydrofuran solution were added over Yz hour. After 2 hours, 250 ml of 1 M hydrochloric acid and 300 ml of brine were added, the resulting mixture was extracted with 250 ml of ethyl acetate, the extracts were concentrated to half volume in vacuo, washed with brine, dried over MgSO _4. The solvent was removed in vacuo,

-36- X, f then the residue was mixed with 60 ml of diethyl ether to give a white solid. This was recrystallized from ethyl acetate to give 3.4 g of the title compound.

Mass spectrum MH ⁺ : (measured) 303 MH ⁺ : (calculated) 303 Compound K9: reI-(3R,3aR,6aS)-6-Isopropyl-4-methanesulfonyl-5-oxo-hexahydropyrrolo[3,2-b]pyrrole-1-carboxylic acid benzyl ester

15.01 g of compound KI. in 950 ml of anhydrous tetrahydrofuran were stirred at -74°C under nitrogen and 69.5 ml (1.0 mol) of LHMDS/tetrahydrofuran solution were added dropwise. The resulting mixture was stirred at -74°C for 10 min, then allowed to warm to 0°C over 45 min and left at this temperature for 20 min. It was then cooled to -70°C, 9.61 ml of methanesulfonyl chloride were added dropwise and stirred at this temperature for 1.5 h. It was then warmed to -50°C, 450 ml of saturated ammonium chloride solution were added, allowed to warm to room temperature and the mixture was partitioned between 300 ml of water and 750 ml of ethyl acetate. The aqueous phase was extracted with a further 750 ml of acetate, then the organic extracts were combined, washed with 450 ml of brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The resulting cream-coloured solid was purified by flash chromatography (silica gel Merck 9385, ethyl acetate/cyclohexane 1/3, Ά, 1/1 then 3/1) to give 13.65 g of the title compound as a white, crystalline solid.

Tlc (dichloromethane) Rf 0.22 Mass spectrum MNH ₄ ⁺ : (measured) = 398 MNH ₄ ⁺ : (calculated) = 398

- 37 - /.· * .· '<··'

Compound K10 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one

Compound K9 (13.63 g) was suspended in 900 mL of ethyl acetate, 3.16 g of 20% palladium hydroxide (wet) on carbon was added, and the resulting black suspension was stirred vigorously under hydrogen atmosphere at room temperature for 90 min. The mixture was then filtered through Harbolite J2 resin and concentrated in vacuo to give the title compound (8.63 g) as a fine white powder.

Tlc (Methanol/dichloromethane=1/9) Rf 0.50

Mass spectrum MH ⁺ :(measured) = 247 MH ⁺ : (calculated) = 247

Compound Kll. rel-5-(6R-Isopropyl-4-methanesulfonyl-5-oxo-hexahydro-(3aS,6aR)-pyrrolo[3,2-b]pyrrole-1-carbonyl)-furan-2-carbaldehyde

To 100 mg of compound K10 in 5 ml of acetonitrile was added 74 mg of 5-formyl-2-furonic acid and 156 mg of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride while stirring. The resulting mixture was stirred for 3 hours, then the acetonitrile was removed in vacuo, the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution, the organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (Merck 9385 silica gel, eluent dichloromethane/acetonitrile=9/l) to give 80 mg of the title compound as a white solid.

Mass spectrum MH ⁺ : (measured) 369 MH ⁺ : (calculated) 369

-38K12. Compound rel-(3R,3aR,6aS)-3-(6-Isopropyl-4-methanesulfonyl-5-oxo-hexahydropyrrolo[3,2-b]pyrrole-1-carbonyl)-furan-2-carbaldehyde

Compound K10 (540 mg) was dissolved in 40 ml of acetonitrile and 400 mg of 2-formyl-3-furanic acid and 841 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added with stirring. The mixture was stirred for 16 h, then the acetonitrile was removed in vacuo, the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by flash chromatography (Merck 9385 silica gel; eluent dichloromethane/acetonitrile=9/l) to give 626 mg of the title compound as a cream solid.

Mass spectrum MH ⁺ : (measured) 369 MH ⁺ : (calculated) 369.

K13. compound rel-(3R,3aR,6aS)-5-(6-Isopropyl-4-methanesulfonyl-5-oxo-hexahydropyrrolo[3,2-b]pyrrole-1-carbonyl)-thiophene-2-carbaldehyde

250 mg of compound K10 were dissolved in 10 ml of acetonitrile, 260 mg of 5-formylthiophene-2-carboxylic acid and 389 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added and the resulting mixture was stirred for 3 hours. The acetonitrile was then removed in vacuo, the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane, the organic phases were

-39, washed with brine, dried over MgSO4 and concentrated in vacuo. The residual foam was purified by flash chromatography (Merck 9385, silica gel, dichloromethane/acetonitrile=9/l) to give 280 mg of the title compound as a cream solid.

Mass spectrum MH ⁺ : (measured) 385 MH ⁺ : (calculated) 385.

Compound K14 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(1H-pyrrole-2-carbonyl)hexahydropyrrolo[3,2-b]pyrrol-2-one 60 mg of pyrrole-2-carboxylic acid, 81 mg of 1-hydroxybenzotriazole, 115 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 101 mg of triethylamine are dissolved in 3 ml of dimethylformamide, stirred for 5 minutes, then 100 mg of compound K10 are added. The resulting mixture is stirred for 6 hours, then partitioned between 25 ml of 8% sodium bicarbonate solution and 50 ml of ethyl acetate, the organic phase is separated, washed with 2x50 ml of water, and the solvent is removed in vacuo. The remaining solid was suspended in 25 ml of diethyl ether, stirred for 10 minutes, then filtered with suction and the residue was dried to give 123 mg of the title compound as a white powder. Mp: 200-203°C.

Mass spectrum MH ⁺ : (measured) 340 MH ⁺ : (calculated) 340.

Compound K15: reI-(3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-(1-methyl-1H-pyrrole-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one

150 mg l-methylpyrrole-2-carboxylic acid, 180 mg 1-hydroxybenzotriazole, 250 mg l-(3-dimethylaminopropyl)-3-ethyl

-40carbodiimide hydrochloride and 240 mg triethylamine were dissolved in 5 ml dimethylformamide, stirred for 15 minutes, then 246 mg of compound K10 were added. The mixture was stirred for 18 hours, then partitioned between 135 ml 2% sodium bicarbonate solution and 150 ml ethyl acetate, the organic phase was separated, washed with 2x120 ml water, dried over Na ₂ SO 4 , the solvent was removed in vacuo to give a semi-solid, which was suspended in 20 ml diethyl ether and the resulting suspension was stirred for 10 minutes. The ether was then separated by decantation and replaced with another 10 ml ether. The resulting suspension was stirred for 10 minutes, then the ether was separated by decantation again, and the residue was dried to give 227 mg of the title compound as a light brown solid. Mp: 176-178°C.

Mass spectrum MH ⁺ : (measured) 354 MH ⁺ : (calculated) 354.

KI Compound 6

2-(2,2-Dimethylpropionyloxymethyl)thiazole-4-carboxylic acid A mixture of 1.85 g α-bromopiruric acid and 1.75 g l-(tert-butylcarbonyloxy)thioacetamide and 10 g activated 4 Å molecular sieves in 100 ml ethanol was stirred for 24 hours. The solvent was then removed in vacuo and replaced with 100 ml dichloromethane. The resulting suspension was stirred for 5 minutes, filtered through Harborlite J2, the filtrate was concentrated, the residual solid was dissolved in ethyl acetate, dried over Na ₂ SO 4 and the solvent was removed in vacuo to give 1.83 g of the title compound as a light yellow waxy solid. Mp: 155-158°C.

Mass spectrum MH ⁺ : (measured) 24-4 MH ⁺ : (calculated) 244.

-41 Compound K17

2-Hydroxymethylthiazole-4-carboxylic acid

1.78 g of KI6. and 1.80 g of potassium carbonate were dissolved in 90 ml of methanol and 30 ml of water and stirred at reflux for 4.5 hours, then cooled, concentrated to a volume of 30 ml, acidified with 2 M hydrochloric acid and extracted with 5x60 ml of dichloromethane, then concentrated in vacuo, the residual solid was extracted with a 2/1 mixture of hot industrial methylated spirits and ethyl acetate (2x150 ml), the extracts were combined with the dichloromethane extracts and the solvent was removed in vacuo. The residual gum was crystallized from diethyl ether to give 834 mg of the title compound as a brown powder. Mp: 121-127°C.

Mass spectrum MH ⁺ : (measured) 160 MH ⁺ : (calculated) 160.

KI Compound 8 rel-(3S,3aS,6aR)-4-(2-Hydroxymethyl-thiazole-4-carbonyl)-3-isopropyl-1-methanesulfonyl-hexahydropyrrolo[3,2-b]pyrrol-2-one

787 mg of compound K17, 1 g of compound K10, 655 mg of triethylamine, 718 mg of 1-hydroxybenzotriazole and 997 ml of 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride) were dissolved in 5 ml of dimethylformamide and stirred for 17 hours, then partitioned between 250 ml of 8% sodium hydrogen carbonate solution and 250 ml of ethyl acetate. The aqueous phase was separated, extracted with 250 ml of ethyl acetate, the organic phases were combined, washed with 0.5 M hydrochloric acid (2x200 ml) and water (2x200 ml), dried over Na2SÜ4 and the solvent was removed in vacuo. The residual foamy material was suspended in 100 ml of diethyl ether.

-42 for 5 minutes with stirring, then the resulting suspension is filtered with suction. The residue is 1.23 g of the title compound in the form of a brown powder. Mp: 197-201 °C.

Mass spectrum MH ⁺ : (measured) 388 MH ⁺ : (calculated) 388.

Compound K19

2-Dimethylaminomethylthiazole-4-carboxylic acid

A mixture of 370 mg of a-bromopyruvic acid, 300 mg of l-(dimethylamino)thioacetamide hydrochloride and 200 mg of sodium bicarbonate in 25 ml of ethanol was heated under reflux for 1.5 hours with stirring. 213 mg of potassium carbonate was then added and reflux was continued for 0.70 hours. The mixture was then cooled, the solvent was removed in vacuo, the residue was stirred in 30 ml of ethyl acetate for 0.5 hours, and the solvent was then separated by decantation. The residual solid was partitioned between 16.1 ml of 0.5 M hydrochloric acid and 20 ml of ethyl acetate, the aqueous phase was separated, concentrated in vacuo, the residual gum was treated with 20 ml of methanol and then filtered. The filtrate was concentrated in vacuo to give 430 mg of the title compound as a dark brown powder.

Mass spectrum MH ⁺ : (measured) 187 MH ⁺ : (calculated) 187.

Compound K20

5-Formyl-isoxazole-3-carboxylic acid mg ethyl 5-formylisoxazole-3-carboxylate is dissolved in 3 ml 1,4-dioxane and 1 ml 2 M hydrochloric acid and heated under reflux for 5 hours with stirring, then cooled and the solvent is removed in vacuo. The residue is stirred with diethyl ether, the solvent is removed, the residue

-43 material 18 mg of the title compound as an orange-brown solid.

Tlc (dichloromethane/methanol=9/1) Rf = 0.32.

Compound K21 rel-(3R,3aR,6aS)-3-(6-Isopropyl-4-methanesulfonyl-5-oxo-hexahydropyrrolo[3,2-b]pyrrole-1-carbonyl)-isoxazole-5-carbaldehyde

670 mg of compound K10 was dissolved in 50 ml of acetonitrile, 500 mg of compound K20 and 1.04 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added with stirring and stirred for 4 hours. The acetonitrile was then removed in vacuo, the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution, the organic phase was separated, passed through a Varian SPE elution silica gel cartridge and eluted successively with dichloromethane, chloroform, diethyl ether, ethyl acetate, acetonitrile and ethanol. The fractions containing the desired product were combined and concentrated to give 660 mg of the title compound as a white solid.

Tlc (dichloromethane/acetonitrile=9/l) Rf = 0.33.

Compound K22. l-Methyl-5-styryl-lH-pyrazole-3-carboxylic acid ethyl ester g (E)-ethyl-2,4-dioxo-6-phenylhex-5-enoate and 9 g methylhydrazine are dissolved in 250 ml ethanol, heated under reflux for 2 hours, then the solvent is removed in vacuo, the residual material is purified by flash chromatography on silica gel (diethyl ether/cyclohexane=1/1). The fractions containing the more polar of the two main components are collected together.

The mixture was stirred at -44°C, the solvent was evaporated to give 25.4 g of the title compound as yellow crystals, (diethyl ether/cyclohexane=1/1) Rf=0.14.

Compound K23 from this reaction was also isolated.

Compound K23

2-Methyl-5-styryl-2H-pyrazole-3-carboxylic acid ethyl ester

The fractions containing the less polar of the two main components were combined and the solvent was removed to give 11.4 g of the title compound as a yellow oil.

Tlc (diethyl ether/cyclohexane=1/1) Rf = 0.62.

Compound K24

5-Formyl-1-methyl-1H-pyrazole-3-carboxylic acid ethyl ester

Compound K22 (156 mg) was dissolved in 10 mL of ethyl acetate and ozone was bubbled through the solution while stirring at -78°C for 2 h. Nitrogen was then bubbled through, followed by the addition of 500 mg of triphenylphosphine, the solution was warmed to room temperature and the solvent was evaporated in vacuo. The product was passed through a Varian SPE bonded elution silica gel cartridge and eluted sequentially with dichloromethane, chloroform and diethyl ether. The fractions containing the desired products were combined and concentrated to give 127 mg of the title compound as white crystals.

