SK3192000A3 - Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase - Google Patents

Abstract

There are provided according to the invention compounds of formula (I) wherein R<1>, R<2> and R<3> are as defined in the specification. Compounds of formula (I) are useful, inter alia, in the treatment of inflammatory disorders of the respiratory tract.

Description

Technical field

The present invention relates to bicyclic derivatives having therapeutic effect, to a process for their preparation and to pharmaceutical compositions containing them and intended for the treatment of inflammatory conditions.

BACKGROUND OF THE INVENTION

Inflammation is a primary response to tissue injury or microbial infection and is characterized by leukocytes exiting the vessels through the endothelium. These are neutrophils, eosinophils, basophils, monocytes and lymphocytes. In various forms of inflammatory reactions, tissue infiltration occurs with different types of leukocytes.

Inflammatory conditions can be caused by a variety of causes, such as infection, tissue damage, as well as autoimmune reactions. During the inflammatory process, neutrophils escape from the bloodstream to the tissue at the site of damage. Neutrophils contain a large number of different intracellular granules and, when activated at the site of inflammation, the granules are secreted into the tissue. Different granules contain different types of enzymes and other proteins, some of which have antibacterial properties.

One of the enzymes found in azurophilic granules is neutrophil elastase. This enzyme has a broad spectrum of activity in the body, for example, in the lung tissue, this enzyme increases mucus production and alters cell types in the lining of the lungs. The enzyme can also cause changes in vascular permeability in various tissues and is, in principle, an effective destructive agent against a variety of connective tissue components. Although endogenous elastase inhibitors, including antitrypsin and a protease inhibitor of leukocytes, exist within the body, elastase is believed to be involved in various disease states including inflammatory diseases of the airways, joints and skin. The enzyme is also

- responsible for most of the symptoms of ARDS and other acute inflammatory conditions after injury and / or infection.

We have now found a new class of compounds that have the ability to inhibit neutrophil elastase. These substances could have a beneficial effect on the above-mentioned diseases or improve the symptoms of these diseases.

SUMMARY OF THE INVENTION

The present invention provides pyrrolopyrrone derivatives of formula (I)

(relative stereochemistry is indicated), where

R ¹ represents alkyl of 1 to 6 carbon atoms,

R ² is alkyl or alkenyl each having 2 to 4 carbon atoms,

X is CO or SO ₂

Het is an optionally substituted, 5 to 10 membered monocyclic or bicyclic aromatic ring system containing 1 to 4 heteroatoms from O, N and S, n is an integer of 0 to 4,

R ³ a R ⁴ are independently hydrogen, alkyl of 1 to 8 carbon atoms, - (CH 2) 4CONR ⁵ R ^6, CO-C 1 -C 4 alkyl or (CH2) _o-2 Ph, wherein Ph is phenyl optionally substituted with one or more C 1 -C 4 alkyl radicals or halogen atoms or NR ³ R ⁴ together form azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, piperazinyl, optionally N-substituted with C 1-6 alkyl carbon, phenyl, optionally substituted halogen or C 1 -C 4 alkyl; or

-3benzyl optionally substituted on the benzene ring with halogen or C 1 -C 4 alkyl or NR ³ R ⁴ together form the above-described ring substituted on carbon by one or more C 1 -C 4 alkyl substituents, CONR ⁵ R ⁶ or COOR ⁶ ,

R ⁵ and R ⁶ independently represent hydrogen or C 1 -C 4 alkyl, and salts and solvates thereof.

In the general formula I, the relative stereochemistry of the center of chirality is shown. The invention includes the compounds of the invention in racemic form and in forms in which one of the enantiomers predominates or is exclusively present. In general, it is preferable to obtain the compounds of the formula I in enantiomerically pure form, in particular in the form as shown in formula I.

The invention also includes physiologically acceptable salts of the compounds of formula I. They may be salts with inorganic or organic acids such as hydrochlorides and tartrates.

The term "alkyl" refers to straight or branched chain alkyl radicals and, if the radical contains more than 3 carbon atoms, may also be cycloalkyl.

Suitable alkyl groups R ¹ are methyl, ethyl or propyl.

Examples of Het groups include furanyl, imidazoline, thiophenyl, pyrrolyl, thiazolyl, isoxazolyl, pyrazolyl, pyridinyl and pyrazinyl.

The Het group may be attached to the pyrrolidine ring via the X group at any position. Examples of such linkages include 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.

Examples of substituents for the Het group include alkyl of 1 to 6 carbon atoms, for example methyl or ethyl, alkoxy of 1 to 6 carbon atoms, for example methoxy, nitro and halogen such as chlorine, bromine, fluorine and iodine. The substituents may be on a carbon atom or on a nitrogen atom.

»

Examples of substituted Het groups include 1-methylpyrolyl or 1-methylpyrazolyl.

An example of the side chain positions of Formula I may be for furan-2-yl position 5, for furan-3-yl position 2, for thiophen-2-yl position 5, for pyrrol-2-yl position 4 or 5, for 1-methylpyrol-2-yl position 5, for thiazol-4-yl position 2, for isoxazol-3-yl position 5, for 1-methylpyrazol-3-yl position 5, for 1-methylpyrazol-5-yl position 3 , for pyridin-3-yl position 6 and for pyrazin-2-yl position 5.

Where R ³ and R ^{4 are} independently C 1 -C 8 alkyl radicals, these may be, for example, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, CH (iPr) 2 and cyclohexyl.

Where R ³ and R ⁴ are independently (CH ₂₎ 2 Ph-can be a phenyl, benzyl and (4-fluoro-phenyl) methyl.

When NR ³ R ⁴ together form N -substituted piperazinyl, examples of these groups are N-phenylpiperazinyl and N-methylpiperazinyl.

When NR ³ R ⁴ together form rings substituted on carbon atoms, they may be methyl, CONH ₂ and COOMe. An example is 4-methylpiperidin-1-yl.

It prefers that R ¹ is methyl or ethyl and especially methyl.

It prefers that R ² is isopropyl or propyl, especially isopropyl.

A preferred value for X is CO.

Het is preferably a 5 or 6 membered monocyclic aromatic ring containing 1 or 2 heteroatoms from O, N and S, preferably thiazolyl, isoxazolyl, pyrazolyl or pyrazinyl, particularly preferred is thiazolyl, especially thiazol-4-yl or pyrazinyl.

Another preferred value for Het is pyridinyl and especially 3-pyridinyl.

A particularly preferred value for Het is pyrazinyl, ideally Het means pyrazin-2-yl in which the side chain is at the 5-position.

Another preferred value for Het is oxazolyl and especially oxazol-4-yl.

A preferred value for n is 1 to 3, in particular 1 or 2, and most preferably 1.

R ³ and R ⁴ are preferably independently hydrogen or C 1 -C 8 alkyl, preferred values for NR ³ R ⁴ are pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, which may optionally be N-substituted with C 1 -C 8 alkyl or a phenyl radical, optionally substituted by halogen or a C1 -C4 alkyl radical. In case that

-5R ³ and R independently represent a hydrogen atom or a C 1 -C 8 alkyl group, the preferred NR ³ R ⁴ groups are ΝΜβ2, N (n-butyl) 2, NHMe, NH (cyclopropyl), NHCH (iPr) ₂ and N (cyclohexyl) ₂ .

A group of compounds of formula I of particular interest are compounds of formula IA wherein Het is oxazol-4-yl with a side chain at the 2-position.

R * R ³ N (CH ₂ ) _n

(relative stereochemistry is indicated) wherein the individual symbols are as defined above.

A preferred value for X is CO. ^R2 is preferably isopropyl or propyl, especially isopropyl. It prefers that R ¹ is methyl or ethyl, especially methyl. N is preferably an integer of 1 to 3, more preferably 1 or 2 and most preferably 1. Preferably R ³ and R ⁴ are independently hydrogen or alkyl of 1 to 8 carbon atoms, or in the case of NR ³ R ⁴ may be pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, optionally N-substituted with C 1 -C 8 alkyl or phenyl, optionally further substituted with halogen or C 1 -C 4 alkyl. Particularly preferred for NR ³ R ⁴ is pyrrolidinyl, piperidinyl, N-phenylpiperazinyl, N (butyl) 2, NMe (cyclopropyl) or N (cyclohexyl) ₂ , particularly preferred is pyrrolidinyl.

The ability of the compounds of the invention to inhibit neutrophil elastase can be demonstrated, for example, using the following in vitro and in vivo assays.

-6In vitro neutrophil elastase assay

Materials:

mM Tris / HCl pH 8.6

150 mM NaCl

11.8 nM purified human neutrophil elastase

The appropriate concentrations of the test substances are diluted with water from a stock solution of these substances at a concentration of 10 mM in dimethylsulfoxide. The values given are final concentrations after addition of substrate solution.

The above mixture is incubated for 15 minutes at 30 ° C and then the remaining elastase activity is measured for 10 minutes in a BioTek 340i after the addition of 0.6 mM MeO-succinyl-alanyl-alanyl-propyl-valyl-p-nitroanilide. The rate of increase in absorbance at 450 nm is proportional to the elastase activity. The enzyme activity was plotted graphically against concentration of inhibitor and the curve thus obtained can be determined by the appropriate value of the IC ₅ by means of a computer program.

Efficacy of human elastase inhibitors in vivo

Oral administration of inhibitors in the case of IL-8 induced pulmonary infiltrate to determine intracellular elastase inhibition

Adult hamsters weighing 100 to 150 g were randomly assigned to groups of 4 and were not fed overnight. Thereafter, the animals were anesthetized with 3% isofluorane gas and orally given only the vehicle, i.e., the vehicle. 1 ml of water per 100 g of weight, or a vehicle containing dissolved test substances is also administered. Simultaneously or sequentially anesthetized animals are injected intratracheally with a solution of 1 milligram of recombinant human IL-8 in 100 µl of sterile physiological saline. Six hours after IL-8 administration, the animals were sacrificed by intraperitoneal administration of pentabarbiton. The lungs were washed twice

2.5 ml of sterile physiological saline and the femurs of the animals were also removed.

Intracellular elastase was prepared from neutrophils obtained by washing and from the bone marrow of the femur. Neutrophils were disrupted by ultrasound and

By centrifugation, the intracellular granules were obtained. These granules were disrupted by repeated freezing and dissolving and sonication. Elastase and myeloperoxidase tests were then performed on samples of this material to demonstrate the efficacy of the test substances.

Assay for inhibition of human elastase from blood

The test was performed by adding fresh heparinized human blood at 200 ° C to a 10 μΙ of an appropriately diluted sample of the test substance. Each test was performed in triplicate. Six control samples, which contained only water instead of the active substance, were also examined. All samples were mixed by pipette and then incubated for 30 minutes at 37 ° C. Then, a cold cell disruption buffer containing 750 μΙ 155 mM ammonium chloride, 0.12 mM EDTA and 10 mM potassium bicarbonate was added at pH 7.4. The tubes were capped, inverted several times to mix the contents, and then held at 4 ° C for 15 minutes, inverted every 5 minutes. After centrifugation for 10 minutes at 250 g at 4 ° C, the resulting cell pellet was washed with 300 μΙ of saline and then centrifuged again at 100 g at 4 ° C for 10 minutes. The pellet is washed 2 more times and then the resulting cell pellet is suspended in 200 μΙ of buffer containing 100 mM, 300 mM NaCl, 1% HTAB at pH 8.6. The samples are then stored at -20 ° C. The samples are frozen 4 times and allowed to dissolve again, then the elastase activity is measured colorimetrically in a mixture containing 50 mM tris, 150 mM NaCl and 0.6 mM MeO-Succ-Ala-Ala-Ala-Pro-ValpNA at pH 8 6, measure the rate of increase in absorbance at 405 nm.

The compounds of the invention may have a potentially beneficial therapeutic effect for diseases in which elastase activity is believed to occur. In particular, bronchitis, including chronic inflammation. Chronic obstructive pulmonary disease COPD is another disease likely to be beneficial.

Examples of other disease states in which administration of the compounds of the invention might be beneficial include other airway inflammatory conditions, such as bronchitis including chronic inflammation, bronchiectasis, asthma and lung tissue hyperactivity, acute pulmonary insufficiency, septic shock, and inflammatory conditions.

Other inflammatory or destructive conditions of the lung tissue, such as bulging, cystic fibrosis, as well as inflammatory or destructive conditions of other tissues, such as skin or lupus diseases, and gum disease including gum inflammation.

As further examples of disease states in which the compounds of the invention could have a beneficial effect on wound healing and treatment of burns, cardiovascular diseases such as myocardial infarction, stroke, peripheral vascular diseases including arterial occlusion of atherosclerosis, post-traumatic injury reperfusion, difficulty in cardiopulmoral bypass and septicemia.

The compounds of the invention may also be administered in connective tissue disorders such as rheumatoid arthritis, osteoarthritis and spondylitis, and then kidney inflammatory conditions, such as glomerulonephritis.

The compounds of the invention may also be used to treat some types of leukemia, including acute myelogenous leukemia, acute myelomonocytic leukemia and chronic monocytic leukemia, as well as preventing or inhibiting metastasis of solid tumors such as lung, mammary, prostate and stomach tumors and also melanomas.

A particular embodiment of the invention is the use of the compounds of formula I for the treatment of chronic bronchitis. Chronic bronchitis is a condition that results from the exposure of harmful chemicals or other substances to the airways. This condition may also occur secondary to another disease. Symptoms of this disease are caused by too much secretion on the airway surface. This large amount of secretion is usually not effectively eliminated, resulting in reduced gas exchange in the lungs and difficulty in breathing and insufficient oxygen supply to the tissues and, as a consequence, frequent microbial infections and almost permanent cough associated with expectoration of substantial amounts of material. A likely mechanism for too much secretion in the bronchi is the output of neutrophils into the airways in the event of irritation of the lining of these airways. Neutrophils secrete elastase on the airway surface and this enzyme then causes increased secretion on the airway surface as well as dramatic changes in the lining of these airway lining. Inhibition of elastase activity by administration of the compounds of the invention could improve symptoms

-9chronic bronchitis. Decreased lung function in COPD, for example in chronic bronchitis with some bronchial occlusion is also caused by elastase-induced lung damage leading to airway constriction and inflammatory conditions. Also in this case, it will be possible to improve overall lung function by administering elastase inhibitors.

As already mentioned, the compounds of the invention are potent inhibitors of elastase, in particular neutrophil elastase. These substances can be used in human or veterinary medicine, in particular for the treatment of conditions in which elastase is involved, such as chronic bronchitis.

It goes without saying that, where the possibility of treating a disease is mentioned, prevention is also to be understood.

The invention also relates to the use of the compounds of the formula I or their physiologically acceptable salts or solvates for the manufacture of a medicament for the treatment of diseases in which elastase is involved, for example for the treatment of chronic bronchitis.

The compounds of the present invention may be formulated into a pharmaceutical composition by any conventional means. The invention also provides a pharmaceutical composition comprising, as an active ingredient, compounds of Formula I or physiologically acceptable salts or solvates thereof together with one or more pharmaceutically acceptable substances or carriers.

These pharmaceutical compositions are usually prepared by ordinary mixing of all ingredients.

For example, the compounds of the invention may be formulated into pharmaceutical compositions for oral, mucosal, parenteral, topical or rectal administration.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents such as syrups, acacia gum, gelatin sorbitol, tragacanth, starch slime or polyvinylpyrrolidone, fillers such as lactose, microcrystalline cellulose, sugar, corn starch, magnesium phosphate, acid stearic, talc, polyethylene glycol or silica, disintegrating agents such as potato starch, cross-linked carmalose sodium or sodium starch glycolate, and also wetting agents such as sodium lauryl sulfate. Tablets may be coated

- in the usual way. Liquid compositions for oral administration may be in the form of, for example, oily or aqueous suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product to be diluted with water or other suitable vehicle just prior to use. These liquid compositions may contain conventional additives such as suspending agents, for example sorbitol syrup, methylcellulose, gelatin, glucose syrup, hydroxymethylcellulose, carboxymethylcellulose, aluminum stearate gel or edible hydrogenated oils, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia, acacia also of a non-aqueous nature, including edible oils such as almond oil, fractionated coconut oil, oil esters, propylene glycol or ethyl alcohol, and also preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid. Furthermore, the pharmaceutical compositions may contain buffers, flavorings, colorants and / or sweeteners, for example mannitol as appropriate.

For administration by the oral mucosa, the pharmaceutical composition may take the form of a tablet or lozenge tablet made in a conventional manner.

The compounds of the invention may also be formulated into suppositories, for example using a conventional suppository base such as cocoa butter or other glycerides.

The compounds of the invention may also be formulated for parenteral administration by injection or continuous infusion, for which purpose the compositions may be presented in unit dose ampoules or vials, prefilled syringes or larger containers containing multiple doses, as well as preservative. The composition may take the form of a solution, suspension or emulsion in an aqueous or non-aqueous vehicle, and may also contain various excipients such as antioxidants, buffers, antimicrobials, and / or toxicity-reducing agents. The active ingredient may also be presented in the form of a powder which is intended to be mixed with a suitable vehicle just before use, for example sterile pyrogen-free water. When the active ingredient is administered in solid form, the sterile powder is aseptically filled into sterile containers and the vehicle is delivered separately or the sterile solution is aseptically filled into containers and then lyophilized.

- 11 Powders for inhalation or insufflation may be delivered for topical administration. They may also be ointments, creams, emulsions, aerosols, pessaries or capsules for use in inhalation devices, or they may be drops in the nose or eye.

Ointments and creams may be formed, for example, by mixing the active ingredient with an aqueous or oily base, and various thickening and / or gel forming agents and / or solvents may be added as additives. For example, the ointment or cream base may comprise water and / or oil, for example liquid paraffin or vegetable oil, such as peanut oil or castor oil, or some solvent, such as polyethylene glycol. Useful thickeners include soft paraffin aluminum stearate, cetostearyl alcohol, polyethylene glycols, microcrystalline wax and beeswax.

Emulsions may be prepared using an aqueous or oily base and generally may contain one or more emulsifying agents, stabilizer, dispersing agents, suspending agents, and thickeners.

Powders for topical administration may be made using any suitable powder base, for example talc, lactose or starch. Any aqueous or non-aqueous base which may contain dispersing agents, solubilizing agents or suspending agents may be used to make the droplets.

Sprays or aerosols can be formulated as aqueous solutions or suspensions or as aerosols applied from a pressurized container using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, 1, 2, 3 1,1,2-tetrafluoroethane, carbon dioxide or other suitable gas.

Capsules for use in inhalation or insufflation devices may be, for example, gelatin capsules into which a powder mix of a compound of the invention and a suitable base, which may be lactose or starch, may be placed.

The pharmaceutical compositions of the invention may also be used in combination with other active agents, for example anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2-adrenergic agents and xanthines such as theophylline, mucolytic agents, antimuscarinic agents, antileukotrienes .

12 cell adhesion inhibitors such as ICAM antagonists, antioxidants such as N-acetylcysteine, fillers and / or antimicrobials and antiviral agents.

The pharmaceutical agents of the invention may also be used in combination with genetic therapy.

Thus, according to the invention, it is possible to use combinations comprising compounds of the formula I or a physiologically acceptable salt or solvate thereof and, in addition, another active ingredient.

Said combination may be formulated into a pharmaceutical composition which will then contain as active ingredient a combination of a compound of the invention and other active ingredients.

Alternatively, however, such combinations may be administered separately, simultaneously or sequentially. Appropriate doses of known active ingredients are readily determined by the attending physician.

