WO1998032738A1

WO1998032738A1 - New compounds with hemoregulating effect

Info

Publication number: WO1998032738A1
Application number: PCT/EP1998/000511
Authority: WO
Inventors: Johann Hiebl; Hermann Kollmann; Franz Rovenszky; Michael Hartmann
Original assignee: Nycomed Austria Gmbh
Priority date: 1997-01-27
Filing date: 1998-01-27
Publication date: 1998-07-30
Also published as: NO993782D0; NO993650D0; JP2001509795A; EP0958283A1; NO993650L

Abstract

Disclosed are compounds of formula (I), which have a hemoregulating function, as well a their use and production.

Description

NEW CONNECTIONS WITH HEMOREGULATORY EFFECT

The invention relates to new compounds with hemoregulatory activity, which can be used to stimulate haematopoiesis and to treat viral, bacterial and fungal infections.

The haematopoietic system is a lifelong cell renewal process in which a defined stem cell population induces a larger population of mature, differentiated blood cells (Dexter ™. Stern cells in normal growth and disease, Br. Med. J. 1987, 195: 1192-1194) with at least 7 different cell lines (erythrocytes, basophilic granulocytes, neutrophilic granulocytes, monocytes / macrophages, osteoclasts and lymphocytes (Metcalf D. The Molecular Control of Biood Cells, 1988, Harvard University Press, Cambridge, MA). Examples of such stem cells can be found in the myelopoetic cells of the bone marrow, as well as in the epithelial and epidermal cells, so the stem cells are ultimately responsible for the regeneration of the bone marrow after treatment with cytostatic compounds or after a bone marrow transplant.

Influencing or controlling the division of such stem cells is of great therapeutic interest. Several biologically active compounds have already been identified, which play a key role by stimulating or blocking one of the steps of cell division and differentiation. Myelopoiesis has been particularly intensively investigated in this connection, with the following compounds being found to date: colony-stimulating factors (CSF) such as granulocyte-colony-stimulating factor (G-CSF), macrophage-colony-stimulating factor (M-CSF), granulocyte-macrophage- colony stimulating factor (GM-CSF) (e.g. LM Souza in Human Cytokines, Blackwell Scientific Publications, 1992, pp. 221ff, Oxford, Ed.BB Aggarwal, JU Gutterman), Interleukin 11 (IL-11) (Paul et al “Proc. Natl. Acad. Sci. USA Vol. 87, p. 7521, born 1990), lactoferrin (Broxmeyer et al., Blood Cells Vol. 11, p. 429, born 1986), prostaglandins (Pelus et al., J. Immunol., Vol. 140, p. 479, born 1988), α-, ß - and γ-interferon (Pelus et al. and Broxmeyer et al., J. Immunol., Vol.131, S.1300, Jg.1983), growth factor large-ß (Ottman et al., Vol.140, S. 2661, born 1988), and activin and inhibin (Broxmeyer et al., Proc. Natl. Acad. Sci. USA, Vol. 86, p.779, born 1989). The main dose-limiting toxicity of most known anti-neoplastic drugs is associated with an inhibition of bone marrow formation, which, if it persists for a prolonged period, can trigger life-threatening infectious and haemorrhagic complications. This inhibition is predictable and limits the doses that can be administered in more than 50% of phase I trials of cytotoxic compounds (Merrouche Y, Catimel G., Clavel M., Haemotopoetic growth factors and chemoprotectants; should we move toward a two step process for phase I trials in oncology? Ann. Oncol. 1993, 4: 471-474). The risk of infection is directly dependent on the degree of inhibition of bone growth and the severity and duration of the lack of neutrophils (Brody GP, Buckley M., Saethe YS., Freireich EJ., Quantitative relationship between circulating leueocytes and infections with acute leucemia, Ann. In. Med. 1965, 64: 328-334).

Strategies to reduce and even prevent the extent of myelotoxicity include the use of hematopoietic growth factors and / or other hematopoietic cytokines. Such treatments are becoming more common practice as they open up the potential for higher dosing of cytostatic or cytotoxic compounds, thereby improving the therapeutic efficiency of the neoplastic compounds and reducing the symptoms associated with the use of such cytostatic or cytotoxic therapy .

Clinical studies have proven that the administration of G, GM and / or M-CSF in patients with malignancies who are a have undergone cytotoxic chemotherapy or in patients after bone marrow transplantation, the duration of the lack of neutrophil cells is reduced, the regeneration of the bone marrow is accelerated and the risk of infectious complications is reduced. (Steward WP., Granulocyte and granulocyte-macrophage colony stimulating factors, Lancet 1993, 342: 153-157; Munn DH., Cheung NKV., Preclinical and clinical studies of macrophage colony stimulating factor, Semin. Oncol. 1992, 19: 395 -407).

It has now been possible to find new compounds which stimulate the myelopoetic cells and are therefore valuable in the treatment and prevention of viral, bacterial or fungal infections.

The invention therefore relates to compounds of the formula (I)

*: - _N I ^• «* ^•

o o

in the

R _Ϊ a group OR, where

R is hydrogen, a saturated or unsaturated C _1-18 alkyl radical, triallyl kylsilyl, Diphenylalkylsilyl, a benzyl radical or a cycloalkyl radical, the optionally substituted one or more times by halogen or alkoxy NEN be Kgs ^¬, or

R ₁ is an N-terminal peptide residue of 1-10 optionally correspondingly ge ^¬ protected natural or unnatural α- or ß-amino acids, R ₂ and R ₂ 'are independently tert-butyloxycarbonyl, benzyloxycarbonyl carbonyl, fluorenyloxycarbonyl, or a group (C = O) -R ₃ , where R ₃ C _1-4 alkyl, phenyl, or a 5-10 membered mono- or bicyclic saturated, fully or partially unsaturated heterocyclic ring system with up to 4 heteroatoms such as N, O, S, which may be substituted one, more than once or mixed can by alkyl, alkoxy, alkoxyalkyl, oxo, oxime, O-alkyloxime, hydroxy, amino, monoalkylamino, dialkylamino, acylamino or aminoacyl, 7, 8, 9, 10-membered moncyclic ring systems being excluded, or

R ₂ 'is hydrogen, and

R _{2 is} tert-butyloxycarbonyl, benzyloxycarbonyl, fluorenyloxycarbonyl, or a group

(C = 0) -R ₃ , where R _{3 is} C _1-4 alkyl, phenyl, or a 5-10 membered mono- or bicyclic saturated, fully or partially unsaturated heterocyclic ring system with up to 4 heteroatoms such as N, O, S, which may optionally be mono-, polysubstituted or mixed by alkyl, alkoxy, alkoxyalkyl, oxo, oxime, O-alkyloxime, hydroxy, amino, monoalkylamino, dialkylamino, acylamino or aminoacyl, where 7, 8, 9, 10-membered moncyclic Ring systems are excluded, or