Tlc (diethyl ether/cyclohexane=1/1) Rf = 0.58.

Compound K25

5-Formyl-1-methyl-1H-pyrazole-3-carboxylic acid

1.02 g of compound K24 was dissolved in 10 ml of 1,4-dioxane and 10 ml of 2 M hydrochloric acid and refluxed for 24 hours with stirring.

The mixture was then cooled and the solvent was removed in vacuo to give 0.85 g of the title compound as a light yellow solid.

Tlc (dichloromethane/methanol=/l) Rf = 0.19 (band)

K26. compound rel-(3R,3aR,6aS)-5-(6-Isopropyl-4-methanesulfonyl-5-oxo-hexahydropyrrolo[3,2-b]pyrrole-1-carbonyl!)-2-methyl2H-pyrazole-3-carbaldehyde

Compound K10 (783 mg) was dissolved in 60 ml of acetonitrile, compound K25 (645 mg) and 1.22 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. The mixture was stirred overnight, the acetonitrile was removed in vacuo, the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution, the organic phase was separated and passed through a Varian SPE-bonded silica gel cartridge and eluted sequentially with dichloromethane, chloroform, diethyl ether and ethyl acetate. The fractions containing the desired product were combined and concentrated to give 315 mg of the title compound as a white solid.

Tlc (dichloromethane/acetonitrile=9/l) Rf = 0.24.

K27. compound rel-(3R,3aR,6aS)-5-(6-Isopropylmethanesulfonyl-5-oxo-hexahydropyrrolo[3,2-b]pyrrole-1-carbonyl)-2-methyl-2H-pyrazole-3-carbaldehyde

124 mg of compound K23 was dissolved in 15 ml of ethyl acetate and ozone was bubbled through the solution at -78°C for 3 hours. Nitrogen was then bubbled through the solution, 500 mg of triphenylphosphine was added and the solution was warmed to room temperature,

-46then the solvent was evaporated in vacuo. The product was then passed through a Varian SPE-bonded elution silica gel cartridge and eluted sequentially with dichloromethane, chloroform and diethyl ether. The fractions containing the desired product were combined and concentrated to give 62 mg of the title compound as white crystals.

Tlc (diethyl ether/cyclohexane=1/1) Rf = 0.70.

Compound K28

5-Formyl-2-methyl-2H-pyrazole-3-carboxylic acid g of compound K27 was dissolved in 10 ml of 1,4-dioxane and 10 ml of 2 M hydrochloric acid and heated at reflux overnight. The mixture was then cooled and the solvent was evaporated in vacuo to give 0.8 g of the title compound as a pale yellow solid.

Tlc (dichloromethane/methanol=9/l) Rf = 0.54 (band).

K29. compound rel-(3R,3aR,6aS)-5-(6-Isopropyl-4-methanesulfonyl-5-oxo-hexabidropyrrolo[3,2-b]pyrrole-1-carbonyl)-1-methyl-1H-pyrazole-3-carbaldehyde

812 mg of compound KI0. were dissolved in 45 ml of acetonitrile, 660 mg of compound K28. and 1.26 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added and the mixture was stirred for 22 hours. The acetonitrile was then removed in vacuo and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic phase was separated, passed through a Varian SPE-bonded silica gel cartridge and eluted sequentially with dichloromethane, chloroform, diethyl ether and ethyl acetate. The desired product was obtained.

The fractions from 47 were combined and concentrated to give 955 mg of the title compound as a white solid.

Tlc (dichloromethane/acetonitrile=9/l) Rf = 0.22.

Compound K30

6-Bromomethylnicotinic acid

A mixture of 3.8 g of methyl 2-(bromomethyl)pyridine-5-carboxylate and 16.5 ml of bis(tri ^-n- butylon)oxide in 80 ml of toluene was stirred at 80°C for 24 hours, then cooled and extracted with 2x50 ml of 2 M hydrochloric acid. The aqueous extracts were combined, washed with 40 ml of toluene, and concentrated in vacuo to give 3 g of the title compound as a tan solid.

Mass spectrum MH ⁺ : (measured) 216.218 MH ⁺ ; (calculated) 216.218.

Compound K31 rel-(3R,3aR,6aS)-4-(6-Chloromethylpyridine-3-carbonyl)-3-isopropylmethanesulfonylhexahydropyrrolo[3,2b]pyrrol-2-one

177 mg of compound K30 and 236 mg of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are suspended in 5 ml of acetonitrile and 100 mg of compound K10 are added with stirring. The resulting compound is stirred for 2 hours, then the acetonitrile is removed in vacuo, the residue is partitioned between 40 ml of dichloromethane and 40 ml of 2 M sodium carbonate solution, the organic phase is separated, washed with 20 ml of 2 M sodium carbonate solution and 20 ml of water, dried over MgSO ₄ and concentrated. The residual oily material is purified by flash chromatography (dichloromethane/acetonitrile=7/3), thus obtaining 76 mg of the title compound as a white foam.

-48T.lc (dichloromethane/acetonitrile=7:3) Rf = 0.45.

Compound K32

5-Bromomethylpyrazine-2-carboxylic acid methyl ester

A mixture of 5.3 g of methyl (5-methyl) pyrazine-2-carboxylate, 6.3 g of N-bromosuccinimide and 0.33 g of dibenzoyl peroxide in 125 ml of carbon tetrachloride was heated to reflux with stirring and then irradiated with a 200 W tungsten lamp for 5 hours. The mixture was then cooled, washed with 2x20 ml of 10% sodium sulfite solution, 20 ml of water and then with 15 ml of saturated brine, dried over MgSO ₄ and concentrated. The residual oil was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate=3/2) to give 3.8 g of the title compound as a brown solid.

Tlc (cyclohexane/ethyl acetate=3/2) Rf = 0.28.

Compound K33

5-Bromomethylpyrazine-2-carboxylic acid hydrochloride

A mixture of 3.48 g of compound K32 and 6 g of sodium hydroxide in 40 ml of water was stirred for 2 hours, then acidified with 2 M hydrochloric acid, extracted with 4x30 ml of ethyl acetate, the extracts were combined, washed with 15 ml of saturated brine, dried over MgSO ₄ and the solvent was removed in vacuo to give 2.58 g of the title compound as a pale solid.

Mass spectrum MH ⁺ : (measured) 217.219 MH ⁺ : (calculated) 217.219.

Compound K34 rel-(3R,3aR,6aS)-4-(5-Chloromethylpyrazine-2-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one

-49800 mg of compound K10 and 934 mg and 934 mg of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are dissolved in 10 ml of acetonitrile, 1.23 g of compound K33 are added with stirring and stirred for 18 hours. The acetonitrile is then removed in vacuo, the residue is partitioned between 20 ml of dichloromethane and 25 ml of 2 M sodium carbonate solution, the aqueous phase is separated and extracted with 2x20 ml of dichloromethane. The organic phases are combined, washed with 15 ml of water and then with 15 ml of saturated brine, dried over MgSO ₄ and concentrated. The residual oil is purified by flash chromatography on silica gel (dichloromethane/acetonitrile=7/3), thus obtaining 562 mg of cv as a white foam.

Tlc (dichloromethane/acetonitrile=7/3) Rf = 0.42.

Compound K35

2R-(2,2,2-Trifluoroacetylamino)succinamic acid

37.9 g of D-asparagine (powdered and dried at 110°C for 48 hours) was suspended in 144 ml of methanol (dried on 3 A molecular sieves for 5 hours) and 40.2 ml of triethylamine were added under nitrogen with stirring, followed by 36 ml of methyl trifluoroacetate. The resulting mixture was stirred for 48 hours, then 145 ml of anhydrous methanol and 115 g of Dowex 50 H ⁺ resin (dried at 56°C for 24 hours) were added, the resulting mixture was stirred for 10 minutes, filtered, and the solvent was removed in vacuo to give the crude title compound as a white solid. This crude product was combined with another product from a similar reaction and recrystallized from hot water to give 106 g of the title compound as a white crystalline solid.

-50Mass spectrum MNH ₄ ⁺ : (measured) 245 MNH ₄ ⁺ : (calculated) 246

Compound K36

2R-(2,2,2-Trifluoroacetylamino)succinamic acid methyl ester

Compound K35 (95.14 g) was dissolved in 1150 ml of methanol (dried over 3 A molecular sieves), cooled to -70°C, 162 mg of acetyl chloride was added slowly, keeping the reaction temperature below -60°C. The mixture was then allowed to warm to -20°C and kept at this temperature for 48 hours. The solvent was then removed in vacuo to give a clear, colorless oil containing the title compound. This material was stirred with diethyl ether, and the resulting white solid was recrystallized from boiling water to give 42 g of the title compound as a white, crystalline solid.

Mass spectrum MH ⁺ : (measured) 243 MH ⁺ : (calculated) 243

Compound K37

3-Cyano-2R-(2,2,2-trifluoroacetylamino)propionic acid methyl ester g K36. Compound was suspended in 20 ml dichloromethane, 4.92 ml pyridine and 4.92 g p-toluenesulfonyl chloride were added with stirring, then another 15 ml dichloromethane was added and the resulting brown solution was stirred at room temperature for 48 hours. The mixture was then diluted with 25 ml dichloromethane, washed with 74 ml 1 M aqueous H ₃ PO ₄ solution, dried over Na ₂ SO ₄ , filtered and the solvent was removed in vacuo to give 3.57 g of a crude brown solid containing the title compound, which was purified by flash chromatography.

-51 (SiO ₂ , Merck, 9385, ethyl acetate/cyclohexane 1/3 then /4½). The eluate was concentrated in vacuo to give 1.62 g of the title compound as a white crystalline solid.

Tlc (1/1 ethyl acetate/cyclohexane) Rf 0.5

Mass spectrum MNH ₄ ⁺ : (measured) 242 MNH ₄ ⁺ : (calculated) 242

Compound K38

2,2,2-Trifluoro-N-(2-oxo-pyrrolidin-3R-yl)-acetamide

Compound K37 (200 mg) was dissolved in 10 mL of ethanol and stirred under hydrogen atmosphere in the presence of 5% rhodium/alumina (1 g) catalyst for 3 h. The catalyst was then filtered off and the filtrate was concentrated in vacuo to give a crude gum containing the title compound. The mixture was purified by flash chromatography (SiO ₂ , Merck, 9385, acetonitrile) and the eluate was concentrated in vacuo to give 40 mg of the title compound as a white solid.

TLC (Acetonitrile).

Rf 0.63 Mass spectrum MNH ₄ ⁺ : (measured) 214 MNH ₄ ⁺ : (calculated) 214

Compound K39

2-Oxo-3R-(2,2,2-trifluoroacetylamino)pyrrolidine-1-carboxylic acid benzyl ester

1.04 g of compound K3 8 was dissolved in tetrahydrofuran and 3.31 ml (1.6 mol) of n-butyllithium/hexane was added at -70°C with stirring. After 5 minutes, 833 μΐ of benzyl chloroformate were added and the material was allowed to reach room temperature·*»* ·· Λ»» cn /* . * '··:*· *·'

- JZ - t Μ· '· let. After 2½ hours the mixture was diluted with 100 ml ethyl acetate and washed with 2x150 ml 1 M hydrochloric acid. The organic extracts were combined, dried over MgSO ₄ , filtered, and concentrated in vacuo to give an orange/white crude solid which was triturated with diethyl ether to give 1.25 g of the title compound as a white solid.

Mass spectrum MNH ₄ ⁺ : (measured) 348 MNH ₄ ⁺ : (calculated) 348

Chiral HPLC (Chiracel AD, eluent system ethanol/heptane=15/85, flow rate 1 ml/min), retention time: R enantiomer=10.18 min (71.8%); S enantiomer: 12.50 min (28.2%).

Compound K40

2-Ethoxy-3R-(2,2,2-trifluoroacetylamino)pyrrolidine-1-carboxylic acid benzyl ester

100 mg of compound K39 was dissolved in 1 ml of anhydrous tetrahydrofuran, cooled to -20°C, lithium borohydride (2 M/THF, 0.15 ml) was added, then after 0.5 h ethanol was added, then 33 μΐ of concentrated sulfuric acid was added and the resulting solution was stirred at room temperature for 3.5 h. The pH of the mixture was then adjusted to pH=8-9 by adding saturated aqueous sodium bicarbonate, the organic solvent was removed in vacuo, the residue was partitioned between 20 ml of ethyl acetate and 10 ml of water, the aqueous phase was extracted with another 10 ml of ethyl acetate. The organic phases were combined, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give 101 mg of the title compound as a clear oil, which was used without further purification.

-53 Mass spectrum MNH ₄ ⁺ : (measured) 378 MNH ₄ ⁺ (calculated) 378 Compound K40 (Alternative synthesis) 2-Ethoxy-3R-(2,2,2-trifluoroacetylamino)-pyrrolidine-1-carboxylic acid benzyl ester

Compound K39 (214.8 g) was stirred in 1200 ml of anhydrous THF and cooled to -30°C, then lithium borohydride (2 M/THF, 336 ml) was added (after an initial temperature rise to -12°C, the temperature was maintained below -17°C during the addition). The mixture was then stirred at -20°C for 90 minutes, then 760 ml of ethanol was added while maintaining the temperature below -19°C. To the cold mixture was then added 75 ml of concentrated sulfuric acid in 215 ml of ethanol slowly while maintaining the internal temperature below -18°C. The cooling bath was then removed and the mixture was stirred for a further 90 minutes, at which time the internal temperature rose to +15°C. Then, 1600 ml of saturated sodium bicarbonate solution was carefully added to the mixture over 35 minutes, and the volatiles were removed in vacuo. The remaining aqueous phase was extracted with ethyl acetate (1000 ml + 2x800 ml), the extracts were combined, washed with brine (800 ml), dried over Na ₂ SO ₄ overnight, and the solvent was removed in vacuo to give 211.6 g of the title compound as an orange oil.

