DE19616133A1 - New leukotriene B¶4¶ derivatives, processes for their preparation and their use as medicines - Google Patents

Abstract

New optically active leukotriene-B4 analogues having formula (I) are disclosed, and optionally their salts with physiologically neutral bases. In the formula, R<1> stands for the radical COOR<3>, in which R<3> stands for a hydrogen atom or for a (C1-C4)-alkyl group, or R<1> stands for the radical CH2OH; R<2> stands for a hydrogen atom or an acyl radical with 1-4 C atoms; A stands for an alkylene group with 1-4 C atoms in the chain; X stands for N or CH; and <u>-----</u> stands for a simple or double bond.

Description

The invention relates to new leukotriene B₄ derivatives, a process for their preparation and their Use as a medicine. The new compounds are optically active structure analogs from previously known leukotriene B₄ agonists (WO 91/146 76). Leukotriene-B₄ (LTB₄) was developed by B. Samuelson and co-workers discovered the arachidonic acid metabolite. In biosynthesis by the enzyme 5-lipoxygenase, initially as the central intermediate, the leukotriene-A₄ formed, which is then converted into the LTB₄ by a specific hydrolase.

The nomenclature of leukotrienes can be found in the following work:

• a) B. Samuelson et al., Prostaglandins 19, 645 (1980); 17, 785 (1979)
• b) C.N. Serhan et al., Prostaglandins 34,201 (1987).

The physiological and in particular the pathophysiological significance of leukotriene B₄ is described in summarized some recent work: a) The Leukotriens, Chemistry and Biology eds. L. W. Chakrin, D.M. Bailey, Academic Press (1984). b) J.W. Gillard et al., Drugs of the Future 12, 453 (1987). c) B. Samuelson, Sciences 237, 1171 (1987). d) C. W. Parker, Drug Development Research 10, 277 (1987). It follows that LTB₄ is an important inflammatory mediator for inflammatory Diseases is where leukocytes migrate into the diseased tissue.

The effects of LTB₄ are at the cellular level through the binding of LTB₄ to one specific receptor triggered.

LTB₄ is known to cause leukocyte adhesion to the blood vessel wall. LTB₄ is chemotactically active, d. H. it triggers a directed migration of leukocytes towards one Gradients of increasing concentration. It also changes due to its chemotactic Activity indirectly affects vascular permeability, being synergistic with prostaglandin E² is observed. LTB₄ obviously plays in inflammatory, allergic and immunological Processes play a crucial role.

Leukotrienes and especially LTB₄ are involved in skin diseases involving inflammatory Processes (increased vascular permeability and edema, cell infiltration), increased proliferation of the Skin cells and itching are associated, such as with eczema, erythema, psoriasis, pruritus and acne. Pathologically increased leukotriene concentrations are the cause of many Dermatids are either causally involved, or there is a connection between persistence dermatids and leukotrienes. Significantly increased leukotriene concentrations were found measured for example in the skin of patients with psoriasis or atopic dermatitis.

Leukotrienes and especially LTB₄ are also involved in diseases of internal organs for which one acute or chronic inflammatory component has been described, e.g. B. joint diseases (Athritis); Diseases of the respiratory tract (asthma, rhinitis and allergies); inflammatory Intestinal diseases (colitis); as well as reperfusion damage (to heart, intestinal or kidney tissue), the caused by intermittent pathological occlusion of blood vessels.

Furthermore, leukotrienes and especially LTB₄ in the disease of multiple sclerosis involved and in the clinical appearance of the shock (triggered by infections, Burns or complications from kidney dialysis or other issues discussed Perfusion techniques).  

Leukotrienes and especially LTB₄ continue to have an impact on the formation of white Blood cells in the bone marrow, on the growth of smooth muscle cells, of keratinocytes and B lymphocytes. LTB₄ is therefore for diseases with inflammatory processes and Diseases involved with pathologically increased formation and growth of cells.

Diseases with this appearance represent z. B. Leukemia or atherosclerosis.

The Usefulness and Potential Use of Leukotriene B₄ Agonists for the Treatment of Fungal diseases of the skin have been described (H. Katayama, Prostaglandin 34, 797 (1988).

Further applications for LTB₄ agonists result from the LTB₄-stimulated activation of Components of the immune system for various indications, such as infectious diseases, Burn injuries, in tumor therapy or e.g. B. in AIDS therapy. AIDS sufferers e.g. B. a decreased release of LTB₄ when stimulating neutrophils is reported (AIDS, 1989, 3, 651).