For example, the compounds of the invention will be administered at doses of 0.01 to 50 mg / kg, preferably 0.05 to 25 mg / kg orally once or more per day. The exact dose will depend on the age and general condition of the patient, the route of administration and the disease being treated, and oral administration will usually be most preferred in the treatment of bronchitis. For other diseases such as ARDS, for example, intravenous administration may be advantageous.

The compounds of the invention have a very advantageous duration of action.

The compounds of formula (I) and solvates thereof may be prepared by the methods set forth below. These methods also form part of the invention.

The process for the preparation of the compounds of the formula (I) consists in:

i) condensing a compound of formula II

(relative stereochemistry is indicated)

-13 with a compound of formula R ⁴ R ³ N (CH 2) n Het COOH or an acid derivative thereof, for example a chloride, activated ester or anhydride or mixed anhydride, or with a compound of formula R ⁴ R ³ N (CH 2) _n HetXY where Y is reactive a group such as a halogen atom such as chlorine or a protected derivative thereof, or ii) sulfonylated with a compound of formula III

R ⁴ R ³ N (CH ₂ ) _n

Het-X

(III) (relative stereochemistry is indicated) or a protected derivative thereof by treatment with YO2SR ¹ , wherein Y is a reactive group, for example a halogen atom such as chlorine, or iii) cyclizes a compound of formula IV

(relative sterochemistry is indicated) or an ester thereof formed at the carboxyl group, or (IV)

(14iv) the corresponding compound of formula (V) is oxidized

R ⁴ R ³ N- (CH 2) _n -Het-X

N i

X ^and k

(V) (relative sterochemistry is indicated) wherein X ^a is a sulfur atom or SO or s

v) reacting a compound of formula VI

L (CH ₂ ) _n -Het-X.

(VI) (relative stereochemistry is indicated) wherein L is a leaving group, with a compound of formula R ⁴ R ³ NH, or vi) preparing a compound of formula I wherein n is an integer from 1 to 4 by reducing the reaction product of the corresponding compound of formula VII

(Vil)

-15 (relative sterochemistry is indicated) with a compound of formula R ⁴ R ³ NH, or vii) to prepare a compound of formula I wherein n is 1 by reaction of the corresponding compound of formula VIII

Het-X.

(VIII) (relative stereochemistry is indicated) with formaldehyde or paraformaldehyde together with a compound of formula R ⁴ R ³ NH in an acidic environment, or viii) deprotecting a protected compound of formula I, or ix) isolated in a pure form from a mixture of enantiomers one of the enantiomers, and then, if necessary, converting the resulting free base of a compound of formula I into a physiologically acceptable salt thereof, or conversely, the salt is converted into the free base of a compound of formula I or one salt is converted into another physiologically acceptable salt. salt.

Method i)

The condensation reaction with a compound of formula R ⁴ R ³ N (CH ₂ ) _n HetCOOH is conveniently carried out in the presence of a coupling agent, for example 1- (3- N, N -dimethylaminopropyl) -3-ethylcarbodiimide, and preferably also in the presence of HOBT and solvent. such as dichloromethane, DMF, MeCN or tetrahydrofuran at 0 ° C to room temperature. When an acid derivative such as chloride, activated ester, anhydride or mixed anhydride is used, the reaction conditions

Modify accordingly, for example, by carrying out the reaction in the presence of a base. When both R ³ and R ⁴ are hydrogen atoms, it is usually preferable to protect the nitrogen atom, for example by coupling a BOC group.

When a compound of formula R ⁴ R ³ N (CH ₂ ) n HetSO ₂ Y is used, the reaction is conveniently carried out in the presence of a base such as triethylamine and in a solvent such as DCM at 0 ° C to room temperature.

Method ii)

Sulfonylation is generally carried out in the presence of LHMDS or NaH in a solvent, for example, tetrahydrofuran at -78 to 0 ° C.

If one of R ³ and R ^4, or both, is hydrogen, it may be necessary to protect the nitrogen atom, for example, by BOC.

Method iii)

The cyclization reaction is carried out in the presence of 2-chloro-1-methylpyridinium iodide or EDC in a solvent such as dichloromethane at 0 ° C to reflux. This reaction can also be carried out using the carboxylic acid thioesters of formula IV. It is also possible to use another acid derivative, for example a halide such as chloride.

Method (iv)

The oxidation reaction may be carried out in the usual manner, for example by treatment with a peracid.

Method v)

In this process, a preferred leaving group is a halogen atom such as chlorine, bromine or iodine, mesylate or tosilate. The reaction may be carried out by mixing the reactants, optionally in the presence of a base such as triethylamine or potassium carbonate in an inert solvent such as DMF or MeCN.

-17 Method VI)

This reaction can be carried out by mixing the components in an inert solvent such as DCM at room temperature or higher. The reduction can be carried out directly in the reaction mixture using a mild reducing agent, for example NaBH ₃ CN or NaBH (OAc) 3. Method vii)

The reaction of the heterocyclic compound of formula VIII with formaldehyde or paraformaldehyde and an amine can be carried out under standard Mannich conditions, for example under reflux in an acidic medium, typically in a mixture of acetic acid and ethanol, when the amine is used in the acid salt form. , for example in the form of the hydrochloride, acetic acid may be omitted.

Method viii)

Protecting groups, particularly those useful for protecting the nitrogen atom, as well as methods for cleavage of these groups, have been described in T. W. Greene, "Protective Groups in Organic Synthesis", 2nd edition 1991, J. Willey and Sons.

Method ix)

Purification of the individual enantiomer may be achieved by conventional methods, for example by chiral chromatography, such as chiral HPLC or crystallization with a homochiral acid, for example tartaric acid.

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

Intermediates of formula (II) may be readily prepared as shown in Scheme 1 below.

-18 Scheme 1

(XIV) (h)

R K, CO, alkyl

'W (XIX) (k)

R% (H) (m)

(XXI)

- 19Grade a)

This is the usual introduction of protecting groups, where P ² is BOC, the reaction may be carried out by treatment with (BOC) ₂ O in the presence of a base such as NaOH in a polar solvent system, for example in a mixture of dioxane and water.

Step b)

The conversion may be accomplished by treatment with ammonium bicarbonate in the presence of a suitable solvent, for example, a mixture of pyridine and DMF and in the presence of (BOC) ₂ O or a suitable equivalent.

Step c)

This is a routine introduction of a protecting group. When P ¹ is CBZ, the reaction proceeds well with nBuLi and then CBZ-Cl in the presence of an inert solvent such as THF at a temperature below -50 ° C.

Step d)

The reaction may be carried out by treatment with RX, for example Mel, benzyl iodide or Me ₂ SO 4, which are capable of converting the sulfur atom in the SMe group into a sulfonium ion in a suitable solvent such as propanone or acetonitrile. The group R will usually be an alkyl or aralkyl group, X is a halogen atom, especially iodine or a sulfate moiety. In this reaction, it is convenient, although not necessary, to protect the amide group.

Step e)

Ring closure can be accomplished by treatment with Dowex 2 x 8400 mesh resin in OH 'form in a suitable solvent such as methyl cyanide. It is also possible to close the ring with potassium carbonate in a suitable solvent such as methyl cyanide.

Step f)

The protecting groups may be removed in a conventional manner, for example the BOC group is removed by treatment with HCl, for example dioxane.

-20Grade g)

The reaction may be carried out by treatment with an alkyl trifluoroacetic acid ester, for example its methyl ester, or treatment with trifluoroacetic anhydride in the presence of a suitable base such as N-methylmorpholine.

Step h)

The conversion is accomplished by treatment of a compound of formula XV with a reducing agent such as lithium borohydride followed by treatment with concentrated sulfuric acid in the presence of an alkyl alcohol such as ethanol as solvent.

Step i)

The reaction of the compound of formula XVI and XVII takes place in a Lewis acid, for example boron trifluoride dietherate in an inert solvent such as dichloromethane or methyl cyanide. The alkyl group in the O-alkyl group and in the OSi (alkyl) 3 group usually contains 1 to 6 carbon atoms. In compound XVII, the preferred alkyl groups in the silylalkyl group are methyl, isopropyl and tert-butyl. Preferred Oalkyl groups are especially OEt and the preferred OSi (alkyl) 3-group is OSi (i-Pr) ₃ or OSi (Me) 2 (t-Bu). It is also possible to use a variant of the compound of formula XVII in which the O-alkyl group is replaced by OSi (alkyl) 3.

Compounds of formula (XVII) may be prepared by reacting the corresponding ester formed on the carboxyl group, i. the ethyl ester or any alkyl ester is treated with a strong base such as LHMDS followed by a trialkylsilyl chloride such as trimethylsilyl chloride or a trialkylsilyl triflate. The reaction is typically carried out at low temperatures below 0 ° C in an inert solvent such as THF in the presence of DMPU.

Step j)

This is a common deprotection with a base such as potassium carbonate.

-21 Stage k)

Ring closure can be accomplished by treatment with an Grignard alkyl group introduction reagent, for example, tert-butylmagnesium chloride in an inert solvent such as THF in the presence of tetramethylenediamine at -20 to 25 ° C.

Stage I)

This is a sulfonylation reaction of lactam. This reaction proceeds well with R ¹ SO ₂ -Y, where Y is a reactive group, preferably a chlorine atom, in the presence of LHMDS, NaH or KH in a solvent such as THF at a temperature of -78 to 0 ° C.

Stage m)

This is to remove the protecting group from the nitrogen atom in a conventional manner. When P ¹ is CBZ, the protecting group can be removed by hydrogenation using a palladium hydroxide catalyst in a solvent such as ethyl acetate or THF.

Compounds of formula XV can be prepared as described in Scheme 2.

(A)

-►

O (XXIII)

2 HCl

NHCOCF, (c)

HN (XXV)

₂ (XXIV) (XV)

-22Grade a)

The reaction proceeds under conventional conditions to form alkyl esters, for example by treatment with an alcohol such as methanol in the presence of SOCl ₂ . R @ ^{13 is} preferably C1 -C6 alkyl, in particular methyl.

Step b)

Cyclization can be accomplished by mixing in water with Dowex 2x8 resin (preferably 400 mesh).

Step c)

The TFA-protected amine is formed by treating methyl XXI in methyl polar trifluoroacetate in a polar protic solvent such as MeOH.

Step d)

A suitable protecting group P ¹ includes CBZ. In this case, a compound of formula XXV can be treated with a strong base such as LHMDS or nBuLi in an inert solvent such as THF followed by treatment with CBZ-Cl.

Another possible process for the preparation of the compound of formula XX, the preparation of which has already been described in Scheme 1, is shown in the following Reaction Scheme 3.

Scheme 3

(C)

(XXVII) XXVIII XXIX

-23 Scheme 3 - continued

Step a)

Compounds of formula XXVI are known or can be prepared in an analogous manner to known compounds. P ¹ represents a N-protecting group, preferably CBZ. Step a) is another possibility of introducing a protecting group on a nitrogen atom. P ² in formula XXVII is a different N-protecting group, preferably BOC. When P ² is BOC, the reaction is carried out using (BOC) ₂ O.

The reaction proceeds well in the presence of a base such as triethylamine or 4-dimethylaminopyridine in a solvent such as ethyl acetate at 0-25 ° C.

Step b)

The conversion is preferably carried out by treating pyridinium p-toluenesulfonate in a solvent such as a mixture of acetone and water at a temperature of 25 to 75 ° C.

Step c)

This is a condensation rearrangement conveniently carried out using a 2-phenylsulfinylacetic acid ester, PhSOChhCO ³ R ¹³ and piperidine in a solvent such as acetonitrile, preferably at room temperature. R ¹³ is preferably C 1 -C 6 alkyl, especially methyl.

Step d)

It is a Mitsunobu substitution reaction using phthalimide PPh ₃ and dialkyl azodiacarboxylate as DEAD in the presence of a solvent such as THF at 0 to 40 ° C.

Step e)

At this stage, the protecting group is removed, preferably using a strong acid such as TFA in a solvent such as DCM at a temperature of 0 to 40 ° C. R ¹³ represents alkyl of 1 to 6 carbon atoms, in particular ethyl.

Step f)

The cyclization reaction readily proceeds as an intramolecular Michael reaction. A suitable reagent is NaH in a solvent such as THF at 0-25 ° C.

Step g)

At this stage, two reactions take place, namely the removal of the protecting group from the nitrogen atom and the reintroduction of the protecting group. The phthalimido group is removed by treatment with hydrazine hydrate in a solvent such as ethanol at

-25 ° C to reflux temperature. The protecting group P ³ is bound in a conventional manner. In the case where P ³ is BOC, preferably BOC ₂ O is used to carry out the reaction.

Step h)

The R ² side chain can be attached by alkylation, and R ² -Y, where Y is a reactive group such as bromine or iodine, is used as the reagent. The reaction is carried out using a base, preferably a strong base such as LHMDS. If this material is used, DMPU in THF is used as the co-solvent. A suitable reaction temperature is in the range of -78 to 50 ° C. Under these conditions, it is usually possible to control the reaction stereochemically well.

Step i)

This is hydrolysis followed by removal of the protecting group from the nitrogen atom. The hydrolysis is carried out in a conventional manner, for example using KOH in aqueous ethanol at a temperature of 25 to 80 ° C. The protecting group is also removed in a conventional manner, for example by treatment with HCl in dioxane at 0 to 50 ° C or, if the protecting group is trifluoroacetate, by treatment with a base.

Step j)

This cyclo-condensation reaction is usually carried out in the presence of 2-chloro-1-methylpyridinium iodide and a suitable base such as N, N -diisopropylethylamine in a solvent such as dichloromethane at 0 ° C to reflux. It has also been shown that the compound of formula XXXV can be used as the carboxylic acid ester. In this case, it is not necessary to carry out the ester hydrolysis in step i). Preferred conditions for the cyclocondensation reaction include the use of a Grignard reagent for alkylation such as tert-BuMgCl in THF at a temperature in the range of -20 to 25 ° C.

Another possible process for the preparation of compounds of formula XXXIII is shown in the following Reaction Scheme 4.

-26Scheme 4

(A)

CO, H

--H ₂ Ni ₃ ² NHP ³ (XXXVII) diaminobutyric acid

CH, OH

P ¹ hn

NH'P ³ XXXIX

Step a)

Compounds of formula XXXVI are known compounds or can be prepared in the same manner as known compounds. P ³ is the above protecting group such as BOC. The reaction proceeds well using phenyl iodosyl bis (trifluoroacetate), PIFA and a base such as pyridine in an aqueous solvent such as a mixture of water and THF, dioxane or acetonitrile. The method has been described in Stansfield CF Organic Preparations and Procedures Int., 1990, 22 (5), 593-603.

Step b)

P ¹ is a protecting group such as CBZ. The deprotection is carried out in a conventional manner. The reaction is carried out in a water-miscible solvent such as THF, DMF or dioxane using N - (benzyloxycarbonyloxy) succinimide, benzyloxycarbonyl chloride or any other source of benzyloxy-27carbonyl group, the pH is adjusted to the alkaline side by addition of sodium carbonate.

It is also possible to proceed such that the compound of formula XXXVIII in the alternative, step b ¹⁾ prepared in conventional manner from diaminobutyric acid benzyl ester.

Step c) The reaction proceeds well in two steps. In the first step, the compound of formula XXXVIII is reacted at low temperature with N-methylmorpholine and then with an alkyl chloroformate, for example ethyl chloroformate, in an organic solvent such as DCM, dioxane or THF. In the second step, the product is reduced, usually by treatment with sodium borohydride at a reduced temperature, for example -20 to 10 ° C in a solvent such as THF.

Step d)

The oxidation reaction can be carried out in any manner, for example using oxalyl chloride in DMSO and methylene chloride under nitrogen at a temperature below -30 to -70 ° C followed by triethylamine treatment. The intermediate of formula XXXX is not isolated.

Step e)

The reaction is carried out using a Wittig reagent such as triphenylphosphorane R ¹³ O ² CCH = PPh 3 or a Wadsworth-Emmons reaction.

Step f)

This Michael reaction can be carried out using LHMDS or other strong base in an organic solvent such as THF, ether or toluene and preferably in the presence of a complexing agent such as TMEDA.

Intermediates of formula III can be prepared by reacting deprotected compound XXII of Scheme 1 with R ⁴ R ³ N (CH 2) n Het COOH or R ⁴ R ³ N (CH 2) n Het XY as described above.

The initial N-deprotection can be carried out according to Scheme 1, step m).

The intermediates of formula IV may be obtained from a compound of formula XIX, optionally protected, in a manner analogous to that described for the preparation of a compound of formula III from a compound of formula XX in Scheme 1.

Compounds of formula V wherein X ^a is S may be obtained by reacting a compound of formula III with a compound R ¹ SSR ¹ under conventional nucleophilic exchange conditions. Compounds of formula V wherein X ^a is SO are prepared by oxidizing a compound wherein X ^a is S.

Compounds of formula VI, VII and VIII are prepared from a compound of formula II by conventional methods. The mesilate and tosilate derivatives are obtained from the corresponding alcohol by treatment with MeSO 2 Cl or p-methylbenzenesulfonyl chloride.

Compounds of formula R ⁴ R ³ N (CH 2) n Het COOH and their derivatives derived from acid function and compounds of formula R ⁴ R ³ N (CH 2) _n HetXY are known compounds or can be prepared by known methods.

Obviously, Schemes 1, 2, 3 and 4 could be further modified to obtain homochiral products using homochiral starting materials, for example S-methionine in Scheme 1 or S-diaminobutyric acid in Scheme 4, or by carrying out an additional chiral separation degree.

When the compounds of formula 14 are prepared in racemic form by the method of Scheme 1 from racemic methionine, it has been found that the isomers of the compound of formula XIV can be separated by a dynamic procedure. One may proceed by treating the racemic compound of formula XIV with a homochiral di-p-toluoyltartaric acid in the presence of 3,5-dichloro-2-hydroxybenzaldehyde as a catalyst in an inert solvent such as THF. A homochiral salt of the compound of formula XIV is obtained. The compound of formula XV can then be obtained by subsequent treatment with trifluoroacetic acid methyl ester in the presence of N-methylmorpholine.

Both enantiomers of the compound of formula XIV can also be prepared using Smetethion in a similar manner.

Obviously, the above processes for the preparation of the compounds of formula (I) may be further modified by employing a number of protecting groups or omitting them or by using other groups to achieve optimum conditions as described in TW Greene &quot; Protective &quot; Groups in Organic Synthesis, 2nd Edition (1991), J. Wiley and Sons.

The invention also provides novel chiral intermediates useful for the chiral procedures described above and for the resolution of mixtures containing both isomers.

The present invention also provides a process for the preparation of said intermediates.

The advantage of the compounds according to the invention is that said compounds have a higher activity, a higher selectivity, a lower amount of undesirable side effects, a longer duration of action and are more readily bioavailable in a preferred mode of administration, so that they have a pharmacodynamic or pharmacokinetic properties as known compounds.

The invention is illustrated by the following examples, which are not intended to limit the scope of the invention. The following abbreviations will be used in these examples.

List of abbreviations

BOC tert-butyloxycarbonyl

CBZ benzyloxycarbonyl (BOC) ₂ O di-tert-butyl dicarbonate

THF tetrahydrofuran

LHMDS lithium bis (trimethylsilyl) amide

DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2- (1 H) -pyrimidinone

DMAP 4-dimethylaminopyridine

DMF dimethylformamide

EDC 1- (3- N, N -dimethylaminopropyl) -3-ethylcarbodiimide

DEAD diethyl azodicarboxylate

DCM dichloromethane

TMEDA tetramethylethylenediamine

DMSO dimethylsulfoid

HOBT 1-hydroxybenzotriazole

NaBH (OAc) 3 sodium triacetoxyborohydride

Silica plates are used in thin layer chromatography in the examples and the preparation of intermediates.