R _{2 is} a C-terminal peptide residue from 1-10 optionally appropriately protected natural or unnatural α- or β-amino acids, which can optionally be acylated by a group (C = O) -R ₃ , Q is a group - (CH ₂ ) _m , where m is an integer from 0 to 20 or a group - (CH ₂ ) _n -X- (CH ₂ ) _p - where n and p independently of one another are a number from 0 to 14, and one or more hydrogen atoms by alkyl , or halogen or alkoxy or hydroxy may be substituted, and X is a group C (R ₄ ) ₂ , where R is methyl, ethyl, propyl, i-propyl, butyl, cycloalkyl, or a group C = O or a saturated, partially or completely unsaturated 3-10 membered mono- or bicyclic ring system with 0-6 heteroatoms N, S and / or O or a group

YO, S or CH ₂

Z O or S q is an integer from 1 to 4, r is an integer from 1 to 3.

In the formula I, R. denotes a group O- R, where R. ' Hydrogen, a straight-chain or branched C _1-18 alkyl radical, for example methyl, ethyl, propyl, i-propyl, butyl, pentyl, hexyl, heptyl, octyl, 1-methylethyl, 1-methylpropyl, 2-methylpropyl, 1, 1-dimethylethyl , 2,2-dimethylpropyl, 1,2-dimethylpropyl, u. Like., a benzyl radical or a cycloalkyl radical, for example a cyclopentyl or cyclohexyl radical or trialkylsilyl, or diphenylalkylsilyl. These radicals can optionally be mixed one or more times or mixed by halogen, for example F or Cl, including perhalogenated radicals, or by alkoxy, for example methoxy, ethoxy and the like. Like. Be substituted.

R 1 can also mean an N-terminal peptide residue of 1-10 natural or unnatural α- or β-amino acids, which can optionally be protected by appropriate protective groups. Examples of amino acids from which such a peptide residue can be constructed are, for example, β-alanine, aspartic acid, glutamic acid, lysine, pyroglutamic acid, serine, and the like. Like. R ₂ and R ₂ 'mean tert-butyloxycarbonyl, benzyloxycarbonyl, fluorenyloxycarbonyl, or a group (C = O) -R ₃ , where R _{3 is} a C 1-4 alkyl radical, phenyl, or a 5-10 membered mono- or bicyclic saturated, fully or partially unsaturated heterocyclic ring system with up to 4 heteroatoms such as N, O, S, which can optionally be substituted one, more than once or in a mixture by alkyl, alkoxy, alkoxyalkyl, oxo, oxime, O-alkyloxime, hydroxy, amino, monoalkylamino, dialkylamino, acylamino or aminoacyl, 7, 8, 9, 10-membered moncyclic ring systems being excluded.

Examples of such radicals are cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, tetrahydrofuryl, thiolanyl, pyrrolidinyl, dihydrofuryl, dihydrothienyl, dihydropyrrolyl, dihydrooxazolyl, dihydrothiazolyl, dihydropyropyryl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl morpholinyl, piperazinyl, dihydropyranyl, tetrahydropyridinyl, isoxazolyl, oxa- zolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, pyranyl, cyclohexyl xadienyl, phenyl, thiopyranyl, dihydropyridinyl, pyridinyl, pyridazinyl, pyrimidine dinyl, pyrazinyl, oxadiazolyl, tetrazolyl, Triazinyl, benzo [b] thienyl, benzofuryl, isobenzofuryl, indazolyl, quinolizinyl, quinolinyl, isoquinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, indolyl, isoindolyl, and indolizinyl, which may optionally be substituted as indicated above. R ₂ 'can also mean hydrogen, where R _{2 can} then also mean, in addition to the meanings given above, a C-terminal peptide residue of 1-10 natural or unnatural α- or β-amino acids, which may be represented by a group (C = 0) - R _{3 is} acylated, for example with the meaning R ₃ pyridine-2-yl and can be protected by appropriate protective groups. Examples of such amino acids from which such a peptide residue can be constructed are, for example, β-alanine, aspartic acid, glutamic acid, lysine, pyroglutamic acid, serine and the like. the like

Q represents a group - (CH ₂ ) _m , where m represents an integer from 0 to 20 or a group - (CH ₂ ) _n -X- (CH ₂ ) _p - where n and p independently of one another represent a number of 0 - 14 mean, and one or more hydrogen atoms can be substituted by alkyl, or halogen or alkoxy or hydroxy. X denotes a group C (R ₄ ) ₂ , where R ₄ denotes methyl, ethyl, propyl, i-propyl, butyl, cycloalkyl, or a group C = 0 or a saturated, partially or completely unsaturated 3-10 membered mono- or bicyclic ring system with 0-6 heteroatoms N, S and / or O or a group

in which

YO, S or CH ₂

Z O or S q is an integer from 1 to 4 and r is an integer from 1 to 3.

Particularly preferred compounds are

O

H H PyrGluAsp N PicSerAspN

Lvs ys

Lys Lys

PyrGluAsp N PicSerAspN H H

O

The invention further relates to a process for the preparation of the compounds of the formula I, which is characterized in that a) a dialdehyde of the formula II

in Q has the meaning given above with a correspondingly N-protected α-phosphonoglycine ester of the formula III

in which R _{1 (} R ₂ and R ₂ ', which have the meanings given above and R _{5 is} methyl or ethyl), b) optionally cleaves the ester groups, c) optionally converts the resulting compound with bases into a pharmaceutically acceptable salt.

Procedure A:

The correspondingly protected 2- (dimethoxyphosphinyl) acetate (phosphonoglycine), manufactured according to Schmidt, U .; Lieberknecht, A .; Wild, J. Synthesis, 1984, 53-60) was dissolved in an anhydrous organic solvent, for example THF, methylene dichloride and a base, for example tetramethylguanidine, DBN, DBU, was added. The mixture was stirred for 10 min at room temperature and then cooled to -10 ° C. A corresponding dialdehyde, for example butane dial, etc., was slowly added. The mixture was stirred at room temperature until no more starting material was detectable. The mixture was then poured onto ethyl acetate or methylene chloride and washed with a suitable extractant, for example dilute HCl solution. The organic phase was separated off and the aqueous phase was washed with a suitable extractant, for example ethyl acetate or methylene chloride. The combined organic phases were dried with a suitable drying agent, for example Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. After crystallization from a suitable solvent, for example from toluene / ethyl acetate, the desired di-unsaturated end product was obtained.