Tlc (4/1; CH ₂ Cl ₂ /Et ₂ O) Rf = 0.64 and 0.43

Compound K41 (2S,3R)-2-(rel-1S-Ethoxycarbonyl-2-methylpropyl)-3-(2,2,2-trifluoroacetylamino)pyrrolidine-1-carboxylic acid benzyl ester

-5490 mg of compound K40. 0.22 g of 1-ethoxy-3-methyl-butyl-1-enyloxy)-triisopropylsilane (compound K95 from international application WO97/36903) and 1.1 ml of dichloromethane are cooled to 5°C, 0.15 ml of boron trifluoride dietherate are added, then after 55 minutes 15 ml of 2 M aqueous sodium bicarbonate are added and the mixture is diluted with 10 ml of dichloromethane. The aqueous phase is separated, the organic phase is washed with 10 ml of saturated aqueous sodium chloride solution, the organic extract is dried over MgSO ₄ , filtered, concentrated in vacuo, thus obtaining 106 mg of the title compound as a colorless oil.

Mass spectrum MH ⁺ : (measured) 445 MH ⁺ : (calculated) 445

Compound K41 (Alternative synthesis) (2S,3R)-2-(rel-1S-Ethoxycarbonyl-2-methylpropyl)-3-(2,2,2-trifluoroacetylamino)pyrrolidine-1-carboxylic acid benzyl ester

97.9 g of compound K40, 233 g of (Z)-(1-ethoxy-3-methylbutyl-1-enyloxyltriisopropylsilane) and 600 ml of dichloromethane were cooled to 5°C under nitrogen, 200 ml of boron trifluoride diethyl etherate were added over 15 minutes, then after a further 15 minutes 450 ml of 2 M sodium carbonate were added and the temperature was kept below 20°C. The mixture was then filtered through Hyflon, the mixture was washed with dichloromethane (2x200 ml), then the washed material was added to the two-phase mixture, the aqueous phase was separated and extracted with 2x400 ml of dichloromethane. The extracts were combined, washed with brine (2x2540 mL), dried over MgSO ₄ , and concentrated in vacuo to give 154 g of the title compound.

-55Tlc SiO ₂ (1/3; ethyl acetate/cyclohexane) Rf = 0.49 (β-anomer), 0.42 (α-anomer).

Mass spectrum: (measured) MH ⁺ = 445 (calculated) MH ⁺ = 445

Compound 42 (2S,3R)-3-Amino-2-(1-ethoxycarbonyl-2-methylpropyl)-pyrrolidine-1-carboxylic acid benzyl ester mg of compound K41, 300 mg of potassium carbonate, 2 ml of ethanol and 2 ml of water are heated under reflux for 2¼ hours, then the ethanol and water are removed in vacuo, the residue is partitioned between 10 ml of ethyl acetate and 10 ml of water, the aqueous phase is adjusted to a pH of about 9-10 with 2 M aqueous sodium hydroxide solution, extracted with 3x20 ml of diethyl ether, the organic phases are combined, dried over MgSO ₄ , filtered and concentrated in vacuo, thus obtaining 56 mg of the title compound as a clear oil.

Compound K42 (Alternative synthesis) (2S,3R)-3-Amino-2-(1-ethoxycarbonyl-2-methylpropyl)-pyrrolidine-1-carboxylic acid benzyl ester

153 mg of compound K41, 183.3 g of potassium carbonate, 100 ml of ethanol and 1000 ml of water are heated under reflux for 5 hours, then the organic phase is separated, concentrated in vacuo, the residue, the aqueous phase and 200 ml of brine are extracted with ether (2x500 ml, + 250 ml), the extracts are combined and extracted with 3x500 ml of 1 M hydrochloric acid. The acidic extracts are combined, the pH is adjusted to pH=8 by adding 150 g of solid sodium bicarbonate, then extracted with dichloromethane (600 ml, + 3x300 ml).

-56A dichloromethane extracts were combined, dried over MgSO ₄ , and concentrated in vacuo to give 87.9 g of the title compound.

Tlc SiO ₂ (100/8/1 dichloromethane/ethanol/ammonia) Rf = 0.55 Mass spectrum: (measured) MH ⁺ = 349 (calculated) MH ⁺ = 349 Compound K43 (3aR,6S,6aS)-6-Isopropyl-5-oxo-hexahydropyrrolo[3,2-b]pyrrole-1-carboxylic acid benzyl ester mg Compound K42 was dissolved in 1 ml tetrahydrofuran and 1 ml tetramethylenediamine, then 1 M tert-butylmagnesium chloride in tetrahydrofuran (0.4 ml) was added. The resulting material was stirred for 3 hours, then 1 ml saturated ammonium chloride solution was added, the aqueous phase was separated, extracted with 4 ml ethyl acetate, the organic extracts were combined and concentrated in vacuo. The residue was partitioned between 10 ml of dichloromethane and 10 ml of 2 M hydrochloric acid, the aqueous phase was separated, extracted with 3x5 ml of dichloromethane, the organic phases were combined, dried over MgSO ₄ , filtered and concentrated in vacuo. The crude white solid obtained, containing the title compound, was purified by flash chromatography (SiO ₂ , Merck, 9385, ethyl acetate/cyclohexane=1/1) to give 16 mg of the title compound as a white solid.

TLC (2:1 ethyl acetate:cyclohexane) Rf 0.38

Chiral HPLC (chiral AD column, eluent system ethanol/heptane=10/90, flow rate 1 ml/min). Retention time: RRS lactam - 9.92 min (73.6%). SSR lactam =13.12 min (26.4%)

- 57 Compound K44 (3aR,6S,6aS)-6-Isopropyl-4-methanesulfonyl-5-oxo-hexahydropyrrolo[3,2-b]pyrrole-1-carboxylic acid benzyl ester

0.46 g of compound K43. was stirred in 30 ml of anhydrous tetrahydrofuran, 1 ml of lithium hexamethyldisilazide in tetrahydrofuran (2 ml) was added at -70°C under nitrogen, the resulting solution was warmed to 0°C over 15 min, then cooled back to 70°C and 0.30 ml of sulfonyl chloride was added. After 1.5 h, 30 ml of aqueous ammonium chloride was added, the resulting mixture was extracted with 3x5 ml of ethyl acetate, the extracts were combined, washed with 2x25 ml of brine, dried over MgSO ₄ and the solvent was removed in vacuo. The residue was flash chromatographed on silica gel (1/1 ethyl acetate/cyclohexane) to give 0.34 g of the title compound as a white solid.

Tlc SiO ₂ (1/1 ethyl acetate/cyclohexane) Rf 0.4

Mass spectrum MNH ₄ ⁺ : (measured) = 398 MNH ₄ ⁺ : (calculated) = 398

Compound K45 (3S,3aS,6aR)-3-Isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one

0.31 g of compound K44 in the presence of 0.24 g of 10% palladium hydroxide on carbon catalyst was stirred with 25 ml of 1,4-dioxane and 25 ml of ethyl acetate under a hydrogen atmosphere for 3 hours, then the catalyst was filtered through Hyflo and concentrated in vacuo to give 0.20 g of the title compound as a pale yellow solid.

-58T.lc SiO ₂ (9/1 chloroform/methanol) Rf = 0.36

Mass spectrum MH ⁺ : (measured) = 247 MH ⁺ : (calculated) =

247

Compound K46 (3S,3aS,6aR)-4-(5-Chloromethyl-pyrazine-2-carbonyl)-3-isopropyl-methanesulfonyl-hexahydropyrrolo[3,2-b]pyrrol-2-one

900 mg of compound K45 and 1.25 g of 1-(3-dimethylamino- < propyl)-3-ethylcarbodiimide hydrochloride are mixed in 25 ml of acetonitrile and 1.16 g of compound KI are added while stirring. The resulting mixture is stirred for 1 hour, then another 25 ml of acetonitrile are added, stirring is continued for 19 hours, then the acetonitrile is removed in vacuo and the residue is partitioned between 30 ml of dichloromethane and 30 ml of 2 M sodium carbonate solution. The aqueous phase is separated, extracted with 2x30 ml of dichloromethane, the organic phases are combined, dried over MgSO ₄ , filtered and concentrated. The remaining brown foam was purified by flash chromatography (Merck 9385, silica gel, 20% acetonitrile/dichloromethane) and the desired fractions were evaporated to dryness in vacuo to give 1.095 g of the title compound as a white foam.

Tlc (20% acetonitrile/dichloromethane) Rf = 0.52.

Mass spectrum MH ⁺ : (measured) 401.403, MH ⁺ (calculated) 401.403

Compound K47 5-(tert-Butoxycarbonylcyclopropylamino)methylpyrazine-2-carboxylic acid

-5960 mg of 2-methylpyrazine-5-carboxylic acid are suspended in 300 ml of acetic acid and bromine is added while stirring. The reaction mixture is then stirred at 80°C for 1 hour, then the solvent is evaporated in vacuo, the residue is partitioned between * 250 ml of ethyl acetate and 250 ml of 2 M aqueous HCl, the aqueous phase is extracted with a further 5x250 ml of ethyl acetate, the organic phases are combined, washed with 100 ml of 2 M HCl and then with 100 ml of saturated brine, dried over MgSO ₄ and the solvent is removed in vacuo. The remaining brown solid is mixed with 900 ml of acetonitrile and 60 ml of triethylamine and 30 ml of cyclopropylamine are added. The resulting material was stirred at room temperature for 20 hours, then 30 ml of cycloporylamine was added and stirred for a further 15 minutes. The volatile material was then evaporated in vacuo, the residue was partitioned between 200 ml of ethyl acetate and 300 ml of 2 M aqueous HCl, the organic phase was extracted with a further 4x200 ml of HCl, the aqueous extracts were combined, washed with 50 ml of ethyl acetate, cooled in an ice bath and basified with 120 ml of 10 M aqueous sodium hydroxide. The solution was then washed with 3x200 ml of ethyl acetate and 200 ml of diethyl ether, the residual volatile material was removed in vacuo to give a brown aqueous solution. To this solution, 500 ml of 1,4-dioxane and 71 g of di-tert-butyl dicarbonate are then added, the mixture is stirred at room temperature for 20 minutes, then another 10 g of di-tert-butyl dicarbonate are added and stirring is continued for another 24 hours. 85 g of citric acid are then added to the material while stirring, and then extracted with ethyl acetate (2x200 ml + 3x150 ml + 2x100 ml). The extracts are then combined,

-60MgSO ₄ , filtered and the solvent removed in vacuo to give a brown oil which was purified by flash chromatography (silica gel, Merck 9385, 100/8/1 = dichloromethane/methanol/acetic acid). The desired fractions were evaporated to dryness in vacuo to give a light brown solid which was vigorously stirred with 5/1 = cyclohexane/diethyl ether until evenly distributed. The solid was then filtered and dried in vacuo to give 16.65 g of the title compound as an orange/brown solid.

Tlc (100/8/l=dichloromethane/methanol/acetic acid) Rf =0.31. Mass spectrum MH ⁺ : measured 294 MH ⁺ : calculated 294

Compound K48

Cyclopropyl-[5-(6S-isopropyl-4-methanesulfonyl-5-oxo-hexahydro-(3aR,6aS)pyrrolo[3,2-b]pyrrole-1-carbonyl)-pyrazin-2-ylmethyl]-carbamic acid butyl ester

11.36 g of compound K45, 13.53 g of compound K47 and 19.3 g of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate are mixed with 260 ml of acetonitrile and 16 ml of Ν,Ν-diisopropylethylamine are added at room temperature. The resulting material is stirred for 2 hours, then the solvent is removed in vacuo, the residue is diluted with 250 ml of dichloromethane, washed with 250 ml of 1 M sodium carbonate solution, the aqueous phase is extracted with dichloromethane (3x150 ml). The organic phases are combined, washed with 50 ml of 1 M sodium carbonate solution, dried over MgSO ₄ , filtered and the solvent is removed in vacuo. The remaining yellowish-brown solid was purified by flash chromatography (Merck 9385,

-61 silica gel, 50% ethyl acetate/cyclohexane), the desired fractions were evaporated to dryness in vacuo to give 21.55 g of the title compound as a white foam.

Mass spectrum MH ⁺ : (measured) 522, MH ⁺ (calculated) 522 [a] _D ²⁰ +69.5 (c = 0.8, MeCN)

Compound K49

2-Pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid ethyl ester

43.9 g of 2-(bromomethyl)oxazole-4-carboxylic acid ethyl ester were dissolved in 300 ml of acetonitrile, 15.7 ml of pyrrolidine were added while stirring, and after 10 minutes of stirring, a further 7.8 ml of pyrrolidine were added. After 30 minutes, the solvent was removed in vacuo, the remaining orange oil was partitioned between 400 ml of 1 M sodium carbonate and 500 ml of dichloromethane, the phases were separated, the organic phase was washed with 100 ml of water, dried over MgSO ₄ , filtered and the solvent was removed in vacuo to give 24 g of the title compound as an orange oil.