DETAILED DESCRIPTION OF THE INVENTION

Intermediate 1

2,4-Diaminobutyric acid methyl ester dihydrochloride

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

Mass Spectrum Free Base MH ⁺ (found) 133, MH ⁺ (calcd) 133.

Intermediate 2

3-Amino-pyrrolidin-2-one

A mixture of 1 g of intermediate 1, 70 ml of water and 16.4 ml of Dowex 2x8, 400 mesh anion exchange resin was stirred for one hour. The resin was filtered off and the filtrate was concentrated in vacuo to give 0.40 g of the title compound as a white solid.

TLC (ethyl acetate: methanol) R f 0.07.

Intermediate 3

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

181 g of intermediate 2, 218 ml of methyl trifluoroacetate and 2.6 l of methanol are suspended in a suspension for 2 hours. The solvent was removed in vacuo to give 355 g of a beige solid as the title compound.

MNH ₄ ⁺ (found) 214, MNH 4 (calcd) 214.

-31 Intermediate 4

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

To the reaction mixture of 3.5 g of intermediate 3 and 100 ml of tetrahydrofuran at -70 ° C was added 20 ml of LHMDS. After 0.25 h, 2.8 mL of benzyl chloroformate was added. The reaction mixture was warmed to room temperature for 1 hour, then 25 mL of 1M hydrochloric acid was added. The reaction mixture was extracted three times with 25 ml of ethyl acetate, the combined extracts were washed with 2% ammonia solution, 2M hydrochloric acid solution and saturated sodium chloride solution and then dried over magnesium sulfate. After removal of the solvent, the white solid was crystallized from 5: 1 ethyl acetate: hexane to give 4.2 g of the title compound as white crystals.

TLC (ethyl acetate: methanol 9: 1) Rf 0.7.

Intermediate 5

2-Ethoxy-3- (2,2,2-trifluoro-acetylamino) -pyrrolidine-1-carboxylic acid benzyl ester

To a solution of Intermediate 4 (34 g) in ethanol (1070 ml) was added sodium borohydride (9.86 g) at -5 ° C. 20 ml of 4M hydrogen chloride solution are added dropwise

1,4-dioxane. Repeatedly add twice 5 ml and once 10 ml of a 4M solution of hydrogen chloride in 1,4-dioxane and 2 g of sodium borohydride. After 3 hours, 11 ml of concentrated sulfuric acid was added and the reaction mixture was warmed to room temperature for 2 hours. After addition of 300 ml of saturated aqueous sodium bicarbonate solution, the ethanol and dioxane are removed in vacuo. The residue was diluted with 500 mL of water and extracted three times with 500 mL of ethyl acetate. The combined extracts were washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel 9385 eluting with ether to give the title compound as a 21 g solid.

MNH ₄ ⁺ (found) 378, MNH? (calculated) 378.

-32Medziprodukt 6

Trans-2- (1-ethoxycarbonyl-2-methylpropyl) -3- (2,2,2-trifluoroacetylamino) pyrrolidine-1-carboxylic acid benzyl ester

10 g of intermediate 5, 11 ml of ethyltrimethylsilylisopropyl ketene acetal and 250 ml of dichloromethane are cooled to 5 DEG C., followed by the addition of 17 ml of boron trifluoride dietherate and 11 ml of ketene acetal over 0.25 hours. After an additional 1 hour, 200 ml of 1M hydrochloric acid solution are added and the organic portion is separated and washed with saturated sodium chloride solution and dried in vacuo to give 16.7 g of the title compound as an oil.

TLC (ether: cyclohexane 2: 1) Rf 0.18 and 0.27.

Intermediate 7

Trans-3-amino-2- (1-ethoxycarbonyl-2-methylpropyl) pyrrolidine-1-carboxylic acid benzyl ester

The reaction mixture of Intermediate 6 (31 g), potassium carbonate (71 g), water (930 ml) and ethanol (930 ml) was heated at 60 ° C for 3 hours. The ethanol was removed in vacuo and the aqueous residue was extracted three times with 300 mL of ethyl acetate. The combined extracts were washed with saturated brine, dried over magnesium sulfate, and concentrated in vacuo to give 17.5 g of the title compound as a brown oil.

Mass Spec MH ⁺ (found) 349, MH ⁺ (calc) 349.

Intermediate 8

Rel- (3R, 3aR, 6aS) -6-isopropyl-5-oxohexahydropyrrolo [3,2-b] pyrrole-1-carboxylic acid benzyl ester

To a solution of 17.5 g of intermediate 7 in 1800 ml of tetrahydrofuran cooled to -5 ° C was added a 0.5 M tert-butylmagnesium chloride solution in 204 ml of tetrahydrofuran over 0.5 hours. After 2 hours, 250 ml of 1M hydrochloric acid solution and 300 ml of saturated sodium chloride solution are added and the reaction mixture

Extracted with 250 mL of ethyl acetate. After concentrating the extracts to half volume in vacuo, the extracts are washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was triturated with 60 mL of diethyl ether to give a white solid. This product was crystallized from ethyl acetate to give 3.4 g of the title compound.

MH ⁺ (found) 303, MH ⁺ (calc) 303.

Intermediate 9

Rel- (3R, 3aR, 6aS) -6-Isopropyl-4-methanesulfonyl-5-oxohexahydropyrrolo [3,2-b] pyrrole-1-carboxylic acid benzyl ester

To a stirred solution of 15.01 g of intermediate 8 in 950 ml of anhydrous tetrahydrofuran was added dropwise 69.5 ml of 1.0 M LHMDS in tetrahydrofuran under nitrogen at -74 ° C. After stirring at -74 ° C for 10 minutes, the reaction mixture was allowed to warm to 0 ° C over 45 minutes and then left at this temperature for 20 minutes. The reaction mixture was then cooled to -76 ° C, 9.61 mL of methanesulfonyl chloride was added dropwise, and then stirred at this temperature for 1.5 hours. The reaction mixture was then warmed to -50 ° C, quenched with 480 mL of saturated ammonium chloride solution and allowed to warm to room temperature. The reaction mixture was partitioned between 300 mL of water and 750 mL of ethyl acetate. The aqueous portion was further extracted with 750 mL of ethyl acetate, and the combined organic extracts were washed with 450 mL of saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to give a beige solid. The product was purified by flash column chromatography on silica (Merck 9385) eluting with 1: 3, 1: 2, 1: 1 and then 3: 1 ethyl acetate: cyclohexane to give the title compound as 13.65 g of a white crystalline solid .

TLC (dichloromethane) Rf 0.22.

MNH ₄ ⁺ (found) 398, MNH / (calc) 398.

Intermediate 10

Rel- (3 / ?, 3afia, 6a S) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one

A suspension of 13.63 g of intermediate 9 in 900 ml of ethyl acetate is added to 3.16 g of 20% palladium hydroxide on charcoal and the resulting black suspension is stirred vigorously under a hydrogen atmosphere at room temperature for 90 minutes. The reaction mixture was then filtered through Harborlite J2 and concentrated in vacuo to give 8.63 g of the title compound as a fine white powder.

TLC (1: 9 MeOH) Rf 0.50.

Mass Spectrum: MH ⁺ (found) 247, MH ⁺ (calculated) 247.

Intermediate 11

Rel-5- (6R-Isopropyl-4-methanesulfonyl-5-oxohexahydro- (3aS, 6R) -pyrrolo [3,2-b] pyrrole-carbonyl) furan-2-carbaldehyde

To a stirred solution of 100 mg of intermediate 10 in 5 ml of acetonitrile was added 74 mg of 5-formyl-2-furoic acid and 156 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. The reaction mixture was stirred for 3 days. The acetonitrile was removed in vacuo and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic portion was washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel 9385 eluting with dichloromethane: acetonitrile 9: 1 to give 80 mg of the title compound as a white solid.

Mass Spec MH ⁺ (found) 369, MH ⁺ (calc) 369.

Intermediate 12

Rel- (3R, 3a / ?, 6a S) -3- (6-isopropyl-4-methanesulfonyl-5-oxo-hexahydropyrrolo [3,2- b] pyrrole-1-carbonyl) -furan-2-carbaldehyde

To a stirred solution of 540 mg of intermediate 10 in 40 ml of acetonitrile was added 400 mg of 2-formyl-3-furoic acid and 841 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride: The reaction mixture was stirred for 16 hours. The acetonitrile was removed in vacuo and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The aqueous portion was extracted with dichloromethane, combined

The organics were washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica (Merck 9385) eluting with dichloromethane: acetonitrile 9: 1 to give 626 mg of the title compound as a beige solid.

Mass Spec MH ⁺ (found) 369, MH ⁺ (calc) 369.

Intermediate 13

Rel- (3 R, 3a R, 6a S) -5- (6-isopropyl-4-methanesulfonyl-5-oxo-hexahydropyrrolo [3,2- b] pyrrole-1-carbonyl) thiophene-2-carbaldehyde

To a stirred solution of 250 mg of intermediate 10 in 10 ml of acetonitrile was added 206 mg of 5-formylthiophene-2-carboxylic acid and 389 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. The reaction mixture was stirred for 3 hours. The acetonitrile was removed in vacuo and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The aqueous portion was extracted with dichloromethane. The combined organics were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give a foam. The product was purified by flash column chromatography on silica (Merck 9385) eluting with a 9: 1 mixture of dichloromethane and acetonitrile to give 280 mg of the title compound as a beige solid.

Mass Spec MH ⁺ (found) 385, MH ⁺ (calc) 385.

Intermediate 14

Rel- (3 / ?, 3a R, 6a S) -3-isopropyl-1-methanesulfonyl-4- (1 H-pyrrol-2-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one

A solution of 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 in 3 ml of dimethylformamide is stirred for five minutes and then 100 mg of intermediate 10 are added. The mixture was stirred for 6 hours then partitioned between 25 mL of 8% sodium bicarbonate solution and 50 mL of ethyl acetate. The organic fraction shall be

The mixture was washed twice with 50 ml of water and the solvent was removed in vacuo to give a solid. The suspension of 25 ml of solid in diethyl ether was stirred for 10 minutes and then suction filtered. The residue was dried to give 123 mg of the title compound as a white powder, mp 200-203 ° C.

Mass Spec MH ⁺ (found) 340, MH ⁺ (calculated) 340.

Intermediate 15

Rel- (3S, 3aS, 6a) -3-Isopropyl-1-methanesulfonyl-4- (1-methyl-1H-pyrrole-2-carbonyl) hexahydro-roprolo [3,2-b] pyrrole 2-όη

A solution of 150 mg of 1-methylpyrrole-2-carboxylic acid, 180 mg of 1-hydroxybenzotriazole, 250 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and 240 mg of triethylamine in 5 ml of dimethylformamide is stirred for fifteen minutes, then 246 mg of intermediate 10 are added. The reaction mixture was stirred for 18 hours and then partitioned between 135 mL of 2% sodium bicarbonate solution and 150 mL of ethyl acetate. The organic portion was separated, washed twice with 120 mL of water, dried over sodium sulfate, and the solvent was removed in vacuo to give a semi-solid. The suspension of the semi-solid in 20 ml of diethyl ether is stirred for 10 minutes, the ester is decanted and replaced with another 10 ml of ether. The resulting suspension was stirred for 10 minutes, the ether was decanted again, and the residue was dried to give 227 mg of the title compound as a light brown solid, mp 176-178 ° C.

Mass Spec MH ⁺ (found) 354, MH ⁺ (calc) 354.

Intermediate 16

2- (2,2-Dimethyl-propionyloxymethyl) -thiazole-4-carboxylic acid

A mixture of 1.85 g of α-pyruvic acid, 1.75 g of 1- (tert-butylcarbonyloxy) thioacetate and 10 g of active molecular sieves with a mesh size of 4A in 100 ml of ethanol is stirred for 24 hours. The solvent was removed in vacuo and replaced with 100 mL of dichloromethane. The resulting suspension was stirred for 5 minutes and then filtered through Harborlite J2. The filtrate was evaporated to give a solid which was dissolved in ethyl acetate, dried over sodium sulfate, and the solvent was removed in vacuo to give a solid.

1.37 g of the title compound are obtained as a pale yellow solid, m.p. 155-158 ° C.

Mass Spec MH ⁺ (found) 244, MH ⁺ (calculated) 244.

Intermediate 17

2-Hydroxymethyl-thiazole-4-carboxylic acid

With stirring, a mixture of 1.78 g of intermediate 16 and 1.80 g of potassium carbonate in 90 ml of methanol and 30 ml of water was heated at reflux for 4.5 hours, cooled, concentrated to a volume of 30 ml and acidified with 2M acid solution. acid. The mixture was extracted five times with 60 mL of dichloromethane and then concentrated in vacuo to give a solid which was extracted twice with 150 mL of a 2: 1 mixture of hot methylated ethanol and ethyl acetate. The resulting extracts were combined with the dichloromethane extracts and the solvents were removed in vacuo. The formed gum was crystallized from diethyl ether to give 834 mg of the title compound as a brown powder, mp 121-127 ° C.

Mass Spec MH ⁺ (found) 160, MH ⁺ (calculated) 160.

Intermediate 18

Rel- (3S, 3aS, 6a /?) - 4- (2-hydroxymethyl-4-carbonyl) -3-isopropyl-1-metánsulfonylhexahydropyrolo [3,2-b] pyrrol-2-one

A solution of 787 mg of intermediate 17, 1.00 g of intermediate 10, 655 mg of tiretylamine, 718 mg of 1-hydroxybenzotriazole and 997 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in 5 ml of dimethylformamide was stirred for 17 hours and then partitioned between 250 ml of 8% sodium bicarbonate solution and 250 ml of ethyl acetate. The aqueous portion was separated and extracted with 250 mL of ethyl acetate. The combined organics were washed twice with 200 ml of 0.5 M hydrochloric acid solution and twice with 200 ml of water, dried over sodium sulfate and the solvent was removed in vacuo to give a foam which was stirred for 5 minutes in 100 ml of diethyl ether. . The solid suspension formed is filtered through

-38odsávania. The residue was dried to give 1.23 g of the title compound as a brown powder, mp 197-201 ° C.

Mass Spec MH ⁺ (found) 388, MH ⁺ (calc) 388.

Intermediate 19

2-Dimethylaminomethylthiazole-4-carboxylic acid

With stirring, a mixture of 370 mg of bromopyruvic acid, 300 mg of 1- (dimethylamino) thioaceamide hydrochloride, and 200 mg of potassium bicarbonate was heated under reflux for 1.5 hours, and the mixture was heated under reflux for an additional 0.75 hours. The reaction mixture was cooled and the solvent was removed in vacuo. The residue was stirred with 30 mL of ethyl acetate for 0.5 h. The solvent is decanted. The solid formed was partitioned between 0.5 mL of 0.5 M hydrochloric acid and 20 mL of ethyl acetate. The aqueous portion was separated and concentrated in vacuo to give a gum. The gum was treated with 20 mL of methanol and the reaction mixture was filtered. The filtrate was concentrated in vacuo and the residue was dried to give 430 mg of the title compound as a dark brown powder. Mass Spec MH ⁺ (found) 187, MH ⁺ (calculated) 187.

Intermediate 20

5-Formylisoxazole-3-carboxylic acid

A solution of 25 mg of ethyl 5-formylisoxazole-3-carboxylate in 3 ml of 1,4-dioxane and 1 ml of a 2M hydrochloric acid solution is heated under reflux for 5 hours with stirring. The reaction mixture was cooled and the solvent was removed in vacuo. The residue was triturated in diethyl ether. The solvent was removed and the residue was dried to give 18 mg of the title compound as an orange-brown solid.

TLC (dichloromethane: methanol 9: 1) Rf 0.32.

Intermediate 21

Rel- (3 / ?, 3 / ?, 6a S) -3- (6-isopropyl-4-methanesulfonyl-5-oxo-hexahydropyrrolo [3,2-b] pyrrole-1-carbonyl) isoxazole-5-carbaldehyde

To a stirred solution of 670 mg of intermediate 10 in 50 ml of acetonitrile was added 500 mg of intermediate 20 and 1.04 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. The reaction mixture was stirred for 4 hours. The acetonitrile was removed in vacuo and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. Separate the organic portion and pass through a preformed Varian SPE Bond Elut column, eluting sequentially with dichloromethane, chloroform, diethyl ether, ethyl acetate, acetonitrile, and methanol. The fractions containing the desired product were combined and evaporated to give 660 mg of the title compound as a white solid.

TLC (dichloromethane: acetonitrile 9: 1) Rf 0.33.

Intermediate 22

1-Methyl-5-styryl-1H-pyrazole-3-carboxylic acid ethyl ester

A solution of 40 g of (E) -ethyl-2,4-dioxo-6-phenylhex5-enoate and 9 g of methylhydrazine in 250 ml of ethanol is heated under reflux for 2 hours. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica eluting with diethyl ether / cyclohexane (1: 1). The fractions containing the higher polarity component and solvent were combined and evaporated to give 25.4 g of the title compound as yellow crystals.

TLC (diethyl ether: cyclohexane 1: 1) Rf 0.14.

Intermediate 23 was also produced during this reaction.

Intermediate 23

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

The fractions containing one of the two new lower polarity main components obtained by purification by chromatography 22 were combined and the solvent removed to give 11.4 g of the title compound as a yellow oil.

TLC (diethyl ether-cyclohexane 1: 1) Rf 0.62.

-40Medziprodukt 24

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

Ozone was bubbled through a solution of 156 g of intermediate 22 in 10 ml of ethyl acetate at -78 ° C for 2 hours. Nitrogen gas was then bubbled through the solution and then 500 mg of triphenylphosphine was added. The solution was warmed to room temperature and the solvent was removed in vacuo. The product is passed through a previously prepared Varian SPE Bond Elut column, eluting sequentially with dichloromethane, chloroform and diethyl ether. The fractions containing the desired product were combined and evaporated to give 127 mg of the title compound as white crystals.

TLC (diethyl ether-cyclohexane 1: 1) Rf 0.58.

Intermediate 25

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

A solution of 1.02 g of intermediate 24 in 10 ml of 1,4-dioxane and 10 ml of a 2M hydrochloric acid solution is heated under reflux for 24 hours with stirring. The reaction mixture was cooled and the solvent was removed in vacuo to give the title compound as a light yellow solid (0.85 g).

TLC (dichloromethane: methanol 9: 1) Rf 0.19.

Intermediate 26

Rel- (3R, 3a / ?, 6a S) -5- (6-isopropyl-4-methanesulfonyl-5-oxo-hexahydropyrrolo [3,2- b] pyrrole-1-carbonyl) -2-methyl-2H-pyrazol 3-carbaldehyde

To a stirred solution of 783 mg of intermediate 10 in 60 ml of acetonitrile was added 645 mg of intermediate 25 and 1.22 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride. The reaction mixture was stirred overnight. The acetonitrile was removed in vacuo and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic portion was separated and passed through a Varian SPE Bond Elut silica column eluting sequentially with dichloromethane, chloroform, diethyl-41 ether, and ethyl acetate. The fractions containing the desired product were combined and evaporated to give 315 mg of the title compound as a white solid.

TLC (dichloromethane: acetonitrile 9: 1) Rf 0.24.