Procedure B:

The correspondingly protected 2- (dimethoxyphosphinyl) acetate, manufactured according to Schmidt, U .; Lieberknecht, A .; Wild, J. Synthesis, 1984, 53-60) was dissolved in a water-immiscible solvent, for example dichloromethane, and a base, for example DBN, DBU, NaOH, was added. The Mixture was stirred at 10 ° C for 10 min. The corresponding dialdehyde was slowly added so that the temperature did not rise above 10 ° C. The mixture was stirred at 5-10 ° C for 1 hour and then at room temperature until no more starting material could be detected. The mixture was then extracted with an acidic solution, for example 1N HCl solution, and then washed with a suitable extracting agent, for example saturated NaCl solution. The organic phase was dried with a suitable drying agent, for example Na ₂ SO ₄ , and filtered. The filtrate was concentrated in vacuo and then recrystallized in a suitable solvent.

Hydrolysis of the esters:

The compounds prepared by process A or B were dissolved in a water-miscible solvent, for example methanol, dioxane, tetrahydrofuran. Aqueous LiOH solution (2.5 equivalents) was then added and this mixture was stirred until no more starting product was detectable. The reaction solution was mixed with an acidic solution, for example 1N HCl solution or 5% KHSO ₄ solution, the precipitate formed was filtered off and recrystallized from a suitable solvent, for example methanol, CH ₃ CN.

The compounds of the formula I obtained in this way can be converted into their pharmaceutically acceptable salts in a conventional manner using inorganic or organic bases. Salt formation can be carried out, for example, by using a compound of the formula i in a suitable solvent, such as, for example, water, acetone, acetonitrile, benzene, dimethylformamide, dimethyl sulfoxide, chloroform, dioxane, methanol, ethanol, hexanol, ethyl acetate or in an aliphatic Dissolves ether, for example diethyl ether, or mixtures of such solvents, adds an at least equivalent amount of the desired base, ensures thorough mixing and, after the salt formation has ended, the precipitated salt is filtered off, lyophilized or the solvent solvent distilled off in vacuo. If necessary, the salts can be recrystallized after isolation.

Pharmaceutically acceptable salts are e.g. Metal salts, especially alkali metal or alkaline earth metal salts, such as sodium, potassium, magnesium or calcium salts. Other pharmaceutical salts are, for example, easily crystallizing ammonium salts. These are derived from ammonia or organic amines such as mono-, di- or tri-lower (alkyl, cycloalkyl or hydroxyalkyl) amines, lower alkylenediamines or hydroxy or aryl-lower alkylammonium bases, e.g. Methylamine, diethylamine, triethylamine, ethylenediamine, tris (hydroxymethyl) aminomethane, benzyltrimethylammonium hydroxide and the like.

The compounds of formula I and their pharmaceutically acceptable salts are orally active and can influence the formation of hematopoietic factors.

Because of this pharmacological property, the new compounds, alone or in conjunction with other active substances, can be used in the form of customary galenical preparations as remedies for the treatment of diseases which are influenced by the hematopoietic system and viral, bacterial and fungal infections which occur as a result of such diseases, be used.

The invention therefore also relates to pharmaceutical preparations which contain the compounds of the formula I according to one of claims 1-2 or their salts, alone or mixed with other therapeutically valuable active substances, and also conventional pharmaceutical auxiliaries and / or carriers or diluents.

The compounds according to the invention can be in the form of tablets or capsules, which are a unit dose of the compound together with auxiliary agents. Contain substances and diluents such as corn starch, calcium carbonate, dicalcium phosphate, alginic acid, lactose, magnesium stearate, Primogel or talc, orally administered. The tablets are produced in a conventional manner by granulating the ingredients and pressing, the capsules by filling into hard gelatin capsules of a suitable size.

Another application form of the compounds according to the invention are suppositories which contain adjuvants, such as beeswax derivatives, polyethylene glycol or polyethylene glycol derivatives, linoleic or linolenic acid esters, together with a unit dose of the compound and can be administered rectally.

The compounds according to the invention can also be administered parenterally, for example by intramuscular, intravenous or subcutaneous injection. For parenteral administration, they are best used in the form of a sterile aqueous solution, which can contain other solutes, such as tonic agents, pH adjusters, preservatives and stabilizers. Distilled water can be added to the compounds and the pH can be adjusted to 3 to 6 using, for example, citric acid, lactic acid or hydrochloric acid. Sufficiently dissolved substances, such as dextrose or saline, can be added to make the solution isotonic. In addition, preservatives, such as p-hydroxybenzoates, and stabilizers, such as EDTA, can be added in order to ensure sufficient durability and stability of the solution. The solution thus obtained can then be sterilized and filled into sterile glass ampoules of a suitable size so that they contain the desired solution volume. The compounds according to the invention can also be administered by infusion of a parenteral formulation as described above. For oral administration in humans, it is assumed that the daily dose value of a compound according to the invention is in the range from 0.001 to 100 mg per day for a typical adult patient of 70 kg. Therefore, tablets or capsules can usually contain 0.0003 to 30 mg of active compound, for example 0.01 to 5 mg, for oral administration up to included three times a day. When administered parenterally, the dose may range from 0.001 to 100 mg per 70 kg per day, for example about 0.5 mg.

Because of the pharmacological properties of the compounds according to the invention, the invention also relates to a method for stimulating cell division, preferably myelopoiesis, characterized in that a therapeutically effective amount of a pharmaceutical composition as described above is administered to a patient.

The pharmacological activity of the compounds was demonstrated by the following test:

Induction of haemopoietic synergistic activity in stromal cells Rat bone marrow obtained from the stromal cell line C6.4 is cultivated in 12 perforated plates in RPMI 1640 with 10% FBS (fetal bovine serum). After confluence, the cells were washed and fresh RPMI 1640 was used as the medium. Merged layers of the cells were treated with the appropriate compound. Cell-free supernatants were collected after 18 hours and fractionated with a Cetricon-30 molecular weight membrane. The activity of the hemopoietic synergistic factor (HSF) was determined using a CFU-C assay.

CFU-C assay

Bone marrow cells were obtained from C57B1 / 6 female mice and in

RPMI 1640 suspended with 10% FBS.

Bone marrow cells (7.5E + 4 cells / mL) were cultured with dilutions of the fractions of the supernatant solution obtained according to the test described above in a standard soft agar CFU assay and the number of cell colonies (>

50 cells) counted. The number of cell colonies is proportional to the number available

Amount of HSF. Another object of the invention is the use of the compounds obtained by one of process A or B for the production of optically active diaminodicarboxylic acid derivatives, which are a valuable starting product for the production of peptides, by enantioselective hydrogenation.