Mass spectrum MH ⁺ : (measured) = 225. MH ⁺ : (calculated) = 225.

Compound K50

2-Pyrrolidin-1-yl-methyl-oxazole-4-carboxylic acid methyl ester mg potassium carbonate and 27.5 mg 2-(bromomethyl)oxazole-4-carboxylic acid methyl ester are suspended in 2.5 ml acetonitrile, 14 mg pyrrolidine are added and the mixture is stirred for 6 hours. The solvent is then removed in vacuo, the residue is partitioned between 15 ml ethyl acetate and 5 ml water, the organic phase is dried over Na ₂ SO ₄ , the solvent is removed in vacuo

-62 to give 23 mg of the title compound as a pale brown oil.

Mass spectrum MH ⁺ : (measured) = 211. MH ⁺ : (calculated) = 211.

The following compounds K51-K55 were prepared in a similar manner to intermediate 2 starting from 2-(bromomethyl)oxazole-4-carboxylic acid methyl ester.

Compound K51

2-[(Cyclopropylmethylamino)methyl]oxazole-4-carboxylic acid methyl ester hydrochloride

Extraction in the form of hydrochloride: pale brown gum.

Mass spectrum MH ⁺ : (measured) = 211. MH ⁺ : (calculated) = 211.

Compound K52

2-((Dicyclohexylamino)methyl]oxazole-4-carboxylic acid methyl ester

Pale yellow, waxy, solid.

Mass spectrum MH ⁺ : (measured) = 321. MH ⁺ : (calculated) 321.

Compound K53

Piperidin-1-ylmethyl-oxazole-4-carboxylic acid methyl ester

Pale brown, waxy, solid substance.

Mass spectrum MH ⁺ : (measured) = 225. MH ⁺ (calculated) 225.

Compound K54

2-(4-Phenylpiperazin-1-ylmethyl)oxazole-4-carboxylic acid methyl ester

Pale yellow, waxy, solid.

Mass spectrum MH ⁺ : (measured) = 302. MH ⁺ : (calculated) 302.

Compound -63K55

2-Dibutylaminomethyl-oxazole-4-carboxylic acid methyl ester

Pale yellow, waxy, solid.

Mass spectrum MH ⁺ : (measured) = 269. MH ⁺ : (calculated) 269.

Compound K56

2-Pyrrolidin-1-ylmethyl-oxazol-4-carboxylic acid/2-pyrrolidin-1-ylmethyl-oxazol-4-carboxylic acid sodium salt

First production

14.8 g of potassium carbonate were added to 24 g of compound K49 dissolved in 150 ml of ethanol and 150 ml of water. The mixture was heated to reflux for 4 hours with stirring, then the solvent was removed in vacuo, the resulting orange/brown material was azeotropically purified with toluene (three times) and dried in vacuo. The resulting solid was stirred vigorously with 100 ml of ether, filtered and dried in vacuo to give a mixture of the title compound and potassium bicarbonate as a brown solid (34.5 g). This material was used without further purification.

Second Preparation: Compound K50 (mg) was dissolved in 1.5 mL of dioxane and 1.0 M sodium hydroxide (0.3 mL) and stirred for 5 h. The solution was then neutralized (to approximately pH 7) with 2 M hydrochloric acid added dropwise. The solvent was removed in vacuo and the solid was dried in vacuo to give a mixture of the title compound and sodium chloride as a light yellow solid, 40 mg.

-64Mass spectrum MH ⁺ : (measured) =197. MH ⁺ : (calculated) = 197.

The following compounds K57-K59 were prepared in a similar manner to compound K56 (second preparation) starting from compounds K53-K55.

Compound K57

2-Piperidine-1-yl-methyl-oxazole-4-carboxylic acid

Cream-colored solid.

Mass spectrum MH ⁺ : (measured) = 211. MH~ (calculated) = 211.

Compound K58

2-(4-Phenyl-piperazm-1-yl-methyl)-oxazo-4-carboxylic acid

White solid.

Mass spectrum MH ⁺ : (measured) = 288. MH ⁺ : (calculated) = 288.

Compound K59

2-Dibutylaminomethyloxazole-4-carboxylic acid

Pale yellow, semi-solid substance.

Mass spectrum MH ⁺ : (measured) = 255. MH ⁺ (calculated) 555.

Examples

Hereinafter, dihydrochloride salts are denoted by the symbol 2:1 after the chemical name.

Example 1 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(5-pyrrolidin-1-ylmethylfuran-2-carbonyl)hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride mg KI Compound 1 and 17 mg pyrrolidine are dissolved in 6 ml dichloromethane, stirred for 2 hours, then 69 mg sodium triacetoxyborohydride are added and stirred overnight. The resulting material was washed with 8% aqueous sodium bicarbonate solution and then with water, the organic phase was passed through a Varian SPE-bound elution silica gel cartridge (pretreated with 1 column volume of dichloromethane), then eluted successively with dichloromethane, chloroform, diethyl ether/ethyl acetate=1/1 mixture, ethyl acetate, acetonitrile, then methanol, the fractions containing the desired products were combined and concentrated. The residual gum was treated with 1 M hydrochloric acid/diethyl ether mixture, thus obtaining 80 mg of the title compound as a yellow solid.

Mass spectrum MH ⁺ : (measured) 424 MH ⁺ (calculated) = 424 Tlc (dichloromethane/methanol=9/l): Rf = 0.27.

The following compounds of Examples 2-4 are prepared as described in Example 1 from Compound KI 1.

Example 2 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(5-morpholin-4-ylmethylfuran-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Creamy solid.

Mass spectrum MH ⁺ : (measured) - 440 MH ⁺ : (calculated) = 440

Tlc (dichloromethane/methanol=9/1): Rf = 0.60.

Example 3 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-[5-(4-phenylpiperazin-1-ylmethyl)furan-2-carbonyl]-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Red solid.

-66- .......- Mass spectrum MH ⁺ : (measured) =515 MH ⁺ : (calculated) = 515

Tlc (dichloromethane/methanol=9/1): Rf = 0.65.

Example 4 rel-(3R,3aR>6aS)-3-Isopropyl-1-methanesulfonyl-4-[5-(4-methyl-piperazin-1-5-yl-methyl)-furan-2-carbonyl]-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

White solid.

Mass spectrum MH ⁺ : (measured) = 453 MH ⁺ (calculated) = 453 Tlc (dichloromethane/methanol=9/l): Rf = 0.16.

Example 5 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(2-morpholin-4-ylmethylfuran-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride A mixture of 12 mg of compound K12 and 13 mg of morpholine in 3.5 ml of dichloromethane was stirred for 1.5 hours, then 43 g of sodium triacetoxyborohydride were added and stirring was continued overnight. The mixture was then diluted with dichloromethane, extracted with 2 M hydrochloric acid, the aqueous extracts were basified with 8% aqueous sodium bicarbonate solution and extracted with dichloromethane. The dichloromethane extracts were washed with brine, dried over Na ₂ SO ₄ , and the solvent was removed in vacuo. The residue was treated with 1M hydrochloric acid/diethyl ether to give 32 mg of the title compound as a cream solid.

Mass spectrum MH ⁺ : (measured) = 440 MH ⁺ : (calculated) 1 = 440

Tlc (dichloromethane/ethanol/ammonia=100/8/1): Rf = 0.68.

-67 The following compounds of Examples 6-10 were prepared from compound KI2 as described in Example 5.

Example 6 rel-(3R,3aR,6aS)-4-(2-Dimethylaminomethyl-furan-3-carbonyl)-3-isopropyl-1-methanesulfonyl-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Creamy solid.

Mass spectrum MH ⁺ : (measured) = 398 MH ⁺ (calculated) = 398

Tlc (dichloromethane/ethanol/ammonia=100/8/l): Rf = 0.70.

Example 7 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(2-piperidin-1-ylmethylfuran-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Beige colored solid.

Mass spectrum MH ⁺ : (measured) = 438 MH ⁺ : (calculated) = 438

Tlc (dichloromethane/ethanol/ammonia = 100/8/1): Rf = 0.68.

Example 8 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(2-pyrrolidin-1-ylmethylfuran-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Yellow solid.

Mass spectrum MH ⁺ : (measured) = 424 MH ⁺ : (calculated) = 424

Tlc (dichloromethane/ethanol/ammonia=100/8/1): Rf = 0.67.

Example 9

rel-(3R,3aR,6aS}-3-Isopropyl-1-methanesulfonyl-4-[2-(4-phenyl-piperazin-1-ylmethyl)-furan-3-carbonyl]-hexahydropyrrolo[3,2-b]pyrro-2-one hydrochloride

Yellow solid.

Mass spectrum MH ⁺ : (measured) = 515 MH ⁺ : (calculated) = 515

Tlc (dichloromethane/ethanol/ammonia=100/8/1): Rf = 0.86.

Example 10 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-[2-(4-methylpiperazin-1-ylmethyl)furan-3-carbonylhexahydropyrrolo[3,2-bpyrrol-2-one hydrochloride

Creamy solid.

Mass spectrum MH ⁺ : (measured) = 453 MH ⁺ : (calculated) = 453

Tlc (dichloromethane/ethanol/ammonia = 100/8/1): Rf = 0.50.

Example 11 rel-(3R,3aR,6aS)-4-(5-Dimethylaminomethyl-thiophene-2-carbonyl)-3-isopropyl-1-methanesulfonyl-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride mg KI A mixture of compound 3, 36 mg dimethylammonium chloride and 66 mg sodium triacetoxyborohydride in 6 ml dichloromethane was stirred overnight, then diluted with dichloromethane and extracted with 2 M hydrochloric acid. The aqueous extracts were washed with dichloromethane, then basified with 2 M sodium carbonate solution and extracted with dichloromethane. The dichloromethane extracts were washed with brine, dried over MgSO ₄ , the solvent was removed in vacuo, the remaining gum

The material was treated with 1M hydrochloric acid/diethyl ether to give 15 mg of the title compound as a yellow solid.

Mass spectrum MH ⁺ : (measured) = 414 MH ⁺ (calculated) = 414

Tlc (dichloromethane/ethanol/ammonia=100/8/1): Rf = 0.44.

The following compound of Example 12 was prepared from compound KI3 as described in Example 11.

Example 12 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(5-piperidin-1-yl-methylthiophene-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Yellow solid.

Mass spectrum MH ⁺ : (measured) = 454 MH ⁺ : (calculated) = 454

Tlc (dichloromethane/ethanol/ammonia=100/8/1): Rf = 0.52.

Example 13 reI-(3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-(5-morpholin-4-ylmethyl-1Hpyrrole-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride mg of compound KI4, 28 mg of paraformaldehyde and 40 mg of morpholine in 4 ml of ethanol and 1.5 ml of glacial acetic acid were stirred at reflux for 18 hours, then the mixture was cooled to room temperature, partitioned between 8% aqueous sodium bicarbonate solution (25 ml) and ethyl acetate (25 ml). The aqueous phase was further extracted with 30 ml of ethyl acetate, then the organic phases were combined, dried over _Na2SO4 and the solvent was concentrated in vacuo. The remaining gummy material was purified by flash chromatography (Merck 9385 silica gel,

dichloromethane/ethanol/ammonia=200/8/1) to give 21 mg of a white powder, which was treated with 1 M hydrochloric acid/diethyl ether to give 22 mg of the title compound as a white powder.

Melting point: 184-188°

Mass spectrum MH ⁺ : (measured) = 439 MH ⁺ (calculated) = 439

The following compounds of Examples 14-20 were prepared from compound K14 as described in Example 13.

Example 14 rel-(3S,3aS,6aR)-4-(5-Dimethylaminomethyl-1H-pyrrole-2-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

White powder. Melting point: 233-236°C.

Mass spectrum MH ⁺ : (measured) = 397 MH ⁺ (calculated) = 397 Tlc (Dichloromethane/ethanol/ammonia=100/8/1) Rf = 0.45 Example 15 reI-(3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-(5-piperidin-1-yl-methyl-1H-pyrrole-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

White powder. Melting point: 160-164°C

Mass spectrum MH ⁺ : (measured) = 437 MH ⁺ : (calculated) = 437

Example 16 rel-(3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-(5-pyrrolidin-1-ylmethyl-1H-pyrrole-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

White powder. Melting point: 175-178°C

Mass spectrum MH ⁺ : (measured) = 423 MH ⁺ (calculated) = 423

Example 17

-71 rel-(3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-[5-(4-phenylpiperazin-1-ylmethyl)-1H-pyrrole-2-carbonyl]-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2)

Creamy powder. Melting point: 156-160°C

Mass spectrum MH ⁺ : (measured) = 514 MH ⁺ (calculated) = 514

Example 18 reI-(3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-[5-(4-methylpiperazin-1-ylmethyl)-1H-pyrrole-2-carbonyl]-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2)

Creamy powder. Melting point: 177-181°C

Mass spectrum MH ⁺ : (measured) = 452 MH ⁺ : (calculated) = ⁴⁵²

Example 19 rel-(3S,3aS,6aR)-4-(5-Dibutylaminomethyl-1H-pyrrole-2-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Light yellow powder. Melting point: 116-120°C

Mass spectrum MH ⁺ : (measured) = 481 MH ⁺ : (calculated) =

481

Example 20 rel-(3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-(5-methylaminomethyl-1H-pyrrole-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Creamy powder. Melting point: 210-215°C

Mass spectrum MH ⁺ : (measured) = 383 MH ⁺ (calculated) = 383

Example 21

-72rel-(3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-(1-methyl-5-piperidin-1-ylmethyl-1H-pyrrole-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride mg KI A mixture of compound 5, 15 mg para-formaldehyde and 23 mg piperidine in 3 ml ethanol and 1.5 ml glacial acetic acid was heated under reflux for 22 hours, then cooled to room temperature and partitioned between 30 ml 8% aqueous sodium bicarbonate solution and 20 ml ethyl acetate. The organic phase was dried over _Na2SO4 , the solvent was evaporated in vacuo, the residual gum was purified by flash chromatography (Merck 9385 silica gel; dichloromethane/ethanol/ammonia=100/8/1) to give 26 mg of a white solid, which was treated with 1 M hydrochloric acid/diethyl ether to give 28 mg of the title compound as a white powder.