Intermediate 27

Rel- (3R, 3a / ?, 6a S) -5- (6-isopropyl-4-methanesulfonyl-5-oxo-hexahydropyrrolo [3,2- b] pyrrole-1-carbonyl) -2-methyl-2H-pyrazol 3-carbaldehyde

Ozone was bubbled through a solution of 124 mg of intermediate 23 in 15 ml of ethyl acetate at -78 ° C for 3 hours. Nitrogen gas was bubbled through the solution, and then 500 mg of triphenylphosphine was added. The solution was warmed to room temperature and the solvent was removed in vacuo. The product was passed through a Varian SPE Bond Elut silica column eluting sequentially with dichloromethane, chloroform, and diethyl ether. The fractions containing the desired product were combined and evaporated to give 62 mg of the title compound as white crystals.

TLC (diethyl ether-cyclohexane 1: 1) Rf 0.70.

Intermediate 28

5-Formyl-2-methyl-2H-pyrazole-3-carboxylic acid

While stirring, a solution of 1.0 g of intermediate 27 in 10 ml of 1,4-dioxane and 10 ml of a 2M hydrochloric acid solution is heated at reflux overnight. The reaction mixture was cooled and the solvent was removed in vacuo to give the title compound as 0.8 g of a pale yellow solid.

TLC (dichloromethane: methanol 9: 1) Rf 0.54.

Intermediate 29

Rel- (3R, 3aR, 6aS) -5- (6-Isopropyl-4-methanesyl-phenyl-5-oxo-hexahydropyrrolo [3,2-b] pyrrol-1-carbonyl) -1-methyl-1 H- / pyrazol-3-carbaldehyde

To a stirred solution of 812 mg of intermediate 10 in 45 ml of acetonitrile was added

660 mg of intermediate 28 and 1.26 g of 1- (3-dimethylaminopropyl) -3-ethyl-42-carbodiimide hydrochloride. The reaction mixture was stirred for 22 hours. The acetonitrile was removed in vacuo and the residue was partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic portion was separated and passed through a Varian SPE Bond Elut silica column eluting sequentially with dichloromethane, chloroform, diethyl ether, and ethyl acetate. The fractions containing the desired product were combined and evaporated to give 955 mg of the title compound as a white solid.

TLC (dichloromethane: acetonitrile 9: 1) Rf 0.22.

Intermediate 30

6-Bromomethylnicotinic acid

With stirring, a mixture of 3.8 g of methyl 2- (bromomethyl) pyridine-5-carboxylate and 16.5 ml of bis (tri-n-butyltin) oxide in 80 ml of toluene is heated at 80 ° C for 24 hours. The reaction mixture was cooled and extracted twice with 50 ml 2M hydrochloric acid solution. The combined aqueous extracts were washed with 40 mL of toluene and concentrated in vacuo to give 3.0 g of the title compound as a tan solid.

Mass Spec MH ⁺ (found) 216.218, MH ⁺ (calc) 216.218.

Intermediate 31

Rel- (3 R, 3a R, 6a S) -4- (6-chloromethyl-pyridin-3-carbonyl) -3-isopropyl-1-metánsylfonylhexahydropyrolo [3,2- b] pyrrole-1-one

To a stirred suspension of 177 mg of intermediate 30 and 236 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in 5 ml of acetonitrile was added 100 mg of intermediate 10. The reaction mixture was stirred for 2 hours. The acetonitrile was removed in vacuo and the residue was partitioned between 40 mL of dichloromethane and 40 mL of 2M sodium carbonate solution. The organic layer was separated, washed with 20 ml of sodium carbonate solution and 20 ml of water, dried over magnesium sulfate and concentrated to an oil. This product was purified by flash column chromatography on silica eluting with dichloromethane: acetonitrile (7: 3) to give the title compound (76 mg) as a white foam.

TLC (dichloromethane: acetonitrile 7: 3) Rf 0.45.

-43Medziprodukt 32

5-Bromomethyl-pyrazine-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 benzoyl peroxide in 125 ml of carbon tetrachloride is heated and stirred under reflux and the mixture is irradiated with a 200 W light bulb for 0.5 hour. tungsten fiber. The reaction mixture was cooled, washed twice with 20 ml of 10% sodium sulfite solution, 20 ml of water and 15 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated to an oil. The product was purified by flash column chromatography on silica eluting with 3: 2 cyclohexane: ethyl acetate to give 3.8 g of the title compound as a brown solid. TLC (cyclohexane: ethyl acetate 3: 2) Rf 0.28.

Intermediate 33

5-Bromomethylpyrazine-2-carboxylic acid hydrochloride

A mixture of 3.48 g of intermediate 32 and 6.00 g of sodium hydroxide in 40 ml of water was stirred for 2 hours, acidified by addition of 2M hydrochloric acid solution and extracted four times with 30 ml of ethyl acetate. The combined extracts were washed with 15 mL of saturated sodium chloride solution, dried over magnesium sulfate, and the solvent removed in vacuo to give 2.58 g of the title compound as a pale yellow solid. Mass Spec MH ⁺ (found) 217.219, MH ⁺ (calc) 217.219.

Intermediate 34

Rel- (3 / ?, 3 / ?, 6a S) -4- (5-chlórmetylpyrazín-2-carbonyl) -3-isopropyl-1-metánsylfonylhexahydropyrolo [3,2-b] pyrrol-1-one

To a stirred solution of 800 mg of intermediate 10 and 934 mg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in 10 ml of acetonitrile was added 1.23 g of intermediate 33. The reaction mixture was stirred for 18 hours. The acetonitrile was removed in vacuo and the residue was partitioned between 20 mL of dichloromethane and 25 mL of 2M sodium carbonate solution. The aqueous phase was separated and extracted twice with 20 ml of dichloromethane.

The combined organics were washed with 15 mL of water and 15 mL of saturated sodium chloride solution, dried over magnesium sulfate and concentrated to an oil. This product was purified by flash column chromatography on silica eluting with dichloromethane: acetonitrile (7: 3) to give 562 mg of the title compound as a white foam.

TLC (dichloromethane: acetonitrile 7: 3) Rf 0.42.

Intermediate 35

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

At 110 ° C, 37.9 g of powdered Dasparagine are prepared for 48 hours of drying, which is then suspended in 144 ml of methanol and dried on a 3Å sieve for 5 hours. 40.2 ml of triethylamine are added to the stirred suspension under nitrogen, followed by 36 ml of methyltrifluoroacetate. The resulting mixture was allowed to stir for 48 hours. 145 ml of anhydrous methanol was added to the reaction mixture, followed by 115 g of Dowex 50 H + form dried at 56 ° C for 24 hours. The resulting mixture was stirred for 10 minutes, filtered, and the solvent removed in vacuo to give the crude solid containing the title compound. This crude product was combined with the crude product prepared by a similar procedure and crystallized from hot water to give the title compound as 106 g of a white crystalline solid.

MNH ₄ ⁺ (found) 245, MNH ₄ ⁺ (calc) 246.

Intermediate 36

2R- (2,2,2-Trifluoroethylamino) succinic acid methyl ester

A solution of 95.14 g of intermediate 35 in 1150 ml of methanol is dried over 3Å molecular sieves having a mesh size of 3Å and then cooled to -70 ° C with stirring. While maintaining the reaction temperature below -60 ° C, 162 mL of acetyl chloride is slowly added. The reaction mixture was allowed to warm to -20 ° C and left at this temperature for 48 hours. The solvent was removed in vacuo to give a clear and colorless oil containing the title compound. This product is triturated

-45 with diethyl ether and the white solid formed was allowed to crystallize from boiling water to give the title compound as a white crystalline solid (42 g).

Mass spectrum: MH ⁺ (found 243, MH ⁺ (calcd) 243.

Intermediate 37

3-Cyano-2 H- (2,2,2-trifluoroacetylamino) propionic acid methyl ester

To a stirred suspension of 3.0 g of intermediate 36 in 20 ml of dichloromethane was added 4.92 ml of pyridine and 4.92 g of p-toluenesulfonyl chloride. an additional 15 ml of dichloromethane was added and the brown solution was allowed to stir at room temperature for 48 hours. The reaction mixture was diluted with 25 mL of dichloromethane, washed with 74 mL of a 1 M aqueous solution of phosphoric acid, dried over sodium sulfate, filtered, and the solvent removed in vacuo to give 3.57 g of a brown solid containing the title compound. The crude mixture was purified by flash silica column chromatography (Merck 9385) eluting with a mixture of ethyl acetate and cyclohexane at a ratio of 1: 3 and then 1: 2.5. Evaporation in vacuo gave the title compound (1.62 g) as a white crystalline solid.

TLC (1: 1 ethyl acetate: cyclohexane) Rf 0.5.

MNH ₄ ⁺ (found) 242, MNH 4 (calcd) 242.

Intermediate 38

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

A solution of 200 mg of intermediate 37 in 10 ml of ethanol was stirred under an atmosphere of hydrogen for 3 hours in the presence of 1.00 g of 5% born on alumina. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give a crude gum containing the title compound. The reaction mixture was purified by flash column chromatography on silica (Merck 9385) eluting with acetonitrile. The eluent was evaporated in vacuo to give 40 mg of the title compound as a white solid.

TLC (acetonitrile) Rf 0.63.

MNH ₄ ⁺ (found) 214, MNH ₄ ⁺ (calc) 214.

-46Medziprodukt 39

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

To a stirred solution of 1.04 g of intermediate 38 in tetrahydrofuran cooled to -70 ° C was added 3.31 ml of a 1.6 M solution of n-butyllithium in a mixture of hexanes. After 5 minutes, 833 μΙ of benzyl chloroformate was added and the reaction mixture was allowed to warm to room temperature. After 2.5 hours, the reaction mixture was diluted with 100 mL of ethyl acetate and washed twice with 150 mL of 1M hydrochloric acid. The combined extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to give a crude orange-white solid which was purified by trituration with diethyl ether to give 1.25 g of the title compound as a white solid.

Mass Spec. MNH ₄ ⁺ (found) 348, MNH ₄ ⁺ (calc) 348.

Chiral HPLC (Chiracel AD, eluent system: ethane-heptane 15:85, flow rate = 1 mL / min).

Retention time R = 10.08 min (71.8%).

Retention time S = 12.50 min (28.2%).

Intermediate 40

Benzyl 2-ethoxy-3 /? - _(2.2 liters 2-trifluoro-acetylamino) -pyrrolidine-1-carboxylic

Dissolve 100 mg of intermediate 39 in 1 ml of anhydrous tetrahydrofuran in 1 ml of anhydrous tetrahydrofuran, cool to -20 ° C and add 0.15 ml of 2M lithium borohydride solution. After 0.5 hours, 1 ml of ethanol is added, followed by 33 μΙ of concentrated sulfuric acid and the resulting stirred solution is left at room temperature for 3.5 hours. The reaction mixture was brought to pH 8-9 by addition of saturated aqueous sodium bicarbonate and the organic solvent was removed in vacuo. The residue was partitioned between 20 mL of ethyl acetate and 10 mL of water. The aqueous portion was extracted with 10 mL of ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound as 101 mg of a clear oil, which was used in the next synthesis without further purification.

MNH ₄ ⁺ (found) 378, MNH ₄ ⁺ (calc) 378.

-47 Intermediate 40 (alternative method of preparation)

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

A solution of 214.8 g of intermediate 39 in 1200 ml of anhydrous tetrahydrofuran was stirred and cooled to -30 ° C. 336 ml of 2M lithium borohydride solution is added (after an initial temperature rise to -12 ° C, the reaction temperature is kept below -17 ° C during the addition). The reaction mixture was stirred at -20 ° C for 90 minutes, 760 mL of ethanol was added while maintaining the temperature below -19 ° C. A cooled mixture of 75 ml of concentrated sulfuric acid in 215 ml of ethanol is slowly added to the reaction mixture while maintaining the internal temperature below -18 ° C. Remove the cooling bath and stir the reaction for 90 minutes while raising the temperature to +15 ° C. 1600 ml of saturated sodium bicarbonate solution are carefully added over 35 minutes and then the volatiles are removed in vacuo. The aqueous phase was extracted once with 1000 ml and twice with 800 ml of ethyl acetate. The combined extracts were washed with 800 mL of saturated sodium chloride solution, dried over sodium sulfate 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) R f 0.64 and 0.43.

Intermediate 41

(2S, 3R) -2- (rel-15S-ethoxycarbonyl-2-methylpropyl) -3- (2,2,2-trifluoroacetylamino) pyrrolidine-1-carboxylic acid benzyl ester

A mixture of 90 mg of intermediate 40, 0.22 g of (1-ethoxy-3-methyl-but-1-enyloxy) triisopropylsilane (whose preparation is described in International Patent Application No. WO 97/136903 as preparation of intermediate 95) and 1,1 ml of dichloromethane was cooled to 5 ° C and 0.15 ml of boron trifluoride dietherate was added. After 55 minutes, the reaction is quenched by the addition of 15 mL of a 2M aqueous sodium bicarbonate solution and diluted with 10 mL of dichloromethane. The aqueous portion was separated and the organic portion was washed with 10 mL of saturated aqueous sodium chloride solution. The organic extract is dried over

Magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a colorless oil (106 mg).

Mass Spec MH ⁺ (found) 445, MH ⁺ (calc) 445.

Intermediate 41 (alternative preparation)

(2S, 3R) -2- (rel-15S-ethoxycarbonyl-2-methylpropyl) -3- (2,2,2-trifluoroacetylamino) pyrrolidine-1-carboxylic acid benzyl ester

A mixture of 97.9 g of intermediate 40, 233 g of (Z) - (1-ethoxy-3-methylbut-1-enyloxytriisopropylsilane) and 600 ml of dichloromethane was cooled to 5 ° C under nitrogen and 200 ml of boron trifluoride diethyl etherate were added over 15 minutes. . After a further 15 minutes, 750 ml of 2M sodium carbonate solution is added so that the temperature of the mixture does not rise above 20 ° C. The reaction mixture was filtered through Hyflo and the solid was washed twice with 200 mL of dichloromethane. The washings were added to the mixture divided into two phases. The aqueous portion was separated and extracted twice with 400 dichloromethane. The combined extracts were washed twice with 250 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo to give 154 g of the title compound.

TLC SiO ₂ (1: 3, ethyl acetate: cyclohexane) R f 0.49 (β-anomer), 0.42 (α-anomer). Mass Spec (found) MH ⁺ = 445, (calculated) MH ⁺ = 445.

Intermediate 42

(2S, 3R) -3-Amino-2- (1-ethoxycarbonyl-2-methyl-propyl) -pyrrolidine-1-carboxylic acid benzyl ester

A mixture of 97 mg of intermediate 41, 300 mg of potassium carbonate, 2 ml of ethanol and 2 ml of water was heated at reflux temperature for 2.25 hours. The ethanol and water were evaporated in vacuo and the residue was partitioned between 10 mL of ethyl acetate and 10 mL of water. The aqueous extract was brought to pH 9-10 by addition of 2M aqueous sodium hydroxide solution and extracted three times with 20 ml diethyl ether. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to give the title compound as 56 mg of a clear oil.

-49 Intermediate 42 (alternative method of preparation)

(2S, 3R) -3-Amino-2- (1-ethoxycarbonyl-2-methyl-propyl) -pyrrolidine-1-carboxylic acid benzyl ester

A mixture of 153 mg of intermediate 41.183.3 g of potassium carbonate, 1000 ml of ethanol and 1000 ml of water was heated at reflux temperature for 5 hours. The organic portion was then separated and concentrated in vacuo. The residue, the aqueous phase and 200 ml of saturated sodium chloride solution were extracted twice with 500 ml of ether and then once with 250 ml of ether, and the combined extracts were extracted three times with 500 ml of 1M hydrochloric acid solution. The combined acidic extracts are brought to pH 8 by addition of 150 g solid sodium bicarbonate and extracted once with 600 ml followed by three times with 300 ml of dichloromethane. The combined dichloromethane extracts were dried over magnesium sulfate and concentrated in vacuo to give the title compound (87.9).

TLC SiO ₂ (100: 8: 1 dichloromethane: ethanol: ammonia) Rf 0.55.

Mass Spec (found) MH ⁺ = 349, (calculated) MH ⁺ = 349.

Intermediate 43

(3a, 6S, 6aS) -6-Isopropyl-5-oxohexahydropyrrolo [3,2-b] pyrrole-1-carboxylic acid benzyl ester

Dissolve 50 mg of intermediate 42 in 1 ml of tetrahydrofuran in 12 ml of tetrahydrofuran and 1 ml of tetramethylethylenediamine and then add 0.4 ml of a 1M solution of tert-butylmagnesium chloride in tetrahydrofuran. After stirring for 3 hours, the reaction is quenched by addition of 1 mL of saturated ammonium chloride solution. The aqueous portion was separated and the mixture was extracted with 4 mL of ethyl acetate. The combined organic extracts were evaporated in vacuo. The residue was partitioned between 10 mL of dichloromethane and 10 mL of 2M hydrochloric acid. The aqueous layer was separated and extracted three times with 5 ml of dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give a crude white solid containing the title compound. The product was purified by flash column chromatography on silica (Merck 9385) eluting with 1: 1 ethyl acetate: cyclohexane to give 16 mL of the title compound as a 16 mg of a white solid.

-50TLC (2: 1 ethyl acetate: cyclohexane) R f 0.38.

Chiral HPLC (chiracel AD column, 10:90 ethanol / heptane eluent system, flow rate 1 ml / min).

RRS lactam retention time = 9.92 minutes (73.6%).

Lactam SSR retention time = 13.12 minutes (26.4%).

Intermediate 44

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

To 0.46 g of intermediate 43 in 30 ml of anhydrous tetrahydrofuran at -70 ° C under a nitrogen atmosphere was added 2.0 ml of 1M lithium hexamethyldisilazide in tetrahydrofuran. The solution was warmed to 0 ° C for 15 min and then re-cooled to -70 ° C and 0.30 mL of methanesulfonyl chloride was added. After 1.5 h, 30 mL of saturated aqueous ammonium chloride solution was added and the reaction mixture was extracted three times with 5 mL of ethyl acetate. The combined extracts were washed twice with 25 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica eluting with 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) R f 0.4.

Mass spectrum MNH / (found) 398, MNH / (calc) 398.

Intermediate 45 (3S, 3aS, 6aR) -3-Isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-1-one

A mixture of 0.31 g of intermediate 44, 0.24 g of 10% palladium hydroxide on charcoal, 25 ml of 1,4-dioxane and 25 ml of ethyl acetate was stirred under a hydrogen atmosphere for 3 hours. The catalyst was removed by filtration through Hyflo and the filtrate was concentrated in vacuo to give 0.20 g of the title compound as a pale yellow solid.

TLC SiO ₂ (9: 1 chloroform: methanol) R f = 0.36.

Mass Spec MH ⁺ (found) = 247, MH ⁺ (calculated) = 247.

-51 Intermediate 46 (3S, 3aS, 6a) - 4- (5-Chloromethyl-pyrazine-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-1-one

To a stirred solution of 900 mg of intermediate 45 and 1.25 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in 25 ml of acetonitrile was added 1.16 g of intermediate 1. The reaction mixture was stirred for 1 hour, followed by 25 ml of acetonitrile. The reaction mixture was stirred for 19 hours, the acetonitrile was removed in vacuo and the residue was partitioned between 30 mL of dichloromethane and 30 mL of 2M sodium carbonate solution. The aqueous phase was separated and extracted twice with 30 ml of dichloromethane. The combined organics were dried over magnesium sulfate, filtered and concentrated to give a brown foam. The product was purified by flash silica column chromatography (Merck 9385) eluting with 20% acetonitrile / dichloromethane. The fractions containing the desired product were evaporated to dryness in vacuo to give 1.095 g of the title compound (1.095 g) as a white foam.