For this purpose, the corresponding process product from process A or B was dissolved in a suitable solvent, for example: oxygen-free methanol, dioxane, obtained by boiling under a nitrogen atmosphere under reduced pressure. The catalyst was added to this clear solution and the solution obtained was hydrogenated under elevated pressure at room temperature in a Parr apparatus. The solution was filtered through silica gel to remove the dissolved catalyst. The eluate was concentrated under vacuum and the crude product obtained was dissolved in a suitable solvent, for example dioxane / water, and treated with LiOH at room temperature. The mixture was then concentrated again in vacuo and water was added, whereupon the solution was acidified with a suitable acid, for example with aqueous KHS0 ₄ solution. The precipitate thus obtained was filtered, washed with cold water and dried. The mixture was then recrystallized from a suitable solvent, for example acetonitrile, and the corresponding optically active diaminodicarboxylic acid was obtained.

Examples:

Example 1: (2Z.6Z) - 2,7-bis-yridin-2-carbonylamino octa-2,6-dienedioic acid

(± V2-picolylamino-2- (dimethylphosphinyl) acetic acid methyl ester methyl 2-amino-2- (dimethoxyphosphinyl) acetate (1.66g, 8.421 mmol) was dissolved in DMF (10 mL), picolinic acid (1.30g, 10.526) , HOBt (1.61g, 10.526 mmol) and WSC (2.02g, 10.526mmol) were added at -10 ° C. The red reaction solution was stirred for 1 hour at -10 ° C. and overnight at room temperature saturated NaHCO ₃ solution was emptied, stirred for 15 min and then extracted with ethyl acetate (2 × 150 mL), the combined organic phases were washed with brine, the organic phase was stirred with activated carbon and with Na ₂ SO _{4 for} 15 min, the solution was filtered and evaporated 2.07 g of an orange oil was obtained, which was filtered through silica gel with ethyl acetate as the eluent, the concentrated residue (1.6 g) was crystallized from 5 ml of diisopropyl ether and 1.40 g (57%) of colorless kirstalle M.p .: 81 -84 ° C. ¹ H NMR (400 MHz, CDCI ₃ ) δ 3.79-3.86 (m , 9, 3-OCH ₃ ), 5.38 (dd, 1, J = 9.5Hz, J = 22.2Hz, CH), 7.42 (m, 1, picolyl-H), 7.82 (m, 1, picolyl-H), 8.14 (m, 1, picolyl-H), 8.58 (m, 1, picolyl-H), 8.71 (d, 1, J = 8.6Hz, NH). ¹³ C NMR (100 MHz, CDCI ₃ ) δ 49.62, 51.08, 53.31, 54.07, 54.14, 54.20, 122.46, 126.67, 137.29, 148.47, 148.73, 163.88, 163.94, 166.93, 166.95.

(2Z.6ZV2.7-bis- (pyridine-2-carbonylamino) -octa-2.6-dienedioic acid dimethyl ester (±) -2-picolylamino-2- (dimethylphosphinyl) acetic acid methyl ester (2.0g, 6.9mmol) was dissolved in dry THF (80mL), tetramethylguanidine (0.855 mL, 6.8mmol) was added at room temperature and the solution was stirred for 15 min. stirs. The reaction mixture was then cooled to -20 ° C. Butanedial (2.93 mL of a 10% anhydrous solution of butanedial in dry THF (3.4 mmol) was added dropwise. The reaction mixture was kept under stirring for 2 days at room temperature. The resulting precipitate was dried and 0.87 g (28.7%) of the title substance, Mp. 186-187 ° C.

For further purification, the mixture was extracted with ethyl acetate (300 ml) and the organic phase was washed with 100 ml of 5% KHSO ₄ solution and dried with Na ₂ SO ₄ . The concentrated residue was degassed and the crude product was recrystallized from methanol. Yield: 0.2g (6.6% Mp 187-188 ° C. Total yield: 1.07g (35.3%).

¹ H-NMR (400MHz, CDCI ₃ ) δ 2.49 (m, 4, 2 CH ₂ ), 3.77 (s, 6, OCH ₃ ), 6.73 (m, 2, 2 CH), 7.44 (ddd, 2, J = 0.9Hz, J = 4.6Hz, J = 10.0Hz; 2 aromat.-H), 7.85 (dt, 2, J = 1.8Hz, J = 10 Hz, 2 aromat.-H), 8.19 (dd, 2, 2 aromat.-H), 8.58 (dd, 2, 2 aromat.-H), 9.52 (m, 2, 2 NH).

¹³ C-NMR (100MHz, CDCI ₃ ) δ 28.01, 52.42, 122.60, 125.69, 126.52, 136.42, 137.42, 148.27, 149.35, 162.36, 164.83.

(2Z.6Z) -2.7-bis- (yridine-2-carbonylamino-Vocta-2.6-dienedioic acid (2Z, 6Z) -2,7-bis- (pyridine-2-carbonylamino) -octa-2,6-dienedioic acid dimethyl ester ( 276mg, 0.627mmol) was dissolved in a mixture of 10mL dioxane, 10mL MeOH, and 5 mL water, then a LiOH solution (1mL 2N solution, 1.5 equivalents) was added to give a clear yellow solution Stirred at room temperature overnight and then concentrated to 5 ml, 50 ml of water were added. After acidification with 10% -KHSO ₄ solution, a precipitate formed which was filtered and recrystallized from MeOH. Yield: 230 mg (89.1%). Mp 246- 247 ° C.

¹ H NMR (400 MHz, CDCI ₃ ) δ 2.32 (m, 4, 2 CH ₂ ), 6.58 (m, 2, CH), 7.63 (m, 2, 2 picolyl-H), 8.01 (m, 4, 4 picolyl -H), 8.67 (m, 2, 2 picolyl-H), 9.78 (s, 1, NH). ¹³ C NMR (100 MHz, CDCI ₃ ) δ 27.01, 122.30, 127.03, 127.40, 136.03, 138.08, 148.63, 149.38, 162.47, 165.50.

Example 2: f2Z, 4ZV2.5-bis-yridin-2-carbonylaminoV-octa-2.4-dienedioic acid

(2Z.4Z) -2.5-bis (pyridine-2-carbonylamino-Vocta-2.4-dienedioedioate)

(±) -2-picolylamino-2- (dimethylphosphinyl) acetic acid methyl ester (1.04g,

3.60mmol) was dissolved in CH ₂ CI ₂ (50mL), DBN (0.43mL, 3.60mmol) was added and the mixture was stirred for 15 min. Glyoxal (0.2 mL 40% aqueous solution, 1.80mmol) was then added dropwise. The mixture was over

Stirred at room temperature overnight and then washed the dark brown solution with 5% KHS0. The organic phase was separated off with

Na ₂ S0 ₄ dried, filtered and concentrated. 0.63 g of tube residue were obtained, which was recrystallized from methanol.