153°C Mass spectrum MH ⁺ : (measured) = 451 MH ⁺ : (calculated) = 451

The following compounds of Examples 22-25 were prepared from Compound KI 5 as described in Example 21.

Example 22: reI-(3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-(1-methyl-5-morpholin-4-ylmethyl-1H-pyrrole-2-carbonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Light yellow powder. Melting point: 150-154°C

Mass spectrum MH ⁺ : (measured) = 453 MH ⁺ : (calculated) = 453

Example 23

-73 rel-(3S,3aS,6aR)-4-(5-Dimethylaminomethyl-1-methyl-1H-pyrrole-2-carbonyl)-3-isopropyl-1-methanesulfonyl-hexahydropyrrolo[3,2-b]pyrrole-2-one hydrochloride

White powder. Melting point: 137-141°C

Mass spectrum MH ⁺ : (measured) = 411 MH ⁺ : (calculated) = 411

Example 24: reI-(3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-(1-methyl-5-pyrrolidin-1-ylmethyl-1H-pyrrole-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Yellow powder. Melting point: 135-139°C

Mass spectrum MH ⁺ : (measured) = 437 MH ⁺ (calculated) = 437

Example 25 rel-(3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-(1-methyl-5-methylaminomethyl-1H-pyrrole-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

White powder. Melting point: 216-218°C

Mass spectrum MH ⁺ : (measured) = 397 MH ⁺ : (calculated) = 397

Example 26 rel-(3S,3aS,6aR)-4-(4-Dimethylaminomethyl-1H-pyrrole-2-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride A mixture of 10 mg of compound KI4, 25 mg of para-formaldehyde, 38 mg of dimethylammonium chloride and 200 mg of activated 4A molecular sieves in 10 ml of ethanol was stirred at reflux for 24 hours. The mixture was then cooled to room temperature, the solvent was evaporated in vacuo, and the remaining gum was

-Ί4 was purified by flash chromatography using two columns (Merck 9385 silica gel; dichloromethane/ethanol/ammonia=80/8/l for the first column and 100/8/1 for the second column) to give 16 mg of a white powder, which was treated with 1 M hydrochloric acid/diethyl ether to give 16 mg of the title compound as a white powder. Mp: 160-165°C.

Mass spectrum MH ⁺ : (measured) = 397 MH ⁺ : (calculated) = 397

Tlc (dichloromethane/ethanol/ammonia=100/8/l) Rf = 0.20

Example 27 rel-(3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-(2-pyrrolidin-1-ylmethylthiazole-4-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

387 mg of KI 8 and 202 mg of triethylamine were dissolved in 42 ml of dichloromethane and 172 mg of methanesulfonyl chloride were added with stirring. The resulting mixture was stirred for 1.5 hours, then a 7 ml aliquot was removed and added to 30 mg of pyrrolidine dissolved in 2 ml of dichloromethane with stirring. The solution was stirred for 2 days. Then 12 ml of 8% sodium bicarbonate solution was added with vigorous stirring, then the aqueous phase was separated, extracted with 15 ml of dichloromethane, the organic phases were combined, dried over Na ₂ SO ₄ and the solvent was removed in vacuo. A semi-solid material remained, which was stirred with 10 ml of diethyl ether, 10 ml of cyclohexane was added to the resulting suspension and the solvent was separated by decantation. The residual solid was dried in vacuo to give a white solid which was treated with 1M hydrochloric acid/diethyl ether to give 51 mg of the title compound.

Compound 75 is obtained as a cream-colored powder.

Melting point: 130-134°C.

Mass spectrum MH ⁺ : (measured) = 441 MH ⁺ : (calculated) = 441

The following compounds of Examples 28-35 were prepared from compound KI8 as described in Example 27.

Example 28 rel-(3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-(2-morpholine-4-thiazole-4-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Pale powder. Melting point: 138-143°C.

Mass spectrum MH ⁺ : (measured) = 457 MH ⁺ (calculated) = 457

Example 29 rel-(3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-(2-piperidin-1-ylmethylthiazole-4-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Creamy powder. Melting point: 153-158°C

Mass spectrum MH ⁺ : (measured) = 455 MH ⁺ : (calculated) =

455

Example 30 reI-(3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-[2-(4-methyl-piperazin-1-ylmethyl)-thiazole-4-carbonyl]-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2) White powder. Mp: 153-158°C.

Mass spectrum MH ⁺ : (measured) = 470 MH ⁺ : (calculated) =

470

Example 31

-76reI-(3S,3aS,6aR)-4-(2-Cyclopropylaminomethylthiazole-4-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Light gray powder. Melting point: 160-163°C

Mass spectrum MH ⁺ : (measured) = 427 MH ⁺ : (calculated) =

427

Example 32 rel-(3S,3aS,6aR)-4-{2-[(4-Fluoro-benzylamino)-methyl]-thiazole-4-carbonyl]-3-isopropyl-1-methanesulfonyl-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Light yellow powder. Melting point: 141-145°C.

Mass spectrum MH ⁺ : (measured) = 495 MH ⁺ : (calculated) =

495

Example 33 rel-(3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-[2-(4-phenylpiperazin-1-ylmethyl)thiazole-4-carbonyl]hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2)

Creamy powder. Melting point: 156-161°C.

Mass spectrum MH ⁺ : (measured) = 532 MH ⁺ : (calculated) =

532

Example 34 rel-(3S,3aS,6aR)-4-(2-Dibutylaminomethylthiazole-4-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Light yellow powder. Melting point: 81-86°C.

Mass spectrum MH ⁺ : (measured) = 499 MH ⁺ (calculated) = 499

Example 35

-77 rel-{3R,3aR,6aS)-3-isopropyl-4-{2-[(1-isopropyl-2-methylpropylamino)methyl]thiazole-4-carbonyl}-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Creamy powder. Melting point: 192-195°C.

Mass spectrum MH ⁺ : (measured) = 485 MH ⁺ : (calculated) = 485

Example 36 rel-(3S,3aS,6aR)-4-(2-Dimethylaminomethyl-thiazole-4-carbonyl)-3-isopropyl-1-methanesulfonyl-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

127 mg of oxalyl chloride are added to 125 mg of compound KI9 suspended in 10 ml of dichloromethane with stirring, then 1 drop of dimethylformamide is added. The mixture is stirred for 1 hour, then concentrated in vacuo, the residue is suspended in 15 ml of dichloromethane, then 43 mg of compound K10 and 175 mg of sodium bicarbonate are added with stirring. The mixture is then stirred for 16 hours, then 12 ml of 8% sodium bicarbonate solution is added, the aqueous phase is separated, extracted with 15 ml of dichloromethane, the organic extracts are combined, dried over Na ₂ SO ₄ and concentrated. The resulting brown gum was chromatographed on silica gel (Merck 9385, dichloromethane/methanol/ammonia = 160/8/1) to give a brown gum which was treated with 1M hydrochloric acid/ether to give 23 mg of the title compound as a cream solid. Mp: 122-127°C.

-78Mass spectrum MH ⁺ : (measured) = 415 MH ⁺ : (calculated) = 415

Example 37 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(5-morpholin-4-ylmethylisoxazole-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride A mixture of 13 mg of compound K21 and 5 ml of dichloromethane in 5 ml of dichloromethane was stirred for 1.5 hours, then 43 mg of sodium triacetoxyborohydride was added and stirring was continued for 2.5 hours. The mixture was then washed with 8% aqueous sodium bicarbonate solution, the organic phase was passed through a Varian SPE-bound elution silica gel cartridge (pretreated with one column volume of dichloromethane), and then eluted sequentially with dichloromethane, chloroform, diethyl ether, ethyl acetate, acetonitrile and methanol. Fractions containing the desired product were combined, concentrated, and the resulting foam was treated with 1M hydrochloric acid/diethyl ether to give 39 mg of the title compound as a white solid.

Mass spectrum MH ⁺ : (measured) = 441 MH ⁺ (calculated) = 441 Tlc (dichloromethane/methanol=9/l): Rf = 0.65.

The following compounds of Examples 38-44 were prepared as described in Example 37 starting from Compound K21.

Example 38 rel-(3R,3aR,6aS)-4-(5-Dimethylaminomethylisoxazole-3-carbonyl)-3-isopropylmethanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

White solid.

-79- .:.. : JO

Mass spectrum MH ⁺ : (measured) = 399 MH ⁺ : (calculated) = 399

Tlc (dichloromethane/methanol=9/1): Rf - 0.58.

Example 39 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(5-pyrrolidin-1-ylmethylisoxazole-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Creamy solid.

Mass spectrum MH ⁺ : (measured) = 425 MH ⁺ : (calculated) = 425

Tlc (dichloromethane/methanol=9/1): Rf = 0.55.

Example 40 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(5-piperidin-1-yl-methylisoxazole-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

White solid.

Mass spectrum MH ⁺ . (measured) = 439 MH ⁺ (calculated) = 439 Tlc (dichloromethane/ethanol/ammonia=100/8/1): Rf = 0.52. Example 41 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-[5-(4-methyl-piperazin-1-yl-methyl)-isoxazole-3-carbonyl]-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

White solid.

Mass spectrum MH ⁺ (measured) = 454 MH ⁺ (calculated) = 454

Tlc (dichloromethane/methanol=9/l): Rf = 0.13,

Example 42

-80rel-(3R,3aR,6aS)-4-{5-[(4-Fluorobenzylamino)methyl]isoxazole-3-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Creamy solid.

Mass spectrum MH ⁺ : (measured) = 479 MH ⁺ : (calculated) = 479

Tlc (dichloromethane/ethanol/ammonia = 100/8/1): Rf = 0.59.

Example 43 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-[5-(4-phenylpiperazin-1-ylmethyl)isoxazol-3-carbonyl]hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Creamy solid.

Mass spectrum MH ⁺ : (measured) = 516 MH ⁺ : (calculated) = 516

Tlc (dichloromethane/ethanol/ammonia=100/8/1): Rf=0.62.

Example 44 reI-(3R,3aR,6aS)-4-(5-Dibutylaminomethylisoxazole-3-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Creamy solid.

Mass spectrum MH ⁺ : (measured) = 483 MH ⁺ : (calculated) = 483

Tlc (dichloromethane/ethanol/ammonia=100/8/l): Rf = 0.75.

Example 45 rel-(3R,3aR,6aS)-4-(5-Dimethylaminomethyl-1-methyl-1H-pyrazole-3-carbonyl)-3-isopropyl-1-methanesulfonyl-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

- 81 A mixture of 50 mg of compound K26 and 32 mg of dimethylammonium chloride in 5 ml of dichloromethane was stirred for 2 hours, then 55 mg of sodium triacetoxyborohydride was added and stirring was continued for 3 hours. The mixture was then washed with 8% aqueous sodium bicarbonate solution, the organic phase was passed through a Varian SPE cartridge (pre-treated by washing with one column volume of dichloromethane) and eluted successively with dichloromethane, chloroform, diethyl ether, ethyl acetate, acetonitrile and methanol. The fractions containing the desired product were combined and concentrated to give a pale brown oil which was treated with 1 M hydrochloric acid/diethyl ether to give 28 mg of the title compound as a cream solid.

Mass spectrum MH ⁺ : (measured) = 412 MH ⁺ : (calculated) = 412

Tlc (dichloromethane/ethanol/ammonia = 100/8/1): Rf = 0.68.

The following compounds of Examples 46-49 were prepared as described in Example 45 starting from compound K26.

Example 46 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(1-methyl-5-pyrrolidin-1-ylmethyl-1H-pyrazole-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Creamy solid.

Mass spectrum MH ⁺ : (measured) = 438 MH ⁺ : (calculated) =

438

Tlc (dichloromethane/ethanol/ammonia=100/8/1): Rf = 0.65.

Example 47

-82rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(1-methyl-5-morpholin-4-yl-methyl-1H-pyrazole-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Creamy solid.

Mass spectrum MH ⁺ : (measured) = 454 MH ⁺ (calculated) = 454 Tlc (dichloromethane/ethanol/ammonia=100/8/1): Rf = 0.69.

Example 48 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(1-methyl-5-piperidin-1-yl-methyl-1H-pyrazol-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Creamy solid.

Mass spectrum MH ⁺ : (measured) = 452 MH ⁺ : (calculated) =

452

Tlc (dichloromethane/ethanol/ammonia=100/8/1): Rf = 0.67.

Example 49 rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(1-methyl-5-(4-methylpiperidin-1-ylmethyl)-1H-pyrazole-3-carbonyl]hexahydropyrrolo(3,2-b]pyrrol-2-one hydrochloride

Creamy solid.

Mass spectrum MH ⁺ : (measured) = 466 MH ⁺ : (calculated) —

466

Tlc (dichloromethane/ethanol/ammonia=100/8/1): Rf = 0.78.