TLC (20% acetonitrile in dichloromethane) Rf = 0.52.

Mass Spec MH ⁺ (found) 401.403, MH ⁺ (calc) 401.403.

Intermediate 47

5 - [(tert-butoxycarbonylcyclopropylamino) methyl] pyrazine-2-carboxylic acid

To a stirred suspension of 60 g of 2-methylpyrazine-5-carboxylic acid in 300 ml of acetic acid is added bromine. The reaction mixture was heated at 80 ° C for 1 hour. The solvent was evaporated in vacuo and the residue was partitioned between 250 mL of ethyl acetate and 250 mL of a 2M aqueous hydrochloric acid solution. The aqueous portion was extracted five times with 250 mL of ethyl acetate. The combined organics were washed with 100 mL of 2M hydrochloric acid and 100 mL of saturated sodium chloride solution, dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo to give a brown solid. The solid product is stirred in 900 ml of acetonitrile and 60 ml of triethylamine and 30 ml of cyclopropylamine are added. After stirring at room temperature for 20 hours, 30 ml of cyclopropylamine are added and the reaction mixture is stirred for 15 minutes. The volatiles were evaporated in vacuo and the residue was partitioned between 200 mL ethyl acetate and ethyl acetate

-52300 ml of a 2M aqueous hydrochloric acid solution. The organic layer was extracted four times with 200 ml of 2M hydrochloric acid solution, the combined aqueous extracts were washed with 50 ml of ethyl acetate, cooled in an ice bath and brought to basic pH by addition of 120 ml of 10M aqueous sodium hydroxide solution. The solution is washed three times with 200 ml of ethyl acetate and once with 200 ml of diethyl ether. The volatile organic portion was removed in vacuo to give a brown aqueous solution. 500 ml is added to the solution

1,4-dioxane and 71 g of di-tert-butyl dicarbonate. The reaction mixture was stirred at room temperature for 20 hours. 10 g of di-tert-butyl dicarbonate are added and the reaction mixture is stirred for a further 24 hours. 85 g of citric acid are added to the stirred mixture and the mixture is extracted twice with 200 ml, three times with 150 ml and twice with 100 ml of ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered, and the solvent removed in vacuo to give a brown oil which was purified by flash chromatography on a silica column (Merck 9385) eluting with dichloromethane: methanol: acetic acid 100: 8: 1. The fractions containing the desired product were evaporated to dryness in vacuo to give a yellow-brown solid which was vigorously stirred in a 5: 1 mixture of cyclohexane and diethyl ether until final resolution. The solid was removed by filtration and dried under vacuum to give 16.65 g of the title compound as an orange-brown solid.

TLC (dichloromethane / methanol / acetic acid 100: 8: 1) Rf = 0.31. MH ⁺ (found) = 294, MH ⁺ (calculated) = 294.

Intermediate 48 Cyclopropyl- [5- (6S-Isopropyl-4-methanesulfonyl-5-oxo-hexahydro- (3a, 6a)) pyrrolo [3,2-b] pyrrole-1-carbonyl) -pyrazine-2-tert-butyl ester ylmethyl] -carbamic

A mixture of 11.36 g of intermediate 45, 13.53 g of intermediate 47 and 19.3 g of O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate in 260 ml was stirred at room temperature. acetonitrile and 16 ml of Ν, Ν-diisopropylethylamine are added. After stirring for 2 hours, the solvent is removed in vacuo, the residue is diluted with 250 mL of dichloromethane and washed with 250 mL of 1M sodium carbonate solution. The aqueous portion was extracted three times with 150 mL of dichloromethane. The combined organics were washed with 1M sodium carbonate (50 ml), dried over magnesium sulfate, filtered and

The 53 solvent was evaporated in vacuo to give a yellow-brown solid. The solid was purified by flash column chromatography on silica (Merck 9385) eluting with 50% ethyl acetate in cyclohexane. The fractions containing the desired product were evaporated to dryness in vacuo to give 21.55 g of the title compound as a white foam.

Mass Spec MH ⁺ (found) 522, MH ⁺ (calc) 522.

[.alpha.] D @ ²⁰ = +69.5 (c = 0.8, methyl cyanide).

Intermediate 49

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

To a stirred solution of 43.9 g of 2- (bromomethyl) oxazole-4-carboxylic acid ethyl ester in 300 ml of acetonitrile is added 15.7 ml of pyrrolidine. After stirring for 10 minutes, 7.8 ml of pyrrolidine are added. After a further 30 minutes, the solvent was removed in vacuo to give an orange oil. The oil was partitioned between 400 mL of 1M sodium carbonate solution and 500 mL of dichloromethane and the layers were separated. The organic portion was washed with 100 mL water, dried over magnesium sulfate, filtered, and the solvent removed in vacuo to give 24.0 g of the title compound as an orange oil. Mass Spec MH ⁺ (found) = 225, MH ⁺ (calculated) = 225.

Intermediate 50

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

14 mg of pyrrolidine are added to a suspension of 25 mg of potassium carbonate and 27.5 mg of methyl 2 (bromomethyl) oxazole-4-carboxylic acid methyl ester in 2.5 ml of acetonitrile. The reaction mixture was stirred for 6 hours and the solvent was removed in vacuo. The residue was partitioned between 15 mL of ethyl acetate and 5 mL of water. The organic portion was dried over sodium sulfate and the solvent was removed in vacuo to give 23 mg of the title compound as a light brown oil.

MH ⁺ (found) = 211, MH ⁺ (calculated) = 211.

Preparative intermediate 2 provides intermediates 51-55 using 2- (bromomethyl) oxazole-4-carboxylic acid methyl ester as the starting compound.

Intermediate 51

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

Made as hydrochloride, in the form of a light brown gum.

MH ⁺ (found) = 211, MH ⁺ (calculated) = 211.

Intermediate 52

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

Light yellow solid.

MH ⁺ (found) = 321, MH ⁺ (calculated) = 321.

Intermediate 53

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

Light brown solid.

Mass Spec MH ⁺ (found) = 225, MH ⁺ (calculated) = 225.

Intermediate 54

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

Light yellow solid.

MH ⁺ (found) = 302, MH ⁺ (calc) = 302.

Intermediate 55

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

-55Viscent light yellow oil.

MH ⁺ (found) = 269, MH ⁺ (calculated) = 269.

Intermediate 56

2-Pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid / potassium salt of 2-pyrrolidin-1-ylmethyl-oxazole-4-carboxylic acid

Preparation 1

14.8 g of potassium carbonate are added to a solution of 24.0 g of intermediate 49 in 150 ml of ethanol and 150 ml of water. The reaction mixture was heated to reflux for 4 hours with stirring. The solvent was removed in vacuo to give an orange-brown residue which was azeotroped three times with toluene and then dried in vacuo. The solid residue was vigorously stirred with 100 mL of ether and filtered and dried to dryness in vacuo to give a mixture of the title compound and potassium carbonate as 34.5 g of a brown solid. The resulting material was used without further purification.

Preparation 2

After 5 hours of stirring a solution of 22 mg of intermediate 50 in 1.5 ml of dioxane and 0.3 ml of 1M sodium hydroxide solution, the solution is neutralized to a pH of about 7 by dropwise addition of 2M hydrochloric acid solution. The solvent was removed in vacuo and the solid residue was further dried under vacuum to give a mixture of the title compound and sodium chloride as 40 mg of a pale yellow solid.

MH ⁺ (found) = 197, MH ⁺ (calculated) = 197.

The method of Preparation of Intermediate 56 (Preparation 2) provides intermediates 57 to 59 using intermediates 53 to 56 as starting materials.

Intermediate 57

2-Piperidin-1-ylmethyloxazole-4-carboxylic acid

Beige solid.

MH ⁺ (found) = 211, MH ⁺ (calculated) = 211.

-56Medziprodukt 58

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

White solid.

MH ⁺ (found) = 288, MH ⁺ (calculated) = 288.

Intermediate 59

2-Dibutylaminomethyloxazole-4-carboxylic acid

Light yellow semi-solid.

MH ⁺ (found) = 255, MH ⁺ (calculated) = 255.

Examples

In the following, dichloride salts are designated by the term "(2: 1)" following the chemical name.

Example 1

Rel- (3R, 3R, 6R) -3-isopropyl-1-methanesulfonyl-4- (5-pyrrolidin-1-ylmethylfuran-2-carbonyl) hexahydropyrrolo [3,2-b] pyrrole- 2-one

A mixture of 80 mg of intermediate 11 and 17 mg of pyrrolidine in 6 ml of dichloromethane was stirred for 2 hours. After 69 mg of sodium triacetoxyborohydride was added, the mixture was stirred overnight. The reaction mixture was washed with 8% aqueous sodium bicarbonate solution and water. Pass the organic portion through a Varian SPE Bond Elut column (which is eluted beforehand with dichloromethane corresponding to column volume), eluting sequentially with dichloromethane, chloroform, diethyl ether, a 1: 1 mixture of diethyl ether and ethyl acetate, ethyl acetate, acetonitrile, and methanol. The fractions containing the desired product were combined and evaporated to give a gum which was treated with a 1M solution of hydrogen chloride in diethyl ether to give 80 mg of the title compound as a yellow solid.

MH ⁺ (found) = 424, MH ⁺ (calculated) = 424.

TLC (dichloromethane: methanol 9: 1) Rf = 0.27.

Examples 2-4 were prepared as in Example 1 using Intermediate 11 as the starting material.

Example 2

Rel- (3R, 3aR, 6aS) -3-Isopropyl-1-methanesulfonyl-4- (5-morpholin-4-ylmethyl-furan-2-carbonyl) -hexahydropyrrolo [3,2-b] pyrrole-2- hydrochloride one

Beige solid.

Mass spectrum MH ⁺ (found) = 440, MH ⁺ (calculated) = 440. TLC (dichloromethane: methanol 9: 1) Rf = 0.60.

Example 3

Rel- (3R, 3R, 6R) -3-isopropyl-1-methanesulfonyl-4- [5- (4-phenylpiperazin-1-ylmethyl) furan-2-carbonyl] hexahydropyrrolo [3,2-b] pyrrole- 2-one

Red solid.

MH ⁺ (found) = 515, MH ⁺ (calculated) = 515.

TLC (dichloromethane: methanol 9: 1) Rf = 0.65.

Example 4

Rel- (3R, 3af, 6aS) -3-Isopropyl-1-methanesulfonyl-4- [5- (4-methylpiperazin-1-ylmethyl) furan-2-carbonyl] hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

White solid.

MH ⁺ (found) = 453, MH ⁺ (calc) = 453. TLC (dichloromethane: methanol 9: 1) Rf = 0.16.

Example 5

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

A mixture of 50 mg of intermediate 12 and 13 mg of morpholine in 3.5 ml of dichloromethane was added

Stir 1.5 hours. After addition of 43 mg of sodium triacetoxyborohydrate, the mixture was stirred overnight. The reaction mixture was diluted with dichloromethane and extracted with 2M hydrochloric acid solution. The aqueous extract was brought to basic pH by the addition of 8% aqueous sodium bicarbonate solution and extracted with dichloromethane. The dichloromethane extracts were washed with saturated sodium chloride solution and dried over sodium sulfate. The solvent was removed in vacuo to give a solid which was treated with a 1M solution of hydrogen chloride in diethyl ether to give 32 mg of the title compound as a beige solid.

MH ⁺ (found) = 440, MH ⁺ (calculated) = 440.

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

Examples 6 to 10 were prepared as in Example 5 using Intermediate 12 as the starting compound.

Example 6

Rel- (3R, 3aR, 6aS) -4- (2-dimethylaminomethylfuran-3-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

Beige solid.

Mass spectrum MH ⁺ (found) = 398, MH ⁺ (calculated) = 398. TLC (dichloromethane: ethanol: ammonia 100: 8: 1) Rf = 0.70.

Example 7

Rel- (3R, 3R, 6R) -3-isopropyl-1-methanesulfonyl-4- (2-piperidin-1-ylmethylfuran-3-carbonyl) hexahydropyrrolo [3,2-b] pyrrole-2- hydrochloride one

Beige solid.

MH ⁺ (found) = 438, MH ⁺ (calculated) = 438. TLC (dichloromethane: ethanol: ammonia 100: 8: 1) Rf = 0.68.

-59Example 8

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

Yellow solid.

MH ⁺ (found) = 424, MH ⁺ (calculated) = 424.

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

Example 9

Rel- (3R, 3R, 6R) -3-isopropyl-1-methanesulfonyl-4- [2- (4-phenylpiperazin-1-ylmethyl) furan-3-carbonyl] hexahydropyrrolo [3,2-b] pyrrole -2-one

Yellow solid.

MH ⁺ (found) = 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-methyl-piperazin-1-ylmethyl) -furan-3-carbonyl] -hexahydropyrrolo [3,2-b] hydrochloride pyrrol-2-one

Beige solid.

Mass Spec MH ⁺ (found) = 453, MH ⁺ (calculated) = 453.

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

Example 11

Rel- (3R, 3aR, 6aS) -4- (5-dimethylaminomethylthiophene-2-carbonyl) -3-isopropyl-1-methanesulfonylhexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

A mixture of 60 mg of intermediate 13, 36 mg of dimethylammonium chloride and 66 mg of sodium triacetoxyborohydrate in 6 ml of dichloromethane was stirred overnight. The reaction mixture was diluted with dichloromethane and extracted with 2M hydrochloric acid solution. The aqueous extracts were washed with dichloromethane and then brought to basic pH by addition of 2M sodium carbonate solution and extracted with dichloromethane. The dichloromethane extracts were washed with saturated sodium chloride solution, dried over magnesium sulfate, and the solvent was removed in vacuo to give a gum which was treated with 1M hydrogen chloride in diethyl ether to give 15 mg of the title compound as a yellow solid.

MH ⁺ (found) = 414, MH ⁺ (calc) = 414.

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

Example 12 was prepared according to the method of Example 11 using intermediate 13 as the starting compound.

Example 12

Rel- (3R, 3R, 6R) -3-isopropyl-1-methanesulfonyl-4- (5-piperidin-1-ylmethylthiophene-2-carbonyl) hexahydropyrrolo [3,2-b] pyrrole- 2-one

Yellow solid.

MH ⁺ (found) = 454; MH ⁺ (calculated) = 454.

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

Example 13

Rel- (3S, 3aS, 6a) -3-Isopropyl-1-methanesulfonyl-4- (5-morpholin-4-ylmethyl-1H-pyrrole-2-carbonyl) hexahydropyrrolo [3,2-b] pyrrole hydrochloride -2-one

A mixture of 80 mg of intermediate 14, 28 mg of paraformaldehyde and 40 mg of morpholine in 4 ml of ethanol and 1.5 ml of glacial acetic acid was heated under reflux for 18 hours while stirring. The reaction mixture was cooled to room temperature and partitioned between 25 mL of 8% aqueous sodium bicarbonate solution and 25 mL of ethyl acetate. The aqueous portion was extracted with 30 mL of ethyl acetate. The combined organics were dried over sodium sulfate and the solvent was evaporated in vacuo to give a gum. The product was purified by flash column chromatography on silica (Merck 9385), eluting with dichloromethane: ethanol: ammonia (200: 8: 1) to give 21 mg of a white powder, which was treated with 1M hydrogen chloride in diethyl ether,

-61 gave 22 mg of the title compound as a white powder, mp 184-188 ° C.

MH ⁺ (found) = 439, MH ⁺ (calculated) = 439.

Examples 14-20 were prepared according to the method of Example 13 using intermediate 14 as the starting compound.

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, mp 233-236 ° C.

MH ⁺ (found) = 397, MH ⁺ (calc) = 397.

TLC (dichloromethane: ethanol: ammonia 100: 8: 1) Rf = 0.45.

Example 15

Rel- (3S, 3aS, 6a) -3-Isopropyl-1-methanesulfonyl-4- (5-piperidin-1-ylmethyl-1H-pyrrole-2-carbonyl) -hexahydropyrrolo [3,2-b] pyrrole-2- hydrochloride one

White powder, m.p. 160-164 ° C.

MH ⁺ (found) = 437, MH ⁺ (calculated) = 437.

Example 16

Rel- (3S, 3aS, 6a) -3-Isopropyl-1-methanesulfonyl-4- (5-pyrrolidin-1-ylmethyl-1H-pyrrole-2-carbonyl) -hexahydropyrrolo [3,2-b] pyrrole-2- one

White powder, m.p. 175-178 ° C.

Mass Spec MH ⁺ (found) = 423, MH ⁺ (calculated) = 423.

Example 17

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

-62 Beige powder, m.p. 156-160 ° C.

MH ⁺ (found) = 514, MH ⁺ (calculated) = 514.

Example 18

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

Beige powder, m.p. 177-181 ° C.

MH ⁺ (found) = 452; MH ⁺ (calculated) = 452.

Example 19

Rel- (3S, 3aS, 6a) - 4- (5-Dibutylaminomethyl-1H-pyrrole-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

Light yellow powder, mp 116-120 ° C.

MH ⁺ (found) = 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

Beige powder, m.p. 210-215 ° C.

MH ⁺ (found) = 383; MH ⁺ (calculated) = 383.

Example 21

Rel- (3S, 3aS, 6aR) -3-Isopropyl-1-methanesulfonyl-4- (1-methyl-5-piperidin-1-ylmethyl-1H-pyrrole-2-carbonyl) -hexahydropyrrolo [3,2-b] hydrochloride ] pyrrol-2-one

A mixture of 40 mg of intermediate 15, 15 mg of paraformaldehyde and 23 mg of piperidine in 3 ml of ethanol and 1.5 ml of glacial acetic acid was heated under reflux for 22 hours with stirring. The reaction mixture was cooled to room temperature and partitioned

- between 30 ml of an 8% aqueous sodium bicarbonate solution and 20 ml of ethyl acetate. The combined organics were dried over sodium sulfate and the solvent was evaporated in vacuo to give a gum. The product was purified by flash column chromatography on silica (Merck 9385) eluting with dichloromethane: ethanol: ammonia 100: 8: 1 to give 26 mg of a white solid, which was treated with 1M solution of hydrogen chloride in diethyl ether to give 28 mg of a white solid. title compound as a white powder, m.p. 149-153 ° C.

MH ⁺ (found) = 451, MH ⁺ (calculated) = 451.

Examples 22 to 25 were prepared by the method of Example 21 using intermediate 15 as the starting compound.

Example 22

Rel- (3S, 3aS, 6a) -3-Isopropyl-1-methanesulfonyl-4- (1-methyl-5-morpholin-4-ylmethyl-1H-pyrrole-2-carbonyl) -hexahydropyrrolo [3,2-b] hydrochloride b] pyrrol-2-one

Light yellow powder, m.p. 150-154 ° C.

Mass Spec MH ⁺ (found) = 453, MH ⁺ (calculated) = 453.

Example 23

Rel- (3S, 3aS, 6aR) -4- (5-dimethylaminomethyl-1H-pyrrole-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

White powder, m.p. 137-141 ° C.

MH ⁺ (found) = 411, MH ⁺ (calculated) = 411.

Example 24

Rel- (3S, 3aS, 6a) -3-Isopropyl-1-methanesulfonyl-4- (1-methyl-5-pyrrolidin-1-ylmethyl-1H-pyrrole-2-carbonyl) -hexahydropyrrolo [3,2-b] hydrochloride pyrrol-2-one

Yellow powder, m.p. 135-139 ° C.

MH ⁺ (found) = 437, MH ⁺ (calculated) = 437.