Mp .: 190 ° C, decomposition

¹ H-NMR (400 MHz, d ₆ -DMSO) δ 3.69 (s, 6, 2 OCH ₃ ), 7.13 (m, 2, 2 CH), 7.70 (m,

2, aromat.-H), 8.07 (m, 4, aromat.-H), 8.75 (m, 2, aromat.-H), signal not detectable for NH).

¹³ C-NMR (100 MHz, d ₆ -DMSO) δ 52.57, 122.73, 125.30, 127.43, 130.22,

138.23, 148.86, 149.00, 163.65, 164.63.

(2Z.4ZV2.5-bis (pyridine-2-carbonylaminoVocta-2.4-dienedioic acid

(2Z, 4Z) -2,5-bis- (pyridine-2-carbonylamino) -octa-2,4-dienedioate was treated analogously to the procedure given in Example 1.

Yield: 67%, Mp .: 210 ° C (decomposition) ¹ H NMR (400 MHz, d ₆ -DMSO) d 7.19 (m, 2, CH), 7.68 (m, 2, 2 picolyl-H), 8.00-8.14 (m, 4, 4 picolyl-H), 8.74 (d, 2, J = 4.4Hz, 2 picolyl-H), signals for NH and COOH not visible.

¹³ C NMR (100 MHz, d ₆ -DMSO) d 122.58, 124.91, 127.35, 129.94, 138.28, 148.82, 149.11, 162.93, 165.96.

Example 3: (2Z.6Z) -2,7-bis- (benzyloxycarbonylaminoVocta-2,6-dienedioic acid o o% o

. OH

HO γ O _H °

(2Z, 6Z) -2.7-bis- (benzyloxycarbonylaminoVocta-2 _τ 6-dienedioic acid dimethyl ester obtained from butanedial and Z-phosphonoglycine methyl ester. 60.6% of the title substance Mp was obtained at 130-132 ° C. According to process B, 76.3%) of the Title substance Mp. 130-132 ° C obtained. ¹ H-NMR (400 MHz, CDCI ₃ ) δ 2.35 (m, 4, 2 CH ₂ ), 3.75 (s, 6, OCH ₃ ), 5.12 (s, 4, 2 benzyl-CH ₂ ), 6.46 (m, 2 , 2 CH), 6.51 (m, 2, 2NH), 7.25-7.35 (m, 10.aromatic-H). ¹³ C-NMR (100 MHz, CDCI ₃ ) δ 27.25, 52.44, 67.49, 126.50, 128.19, 128.27, 128.54, 134.57, 135.95, 154.10, 164.93.

(2E, 6Z) -2,7-bis (benzyloxycarbonylamino) octa-2.6-dienedioic acid dimethyl ester The compound with an E configured double bond was determined by chromatography (silica gel, eluent: ethyl acetate / petroleum ether = 1/3) from the mother liquor of the above isolated connection.

¹ H-NMR (400MHz, CDCI ₃ ) δ 2.38 (q, 2, J = 7.4Hz, CH ₂ ), 2.70 (q, 2, J = 7.4Hz, CH ₂ ), 3.73 (s, 3, OCH ₃ ) , 3.77 (s, 3, OCH ₃ ), 5.11 (s, 2, benzyl-CH ₂ ), 5.13 (s, 2, benzyl-CH ₂ ), 6.40 (br s, 1, NH), 6.62 (t, 1 , CH), 6.71 (m, 1, CH), 6.81 (br s, 1, NH), 7.26-7.35 (m, 10, aromat.-H).

¹³ C-NMR (100 MHz, CDCI ₃ ) δ 26.84, 28.36, 52.30, 67.00, 67.29, 125.35, 126.28, 128.08, 128.16, 128.23, 128.28, 128.48, 128.55, 129.35, 135.99, 136.09, 136.55, 153.76, 154.20, 164.11 , 164.96. (2Z, 6Z) -2.7-bis (benzyloxycarbonylamino) octa-2.6-dienedioic acid

Was analogous to Example 2 from (2Z, 6Z) -2,7-bis- (benzyloxycarbonyiamino) -octa-

2,6-Diendisäuredimimylester prepared; Mp. 259-264 ° C.

¹ H NMR (400 MHz, d ₆ -DMSO) δ 2.23 (m, 4, 2 CH ₂ ), 3.10-3.40 (br s, 2, 2 COOH),

5.05 (s, 4, 2 benzyl-CH ₂ ), 6.35 (m, 2, 2 CH), 7.28 (m, 10, aromat.-H), 8.53 (br s, 2,

2 NH).

¹³ C NMR (100 MHz, d ₆ -DMSO) Ö26.04, 65.92, 127.80, 127.96, 128.48, 134.70,

136.91, 154.46, 165.77.

Example 4: (2Z. 6Z) -2.7-diacetylamino-octa-2.6-diene-dimethyl disate

Was prepared by method A and method B from Ac-phosphonoglycine methyl ester and butanedial.

Yield. Method A: 80%. Method B: 78%, mp 243-247 ° C.

¹ H-NMR (400MHz, CDCI ₃ ) δ 1.93 (m, 6, 3 COCH ₃ ), 2.20 (m, 4, 2 CH ₂ ), 3.63 (s, 6,

OCH ₃ ), 6.29 (m, 2, 2 CH), 9.20 (m, 2, 2 NH).

¹³ C-NMR (100 MHz, CDCI ₃ ) δ 22.45, 26.06, 51.96, 128.03, 134.36, 164.87,

168.63.

Example 5: (2Z. 6ZV2.7-bis (tert-butyloxycarbonylamino-octa-2.6-dienedioate)

Obtained by process A from butandial and Boc

Phosphonoglycine methyl ester yield: 59%. Mp .: 189-193 ° C.

¹ H-NMR (400MHz, CDCI ₃ ) δ 1.45 (m, 18, 2 O (CH ₃ ) ₃ ), 2.34 (m, 4, 2 CH ₂ ), 3.76 (s,

6, OCH ₃ ), 6.21 (m, 2, 2 CH), 6.45 (m, 2, 2 NH).

¹³ C-NMR (100 MHz, CDCI ₃ ) δ 27.28, 28.22, 52.31, 80.62, 126.52, 133.88,

153.29, 165.26.

Example 6: (2Z, 10Z) -2, 11-diacetylamino-dodec-2, 10-diene-diacid dimethyl ester

Obtained by Method A from octandial and Ac-phosphonoglycin methyl ester Yield: 64%, m.p .: 14-143 ° C. H-NMR (400 MHz, CDCI ₃ ) δ 1.27-1.34 (m, 4, 2 CH ₂ ), 1.40-1.48 (m, 4, 2 CH ₂ ), 1.52-1.62 (m, 4, 2 CH ₂ ), 2.10 (s, 6, 2 COCH ₃ ), 2.09-2.18 (m, 4, 2 CH ₂ ), 3.75 (s, 6, 2 OMe), 6.66 (m, 2, 2 CH), 6.83 (s, 2, 2 NH). ¹³ C-NMR (100 MHz, CDCI ₃ ) δ 23.39, 27.93, 28.76, 28.91, 52.33, 124.89, 139.08, 165.17, 168.46.