Example 50 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-[2-methyl-5-(4-phenylpiperazin-1-ylmethyl)-2H-pyrazole-3-carbonyl]-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

-83 A mixture of 50 mg of compound K29 and 28 mg of phenylpiperazine in 5 ml of dichloromethane was stirred for 2 hours, then 50 mg of sodium triacetoxyborohydride was added and stirring was continued overnight. The mixture was then washed with 8% aqueous sodium bicarbonate solution, the organic phase was passed through a Varian SPE cartridge (pretreated with 1 column volume of dichloromethane), and eluted sequentially with dichloromethane, chloroform, diethyl ether, ethyl acetate, acetonitrile and methanol. The fractions containing the desired product were combined, concentrated, and the residual gum was treated with 1 M hydrochloric acid/diethyl ether to give 16 mg of the title compound as a dark yellow solid.

Mass spectrum MH ⁺ : (measured) = 529 MH ⁺ : (calculated) = 529

Tlc (dichloromethane/ethanol/ammonia 100/8/1): Rf = 0.77.

The following compounds of Examples 51-55 were prepared as described in Example 50 starting from compound K29.

Example 51 rel-(3R,3aR,6aS)-4-(5-Dimethylaminomethyl-2-methyl-2H-pyrazol-3-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Yellow solid.

Mass spectrum MH ⁺ : (measured) =412 MH ⁺ : (calculated) = 412

Tlc (dichloromethane/ethanol/ammonia=100/8/1): Rf = 0.66.

Example 52

-84rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(2-methyl-5-pyrrolidin-1-yl-methyl-2H-pyrazole-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Yellow solid.

Mass spectrum MH ⁺ : (measured) = 438 MH ⁺ (calculated) = 438

Tlc (dichloromethane/ethanol/ammonia=100/8/1): Rf = 0.63.

Example 53 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(2-methyl-5-morpholin-4-ylmethyl-2H-pyrazole-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Yellow solid.

Mass spectrum MH ⁺ : (measured) = 454 MH ⁺ : (calculated) = 454

Tlc (dichloromethane/ethanol/ammonia=100/8/l): Rf = 0.65.

Example 54 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(2-methyl-5-piperidin-1-yl-methyl-2H-pyrazole-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Yellow solid.

Mass spectrum MH ⁺ : (measured) = 452 MH ⁺ (calculated) = 452

Tlc (dichloromethane/ethanol/ammonia=100/8/l): Rf = 0.65.

Example 55 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-[2-methyl-5-(4-methyl-piperazin-1-ylmethyl)-2H-pyrazole-3-carbonyl]-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Yellow solid.

-85Mass spectrum MH ⁺ : (measured) = 467 MH ⁺ : (calculated) = 467

Tlc (dichloromethane/ethanol/ammonia=100/8/l): Rf = 0.29.

Example 56 rel-(3R,3aR,6aS)-4-{6-[(Dicyclohexylamino)methyl]pyridine-3-carbonyl}-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride mg K31. Compound, 104.6 µl dicyclohexylamine, 79 mg sodium iodide and 169 mg potassium carbonate in 2 ml acetonitrile were stirred for 5 days, the solvent was evaporated, the residue was partitioned between 2 ml 2 M sodium carbonate solution and 3 ml dichloromethane, the phases were separated, the organic phase was passed through a Varian SPE cartridge (pre-treated with 1 column volume of dichloromethane) and eluted successively with dichloromethane, chloroform, diethyl ether, ethyl acetate, acetonitrile and methanol. The fractions containing the desired product were combined and concentrated to give a colourless oil which was treated with 1 M hydrochloric acid/diethyl ether to give 60 mg of the title compound as a cream solid.

Mass spectrum MH ⁺ : (measured) = 545 MH ⁺ : (calculated) = 545

Tlc (ethyl acetate): Rf = 0.47.

The following compounds of Examples 57-64 were prepared as described in Example 56 starting from compound K31.

Example 57

-86rel-(3R,3aR,6aS)-4-(6-Dibutylaminomethylpyridine-3-carbonyl)-3-isopropyl-1-inethanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2)

Brown glass.

Mass spectrum MH ⁺ : (measured) = 493 MH ⁺ : (calculated) = 493

Tlc (ethyl acetate) Rf = 0.49

Example 58: reI-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(6-morpholin-4-yl-methylpyridine-3-carbonyl)-hexahydropyrrolo{3,2-b]pyrrol-2-one hydrochloride (1:2)

Orange glass.

Mass spectrum MH ⁺ : (measured) = 451 MH ⁺ : (calculated) =

451

Tlc (ethyl acetate) Rf = 0.38

Example 59 rel-(3R,3aR,6aS)-4-(6-Cyclopropylaminomethylpyridine-3-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo(3,2-b]pyrrol-2-one hydrochloride (1:2)

Light brown solid.

Mass spectrum MH ⁺ : (measured) = 421 MH ⁺ : (calculated) =

421

Tlc (ethyl acetate) Rf = 0.36

Example 60 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(6-piperidin-1-yl-methyl-pyridin-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2)

Green solid.

-87Mass spectrum MH ⁺ : (measured) = 449 MH': (calculated) = 449

Tlc (ethyl acetate) Rf = 0.36

Example 61 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-[6-(4-methylpiperazin-1-ylmethyl)pyridine-3-carbonyl]-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2) Orange glass.

Mass spectrum MH ⁺ : (measured) = 464 MH ⁺ (calculated) = 464 Tlc (ethyl acetate) Rf = 0.05 Example 62 rel-(3R,3aR,6aS)-3-Isopropyl-4-{6-[(1-isopropyl-2-methylpropylamino)methyl]pyridine-3-carbonyl}-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2)

Yellow solid.

Mass spectrum MH ⁺ : (measured) = 479 MH ⁺ : (calculated) = 479

Tlc (ethyl acetate) Rf = 0.42

Example 63 rel-(3R,3aR,6aS)-4-(6-Dimethylaminomethyl-pyridine-3-carbonyl)-3-isopropyl-methanesulfonyl-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2)

Light yellow glass.

Mass spectrum MH ⁺ : (measured) = 409 MH ⁺ : (calculated) =

409

Tlc (ethyl acetate) Rf = 0.21

Example 64

- 88rel-(3R,3aR,6aS)-4-{6-[(4-Fluoro-benzylamino)-methyl]-pyridine-3-carbonyl}-3-isopropyl-1-methanesulfonyl-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride (1/2) Yellow/brown substance.

Mass spectrum MH ⁺ : (measured) = 489 MH ⁺ : (calculated) = 489

Tlc (ethyl acetate) Rf = 0.41

Example 65 rel-(3R,3aR,6aS)-4-(5-Cyclopropylaminomethyl-pyrazine-2-carbonyl-3isopropyl-1-methanesulfonyl-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride mg of compound K34, 23.3 μΐ cyclopropylamine and 25 mg sodium iodide in 1 ml of dichloromethane were stirred for 18 hours, then 23.3 μΐ additional cyclopropylamine was added and stirring was continued for a further 24 hours. The mixture was partitioned between 3 ml of 2 M sodium carbonate solution and 3 ml of dichloromethane, the phases were separated, the organic phase was passed through a Varian SPE packed column (previously pretreated with 1 column volume of dichloromethane), and then successively with dichloromethane, chloroform, diethyl ether, The fractions containing the desired product were combined and concentrated to give 17 mg of a light brown oil which was treated with 1M hydrochloric acid/diethyl ether to give 20 mg of a brown solid.

Mass spectrum MH ⁺ : (measured) = 422 MH ⁺ : (calculated) = 422. Tlc (ethyl acetate): Rf = 0.12.

The following compounds of Examples 66-75 were prepared from compound K34 as described in Example 65.

Example 66 rel-(3R,3aR,6aS)-4-(5-Dibutylaminomethylpyrazine-2-carbonyl)-3-isopropyl-1-methanesulfonyl-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2)

Light brown solid.

Mass spectrum MH ⁺ : (measured) = 494 MH ⁺ (calculated) =

494. Tlc (ethyl acetate) Rf = 0.63

Example 67 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(5-morpholin-4-ylmethylpyrazine-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2)

Creamy solid.

Mass spectrum MH ⁺ : (measured) = 452 MH ⁺ : (calculated) =

452. Tlc (ethyl acetate) Rf = 0.12

Example 68 rel-(3R,3aR,6aS)-4-{5-[(Dicyclohexylamino)methylpyrazine-2-carbonyl}-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2)

Creamy solid.

Mass spectrum MH ⁺ : (measured) = 546 MH ⁺ : (calculated) =

546. Tlc (ethyl acetate) Rf = 0.65

Example 69 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(5-piperidin-1-ylmethylpyrazine-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2)

Creamy solid.

Mass spectrum MH ⁺ (measured) = 450 MH ⁺ (calculated) = 450.

Tlc (ethyl acetate) Rf = 0.12

Example 70 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-[5-(4-methyl-piperazin-1-yl-methyl)-pyrazine-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2)

Brown glass.

Mass spectrum MH ⁺ : (measured) = 465 MH~: (calculated) =

465. Tlc (ethyl acetate) Rf = 0.02

Example 71 rel-(3R,3aR,6aS)-3-Isopropyl-4-{5-[(1-isopropyl-2-methylpropylamino)methyl)pyrazine-2-carbonyl}-1-methanesulfonyl-1-hexahydropyrrolo[3,2-]pyrrol-2-one hydrochloride (1:2)

Creamy solid.

Mass spectrum MH ⁺ : (measured) - 480 MH ⁺ (calculated) =

480. Tlc (ethyl acetate) Rf = 0.45

Example 72 rel-(3R,3aR,6aS)-4-(5-Dimethylaminomethylpyrazine-2-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2)

Light brown solid.

Mass spectrum MH ⁺ : (measured) = 410 MH ⁺ : (calculated) =

410. Tlc (ethyl acetate) Rf = 0.06

Example 73 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-[5-(4-phenyl-piperazin-1-ylmethyl)-pyrazine-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2)

Light brown glass.

-91 Mass spectrum MH ⁺ : (measured) = 527 MH ⁺ : (calculated) = 527. Tlc (ethyl acetate) Rf = 0.27

Example 74 reI-(3R, 3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(5-pyrrolidin-1-ylmethylpyrazine-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2)

Orange/brown solid.

Mass spectrum MH ⁺ : (measured) = 436 MH ⁺ . (calculated) = 436. Tlc (ethyl acetate) Rf = 0.05

Example 75 rel-(3R,3aR,6aS)-3-Isopropyl-1-methanesulfonyl-4-(5-methylaminomethylpyrazine-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride (1:2)

Light brown solid.

Mass spectrum MH ⁺ : (measured) = 396 MH ⁺ (calculated) = 396. Tlc (ethyl acetate) Rf = 0.02

Example 76 (3S,3aS,6aR)-4-(5-Cyclopropylaminomethylpyrazine-2-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

Compound K48 (21.53 g) and 200 ml of 4 M HCl/1,4-dioxane were stirred at room temperature for 2 h, then the solvent was removed in vacuo to give an off-white solid. This was recrystallized from 2.3 L of 5% νίζ/2-propanol to give 15.54 g of the title compound (single enantiomer) as a white solid.

Tlc (silica gel, 200/8/l=dichloromethane/ethanol/0.880 ammonia) Rf = 0.21 » ♦* *·' - 4' »* '

Mass spectrum MH ⁺ : (measured) 422.19, MH ⁺ (calculated) 422.19

[a] _D ²⁰ + 51.3 (c = 0.9, 1/1 H ₂ O/MeCN)

Op: 183-185°C circular dichroism: X _max 250.2 nm (ΔΕ -1.34 M' ¹ cm' ¹ ) λπιαχ285.4 nm (ΔΕ +0.99 M' ¹ cm' ¹ ), (MeCN/H ₂ O)

Elemental analysis for the compound with the formula Ci9H ₂ 7ClN5O4S. HC1 1.3H2O:

Found: C, 47.4; H, 6.4; N, 14.3; S, 6.5; Cl, 7.8; water, 4.9% Calculated: C, 47.4; H, 6.4; N, 14.6; S, 6.7; Cl, 7.4; water, 4.9% Example 76

Alternative production

A mixture of 1.056 g of compound K46, 0.73 ml of cyclopropylamine and 481 mg of potassium iodide in 25 ml of acetonitrile was stirred for 3 hours, then the solvent was removed in vacuo, the mixture was partitioned between 20 ml of saturated sodium bicarbonate solution and 20 ml of dichloromethane, the phases were separated, the aqueous phase was extracted with a further 2x20 ml of dichloromethane, the organic phases were combined, dried over MgSO ₄ and the solvent was removed in vacuo. The residual oil was purified by flash chromatography (Merck 9385 silica gel, 200/8/1 = dichloromethane/ethanol/0.880 ammonia). Fractions containing the desired product were combined and concentrated to give 924 mg of a white solid which was dissolved in 10 mL of dichloromethane and treated with 10 mL of 1M hydrochloric acid/diethyl ether to give 1 g of the title compound (single enantiomer) as a white solid.