-64Example 25

Rel- (3S, 3aS, 6aR) -3-Isopropyl-1-methanesulfonyl-4- (1-methyl-5-methyl-aminomethyl-1H-pyrrole-2-carbonyl) -hexahydropyrrolo [3,2-b] pyrrole- 2-one

White powder, m.p. 216-218 ° C.

MH ⁺ (found) = 397, MH ⁺ (calc) = 397.

Example 26

Rel- (3S, 3aS, 6a) - 4- (4-Dimethylaminomethyl-1 H -pyrrole-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrole-2 hydrochloride -one

A mixture of 80 mg of intermediate 14, 25 mg of paraformaldehyde, 38 mg of dimethylammonium chloride and 200 mg of activated molecular sieves of 4 Å in 100 ml of ethanol was heated to reflux for 24 hours with stirring. The reaction mixture was cooled to room temperature and the solvent was evaporated in vacuo to give a gum. The product was purified by flash chromatography on two silica columns (Merck 9385) eluting the first column with dichloromethane: ethanol: ammonia 80: 8: 1 first column and 100: 8: 1 second column. 16 mg of a white powder are treated with a 1M solution of hydrogen chloride in diethyl ether to give 16 mg of the title compound as a white powder, m.p. 160-165 ° C.

MH ⁺ (found) = 397, MH ⁺ (calc) = 397.

TLC (dichloromethane: ethanol: ammonia 100: 8: 1) Rf = 0.20.

Example 27

Rel- (3S, 3aS, 6a) -3-Isopropyl-1-methanesulfonyl-4- (2-pyrrolidin-1-ylmethyl-thiazole-4-carbonyl) -hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

A stirred solution of 387 mg of intermediate 18 and 202 mg of triethylamine in 42 ml of dichloromethane was treated with 172 mg of methanesulfonyl chloride. After stirring for 1.5 hours, an aliquot of 7 ml was removed and 30 mg of pyrrolidine in 2 ml of dichloromethane was added to the stirred solution. The solution was stirred for two days. It is added with vigorous stirring

-6512 mL of an 8% aqueous sodium bicarbonate solution. The aqueous portion was separated and extracted with 15 mL dichloromethane. The organics were combined and dried over sodium sulfate. The solvent was removed in vacuo to give a semi-solid which was triturated in 10 mL of diethyl ether to give a solid suspension. 10 ml of cyclohexane are added to the suspension and the solvent is decanted. The resulting solid was dried under vacuum to give a white solid, which was treated with 1M hydrogen chloride in diethyl ether to give 51 mg of the title compound as a beige powder, mp 130-134 ° C.

MH ⁺ (found) = 441, MH ⁺ (calculated) = 441.

The resulting compounds of Examples 28-35 were prepared according to the method of Example 27 using intermediate 18 as the starting compound.

Example 28

Rel- (3S, 3aS, 6a) -3-Isopropyl-1-methanesulfonyl-4- (2-morpholin-4-ylmethyl-thiazole-4-carbonyl) -hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

Light yellow powder, m.p. 138-143 ° C.

MH ⁺ (found) = 457, MH ⁺ (calculated) = 457.

Example 29

Rel- (3S, 3aS, 6aR) -3-Isopropyl-1-methanesulfonyl-4- (2-piperidin-1-ylmethyl-thiazole-4-carbonyl) -hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

Beige powder, m.p. 153-158 ° C.

Mass Spec MH ⁺ (found) = 455, MH ⁺ (calculated) = 455.

Example 30

Rel- (3S, 3aS, 6aR) -3-Isopropyl-1-methanesulfonyl-4- [2- (4-methyl-piperirazin-1-ylmethyl) -thiazole-4-carbonyl] -hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride (1: 2)

White powder, m.p. 153-158 ° C.

Mass spectrum MH ⁺ (found) = 470, MH + (calculated) = 470.

Example 31

Rel- (3S, 3aS, 6aR) -4- (2-Cyclopropylaminomethylthiazole-4-carbonyl) -3-iso-propyl-1-methanesulfonyl-4-hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

Light gray powder, m.p. 160-163 ° C.

MH ⁺ (found) = 427, MH ⁺ (calculated) = 427.

Example 32

Rel- (3S, 3aS, 6aR) -4- {2 - [(4-fluorobenzylamino) methyl] thiazole-4-carbonyl} -3-isopropyl-1-methanesulfonyl-4-hexahydropyrrolo [3,2-b] pyrrole- 2-one

Light yellow powder, m.p. 141-145 ° C.

MH ⁺ (found) = 495, MH ⁺ (calculated) = 495.

Example 33

Rel- (3S, 3aS, 6aR) -3-Isopropyl-1-methanesulfonyl-4- [2- (4-phenylpiperirazin-1-ylmethyl) -thiazole-4-carbonyl] -hexahydropyrrolo [3,2-b] pyrrole-2- hydrochloride o (1: 2)

Beige powder, m.p. 156-161 ° C.

MH ⁺ (found) = 532, MH ⁺ (calculated) = 532.

Example 34

Rel- (3S, 3aS, 6aR) -4- (2-Dibutylaminomethylthiazole-4-carbonyl) -3-isopropyl 1-methanesulfonyl-4-hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

Light yellow powder, m.p. 81-86 ° C.

MH ⁺ (found) = 499, MH ⁺ (calculated) = 499.

-67Example 35

Rel- (3R, 3aR, 6aS) -3-Isopropyl-4- {2 - [(1-isopropyl-2-methylpropylamino) methyl] thiazole-4-carbonyl} -1-methanesulfonyl-4-hexahydropyrrolo [3] , 2-b] pyrrol-2-one

Beige powder, m.p. 192-195 ° C.

MH ⁺ (found) = 485, MH ⁺ (calculated) = 485.

Example 36

Rel- (3S, 3aS, 6aft) -4- (2-Dimethylaminomethylthiazole-4-carbonyl) -3-isopropyl-1-methanesulfonyl-4-hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

To a stirred suspension of 125 mg of intermediate 19 in 10 ml of dichloromethane was added 127 mg of oxalyl chloride followed by 1 drop of dimethylformamide. The reaction mixture was stirred for 1 hour and then concentrated in vacuo. The residue was suspended in 15 ml of dichloromethane and treated with 43 mg of intermediate 10 and 175 mg of sodium bicarbonate while stirring. After stirring the reaction mixture for 16 hours, 12 ml of an 8% aqueous sodium hydrogen carbonate solution were added. The aqueous portion was separated and extracted with 15 mL dichloromethane. The combined organic extracts were dried over sodium sulfate and evaporated to give a brown gum which was purified by flash column chromatography on silica (Merck 9385) eluting with dichloromethane: ethanol: ammonia (160: 8: 1) to give a brown gum. The product was treated with a 1M solution of hydrogen chloride in ether to give 23 mg of the title compound as a beige solid, mp 122-127 ° C. MH ⁺ (found) = 415, MH ⁺ (calculated) = 415.

Example 37

Rel- (3R, 3R, 6R) -3-isopropyl-1-methanesulfonyl-4- (5-morpholin-4-ylmethylisoxazole-3-carbonyl) hexahydropyrrolo [3,2-b] pyrrole-2- hydrochloride one

A mixture of 50 mg of intermediate 21 and 13 mg of morpholine in 5 ml of dichloromethane was added

Stir 1.5 hours. After addition of 43 mg of sodium triacetoxyborohydrate, the mixture was 2.5

-68 hours stirring. The reaction mixture was washed with 8% aqueous sodium bicarbonate solution. Pass the organic portion through a Varian SPE Bond Elut column (which was eluted beforehand with dichloromethane corresponding to column volume), eluting sequentially with dichloromethane, chloroform, diethyl ether, ethyl acetate, acetonitrile, and methanol. The fractions containing the desired product were combined and evaporated to give a foam which was treated with a 1M solution of hydrogen chloride in diethyl ether to give 39 mg of the title compound as a white solid.

MH ⁺ (found) = 441, MH ⁺ (calculated) = 441.

TLC (dichloromethane: methanol 9: 1) Rf = 0.65.

The resulting compounds of Examples 38-44 were prepared according to the method of Example 37 using intermediate 21 as the starting compound.

Example 38

Rel- (3R, 3a, 6aS) -4- (5-dimethylaminomethylisoxazole-3-carbonyl) -3-isopropyl-1-methanesulfonylhexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

White solid.

MH ⁺ (found) = 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

Beige solid.

MH ⁺ (found) = 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-ylmethylisoxazole-3-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

-69 White solid.

MH ⁺ (found) = 439, MH ⁺ (calculated) = 439.

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

Example 41

Rel- (3R, 3a, 6aS) -3-isopropyl-1-methanesulfonyl-4- [5- (4-methyl-piperazin-ylmethyl) -isoxazole-3-carbonyl] -hexahydropyrrolo [3,2-b] pyrrole- 2-one

White solid.

MH ⁺ (found) = 454; MH ⁺ (calculated) = 454.

TLC (dichloromethane: methanol 9: 1) Rf = 0.13.

Example 42

Rel- (3R, 3R, 6R) -4- {5 - [(4-fluoro-benzylamino) methyl] isoxazole-3-carbonyl} -3-isopropyl-1-methanesulfonylhexahydropyrrolo [3,2-b] hydrochloride pyrrol-2-one

Beige solid.

MH ⁺ (found) = 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-phenyl-piperazin-1-ylmethyl) -isoxazole-3-carbonyl] -hexahydropyrrolo [3,2-b] pyrrole-2- hydrochloride one

Beige solid.

MH ⁺ (found) = 516, MH ⁺ (calculated) = 516.

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

Example 45

Rel- (3R, 3aR, 6aS) -4- (5-dimethylaminomethyl-1-methyl-1H-pyrazole-3-carbonyl) -3-isopropyl-1-methanesulfonylhexahydropyrrolo [3,2-b] hydrochloride ] pyrrol-2-one

The mixture of Intermediate 26 (50 mg) and dimethylammonium chloride (32 mg) in dichloromethane (5 ml) was stirred for 2 hours. After the addition of 55 mg of sodium triacetoxyborohydrate, the mixture was stirred for 3 hours. The reaction mixture was washed with 8% aqueous sodium bicarbonate solution. Pass the organic portion through a Varian SPE Bond Elut column (which was eluted beforehand with dichloromethane corresponding to column volume), eluting sequentially with dichloromethane, chloroform, diethyl ether, ethyl acetate, acetonitrile, and methanol. The fractions containing the desired product were combined and evaporated to give a light brown oil which was treated with 1M hydrogen chloride in diethyl ether to give 28 mg of the title compound as a white solid.

MH ⁺ (found) = 412, MH ⁺ (calc) = 412.

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

The resulting compounds of Examples 46 to 49 were prepared by the method of Example 45 using intermediate 26 as the starting compound.

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] pyrrole hydrochloride -2-one

Beige solid.

MH ⁺ (found) = 438, MH ⁺ (calculated) = 438.

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

Example 47

Rel- (3R, 3aR, 6aS) -3-Isopropyl-1-methanesulfonyl-4- (1-methyl-5-morpholin-4-ylmethyl-1H-pyrazole-3-carbonyl) hexahydropyrrolo [3,2-b] pyrrole- 2-one

Beige solid.

MH ⁺ (found) = 454, MH ⁺ (calculated) = 454. TLC (dichloromethane: ethanol: ammonia 100: 8: 1) Rf = 0.69.

-71 Example 48

Rel- (3R, 3aft, 6aS) -3-Isopropyl-1-methanesulfonyl-4- (1-methyl-5-piperidin-1-ylmethyl-1H-pyrazole-3-carbonyl) hexahydropyrrolo [3,2-b] pyrrole hydrochloride -2-one

Beige solid.

MH ⁺ (found) = 452; MH ⁺ (calculated) = 452.

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

Example 49

Rel- (3ft, 3aft, 6aS) -3-isopropyl-1-methanesulfonyl-4- [1-methyl-5- (4-methylpiperidin-1-ylmethyl) -1H-pyrazole-3-carbonyl] hexahydropyrrolo [3, 2-b] pyrrol-2-one

Beige solid.

MH ⁺ (found) = 466, MH ⁺ (calculated) = 466.

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

Example 50

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

A mixture of 50 mg of intermediate 29 and 28 mg of phenylpiperazine in 5 ml of dichloromethane was stirred for 2 hours. After the addition of 50 mg of sodium triacetoxyborohydrate, the mixture was stirred overnight. The reaction mixture was washed with 8% aqueous sodium bicarbonate solution. Pass the organic portion through a Varian SPE Bond Elut column (which was eluted beforehand with dichloromethane corresponding to column volume), eluting sequentially with dichloromethane, chloroform, diethyl ether, ethyl acetate, acetonitrile, and methanol. The fractions containing the desired product were combined and evaporated to give a gum which was treated with a 1M solution of hydrogen chloride in diethyl ether to give 16 mg of the title compound as a yellow solid. MH ⁺ (found) = 529, MH ⁺ (calculated) = 529.

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

The resulting compounds of Examples 51-55 were prepared according to the method of Example 50 using intermediate 29 as the starting compound.

Example 51

Rel- (3R, 3R, 6R) -4- (5-dimethylaminomethyl-2-methyl-2H-pyrazole-3-carbonyl) -3-isopropyl-1-methanesulfonylhexahydropyrrolo [3,2-b] pyrrole -2-one

Yellow solid.

MH ⁺ (found) = 412, MH ⁺ (calc) = 412.

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

Example 52

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

Yellow solid.

MH ⁺ (found) = 438, MH ⁺ (calculated) = 438.

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

Example 53

Rel- (3F, 3aR, 6aS) -3-Isopropyl-1-methanesulfonyl-4- (2-methyl-5-morpholin-4-ylmethyl-2H-pyrazole-3-carbonyl) -hexahydropyrrolo [3,2-b] pyrrole hydrochloride -2-one

Yellow solid.

MH ⁺ (found) = 454; MH ⁺ (calculated) = 454.

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

Example 54

Rel- (3R, 3R, 6aS) -3-Isopropyl-1-methanesulfonyl-4- (2-methyl-5-piperidin-1-ylmethyl-2H-pyrazole-3-carbonyl) hexahydropyrrolo [3,2- b] pyrrol-2-one

Yellow solid.

-73 Mass spectrum MH + (found) = 452, MH ⁺ (calculated) = 452.

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

Example 55

Rel- (3R, 3R, 6aS) -3-Isopropyl-1-methanesulfonyl-4- [2-methyl-5- (4-methylpiperazin-1-ylmethyl) -2H-pyrazole-3-carbonyl] hexahydropyrrolo [hydrochloride] [ 3,2-b] pyrrol-2-one

Yellow solid.

MH ⁺ (found) = 467, MH ⁺ (calculated) = 467.

TLC (dichloromethane: ethanol: ammonia 100: 8: 1) Rf = 0.29.

Example 56

Rel- (3R, 3R, 6R) -4- {6 - [(dicyclohexylamino) methyl] pyridine-3-carbonyl} 3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrole- 2-one (1: 2)

A mixture of 90 mg of intermediate 31, 104.6 μΙ of dicyclohexylamine, 79 mg of sodium iodide and 169 mg of potassium carbonate in 2 ml of acetonitrile was stirred for 5 days. The solvent was evaporated and the residue was partitioned between 2 ml of 2M sodium carbonate solution and 3 ml of dichloromethane. The shares shall be separated. Pass the organic portion through a Varian SPE Bond Elut column (which is eluted beforehand with dichloromethane corresponding to column volume), eluting sequentially with dichloromethane, chloroform, diethyl ether, ethyl acetate, acetonitrile, and methanol. The fractions containing the desired product were combined and evaporated to give a colorless oil which was treated with a 1M solution of hydrogen chloride in diethyl ether to give 60 mg of the title compound as a beige solid. MH ⁺ (found) = 545, MH ⁺ (calculated) = 545.

TLC (ethyl acetate) Rf = 0.47.

The resulting compounds of Examples 57 to 64 were prepared according to the method of Example 56 using intermediate 31 as the starting compound.

-74Example 57

Rel- (3R, 3R, 6R) -4- (6-Dibutylaminomethylpyridine-3-carbonyl} -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride (1: 2)

Brown glassy substance.

MH ⁺ (found) = 493, MH ⁺ (calculated) = 493.

TLC (ethyl acetate) Rf = 0.49.

Example 58

Rel- (3R, 3aR, 6aS) -3-Isopropyl-1-methanesulfonyl-4- (6-morpholin-4-ylmethyl-pyridine-3-carbonyl) -hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride ( 1: 2)

Orange glassy fabric.

MH ⁺ (found) = 451, MH ⁺ (calculated) = 451.

TLC (ethyl acetate) R f = 0.38.

Example 59

Rel- (3R, 3R, 6aS) -4- (6-Cyclopropylaminomethyl-pyridine-3-carbonyl} -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride (1: 2)

Light brown solid.

MH ⁺ (found) = 421, MH ⁺ (calculated) = 421.

TLC (ethyl acetate) R f = 0.36.

Example 60

Rel- (3R, 3R, 6R) -3-Isopropyl-1-methanesulfonyl-4- (6-piperidin-1-ylmethyl-pyridine-3-carbonyl) -hexahydropyrrolo [3,2-b] pyrrole-2- hydrochloride o (1: 2)

Green solid.

Mass spectrum MH ⁺ (found) = 449, MH ⁺ (calculated) = 449. TLC (ethyl acetate) R f = 0.36.

-75Example 61

Rel- (3R, 3R, 6R) -3-Isopropyl-1-methanesulfonyl-4- [6- (4-methyl-piperazin-1-ylmethyl) -pyridine-3-carbonyl] -hexahydropyrrolo [3,2-b] hydrochloride ] pyrrol-2-one (1: 2)

Orange glassy fabric.

Mass Spec MH ⁺ (found) = 464, MH ⁺ (calculated) = 464.

TLC (ethyl acetate) Rf = 0.05

Example 62

Rel- (3R, 3R, 6R) -3-isopropyl-4 {6 - [(1-isopropyl-2-methyl-propylamino) methyl] pyridine-3-carbonyl} -1-methanesulfonylhexahydropyrrolo [3, 2-b] pyrrol-2-one (1: 2)

Yellow solid.

MH ⁺ (found) = 479, MH ⁺ (calculated) = 479.

TLC (ethyl acetate) Rf = 0.42.

Example 63

Rel- (3R, 3R, 6R) -4- (6-dimethylaminomethyl-pyridine-3-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride (1: 2)

Light yellow glassy substance.

Mass Spec MH ⁺ (found) = 409, MH ⁺ (calculated) = 409.

TLC (ethyl acetate) R f = 0.21.

Example 64

Rel- (3R, 3aft, 6aS) -4 {6 - [(4-fluoro-benzylamino) methyl] -pyridine-3-carbonyl} hydrochloride

3-Isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrol-2-one (1: 2)

Yellow-brown solid.

MH ⁺ (found) = 489, MH ⁺ (calculated) = 489.

TLC (ethyl acetate) Rf = 0.41.

-76Example 65

Rel- (3R, 3R, 6R) -4- (5-cyclopropyl-aminomethyl-pyrazine-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-pyrrolo [3,2-b] pyrrole-2- o (1: 2)

A mixture of 45 mg of intermediate 34, 23.3 μΙ of cyclopropylamine and 25 mg of sodium iodide in 1 ml of dichloromethane was stirred for 18 hours. An additional 23.3 μΙ of cyclopropylamine was added and the mixture was further stirred for 24 hours. The reaction mixture was partitioned between 3 mL of 2M sodium carbonate solution and 3 mL of dichloromethane. The shares shall be separated. The organic portion was passed through a Varian SPE column (which was eluted beforehand with dichloromethane corresponding to column volume) eluting sequentially with dichloromethane, chloroform, diethyl ether, ethyl acetate, acetonitrile, and methanol. The fractions containing the desired product were combined and evaporated to give 17 mg of a light brown oil which was treated with a 1.0 M solution of hydrogen chloride in diethyl ether to give 20 mg of the title compound as a brown solid. MH ⁺ (found) = 442; MH ⁺ (calculated) = 442.