Example 7: (2Z.10ZV-2.11-bis (tert-butyloxycarbonylaminoVdodec-2.10-dienedioedimate)

Obtained by Method B from octandial and Boc-phosphonoglycine methyl ester

Yield: 65%, mp .: 107-109 ° C. ¹ H NMR (400 MHz, CDCI ₃ ) δ 1.26-1.33 (m, 4, 2

CH ₂ ), 1.37-1.57 (m, 22, 2 OC (CH ₃ ) ₃ , 2 CH ₂ ), 2.16 (q, 4, J = 7.2Hz, 2 CH ₂ ),

3.73 (s, 6, 2 OMe), 5.91 (s, 2, 2 NH), 6.51 (t, 2, J = 7.2Hz, 2 CH).

¹³ C-NMR (100 MHz, CDCI ₃ ) δ 28.10, 28.17, 28.25, 29.08, 52.17, 80.38, 125.67,

137.07, 153.29, 165.38.

Example 8: (2Z.10ZV-2.11-bis-fbenzyloxycarbonyπamino-dodec-2.10-dienedioate dimethyl ester

Obtained by Method B from octandial and Z-phosphonoglycine methyl ester.

Yield: 30%, Mp: 96-97 ° C.

¹ H-NMR (400 MHz, CDCI ₃ ) δ 1.22-1.33 (m, 4, 2 CH ₂ ), 1.36-1.47 (m, 4, 2 CH ₂ ),

2.17 (q, 4, J = 7.3Hz, 2 CH ₂ ), 3.72 (s, 6, 2 OMe), 5.12 (s, 4, 2 benzyl-CH ₂ ),

6.25 (s, 2, 2 NH), 6.60 (t, 2, J = 7.3Hz, 2 CH), 7.25-7.40 (m, 10, aromat.-H).

¹³ C-NMR (100 MHz, CDCI ₃ ) δ 27.95, 28.18, 28.93, 52.19, 67.21, 125.26,

128.02, 128.12, 128.28, 128.42, 136.01, 138.24, 154.08, 165.01.

Example 9: (2Z, 4Z) -2. 5-Diacetylamino-hex-2,4-dienedioate

Obtained by method B from aqueous glyoxal solution and Ac

Phosphonoglycine methyl ester

Yield: 73%, mp: 274-277 ° C.

¹ H NMR (400 MHz, d ₆ -DMSO) δ 1.98 (s, 6, OCCH3), 3.68 (s, 6, 2 OMe), 6.72 (s,

2, 2 CH), 6.87 (s, 2, 2 NH). ¹³ C NMR (100 MHz, d ₆ -DMSO) δ 21.76.51.60, 120.21, 130.38, 164.24, 168.42.

Example 10: (2Z.4Z) -2. 5-bis- (benzyloxycarbonyl) amino-hex-2,4-diene-diacid dimethyl ester

Obtained by method B from aqueous glyoxai solution and Z

Phosphonoglycine methyl ester

Yield: 12%, mp .: 170-175 ° C. H-NMR (400 MHz, CDCI ₃ ) δ 3.76 (s, 6, 2

OMe), 5.16 (s, 4, 2 benzyl-CH ₂ ), 6.66 (s, 2, 2 CH), 7.08 (s, 2, 2 NH), 7.26-7.40 (m,

10, aromatic H).

¹³ C-NMR (100 MHz, CDCI ₃ ) δ 52.86, 67.87, 123.13, 127.78, 128.37, 128.39,

128.56, 135.67, 153.63, 164.66.

Example 11: (2Z. 4Z) -2, 5-bis- (tert-butyloxycarbonylamino) -hex-2,4-dienedioic acid dimethyl ester

Obtained by method B from aqueous glyoxal solution and Boc

Phosphonoglycine methyl ester

Yield: 15%, Mp .: 195-196X.

¹ H-NMR (400 MHz, CDCI ₃ ) δ 1.40 (s, 18, 2 OC (CH ₃ ) ₃ ), 3.74 (s, 6, 2 Ome), 6.38 (s,

2, 2 NH), 6.98 (s, 1, CH).

¹³ C-NMR (100 MHz, CDCI ₃ ) δ 28.06, 52.67, 81.43, 122.53, 127.83, 152.66,

165.03.

Example 12: 1,3-bis- [2-benzyloxycarbonylaminoV-2- (methoxycarbonylethenyl] benzene

Obtained by process B from isophthalaldehyde and Z-

Phosphonoglycine methyl ester

Yield: 55%, Mp: 153-155 ° C.

¹ H NMR (400 MHz, CDCI ₃ ) δ 3.79 (s, 6, 2 OMe), 5.05 (s, 4, 2 benzyl-CH ₂ ), 6.30 (s,

2, 2 CH), 7.26-7.30 (m, 10, aromat.-H, 2 NH), 7.40 (m. 2, 2 aromat.-H), 7.63 (s, 1, aromat.-H). ¹³ C-NMR (100 MHz, CDCI ₃ ) δ 52.66, 67.55, 124.86, 128.25, 128.50, 128.84,

130.41, 130.66, 130.80, 134.13, 135.89, 153.74, 165.50.

Example 13:

1,3-bis- [2-acetylamino-2- (methoxycarbonyπethenyl] benzene Obtained by method B from isophthalaldehyde and acetylphosphonoglycine Yield: 60%, mp: 234-238 ° C.

¹ H-NMR (400 MHz, d ₆ -DMSO) δ 1.97 (s, 6, COCH ₃ ), 3.70 (s, 6, 2 OMe), 7.13 (s, 2, 2 CH), 7.45 (t, 1, J = 7.8Hz, aromat.-H), 7.60 (d, 2, 2 aromat.-H), 7.80 (s, 1, aromat.-H), 9.61 (s, 2, 2 NH).

¹³ C-NMR (100 MHz, d ₆ -DMSO) δ 22.51, 52.29, 127.40, 129.02, 130.19, 130.35, 131.23, 133.89, 165.63, 169.60.

Example 14: 1,4-bis- [2- (benzyloxycarbonylamino) -2-methoxycarbonyl) ethenyl] benzene

Obtained by process B from para-phthalaldehyde and Z-

Phosphonoglycine methyl ester. Yield: 40%, Mp: 198-202 ° C.