Example 77 (3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-(2-pyrrolidin-1-ylmethyl-oxazol-4-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

32.2 g of compound K56 were added rapidly to 13 g of 1-hydroxybenzotriazole dissolved in 350 ml of acetonitrile with stirring, followed by the addition of 21.7 g of (3S,3aS,6aR)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one (Example K122 from International Application WO 97/36903) dissolved in 70 ml of acetonitrile and 37 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and the resulting material was stirred for 20 hours. The solvent was then removed in vacuo, the residue was partitioned between 900 ml of dichloromethane and 600 ml of 1 M sodium carbonate solution, the aqueous phase was separated, extracted with 150 ml of dichloromethane, the organic phases were combined, washed with 250 ml of brine, dried over MgSO ₄ and concentrated in vacuo. The remaining brown solid was purified by flash chromatography (Merck 9385 silica gel, dichloromethane/ethanol/ammonia=150/8/1 → 135/8/1) to give 29.3 g of a cream solid. This material was dissolved in 150 ml of dichloromethane and treated with 75 ml of 1 M hydrochloric acid/ether. The solvent was removed in vacuo, the residual solid was redissolved in 150 ml of dichloromethane and treated with 75 ml of 1M hydrochloric acid/ether. The solvent was removed in vacuo, the residual solid was recrystallized from acetone to give 26.3 g of the title compound as a white solid. Mp: 156-158°C.

-94T.lc (silica gel; dichloromethane/ethanol/ammonia=100/8/1; double elution) Rf = 0.66.

NMR (400 MHz; D-6 DMSO): d 8.78 (s, 1 H), 4.68 (s, 2H), 4.13 (ddd, >11.11.7 Hz, 1 H), 4.08 (dd, J=11.10 Hz, 1 H), 3.80 (ddd, >12.10.5.5 Hz, 1 H), 3.60 (m, 2H), 3.55 (dd, >12.10.5 Hz, 1H), 3.31 (s, 3H), 3.20 (m, 2H), 3.03 (dd, >12.2.5 Hz, 1H), 2.88 (md, >2.5 Hz, 1H), 2.34 (m, 1H), 2.12 (m, 1H), 1.96 (m, 4H), 1.19 (d, >7 Hz, 3H), 0.98 (d, >7 Hz, 3H). Contains 0.16 mol% acetone.

Infrared (KBr diffuse reflection) 3633, 3474, 3149, 3102, 2956, 2882, 2668, 2576, 2475, 1747, 1709, 1639, 1634, 1567, 1442, 1380, 1347, 1161, 1146, 967, 810, 547 cm' ¹ .

Mass spectrum MH ⁺ : (measured) = 425.186372. MH ⁺ (calculated) = 425.185867 (error 1.2 ppm).

Combustion analysis for the compound with the formula CigH28N4O5S.HC1.0.75H2O 0.2Me ₂ CO:

Found: C, 48.65; H, 6.39; N, 11.41; S, 6.19; Cl, 7.13%, calculated: C, 48.43; H, 6.57; N, 11.53; S, 6.60; Cl, 7.29%.

Example 78 rel-(3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-(2-pyrrolidin-1-ylmethyloxazol-4-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride mg of compound K56 (second preparation) was suspended in 4 ml of dichloromethane, 63 mg of oxalyl chloride was added, followed by 1 drop of dimethylformamide and the mixture was stirred for 1.5 hours. The solvent was then removed in vacuo and replaced with 10 ml of toluene. The resulting suspension was stirred vigorously for 10 minutes and the toluene was removed in vacuo.

-95, the residual gum was suspended in 5 ml of dichloromethane and 20 mg of compound K10 and 35 mg of sodium bicarbonate were added. The mixture was then stirred for 3.75 h and then partitioned between 2x10 ml of dichloromethane and 5 ml of water. The organic phases were combined, dried over Na ₂ SO 4 , concentrated in vacuo, the residual solid was stirred with 4 ml of ether for 10 min and the ether was separated by decantation. The residual material was dried in vacuo and the resulting white powder was treated with 1 M hydrochloric acid/diethyl ether to give 17 mg of the title compound as a cream powder. Mp: 116-120°C.

Mass spectrum MH ⁺ : (measured) = 425. MH ⁺ : (calculated) = 425.

The following compounds of Examples 79-81 were prepared as described in Example 78 starting from compounds K10 and K57-59, respectively.

Example 79 rel-(3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-(2-piperidin-1-ylmethyloxazole-4-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

White powder, mp: 140-143°C.

Mass spectrum MH ⁺ : (measured) = 439. MH ⁺ : (calculated) = 439.

Example 80 rel-(3S,3aS,6aR)-3-Isopropyl-1-methanesulfonyl-4-[2-(4-phenyl-piperazin-1-yl-methyl)-oxazol-4-carbonyl]-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

White solid, mp: 156-160°C.

-96Mass spectrum MH ⁺ : (measured) = 516. MH ⁺ : (calculated) = 516.

Example 81 rel-(3S,3aS,6aR)-4-(2-Dibutylaminomethyloxazole-4-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride

White powder, mp: 122-126°C.

Mass spectrum MH ⁺ : (measured) = 483. MH ⁺ : (calculated) = 483.

Example 82 rel-(3S,3aS,6aR)-4-{2-[(Cyclopropylmethylamino)methyl]oxazole-4-carbonyl}-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride mg of compound K51 was dissolved in 1.5 ml of dioxane and 0.4 ml of 1 M sodium hydroxide, stirred for 3.5 hours, then 0.35 ml of hydrochloric acid was added while stirring. The solvents were then removed in vacuo, the residue was stirred with 3 ml of dioxane for 5 minutes, then the solvent was removed in vacuo. The solvent mixing was repeated with a further 3 ml of dioxane, then the solvent was removed in vacuo, and the residue was dried in vacuo. The resulting solid was suspended in 3 ml of dichloromethane, 5 mg of oxalyl chloride was added with stirring, followed by 1 drop of dimethylformamide and the mixture was stirred for a further 1 hour. The solvent was then removed in vacuo, the residue was stirred vigorously with a 1/1 mixture of dichloromethane/toluene (10 ml) for 5 minutes, the solvent was removed in vacuo and the

-97 The remaining gummy material was suspended in 5 ml of dichloromethane and 18 mg of compound K10 and 35 mg of sodium bicarbonate were added. The mixture was then stirred for 0.75 h, allowed to stand at room temperature for 3 days, diluted with 10 ml of dichloromethane and washed with 10 ml of water. The organic phase was dried over Na2SO4, concentrated in vacuo and the residue was purified by flash chromatography (Merck 9385, silica gel, dichloromethane/ethanol/ammonia=1 50/8/1) to give a white powder which was treated with 1 M hydrochloric acid/diethyl ether to give 7 mg of the title compound as a white powder. Mp: 116-119°C.

Mass spectrum MH ⁺ : (measured) = 425. MH ⁺ : (calculated) = 425.

The following compound, Example 83, was prepared as described in Example 82 starting from compounds K10 and K52.

Example 83 rel-(3S,3aS,6aR)-4-{2-[(Dicyclohexylamino)methyl]oxazole-4-carbonyl]-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride White powder, mp: 130-133°C.

Mass spectrum MH ⁺ : (measured) = 535. MH ⁺ (calculated) = 535.

Biological data

1. The compounds of Examples 1-83 were tested in vitro using the elastase assay described above. The IC50 values obtained are summarized in the following table.

Example IC ₅ o Example IC ₅₀ 1 0.123 39 0.021 2 0.081 40 0.030 3 0.164 41 0.014 4 0.065 42 0.057 5 0.039 43 0.051 6 0.071 44 0.099 7 0.082 45 0.019 8 0.086 46 0.014 9 0.129 47 0.024 10 0.114 48 0.030 11 0.139 49 0.051 12 0.104 50 0.054 13 0.032 51 0.021 14 0.021 52 0.012 15 0.021 53 0.015 16 0.019 54 0.011 17 0.068 55 0.020 18 0.022 56 0.038 19 0.057 57 0.041 20 0.013 58 0.045 21 0.029 59 0.028 22 0.043 60 0.037 23 0.026 61 0.030 24 0.024 62 0.041 25 0.009 63 0.025 26 0.017 64 0-048 27 0.008 65 0.013

28 0.011 66 0.076 29 0.014 67 0.019 30 0.017 68 0.087 31 0.016 69 0.022 32 0.009 70 0.013 33 0.005 71 0.050 34 0.013 72 0.012 35 0.056 73 0.074 36 0.013 74 0.012 37 0.017 75 0.093 38 0.014 76 0.011 77 0.010 78 0.014 79 0.016 80 0.100 81 0.076 82 0.084 83 0.137

2. The compounds of Examples 1, 2, 11, 12, 13, 15, 16, 17, 27, 28, 29, 31, 33, 34, 35, 37-50, 56, 57, 59, 60, 62-69, 72, 73, 76, 78, 80 and 81 were tested in vivo in the guinea pig test described above, the effective dose being less than 10 mg/kg and the duration of action being at least 6 hours.

3. The compounds of Examples 1-83 were tested in a human whole blood elastase inhibition assay, as previously described.

- 100. The IC50 values obtained are summarized in the following table.

Example number _IC50 (μM) Example number ΙΟ ₅₀ (μΜ) 1 0.355 41 1.76 2 1,882 42 0.43 3 2,195 43 0.429 4 4,185 44 0.528 5 3 45 0.518 6 4,015 46 0.524 7 3.04 47 1,043 8 3.46 48 0.414 9 3,615 49 0.539 10 5,565 50 1.92 11 1.16 51 >10 ,12 2.4 52 7,637 13 1,103 53 8.23 14 1,885 54 4,205 15 0.452 55 >10 16 0.774 56 0.293 17 0.316 57 0.193 18 2,925 58 2.44 19 0.408 59 0.394 20 6,405 60 0.605 21 0.317 61 5,898 22 0.453 62 0.252 23 0.364 63 1.62 24 0.306 64 0.521

- 101 -

25 1.64 65 0.333 26 >10 66 0.217 26 0.704 67 0.878 28 1.125 68 0.221 29 0.311 69 0.264 30 1.683 70 3.215 31 0.896 71 0.205 32 0.427 72 0.322 33 0 ,257 73 0-282 34 0.546 74 0.205 35 0.81 75 5.025 36 0.296 76 0.139 37 1.187 77 0.245 38 0.224 78 0.411 39 0.358 79 0.502 40 0.222 80 0.4 Example IC₅₀(pM) number 81 0.296 82 0.717 83 0.55

Claims (30)