TLC (ethyl acetate) Rf = 0.12.

The resulting compounds of Examples 66-75 were prepared according to the procedure for EXAMPLE 65 using intermediate 34 as the starting compound.

Example 66

Rel- (3R, 3R, 6R) -4- (5-dibutylaminomethylpyrazine-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride (1: 2) )

Pale brown solid.

MH ⁺ (found) = 494; MH ⁺ (calculated) = 494.

TLC (ethyl acetate) R f = 0.63.

Example 67

Rel- (3R, 3R, 6R) -3-isopropyl-1-methanesulfonyl-4- (5-morphophin-4-ylmethylpyrazine-2-carbonyl) hexahydropyrrolo [3,2-b] pyrrole-2- hydrochloride o (1: 2)

Beige solid.

-77 Mass spectrum MH + (found) = 452, MH ⁺ (calculated) = 452.

TLC (ethyl acetate) Rf = 0.12.

Example 68

Rel - (3R, 3a, 6a, 6aS) -4- {5 - [(dicyclohexylamino) methyl] -pyrazine-2-carbonyl} hydrochloride

3-Isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one (1: 2)

Beige solid.

MH ⁺ (found) = 546, MH ⁺ (calculated) = 546.

TLC (ethyl acetate) Rf = 0.65.

Example 69

Rel- (3R, 3R, 6R) -3-Isopropyl-1-methanesulfonyl-4- (5-piperidin-1-ylmethyl-pyrazine-2-carbonyl) -hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride (1: 2)

Beige solid.

MH ⁺ (found) = 450, MH ⁺ (calculated) = 450.

TLC (ethyl acetate) Rf = 0.12.

Example 70

Rel- (3R, 3R, 6R) -3-Isopropyl-1-methanesulfonyl-4- [5- (4-methyl-piperazin-1-ylmethyl) -pyrazine-2-carbonyl] -hexahydropyrrolo [3,2-b] hydrochloride ] pyrrol-2-one (1: 2)

Brown glassy substance.

MH ⁺ (found) = 465, MH ⁺ (calculated) = 465.

TLC (ethyl acetate) Rf = 0.02.

Example 71

Rel- (3R, 3a, 6aS) -3-isopropyl-4- {5 - [(1-isopropyl-2-methyl-propylamino) methyl] pyrazine-2-carbonyl} -1-methanesulfonyl-hexahydropyrrolo [3] , 2-b] pyrrol-2-one (1: 2)

Beige solid.

Mass spectrum MH ⁺ (found) = 480, MH + (calculated) = 480.

TLC (ethyl acetate) Rf = 0.45.

Example 72

Rel- (3R, 3aR, 6aS) -4- (5-dimethylaminomethyl-pyrazine-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride (1: 2) )

Light brown solid.

MH ⁺ (found) = 410, MH ⁺ (calc) = 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] -hexahydro-pyrrolo [3,2- b] pyrrol-2-one (1: 2)

Light yellow glassy substance.

MH ⁺ (found) = 527, MH ⁺ (calculated) = 527.

TLC (ethyl acetate) R f = 0.27.

Example 74

Rel- (3R, 3aR, 6aS) -3-Isopropyl-1-methanesulfonyl-4- (5-pyrrolidin-1-ylmethyl-pyrazine-2-carbonyl) -hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride ( 1: 2)

Orange-brown solid.

MH ⁺ (found) = 436, MH ⁺ (calculated) = 436.

TLC (ethyl acetate) Rf = 0.05.

Example 75

Rel- (3R, 3aR, 6aS) -3-Isopropyl-1-methanesulfonyl-4- (5-methylaminomethyl-pyrazine-2-carbonyl] -hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride (1: 2)

Light brown solid.

Mass spectrum MH ⁺ (found) = 396, MH ⁺ (calculated) = 396.

TLC (ethyl acetate) Rf = 0.02.

Example 76

(3S, 3aS, 6aR) -4- (5-Cyclopropyl-aminomethyl-pyrazine-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

A solution of 21.53 g of intermediate 48 and 200 ml of a 4.0 M solution of hydrochloric acid in 200 ml of 1,4-dioxane was stirred at room temperature for 2 hours. The solvent was removed in vacuo to give an off-white solid. The solid was crystallized from 2.3 L of hot 5% aqueous 2-propanol solution to give 15.54 g of the title compound as a white solid, mp 183-185 ° C.

TLC (silica, eluent: dichloromethane / ethanol = 0.880 ammonia = 200: 8: 1) Rf = 0.21.

Mass Spec MH ⁺ (found) 422.19, MH ⁺ (calc) 422.19.

[α] D ²⁰ +51.3 (c = 0.9, water: methyl cyanide 1: 1).

Circular Dichroism: A _has x of 250.2 nm (ΔΕ -1.34 M ¹ cm ^1), and _has the x 285.4 nm (ΔΕ +0.99 M ^-1 cm ^-1) (MeCN / water)

Elemental analysis:

found C 47.4; H, 6.4; N, 14.3; S 6.5; Cl 7.8; water 4.9%;

(C19H27ClN5O4S.HCl.1.1H2O requires C 47.4; H 6.4; N 14.6; S 6.7; Cl 7.4; water 4.9%).

Example 76 (alternative preparation method)

A mixture of Intermediate 46 (1.056 g), cyclopropylamine (0.73 ml) and potassium iodide (481 mg) in acetonitrile (25 ml) was stirred for 3 hours. The solvent was evaporated in vacuo and the mixture was partitioned between 2 mL of saturated sodium bicarbonate solution and 20 mL of dichloromethane. The shares shall be separated. The aqueous portion was further extracted twice with 20 mL of dichloromethane. The combined organics were dried over magnesium sulfate, filtered and the solvent removed in vacuo to give an oil. This product was purified by flash column chromatography on silica (Merck 9385) eluting with mixtures

-80 dichloromethane, ethanol and 0.880 ammonia in a ratio of 200: 8: 1. The fractions containing the desired product were combined and evaporated to give 924 mg of a solid which was dissolved in 10 mL of dichloromethane and treated with 10 mL of a 1.0 M solution of hydrogen chloride in diethyl ether. 1.00 g of compound is obtained as a white solid.

Example 77

(3S, 3aS, 6a) -3-Isopropyl-1-methanesulfonyl-4- (2-pyrrolidin-1-ylmethyl-oxazole-4-carbonyl) -hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

To a stirred solution of 13.0 g of 1-hydroxybenzotriazole in 350 ml of acetonitrile was added 32.2 g of intermediate 56 rapidly. A solution of 21.7 g of (3S, 3aS, 6α) - 3-isopropyl-1-methanesulfonyl-hexahydropyrolo [3 2-b] pyrrol-2-one (Intermediate 122 in International Patent Application WO 97/36903) followed by 37.0 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in 70 ml of acetonitrile and then the reaction mixture is stirred 20 hours. The solvent was removed in vacuo and the residue was partitioned between 900 mL of dichloromethane and 600 mL of 1M sodium carbonate solution. The aqueous portion was separated and extracted with 150 mL of dichloromethane. The combined organics were washed with 250 mL of saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give a brown solid. The solid was purified by flash column chromatography on silica (Merck 9385) eluting with a gradient of dichloromethane: ethanol: ammonia from 150: 8: 1 to 135: 8: 1 to give 29.3 g of a beige solid. The solid was dissolved in 150 mL of dichloromethane and the product was treated with 75 mL of a 1M solution of hydrogen chloride in ether. The solvent was removed in vacuo to give a solid which was redissolved in 150 mL of dichloromethane and treated with 75 mL of a 1M solution of hydrogen chloride in ether. The solvent was removed in vacuo to give a solid which was crystallized from acetone to give 26.3 g of the title compound as a white solid, mp 156-158 ° C.

TLC (silica; elution with dichloromethane, ethanol and ammonia in a ratio of

100: 8: 1; double elution) Rf = 0.66.

¹ H NMR (400 MHz, D-6 DMSO): δ 8.78 (s, 1H), 4.68 (s, 2H), 4.13 (ddd, J = 11, 11.7)

Hz, 1H), 4.08 (dd, J = 11.10 Hz, 1H), 3.80 (ddd, J = 12, 10.5, 5.5 Hz, 1H), 3.60 (m,

-81 2Η), 3.55 (dd, J = 12, 10.5 Hz, 1H), 3.31 (s, 3H), 3.20 (m, 2H), 3.03 (dd, J = 12) 2.5 Hz, 1H), 2.88 (md, J = 2.5 Hz, 1H), 2.34 (m, 1H), 2.12 (m, 1H), 1.96 (m, 4H) 1.19 (d, J = 7Hz, 3H), 0.98 (d, J = 7Hz, 3H). It contains 0.16 mol% acetone. Infrared spectrum (diffuse reflectance in potassium bromide) 3633, 3474, 3149, 3102, 2956, 2882, 2668, 2576, 2475, 1747, 1709, 1639, 1634, 1567, 1442, 1380, 1347, 1161, 1146, 967 , 810, 547 cm ^-1 .

MH ⁺ (found) = 425.186372, MH ⁺ (calc) = 425.185867 (error = 1.2 ppm).

Combustion analysis:

found: C 48.65, H 6.39, N 11.41, S 6.19, Cl 7.13%.

C ₁₉ H ₂₈ N ₄ O ₅ S HCl.0.75H ₂ O.0.2Me ₂ CO calculated: C 48.43, H 6.57, N 11.53, S

6.60, Cl 7.29%.

Example 78

(3S, 3aS, 6R) -3-Isopropyl-1-methanesulfonyl-4- (2-pyrrolidin-1-ylmethyl-oxazole-4-carbonyl) -hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

A stirred suspension of 40 mg of intermediate 56 in 4 ml of dichloromethane was treated with 63 mg of oxalyl chloride followed by addition of 1 drop of dimethylformamide. The reaction mixture was stirred for 1.5 hours, the solvent was removed in vacuo and replaced with 10 mL of toluene. The resulting suspension was vigorously spread for 10 minutes. Toluene was removed in vacuo to give a gum which was slurried in 5 mL of dichloromethane treated with 20 mg of intermediate 10 and 35 mg of sodium bicarbonate. The reaction mixture was stirred for 3.75 hours and then partitioned between dichloromethane (2 x 10 mL) and water (5 mL). The combined organics were dried over sodium sulfate and concentrated in vacuo to give a solid. The solid was triturated in 4 mL of ether for 10 min. The ether was decanted. The residue was dried in vacuo to give a white powder which was treated with 1M hydrogen chloride in diethyl ether to give 17 mg of the title compound as a beige powder, mp 116-120 ° C.

MH ⁺ (found) = 425, MH ⁺ (calculated) = 425.

The resulting compounds of Examples 79 to 81 were prepared according to the method of Example 78 using intermediate 10 and 57 to 59, respectively, as starting material.

Example 79

(3S, 3aS, 6a) -3-Isopropyl-1-methanesulfonyl-4- (2-piperidin-1-ylmethyl-oxazole-4-carbonyl) -hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

White powder, m.p. 140-143 ° C.

MH ⁺ (found) = 439, MH ⁺ (calculated) = 439.

Example 80

(3S, 3aS, 6aR) -3-Isopropyl-1-methanesulfonyl-4- [2- (4-phenyl-piperazin-1-ylmethyl) -oxazole-4-carbonyl] -hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

Beige solid, m.p. 156-160 ° C.

MH ⁺ (found) = 516, MH ⁺ (calculated) = 516.

Example 81

(3S, 3aS, 6aR) -4- (2-Dibutylaminomethyl-oxazole-4-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

White powder, mp 122-126 ° C.

MH ⁺ (found) = 483, MH ⁺ (calculated) = 483.

Example 82

(3S, 3aS, 6aR) -4- {2 - [(Cyclopropylmethylamino) methyl] -oxazole-4-carbonyl} 3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

A solution of 21 mg of intermediate 51 in 1.5 ml of dioxane and 0.4 ml of 1M sodium hydroxide was stirred for 3.5 hours. 0.35 ml of hydrochloric acid is added with stirring. The solvent was removed in vacuo. The residue is triturated for 5 minutes at 3

-83ml dioxane. The solvent was removed in vacuo. Using a further 3 ml of dioxane, the trituration is repeated and then the solvent is removed in vacuo and the residue is dried under vacuum to give a solid. A stirred suspension of this solid in 3 mL of dichloromethane was treated with 50 mg of oxalyl chloride followed by 1 drop of dimethylformamide. The reaction mixture was stirred for 1 hour and the solvent was removed in vacuo. The residue is vigorously triturated in 10 ml of a 1: 1 mixture of dichloromethane and toluene for 5 minutes. The solvent was removed in vacuo to give a gum which was slurried in 5 mL of dichloromethane. The product was treated with 18 mg of intermediate 10 and 35 mg of sodium bicarbonate. The reaction mixture was stirred for 0.75 hours and then left at room temperature for 3 days. The product was diluted with 10 mL of dichloromethane and washed with 10 mL of water. The organic portion was dried over sodium sulfate and concentrated in vacuo to give a gum which was purified by flash column chromatography on silica (Merck 9385) eluting with dichloromethane: ethanol: ammonia (150: 8: 1) to give a white powder. The product was treated with 1M hydrogen chloride in diethyl ether to give 7 mg of the title compound as a white powder, mp 116-119 ° C.

MH ⁺ (found) = 425, MH ⁺ (calculated) = 425.

The resulting compound of Example 83 was prepared by the method of Example 82 using intermediate 10 and intermediate 52 as starting materials.

Example 83

(3S, 3aS, 6a) - 4- {2 - [(Dicyclohexylamino) methyl] -oxazole-4-carbonyl} -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one hydrochloride

White powder, m.p. 130-133 ° C.

MH ⁺ (found) = 535, MH ⁺ (calculated) = 535.

Biological tests

In the in vitro elastase assay, the resulting compounds of Examples 1 to 83 were monitored.

The following table summarizes the results of IC ₅ o-84-

Example ICso (μΜ) Example IC ₅₀ (μΜ) 1 0,123 43 0,051 2 0,081 44 0,099 3 0,164 45 0,019 4 0,065 46 0,014 5 0,039 47 0,024 6 0,071 48 0,030 7 0,082 49 0,051 8 0,086 50 0,054 9 0,129 51 0,021 10 0,114 52 0,012 11 0,139 53 0,015 12 0,104 54 0,011 13 0,032 55 0,020 14 0,021 56 0,038 15 0,021 57 0,041 16 0,019 58 0,045 17 0,068 59 0,028 18 0,022 60 0,037 19 0,057 61 0,030 20 0,013 62 0,041 21 0,029 63 0,025 22 0,043 64 0,048 23 0,026 65 0,013 24 0,024 66 0,076 25 0,009 67 0,019 26 0,017 78 0,087 27 0,008 69 0,022 28 0,011 70 0,013 29 0,014 71 0,050 30 0,017 72 0,012 31 0,016 73 0,074 32 0,009 74 0,012 33 0,005 75 0,093 34 0,013 76 0,011 35 0,056 77 0,010 36 0,013 78 0,014 37 0,017 79 0,016 38 0,014 80 0,100 39 0,021 81 0,076 40 0,030 82 0,084 41 0,014 83 0,137 42 0,057

-852. Examples of compounds 1,2, 11, 12, 13, 15, 16, 17,27, 28, 29, 31, 33, 34, 35, 37 to 50, 56, 57, 59, 60 to 69, 72, 73 , 76, 78, 80 and 81 were subjected to in vivo hamster tests as described above. The effective dose has been shown to be less than 10 mg / kg for a duration of effect of at least 6 hours.

3. The compounds of Examples 1-83 were subjected to clinical trials to inhibit elastase in the bloodstream as described above. The IC50 values are summarized in the following table.

Example ΐθδο (μΜ) Example ΙΟ ₅₀ (μΜ) 1 0,355 43 0,429 2 1,882 44 0,528 3 2,195 45 0,518 4 4,185 46 0,524 5 3 47 1,043 6 4,015 48 0,414 7 3.04 49 0,539 8 3.46 50 1.92 9 3,615 51 > 10 10 5.5565 52 7,637 11 1.16 53 8.23 12 2.4 54 4,205 13 1,103 55 > 10 14 1,885 56 0,293 15 0,452 57 0,193 16 0,774 58 2.44 17 0,316 59 0,394 18 2,925 60 0,605 19 0,408 61 5,898 20 6,405 62 0,252 21 0,317 63 1.62 22 0,453 64 0,521 23 0,364 65 0,333 24 0,306 66 0,217 25 1.64 67 0,878 26 > 10 68 0,221 27 0,704 69 0,264 28 1,125 70 3,215 29 0,311 71 0,205 30 1,683 72 0,322 31 0,896 73 0,282

32 0,427 74 0,205 33 0,257 75 5,025 34 0,546 76 0,139 35 0.81 77 0,245 36 0,296 78 0,411 37 1,187 79 0,502 38 0,224 80 0.4 39 0,358 81 0,296 40 0,222 82 0,717 41 1.76 83 0.55 42 0.43

Claims (28)