¹ H NMR (400 MHz, d ₆ -DMSO) δ 3.70 (s, 6, 2 OMe), 5.09 (s, 4, 2 benzyl-CH ₂ ),

7.25 (s, 2, 2 CH), 7.26-7.38 (m, 10, aromat.-H), 7.66 (s, 4, aromat.-H), 9.20 (s, 2,

2 NH).

¹³ C-NMR (100 MHz, d ₆ -DMSO) δ 52.42, 66.12, 126.70, 127.72, 128.02,

128.48, 130.15, 131.35, 134.30, 136.81, 154.67, 165.66.

Example 15: 1,4-bis- [2- (acetylamino) -2- (methoxycarbonyl) ethenyl] benzene Obtained according to process B from para-phthalaldehyde and Ac-phosphonoglycine methyl ester. Yield: 80%, Mp: 275 ° C (decomposition). ¹ H NMR (400 MHz, d ₆ -DMSO) δ 1.99 (s, 6, 2 COCH ₃ ), 3.70 (s, 6, 2 OMe), 7.16 (s, 2, 2 CH), 7.62 (s, 4 , aromat.-H), 9.51 (s, 2, 2 NH).

¹³ C-NMR (100 MHz, d ₆ -DMSO) δ 22.62, 52.48, 127.52, 130.38, 130.86, 134.76, 165.95, 170.08. Example 16: (2Z. 11ZV2.12-bis (benzyloxycarbonylaminoVtridec-2.11-dienedioic acid dimethyl ester)

Obtained by Method B from nonandial and Z-phosphonoglycine methyl ester

Yield: 43%, oil

¹ H-NMR (400 MHz, CDCI ₃ ) δ 1.20-1.35 (m, 6, 3 CH ₂ ), 1.37-1.46 (m, 4, 2 CH ₂ ),

2.08 (s, 6, OCH ₃ ), 2.18 (q, 4, J = 7.4 Hz, 2 CH ₂ ), 3.73 (s, 6, OCH ₃ ), 5.13 (s, 4, 2-benzyl-CH ₂ ), 6.13 (m, 2, 2NH), 6.62 (t, 2, J = 7.4Hz, 2 CH).

¹³ C-NMR (CDCI ₃ ) δ 28.07, 28.28, 28.97, 29.12, 52.25, 67.28, 125.24, 128.57,

128.17, 128.7, 136.08, 138.44, 154.14, 165.07.

Example 17: (2Z. 11ZV2.12-diacetylamino-tridec-2.11-dienedioic acid dimethyl ester

Obtained by Method B from nonandial and Ac-phosphonoglycin methyl ester

Yield: 65%, oil H-NMR (400 MHz, CDCI ₃ ) δ 1.25-1.35 (m, 6, 3 CH ₂ ), 1.38-1.48 (m, 4, 2 CH ₂ ),

2.09 (s, 6, OCH ₃ ), 2.12 (q, 4, J = 7.4Hz, 2 CH ₂ ), 3.74 (s, 6, OCH ₃ ), 6.66 (t, 2, J =

7.4Hz, 2 CH), 6.95 (s, 2, 2NH).

¹³ C-NMR (CDCI ₃ ) δ 23.26, 29.09, 27.99, 28.86, 28.72, 27.99, 52.30, 124.98,

139.34, 165.20, 168.71.

Example 18:

(L. 14Z 2.15-diacetylamino-hexadec-2.14-dienedioic acid dimethyl ester

Obtained by Method B from Dodecandial and Ac-

Phosphinoglycine methyl ester. Yield: 51%, mp .: 123-125 ° C.

¹ H-NMR (400 MHz, CDCI ₃ ) δ 1.20-1.32 (m, 12, 6 CH ₂ ), 1.37-1.46 (m, 4, 2 CH ₂ ),

2.08 (s, 6, OCH ₃ ), 2.05-2.15 (m, 4, 2 CH ₂ ), 3.74 (s, 6, OCH ₃ ), 6.67 (m, 2, 2 CH),

6.88 (m, 2, 2NH).

¹³ C-NMR (CDCI ₃ ) δ 23.36, 28.13, 28.90, 29.25, 29.32, 29.35, 52.29, 124.74,

139.30, 165.18, 168.36. Example 19: ⁽ 2Z. 14ZV2.15-diacetylamino-hexadec-2.14-dienedioic acid dimethyl ester

Obtained by Method B from Dodecandial and Ac-

Phosphinoglycine methyl ester. Yield: 31%, mp: 60-63 ° C.

¹ H-NMR (400 MHz, CDCI ₃ ) δ 1.20-1.33 (m, 12, 6 CH ₂ ), 1.37-1.46 (m, 4, 2 CH ₂ ),

2.18 (q, 4, J = 7.4Hz, 2 CH ₂ ), 3.73 (s, 6, OCH ₃ ), 5.13 (s, 4, 2 benzyl-CH ₂ ),

6.13 (m, 2, 2 NH), 6.62 (t, 2, J = 7.4Hz, 2 CH), 7.27-7.38 (m, 10, aromat.-H).

¹³ C-NMR (400 MHz, CDCI ₃ ) δ 28.19, 28.39, 29.31, 29.34, 29.43, 52.29, 67.34,

125.18, 128.12, 128.22, 128.52, 136.07, 138.60, 154.14, 165.11.

Example 20:

Enantioselective hydrogenation

(2Z, 6Z) -2,7-bis (benzyloxycarbonylamino) octa-2,6-dienedioate (3.5g, 7.05 mmol) was in oxygen-free methanol (200 mL, obtained by boiling under reduced pressure under a nitrogen atmosphere) with gentle heating dissolved under a nitrogen atmosphere. The catalyst Rh [(COD-S, S-Et-DuPHOS) CF ₃ S0 ₄ ^" (approx. 100 mg, approx. 2.5 mol%) was added to this clear solution and the solution obtained was at 4 bar at room temperature in a Parr The solution was filtered over silica gel (50 g, eluent: methanol) to remove the dissolved catalyst, the eluate was concentrated under vacuum and the crude product obtained was dissolved in dioxane / water and treated with 2.5 equivalents of LiOH at room temperature the mixture was again concentrated in vacuo and water was added, whereupon the solution was acidified with aqueous KHSO ₄ solution. The resulting precipitate was filtered, washed with cold water and dried. The product was then recrystallized from acetonitrile and the corresponding di-Z-protected 2. 7-Diaminosuberic acid obtained Yield: 60% The optical purity was determined by chiral capillary electrophoresis: 98% de.

Example 21: The procedure was analogous to Example 20, but Rh [(COD-S, S-Me-DuPHOS) CF ₃ S0 ₄ ] was used as the catalyst. Optical purity: 97.1% de

Example 22:

The procedure was analogous to Example 20, but Rh [(COD-

R, R-DIPAMP) CF ₃ S0 ₄ -] _ used.