- 102Patent claims 1. Compounds of general formula (I), and their salts and solvates - in the formula R1 is alkyl of 1-6 carbon atoms, R is alkyl of 2-4 carbon atoms or alkenyl of 2-4 carbon atoms, X is CO or SO ₂ , Het means an optionally substituted 5-10 membered monocyclic or bicyclic aromatic system containing 1-4 heteroatoms selected from O, N and S atoms, n is a number from O to 4, R ³ and R ⁴ independently represent a hydrogen atom, a C 1-8 alkyl, -(CH2)i.4CONR ⁵ R ⁶ , CO-C 1-4 alkyl, or a group of the general formula (CH2)o- ₂ Ph, where Ph represents a phenyl group substituted with one or more C 1-4 alkyl or halogen atoms or the NR ³ R ⁴ group together represents an azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, piperazinyl group optionally substituted with a C 1-6 alkyl, phenyl (optionally halogen or C 1-4 alkyl) substituted) or with a benzyl group (optionally substituted on the benzene ring with a halogen atom or an alkyl group having 1-4 carbon atoms), or NR ³ R ⁴ together represents a ring as described above, which is also one or more times substituted with 1-4 carbon atoms on the carbon atom is substituted with a carbon alkyl, CONR ⁵ R ⁶ or COOR ⁶ group, R ⁵ and R ⁶ are independently hydrogen or C 1-4 alkyl (relative stereochemistry is indicated in the formula). 2. Compounds of general formula (I) according to claim 1, in which Het is a 5- or 6-membered monocyclic aromatic ring containing one or two heteroatoms selected from O, N and S atoms. 3. Compounds of general formula (I) according to claim 2, in which Het represents a thiazolyl, isoxazolyl, pyrazolyl or pyrazinyl group. 4. Compounds of general formula (I) according to claim 2, in which Het represents a pyridin-3-yl group. 5. Compounds of general formula (I) according to claim 2, in which Het represents an oxazolyl group. 6. A compound of formula (I) according to any one of claims 1, 2 or 5, which corresponds to formula (IA) (relative stereochemistry is indicated in the formula). 7. A compound of formula (I) according to any one of claims 1-6, wherein R ² is isopropyl or propyl. 8. A compound of formula (I) according to any one of claims 1-7, wherein R ² is isopropyl. 9. A compound of formula (I) according to any one of claims 1-8, wherein R ¹ is methyl or ethyl. - 104- 10. Compounds of general formula (I) according to claim 9, in which R ¹ represents a methyl group. 11. Compounds of formula (I) according to any one of claims 1-10, wherein X is CO. 12. Compounds of general formula (I) according to any one of claims 1-11, wherein n is 1-3. 13. Compounds of formula (I) according to any one of claims 1-11, in which R ³ and R ⁴ independently represent a hydrogen atom or a C 1-8 alkyl group or the NR ³ R ⁴ group represents a pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl group, optionally N-substituted with a C 1-8 alkyl or phenyl group (optionally substituted with a halogen atom or a C 1-4 alkyl group). 14. A compound of formula (I) according to claim 1, comprising any of the following: rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(5-pyrrolidin-1-ylmethylfuran-2-carbonyl)hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(5-morpholin-4-yl-methylfuran-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-[5-(4-phenylpiperazin-1-ylmethyl)furan-2-carbonyl]hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-[5-(4-methyl-piperazin-yl-methyl)-furan-2-carbonyl]-hexahydropyrrolo[3,2-b]pyrrol-2-one; - 105 rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(2-morpholin-4-yl-methylfuran-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-4-(2-dimethylaminomethylfuran-3-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(2-piperidin-1-ylmethylfuran-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(2-pyrrolidin-1-ylmethylfuran-3-carbonyl)hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-[2-(4-phenylpiperazin-1-ylmethyl)furan-3-carbonyl]hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-1-[2-(4-methylpiperazin-1-ylmethyl)furan-3-carbonyl]hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-4-(5-dimethylaminomethylthiophene-2-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(5-piperidin-1-yl-methylthiophene-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-3-isopropyl-1-methanesulfonyl-4-(5-morpholin-4-ylmethyl-1H-pyrrole-2-carbonyl)hexahydropyrrolo[3,2-b]pyrrol-2-one; - 106rel-(3S,3aS,6aR)-4-(5-dimethylaminomethyl-1H-pyrrole-2-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-3-isopropyl-1-methanesulfonyl-4-(5-piperidin-1-yl-methyl-1H-pyrrole-2-carbonyl-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-3-isopropyl-1-methanesulfonyl-4-(5-pyrrolidin-1-ylmethyl-1H-pyrrole-2-carbonyl)hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-3-isopropyl-1-methanesulfonyl-4-[5-(4-phenylpiperazin-1-ylmethyl)-1H-pyrrole-2-carbonyl]-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-3-isopropyl-1-methanesulfonyl-4-[5-(4-methylpiperazin-1-ylmethyl)-1H-pyrrole-2-carbonyl]hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-4-(5-dibutylaminomethyl-1H-pyrrole-2-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-3-isopropyl-1-methanesulfonyl-4-(5-methylaminomethyl-1H-pyrrole-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-3-isopropyl-1-methanesulfonyl-4-(1-methyl-5-piperidin-1-ylmethyl-1H-pyrrole-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-3-isopropyl-1-methanesulfonyl-4-(1-methyl-5-morpholin-4-yl-methyl-1H-pyrrole-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one; - 107 rel-(3S,3aS,6aR)-4-(5-dimethylaminomethyl-1-methyl-1H-pyrrole-2-carbonyl-3-isopropyl-1-methanesulfoylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-3-isopropyl-1-methanesulfonyl-4-(1-methyl-5-pyrrolidin-1-ylmethyl-1H-pyrrole-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-3-isopropyl-1-methanesulfonyl-4-(1-methyl-5-methylaminomethyl-1H-pyrrole-2-carbonyl)hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-4-(4-dimethylaminomethyl-1H-pyrrole-2-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-3-isopropyl-1-methanesulfonyl-4-(2-pyrrolidin-1-yl-methylthiazole-4-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-3-isopropyl-1-methanesulfonyl-4-(2-morpholin-4-yl-methylthiazole-4-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS~,6aR)-3-isopropyl-1-methanesulfonyl-4-(2-piperidin-1-yl-methylthiazole-4-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-3-isopropyl-1-methanesulfonyl-(2-(4-methyl-piperazin-1-yl-methyl)-thiazole-4-carbonyl-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-4-(2-cyclopropylaminomethylthiazole)carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; -108rel-(3S,3aS,6aR)-4-{2-[(4-fluorobenzylamino)methyl]thiazole-4-carbonyl}-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2b]pyrrol-2-one; rel-(3S,3aS,6aR)-3-isopropyl-1-methanesulfonyl-4-[2-(4-phenylpiperazin-1-ylmethyl)thiazole-4-carbonyl]hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-4-(2-dibutylaminomethylthiazole)carbonyl-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-4-{2-((1-isopropyl-2-methylpropylaminomethyl]thiazole-4-carbonyl)}-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-4-(2-dimethylaminomethylthiazole-4-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(5-morpholin-yl-methylisoxazol-3-carbonyl-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-4-(5-dimethylaminomethylisoxazole-3-carbonyl)-3-isopropylmethanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(5-pyrrolidin-1-yl-methylisoxazole-3-carbonyl)-hexahydropyrrolo[3,2b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(5-piperidin-1-yl-methylisoxazol-3-carbonyl)-hexahydropyrrolo[3,2b]pyrrol-2-one; -109rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-[5-(4-methyl-piperazin-1-ylmethyl)-isoxazol-3-carbonyl]-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-4-{5-[(4-fluorobenzylamino)methyl]isoxazole-3-carbonyl}-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-[5-(4-phenylpiperazin-1-ylmethyl)isoxazole-3-carbonyl]-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-4-(5-dibutylaminomethylisoxazole-3-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-4-(5-dimethylaminomethyl-1-methyl)-1H-pyrazole-3-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(1-methyl-5-pyrrolidin-1-ylmethyl-1H-pyrazole-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(1-methyl-5-morpholin-4-yl-methyl-1H-pyrazole-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(1-methyl-5-piperidin-1-ylmethyl-1H-pyrazole-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-[1-methyl5-(4-methylpiperidin-1-ylmethyl)-1H-pyrazole-3-carbonyl]hexahydropyrrolo[3,2-b]pyrrol-2-one; - 110rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-[2-methyl-5-(4-phenyl-piperazin-1-yl-methyl)-2H-pyrazole-3-carbonyl]-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-(5-3-dimethylaminomethyl-2-methyl-2H-pyrazole-3-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(2-methyl-5-pyrrolidin-1-yl-methyl-2H-pyrazole-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(2-methyl-5-morpholin-4-yl-methyl-2H-pyrazole-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(2-methyl-5-piperidin-1-yl-methyl-2H-pyrazole-3-carbonyl)-hexahydropyrrolo(3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-[2-methyl-5-(4-methylpiperazin-1-ylmethyl)-2H-pyrazoyl-3-carbonyl]-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-4-{6-[(dicyclohexylamino)methyl]pyridine-3-carbomethyl}-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2b]pyrrol-2-one; rel-(3R,3aR,6aS)-4-(6-dibutylaminomethylpyridine-3-carbonyl)-3-isopropylmethanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(6-morpholin-4-yl-methyl-pyridine-3-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one; - Ill rel-(3R,3aR,6aS)-4-(6-cyclopropylaminomethylpyridine-3-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(6-piperidin-1-yl-methylpyridine-3-carbonyl)-hexahydropyrrolo[3,2b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-[6-(4-methylpiperazin-1-ylmethyl)pyridine-3-carbonyl]hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-4-{6-((1-isopropyl-2-methylpropylamino)methyl]pyridine-3-carbonyl}-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-4-(6-dimethylaminomethylpyridine-3-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-4-{6-[(4-fluorobenzylamino)methyl]pyridine-3-carbonyl}-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-4-(5-cyclopropylaminomethylpyrazine-2-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-4-(5-dibutylaminomethylpyrazine-2-carbonyl)-3-isopropylmethanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(5-morpholin-4-yl-methylpyrazine-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one; - 112rel-(3R,3aR,6aS)-4-{5-[(dicyclohexylamino)methyl]pyrazine-2-carbonyl}-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-(isopropyl-1-methanesulfonyl-4-(5-piperidin-1-yl-methylpyrazine-2-carbonyl)-hexahydropyrrolo[3,2b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-[5-(4-methylpiperazin-1-ylmethyl)pyrazine-2-carbonyl]hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-4-{5-((1-isopropyl-2-methylpropylamino)methyl]pyrazine-2-carbonyl}-1-methanesulfonylhexahydropyrrolo[3,2-]pyrrol-2-one; rel-(3R,3aR,6aS)-4-(5-dimethylaminomethylpyrazine-2-carbonyl)-3-isopropylmethanesulfonyl-lyhexalihydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-[5-(4-phenylpiperazin-1-ylmethyl)pyrazine-2-carbonyl]hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(5-pyrrolidin-1-yl-methylpyrazine-2-carbonyl-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3R,3aR,6aS)-3-isopropyl-1-methanesulfonyl-4-(5-methylaminomethylpyrazine-2-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one and a salt or solvate of the above compounds. 15. The following compound of general formula (I) according to claim 1, or a salt or solvate thereof: -113• »c« * ·* ο· ·* (3S,3aS,6aR)-4-(5-cyclopropylaminomethylpyrazine-2-carbonyl)-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one. 16. The following compound of general formula (I) according to claim 1, or a salt or solvate thereof: (rel-(3S,3aS,6aR)-3-isopropyl-1-methanesulfonyl-4-(2-pyrrolidin-1-yl-methyl-oxazole-4-carbonyl)-hexahydropyrrolo[3,2b]pyrrol-2-one; rel-(3S,3aS,6aR)-3-isopropyl-1-methanesulfonyl-4-(2-piperidin-1-yl-methyl-oxazol-4-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-3-isopropyl-1-methanesulfonyl-4-[2-(4-phenylpiperazin-1-ylmethyl)-oxazole-4-carbonyl]-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-4-(2-dibutylaminomethyl-oxazole-4-carbonyl)-3-isopropyl-1-methanesulfonyl-hexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-4-{2-[(cyclopropylmethylamino)methyl]oxazole-4-carbonyl}-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one; rel-(3S,3aS,6aR)-4-{2-{(dicyclohexylamino)methyl]oxazole-4-carbonyl}-3-isopropyl-1-methanesulfonylhexahydropyrrolo[3,2-b]pyrrol-2-one. 17. The following compound or a salt or solvate thereof belonging to the group of compounds of general formula (I) according to claim 1: (3S,3aS,6aR)-3-isopropyl-1-methanesulfonyl-4-(2-pyrrolidin-1-yl-methyl-oxazole-4-carbonyl)-hexahydropyrrolo[3,2-b]pyrrole-2 -tin. -114- v/····:···.:··: ♦ ··· · «,4 18. The following compound or a salt or solvate thereof belonging to the group of compounds of general formula (I) according to claim 1: (3S,3aS,6aR)-3-isopropyl-1-methanesulfonyl-4-(2-pyrrolidin-yl-methyl-oxazole-4-carbonyl)-hexahydropyrrolo[3,2-b]pyrrol-2-one hydrochloride. 19. A purified single enantiomer of a compound of formula (I) according to any one of claims 1-14 and 16, the absolute stereochemistry of which is as defined in formula (I). 20. Compounds of formula (I) according to any one of claims 1-19 for use as a medicament. 21. A pharmaceutical composition comprising at least one compound of formula (I) according to any one of claims 1 to 19 together with one or more physiologically acceptable diluents or carriers. 22. Use of a compound of general formula (I) according to any one of claims 1-19 for the preparation of pharmaceutical compositions suitable for the treatment of chronic bronchitis or chronic obstructive pulmonary diseases. 23. Use of a compound of general formula (I) according to any one of claims 1-19 for the preparation of pharmaceutical compositions suitable for the treatment of asthma. 24. A process for the preparation of compounds of general formula (I) according to claim 1, characterized in that (i) a compound of general formula (II) is reacted with a compound of general formula R ⁴ R ³ N(CH2) _n HetCOOH or an acid derivative thereof, such as an acid chloride, an activated ester, an acid anhydride or a mixed anhydride or a - 115 R ⁴ R ³ N(CH ₂ ) _n HetXY, where Y is a reactive group, such as a halogen atom, for example a chlorine atom, or a protected derivative thereof, or (ii) a compound of general formula (III) or a protected derivative thereof is sulfonated with a compound of general formula YO2SR ¹ , where Y is a reactive group, such as a halogen atom, for example a chlorine atom, or a protected derivative thereof; or (iii) a compound of general formula (IV) or a carboxylic acid ester thereof is cyclized; or (iv) a compound of general formula (V) - where X is _a sulfur atom or SO group - is oxidized; or (v) a compound of general formula (VI) - where L is a leaving group - is reacted with a compound of general formula R ⁴ R ³ NH; or (vi) to prepare compounds of formula (I) in which n is 1-4, the reaction product of a compound of formula (VII) and a compound of formula R ⁴ R ³ NH is reduced; or (vii) to prepare compounds of formula (I) in which n is 1, a compound of formula (VIII) is reacted with formaldehyde or para-formaldehyde and a compound of formula R ⁴ R ³ NH under acidic conditions; or (viii) optionally removing the protecting groups from the compound of formula (I); or (ix) separating one enantiomer of the compound of formula (I) from a mixture of enantiomers; -116 and, if desired, converting the resulting free base into a physiologically acceptable salt or converting the salt form into another physiologically acceptable salt. 25. Compounds of general formula (III) (with relative stereochemistry indicated) or protected derivatives thereof, wherein R ² , R ³ , R ⁴ , n, Het and X are as defined in claim 1. 26. Compounds of general formula (IV) (with relative stereochemistry indicated) or carboxylic acid esters thereof, wherein R ¹ , R 2 , R 3 , R 4 , n, Het and X are as defined in claim 1. 27. Compounds of general formula (V) (with relative stereochemistry indicated), in which R ¹ , R ² , R ³ , R ⁴ , n, Het and X are as defined in claim 1 and X a is _a sulfur or SO group. 28. Compounds of general formula (VI) (with relative stereochemistry indicated), wherein R, R, n, Het and X are as defined in claim 1 and L is a leaving group. 29. Compounds of general formula (VII) (with relative stereochemistry indicated), wherein R, R, Het and X are as defined in claim 1 and n is a number from 1 to 4. 30. Compounds of general formula (VIII) (with relative stereochemistry indicated), wherein R ¹ , R ² , X and Het are as defined in claim 1. The authorized person: DANUBE Patent and Trademark Office Ltd. O.A 0 1 Olchváry Gézáné ) $ , patent attorney /A ajL