PATENT CLAIMS Pyrolopyroion derivatives of general formula I (relative stereochemistry is indicated), wherein R ¹ represents alkyl of 1 to 6 carbon atoms, R ² is alkyl or alkenyl each having 2 to 4 carbon atoms, X is CO or SO2 Het is an optionally substituted, 5 to 10 membered monocyclic or bicyclic aromatic ring system containing 1 to 4 heteroatoms from O, N and S, n is an integer of 0 to 4, R ³ and R ⁴ independently represent hydrogen, alkyl of 1 to 8 carbon atoms, - (CH 2) 1-4CONR ⁵ R ⁶ , CO-alkyl of 1 to 4 carbon atoms in the alkyl moiety or (CH ₂ ) 0-2 Ph, wherein Ph is phenyl optionally substituted with one or more C 1 -C 4 alkyl or halogen radicals or NR ³ R ⁴ together form azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, morpholinyl, piperazinyl, optionally N-substituted alkyl radicals of 1 up to 6 carbon atoms, phenyl, optionally substituted with halogen or alkyl of 1 to 4 carbon atoms or benzyl, optionally substituted on the benzene ring with halogen or alkyl of 1 to 4 carbon atoms, or NR ³ R ⁴ together form the above-described ring substituted on carbon atoms with one or more substituents selected from the group consisting of alkyl having 1 to 4 carbon atoms, CONR ⁵ R ⁶ or COOR ⁶ , R ⁵ and R ⁶ independently represent hydrogen or C 1 -C 4 alkyl, -88a salts and solvates thereof. 2. A compound according to claim 1 wherein Het is a 5 or 6 membered monocyclic aromatic ring containing 1 or 2 heteroatoms from O, N and S. Pyrolopyrrone derivatives of the general formula I according to claim 2, in which Het represents thiazolyl, isoxazolyl, pyrazolyl or pyrazinyl. 4. A compound according to claim 2 wherein Het is pyridin-3-yl. 5. A compound of the formula I as claimed in claim 2 wherein Het is oxazolyl. 6. A compound according to claim 1, 2 or 5 of formula IA R * R ³ N (CH ₂ ) _n (relative stereochemistry is indicated). Pyrrolopyrrone derivatives of the general formula I according to any one of claims 1 to 6, wherein R ² is isopropyl or propyl. Pyrolopyrrone derivatives of the general formula I according to any one of claims 1 to 7, wherein R ² is isopropyl. -899. A compound of the formula I as claimed in any one of claims 1 to 8 wherein R ¹ is ethyl or methyl. 10. A compound of formula I according to claim 9, wherein R ¹ is methyl. The pyrrolopyrrone derivatives of formula I according to any one of claims 1 to 10, wherein X is CO. The pyrrolopyrrone derivatives of the general formula I according to any one of claims 1 to 11, wherein n is 1 to 3. The pyrrolopyrrone derivatives of the formula I according to any one of claims 1 to 12, wherein R ³ and R ⁴ independently represent hydrogen or C 1 -C 6 alkyl, or NR ³ R ⁴ together form pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, optionally N-substituted on the nitrogen atom with a C 1 -C 8 alkyl radical or a phenyl radical, optionally substituted with a halogen atom or a C 1 -C 4 alkyl radical. 14. A compound according to claim 1 selected from the group consisting of: rel- (3R, 3a, 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-ylmethyl-furan-2-carbonyl) -hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3R, 3a) R, 6aS) -3-Isopropyl-1-methanesulfonyl-4- [5- (4-phenylpiperazin-1-ylmethylfuran-2-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3R, 3a) , 6a S) -3-isopropyl-1-methanesulfonyl-4- [5- (4-methylpiperazin-1-ylmetylfurán2-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one; rel- (3 R 3a R _I, 6a S) -3-isopropyl-1-methanesulfonyl-4- (2-morpholin-4-ylmetylfurán-3-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one, -90rel- (3 /? 3 _I /? _I, 6a S) -4- (2-dimethylaminomethylfuran-3-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one, rel - (3 / ?, 3 /? _l, 6a S) -3-isopropyl-1-methanesulfonyl-4- (2-piperidin-1-ylmetylfurán-3-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one; rel- (3R, 3R, 6aS) -3-Isopropyl-1-methanesulfonyl-4- (2-pyrrolidin-1-ylmethylfuran-3-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- , 3a R, 6a S _I) -3-isopropyl-1-methanesulfonyl-4- [2- (4-phenyl-piperazin-1-ylmethyl) Furansu-karbonylJhexahydropyrolop -blpyrol ^ ^ -one rel- (3 / ?, 3 / ?, 6a -3-Isopropyl-1-methanesulfonyl-4- [2- (4-methylpiperazin-1-ylmethyl) furan-3-carbonyl] hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- 3aR, 6aS) -4- (5-dimethylaminomethyl-thiophene-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3R, 3a); 6aS) -3-isopropyl-1-methanesulfonyl-4- (5-piperidin-1-ylmethylthiophene-2-carbonyl) hexahydro-petroleum rolo [3,2-b] pyrrol-2-one, rel- (3S, 3aS, 6a) ?) - 3-isopropyl-1-methanesulfonyl-4- (5-morpholin-4-ylmethyl-1 / - / - pyrrole-2-carbonyl) hexahydro ydropyrrolo [3,2-b] pyrrol-2-one, rel- (3S, 3aS, 6α) -4- (5-dimethylaminomethyl-1H-pyrrole-2-carbonyl) -3-isopropyl-1- methanesulfonylhexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3S, 3aS, 6a) -3-isopropyl-1-methanesulfonyl-4- (5-piperidin-1-ylmethyl-1H-pyrrole-) 2-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3S, 3aS, 6a) -3-isopropyl-1-methanesulfonyl-4- (5-pyrrolidin-1-ylmethyl-1H) - tert -pyrrole-2-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3S, 3aS, 6a) -3-isopropyl-1-methanesulfonyl-4- [5- (4-phenylpiperazine- 1-yl-methyl) -1H-pyrrole-2-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one; rel- (3S _I, 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, 6a) - 4- (5- dibutylaminomethyl-1H-pyrrole-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3S, 3aS, 6a) - 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-meth 5-yl-piperidin-1-ylmethyl-1Hpyrol-2-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one, -91 rel- (3S, 3aS, 6aR) -3-Isopropyl-1-methanesulfonyl-4- (1-methyl-5-morpholin-4-ylmethyl-1H-pyrrole-2-carbonyl) -hexahydropyrrolo [3,2-b] pyrrole -2-one, rel- (3S, 3aS, 6af) -4- (5-dimethylaminomethyl-1-methyl-1H-pyrrole-2-carbonyl) -3-isopropyl-1-methanesulfonylhexahydropyrrolo [3,2-b] pyrrole- 2-one, rel-1 (S, S, and N - (5-isopropyl-1-methanesulfonyl-4-O-methyl-5-pyrrolidin-1-ylmethyl-1 H -pyrrole-2-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3S, 3aS, 6af) -3-isopropyl-1-methanesulfonyl-4- (1-methyl-5-methylaminomethyl-1H-pyrrole-2-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3S, 3aS, 6a) -4- (4-dimethylaminomethyl-1H-pyrrole-2-carbonyl) -3-isopropyl-1-methanesulfonylhexahydropyrrolo [3,2-b] pyrrole- 2-one, rel- (3S, 3aS, 6af) -3-isopropyl-1-methanesulfonyl-4- (2-pyrrolidin-1-ylmethyl-thiazole-4-carbonyl) -hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3S, 3aS, 6aR) -3-isopropyl-1-methanesulfonyl-4- (2-morpholin-4-ylmethyl-thiazole-4-carbonyl) -hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3S, 3aS, 6aR) -3-isopropyl-1-methanesulfonyl-4- (2-piperidin-1-ylmethyl-4-carbonyl) hexahydro pyrrolo [3,2-b] pyrrol-2-one, rel- (3S, 3aS, 6aR) -3-isopropyl-1-methanesulfonyl-4- [2- (4-methylpiperazin-1-ylmethyl) thiazol-4- carbonyl] hexahydropyrrolo [3,2-b] pyrrol-2-one; rel- (3S, 3aS, 6a ^/:?) - 4- (2-cyklopropylaminometyltiazol-4-carbonyl) -3-isopropyl-1-metánsulfonylhexahydropyrolo [3 2-b] pyrrol-2-one, rel- (3S, 3aS, 6a) -4- [2 - [(4-fluorobenzylamino) methyl] thiazole-4-carbonyl) -3-isopropyl-1-methanesulfonylhexahydropyrrolo [3] 2-b] pyrrol-2-one, rel- (3S, 3aS, 6a) -3-isopropyl-1-methanesulfonyl-4- [2- (4-phenylpiperazin-1-ylmethyl) thiazole-4-carbonyl Hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3S, 3aS, 6α) -4- (2-dibutylaminomethylthiazole-4-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3] 2-b] pyrrol-2-one, rel- (3R, 3aR, 6aS) -3-isopropyl-4- [2 - [(1-isopropyl-2-methylpropylannino) methyl] thiazole-4-carbonyl] -1- methanesulfonylhexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3S, 3aS, 6α) -4- (2-dimethylaminomethylthiazole-4-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] -b] pyrrol-2-one, rel-1S.Saft.eaS-S-isopropyl-1-methanesulfonyl-1S-nno rfolín ^ -ylmetylizoxazol-Skarbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one, -92rel- (3R, 3aR, 6aS) -4- (5-dimethylaminomethylisoxazole-3-carbonyl) -3-isopropyl-1-methanesulfonylhexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3R) 3α, 3α, 6αS) -3-isopropyl-1-methanesulfonyl-4- (5-pyrrolidin-1-ylmethylisoxazole-3-carbonyl) hexahydro-petroleum [3,2-b] pyrrol-2-one, rel- ( 3R, 3R, 6R) -3-isopropyl-1-methanesulfonyl-4- (5-piperidin-1-ylmethylisoxazole-3-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3 (R, 3a) ₍ 6aS) -3-Isopropyl-1-methanesulfonyl-4- [5- (4-methylpiperazin-1-ylmethyl) isoxazole-3-carbonyl] hexahydropyrrolo [3,2-b] pyrrole-2- O, rel- (3R, 3R, 6aS) -4- [5 - [(4-fluorobenzylamino) -methyl] -isoxazole-3-carbonyl] -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrole -2-one, rel- (3R, 3R, 6R) -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-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrole -2-one, rel- (3R, 3aR, 6aS) -4- (5-dimethylaminomethyl-1-methyl-1H-pyrazole-3-carbonyl) -3-isopro polyl-1-methanesulfonylhexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3R, 3R, 6aS) -3-isopropyl-1-methanesulfonyl-4- (1-methyl-5-pyrrolidine- 1-ylmethyl-1H-pyrazole-3-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3R, 3R, 6aS) -3-isopropyl-1-methanesulfonyl-4- (1- methyl-5-morpholin-4-ylmethyl-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- 5-Isopropyl-1-methanesulfonyl-4-methyl-5- (4-methylpiperidin-1-ylmethyl) -1H-pyrazole-3-carbonyl] hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- ( 3 R, 3a / ?, 6a S) -3-isopropyl-1-methanesulfonyl-4- [2-methyl-5- (4-phenyl-piperazin-1-ylmethyl) -2H-pyrazole-3-carbonyl] hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3R, 3R, 6aS) -4- (5-dimethylaminomethyl-2-methyl-2H-pyrazole-3-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [ 3,2-b] pyrrol-2-one, rel- (3R, 3R, 6R) -3-isopropyl-1-methanesulfonyl-4- (2-methyl-5-pyrrolidin-1-ylmethyl-2H) - / -pyrazol 3-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3R, 3R); _l, 6a S) -3-isopropyl-1-methanesulfonyl-4- (2-methyl-5-morpholin-4-ylmethyl-2H-pyrazole-3-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one, -93rel- (3 feet, 3aft, 6a S) -3-isopropyl-1-methanesulfonyl-4- (2-methyl-5-piperidin-1-ylmethyl-2H-pyrazole-3-carbonyl) hexahydropyrrolo [3,2-b] pyrrole 2-one, rel- (3R, 3R, 6R) -3-isopropyl-1-methanesulfonyl-4- [2-methyl-5- (4-methylpiperazin-1-ylmethyl) -2H-pyrazole-3-carbonyl ] hexahydropyrrolo [3 ₁ 2-b] pyrrol-2-one; rel- (3R, 3a / ?, 6a S) -4- [6 - [(dicyclohexylamino) methyl] pyridine-3-carbonyl] -3-isopropyl- 1-methanesulfonylhexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3R, 3R, 6R) -4- (6-dibutylaminomethylpyridine-3-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [ 3,2-b] pyrrol-2-one, rel- (3R, 3R, 6aS) -3-isopropyl-1-methanesulfonyl-4- (6-morpholin-4-ylmethyl-pyridine-3-carbonyl) -hexahydropyrrolo [3,2-b] -b] pyrrol-2-one, rel- (3R, 3R, 6aS) -4- (6-cyclopropylaminomethylpyridine-3-carbonyl) -3-isopropyl-1-methanesulfonylhexahydropyrrolo [3,2-b] pyrrole-2 -one, rel- (3R, 3aR, 6aS) -3-isopropyl-1-methanesulfonyl-4- (6-piperidin-1-ylmethylpyridine-3-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3R, 3aR, 6a S) -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-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3R, 3R, 6aS) -4- (6-dimethylaminomethyl-pyridine-3-carbonyl) ) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one; rel- (3R, 3aR _I, 6a S) -4- [6 - [(4-fluoro-benzylamino) -methyl] -pyridin-3 -carbonyl] -3-isopropyl-1-methanesulfonylhexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3R, 3R, 6aS) -4- (5-cyclopropylaminomethylpyrazine-2-carbonyl) - 3-isopropyl-1-methanesulfonylhexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3R, 3R, 6aS) -4- (5-dibutylaminomethylpyrazine-2-carbonyl) -3-isopropyl- 1-methanesulfonyl-hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3R, 3R, 6aS) -3-isopropyl-1-methanesulfonyl-4- (5-morpholin-4-ylmethyl-pyrazine-2-carbonyl) - hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3R, 3R, 6aS) -4- [5 - [(dicyclohexylamino) methyl] pyrazine-2-carbonyl] -3-isopropyl-1-methanesulfonylhexahydropyrolo [3] , 2-b] pyrrol-2-one, rel- (3R, 3aR, 6a S) -3-isopropyl-1-methanesulfonyl-4- (5-piperidin-1-ylmetylpyrazín-2-carbonyl) -hexahydro-pyrrolo [3,2-b] pyrrol-2-one, -94rel- (3 R, 3a R, 6a S) -3-isopropyl-1-methanesulfonyl-4- (5- (4-methylpiperazin-1-ylmethyl) pyrazine-2-carbonyl] hexahydropyrrolo (3,2-b] pyrrol-2 -one, rel- (3R, 3R, 6R) -3-isopropyl-4- [5 - [(1-isopropyl-2-methylpropylamino) methyl) pyrazine-2-carbonyl] -1-methanesulfonylhexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3R, 3aR, 6aS) -4- (5-dimethylaminomethylpyrazine-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydro-petroleum [3,2-b] pyrrole-2- O, rel- (3R, 3a, 6aS) -3-isopropyl-1-methanesulfonyl-4- [5- (4-phenylpiperazin-1-ylmethyl) pyrazine-2-carbonyl] hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3R, 3R, 6aS) -3-isopropyl-1-methanesulfonyl-4- (5-pyrrolidin-1-ylmethyl-pyrazine-2-carbonyl) -hexahydropyrrolo [3,2-b] pyrrole-2 -one, rel- (3R, 3aR, 6aS) -3-isopropyl-1-methanesulfonyl-4- (5-methylaminomethylpyrazine-2-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one, or salts and solvates of these compounds. 15. A compound according to claim 1 which is rel- (3S, 3aS, 6aF) -4- (5-cyclopropylaminomethylpyrazine-2-carbonyl) -3-isopropyl-1-methanesulfonyl-hexahydropyrrolo [3,2- b] pyrrol-2-one or salts and solvates thereof. A pyrrolopyrrone derivative of the Formula I according to claim 1, selected from: rel- (3S, 3aS, 6a) -3-Isopropyl-1-methanesulfonyl-4- (2-pyrrolidin-1-ylmethyloxazole-4-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- ( 3S, 3aS ₍ 6a) - 3-Isopropyl-1-methanesulfonyl-4- (2-piperidin-1-ylmethyloxazole-4-carbonyl) hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3S, 3aS) 6a) -3-Isopropyl-1-methanesulfonyl-4- [2- (4-phenylpiperazin-1-ylmethyl) oxazole-4-carbonyl] hexahydropyrrolo [3,2-b] pyrrol-2-one, rel- (3S _I 3aS, 6aR) -4- (2-Dibutylaminomethyloxazole-4-carbonyl) -3-isopropyl-1-methanesulfonylhexahydropyrrolo [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-1metánsulfonylhexahydropyrolo [3,2-b] pyrrol-2-one, -95or salts and solvates thereof. A compound of formula I according to claim 1 which is (3S, 3aS, 6aR) -3-isopropyl-1-methanesulfonyl-4- (2-pyrrolidin-1-ylmethyloxazole-4-carbonyl) hexahydropyrrolo [3,2- b] pyrrol-2-one, or salts or solvates thereof. 18. A compound of the formula I as claimed in claim 1, which is (SS.SaS.eaR @ 1 -S-isopropyl-1-methanesulfonyl-4-pyrrolidin-1-ylmethyloxazole-4-carbonyl) hexahydropyrrolo [3,2-b] hydrochloride. pyrrol-2-one. A purified single enantiomer of the pyrrolopyrrone derivative of the formula I according to any one of claims 1 to 14 and 16 in absolute stereochemistry shown in the formula I. A process for the preparation of the pyrrolopyrrone derivatives of the general formula I according to claim 1, characterized in that it is: (i) condensing a compound of formula II (relative stereochemistry is indicated) with a compound of formula R ⁴ R ³ N (CH 2) n HetCOOH or an acid derivative thereof, for example chloride, activated ester or anhydride or mixed anhydride, or a compound of formula R ⁴ R ³ N (CH 2) _n HetXY, wherein Y is a reactive group, for example a halogen atom such as a chlorine atom or a protected derivative thereof, or -96ii) sulfonylating a compound of formula III R ³ R ³ N (CH ₂ ) n Het-X (H 1) (relative stereochemistry is indicated) or a protected derivative thereof by treatment with YO ² R ¹ , wherein Y is a reactive group such as a halogen atom such as chlorine or iii) cyclizing a compound of formula IV (IV) (relative sterochemistry is indicated) or a carboxylic acid ester, or iv) oxidizing the corresponding compound of formula V (V) -97 (relative sterochemistry is given) wherein X ^a is a sulfur atom or SO or s v) reacting a compound of formula VI H i with. (VI) (relative stereochemistry is indicated) wherein L is a leaving group, with a compound of formula R ⁴ R ³ NH, or vi) preparing a compound of formula I wherein n is an integer from 1 to 4 by reducing the reaction product of the corresponding compound of formula VII (VII) (relative sterochemistry is indicated) with a compound of formula R ⁴ R ³ NH, or vii) to prepare a compound of formula I wherein n is 1 by reaction of the corresponding compound of formula VIII -98Het-X (VIII) (relative stereochemistry is indicated) with formaldehyde or paraformaldehyde together with a compound of formula R ⁴ R ³ NH in an acidic environment, or viii) deprotecting a protected compound of formula I or ix) from a mixture of enantiomers isolates one of the enantiomers in pure form and then, if desired, transforms the resulting free base of a compound of formula I into a physiologically acceptable salt thereof, or conversely, the salt is converted into the free base of a compound of formula I or one salt is converted into another physiologically acceptable salt. Pharmaceutical composition, characterized in that it comprises, as its active ingredient, a pyrrolopyrrone derivative of the formula I according to any one of claims 1 to 19 in admixture with at least one physiologically acceptable solvent or carrier. A compound of formula I according to any one of claims 1 to 19 for use as a medicament. Use of the pyrrolopyrrone derivatives of the general formula I according to any one of claims 1 to 19 for the manufacture of a medicament for the treatment of chronic bronchitis or chronic obstructive pulmonary diseases. -9924. Use of the pyrrolopyrrone derivatives of the general formula I according to any one of claims 1 to 19 for the manufacture of a medicament for the treatment of asthma. An intermediate of formula III (relative stereochemistry is indicated) wherein R ² , R ³ , R ⁴ , n, Het and X are as defined in claim 1, or a protected derivative thereof for the preparation of a compound of formula I according to claim 1. An intermediate of formula IV (IV) (relative stereochemistry is indicated) wherein R ¹ , R ² , R ³ , R ⁴ , n, Het and X are as defined in claim 1, or esters thereof formed on the carboxyl group on preparing a compound of formula I according to claim 1. - 100 An intermediate of formula V (V) (relative stereochemistry is indicated) wherein R ¹ , R ² , R ³ , R ⁴ , n, Het and X are as defined in claim 1, and X ^a represents a sulfur atom or SO, preparing a compound of formula I according to claim 1. An intermediate of formula VI (VI) (relative stereochemistry is indicated) wherein R ¹ , R ² , n, Het and X are as defined in claim 1, and L is a leaving group, to prepare a compound of formula I according to claim 1 29. An intermediate of formula VII CHO _(CH2) ^ - Het-X. (VII) (Relative stereochemistry is indicated) wherein R ¹ , R ² , n, Het and X are as defined in claim 1, and wherein n is an integer from 1 to 4, for the preparation of a compound of formula I according to claim 1. 30. The intermediate product of formula VIII Het-X. with. (VIII) (relative stereochemistry is indicated) wherein R ¹ , R ² , Het and X are as defined in claim 1, for the preparation of a compound of formula I according to claim 1.