Optical purity:> 95% de

Example 23:

(2D.7DV2.7-bisfbenzyloxycarbonylamino-1 _τ 8-diacid

The compound was prepared analogously to the process given in Example 20, Rh [(COD-R, R-Et-DuPHOS) CF ₃ SO ₄ ^" ] was used as the catalyst. Optical purity: 99% de.

Example 24:

(2Z.7ZV2.8-bis- (benzyloxycarbonylamino) -nona-2.7-dienedioate dimethyl ester Obtained analogously to Example 3 from glutaraldehyde and Z-phosphonoglycine methyl ester. ¹ H-NMR (400 MHz, CDCI ₃ ) 1.62 (m, 2, CH ₂ ), 2.22 (q, 4, J = 7.4 Hz, 2 CH ₂ ), 3.72 (s, 6, OCH ₃ ), 5.11 (s, 4, 2 benzyl CH ₂ ), 6.26 (br s,. 2, 2 NH), 6.58 (t, 2, J = 7.4 Hz, 2 CH), 7.25-7.36 (m, 10, aromat H).

¹³ C-NMR (100 MHz, CDCI ₃ ) 26.80, 28.06, 52.36, 67.41, 128.16, 128.26, 128.55, 136.03, 137.10, 154.14, 164.96.

Example 25:

(2L, 8L) -2.8-bis (benzyloxycarbonylamino) nonadisate dimethyl ester

The compound was prepared analogously to the hydrogenation given in Example 20, Rh [(COD-S, S-Et-DuPHOS) CF ₃ S0 ₄ ] was used as the catalyst.

Optical purity (HPLC) 97.4% de, 100% ee.

¹ H-NMR (400 MHz, CDCI ₃ ) 1.29 (br s, 6, 3 CH ₂ ), 1.61 (br s, 2, CH ₂ ), 1.67 (br s, 2,

CH2), 3.71 (s, 6, OCH ₃ ), 4.33 (m, 2, CH), 5.09 (s, 4, 2 benzyl CH ₂ ), 5.24 (m, 2,

2 NH), 7.26-7.35 (m, 10, aromatic H).

¹³ C-NMR (100 MHz, CDCI ₃ ) 24.92, 28.63, 32.58, 52.31, 53.78, 67.01, 128.1, 128.18,

128.53, 136.29, 155.86, 172.93.

Example 26:

(2L.8L) -2.8-bis (benzyloxycarbonylaminoV-hexadisate dimethyl ester

Optical purity (HPLC) 97.0% de, 100% ee.

¹ H NMR (400 MHz, CDCI ₃ ) 1.60-1.72 (m, 2, CH ₂ ), 1.93 (m, 2, CH2), 3.71 (s, 6,

OCH ₃ ), 4.37 (m, 2, CH), 5.09 (s, 4, 2 benzyl CH ₂ ), 5.28 (m, 2, 2 NH), 7.27-7.38 (m,

10, aromatic. H).

¹³ C-NMR (100 MHz, CDCI ₃ ) 28.75, 52.51, 53.43, 67.13, 128.10, 128.22, 128.54,

136.15, 155.87, 172.32.

Example 27:

The compound according to Example 1 was subjected to the test described above for determining the HSF and had an activity of 2.97E + 5 HSF units / mL.

Claims

Claims:

1.) Compounds of the formula (I)

in the

R-i is a group O-R., ', Wherein

R is hydrogen, a saturated or unsaturated C _1-18 alkyl radical, trialkylsilyl, diphenylalkylsilyl, a benzyl radical or a cycloalkyl radical, which can optionally be substituted one or more times by halogen or alkoxy, or

R, an N-terminal peptide residue from 1-10 optionally appropriately protected natural or unnatural α- or β-amino acids, R ₂ and R ₂ 'independently of one another tert-butyloxycarbonyl, benzyloxycarbonyl, fluorenyloxycarbonyl, or a group

(C = 0) -R ₃ , where R _{3 is} C _1-4 alkyl, phenyl, or a 5-10 membered mono- or bicyclic saturated, fully or partially unsaturated heterocyclic ring system with up to 4 heteroatoms such as N, O, S, which may optionally be mono-, polysubstituted or mixed by alkyl, alkoxy, alkoxyalkyl, oxo, oxime, O-alkyloxime, hydroxy, amino, monoalkylamino, dialkylamino, acylamino or aminoacyl, where 7, 8, 9, 10-membered moncyclic Ring systems are excluded, or R ₂ 'is hydrogen, and

R _{2 is} tert-butyloxycarbonyl, benzyloxycarbonyl, fluorenyloxycarbonyl, or a

group

R _{2 is} a C-terminal peptide residue from 1-10 optionally appropriately protected natural or unnatural α- or β-amino acids, which can optionally be acylated by a group (C = O) -R ₃ ,

Q is a group - (CH ₂ ) _m , where m is an integer from 0 to 20 or a group - (CH ₂ ) _n -X- (CH ₂ ) _p - where n and p independently of one another are a number from 0 to 14 mean, and one or more hydrogen atoms can be substituted by alkyl, or halogen or alkoxy or hydroxy, and

X is a group C (R ₄ ) ₂ , where R is methyl, ethyl, propyl, i-propyl, butyl, cycloalkyl, or a group C = O or a saturated, partially or completely unsaturated 3 to 10-membered mono- or bicyclic ring system with 0-6 heteroatoms N, S and / or O or a group

YO, S or CH ₂

Z O or S q is an integer from 1 to 4, r is an integer from 1 to 3.

2.) Compounds according to claim 1, with the following formula

o O

H

H PicSerAspN

PyrGluAsp N Lys

Lys

Lys Lys

PicSerAspN

PyrGluAsp N H H

O

3.) Process for the preparation of the compounds of formula I, which is characterized in that a) a dialdehyde of formula II

^• vww \ Q vww ^

H H II, in which Q has the meaning given above with a correspondingly N-protected α-phosphonoglycine ester of the formula III

in which R ^ R ₂ and R ₂ ', which have the meanings given above and R _{5 is} methyl or ethyl, reacts, b) optionally splitting off the ester groups, c) optionally converting the resulting compound with bases into a pharmaceutically acceptable salt.

4.) Use of compounds of formula I according to claim 1 for the production of optically active diaminodicarboxylic acid derivatives by selective hydrogenation using chiral catalysts and subsequent removal of the protective groups from the amino or carboxyl function.

5,) Use according to claim 4, characterized in that the conversion is carried out by homogeneous catalytic hydrogenation.

6.) Pharmaceutical composition containing a compound of formula I according to claim 1 and a pharmaceutically acceptable carrier.

7.) Use of the compounds according to claim 1 for stimulating the myelopoetic system and for the treatment and / or prevention of viral, fungal or bacterial infections.