The invention relates to new, optically active leukotriene B₄ derivatives of the general formula I.

wherein R¹ is COOR³ with R³ as hydrogen or a (C₁-C₄) alkyl group or R¹ is CH₂OH,
R² is a hydrogen atom or an acyl radical with 1-4 C atoms,
A is an alkyl group with 1-4 C atoms in the chain,
XN or CH,
mean a single or double bond, and optionally their salts with physiologically acceptable bases.

The compounds of the formula I have already been described in WO 91/146 762. After that in this However, the methods described in the publication describe the compounds of the formula I as Obtain mixtures of diastereomers.

The optically active leukotriene B₄ derivatives of the formula I according to the invention can now according to a new processes can be obtained as pure enantiomers.  

The new process is characterized in that the racemate of the general formula II,

wherein R¹, A and X have the meanings given above and Z is a bromine atom or an iodine atom symbolizes in the presence of a lipase with vinyl acetate by means of kinetic resolution in the optically active compounds of the formula II and II,

wherein R¹, A, X and Z have the meanings given above and the optically active Compounds of formula II after esterification or the optically active compounds of formula III directly with an optically active tin compound of formula IV or V

in the presence of a palladium catalyst, such as 1,1′-bis (disphenylphosphine) - ferrocene-palladium-II-chloride (EPA 046.069; F. Sato et. al., Chemistry Letters 1987, 1523f).  

The recemischen starting compounds of formula II are prepared by in itself known manner a compound of formula VI,

wherein X and Z have the meanings given above, with a copper-zinc-organic Compound of formula VII

R¹-A-Cu (CN) ZnJ (VII)

wherein R¹ and A have the meanings given above.

The optically active compounds of the formula I according to the invention can also be obtained in this way be that they are obtained by the method in WO 91/146 762 mixtures of diastereomers with the help of high pressure liquid chromatography (HPLC) on "Kromasil" in the diastereomers separates and cleaves the diastereomers into the enantiomers by means of HPLC on optically active columns.

example 1 (5S) -5-Hydroxy-5- {6 - [(1E) - (3R) -3-hydroxy-1-undecenyl] -2-pyndyl} pentanoic acid a) Methyl 5- (6-bromo-2-pyridyl) - (5RS) -5-hydroxy-pentanoate

14.2 g of finely cut zinc foil (Aldrich 0.25 mm, 99.999%) in 20 ml of absolute tetrahydrofuran (THF) is heated with 1.68 g of 1,2-dimbromethane to 65 ° C for one minute, cooled to 25 ° C, mixed with 0.9 ml of chlorotrimethylsilane and stirred for 15 minutes under argon. A solution of 48 g of methyl 4-iodobutyrate in 90 ml of absolute tetrahydrofuran is added dropwise to this activated zinc at 30 ° C. and the mixture is stirred at 35-40 ° C. for 16 hours. The solution of 3-methoxycarbonylpropylzinc iodide in tetra-hydrofruan thus obtained was added dropwise at -20 ° C. to a solution of 11.07 g of copper I-cyanide and 11.07 g of lithium chloride in 120 ml of THF. The mixture is stirred for 5 minutes at 0 ° C, cooled again to -20 ° C, mixed with a solution of 20 g of 6-bromopyridine-2-aldehyde in 40 ml of tetrahydrofuran and 51 ml of boron trifluoride-diethyl ether complex, 5 hours at 0 ° C and stirred for 16 hours at room temperature. The reaction mixture is poured into saturated ammonium chloride solution, the precipitate is vacuumed over diatomaceous earth, the filter residue is washed with ethyl acetate, the organic phase is separated off and the water phase is extracted three times with ethyl acetate. The organic phase is dried over sodium sulfate, concentrated and the crude product is chromatographed on silica gel with hexane / 0-40% ethyl acetate. 24.7 g (80% of theory) of 5- (6-bromo-2-pyridyl) - (5RS) -5-hydroxypentanoic acid methyl ester are obtained as a light yellow oil, in which about 12% of 5- (6-bromo- 2-pyridyl) - (5RS) -5-hydroxypentanoic acid lactone are contained.
IR (film): 3440 (wide), 2945, 2870, 1725, 1580, 1550, 1455, 1405, 1158, 1118, 982, 790, 690 cm ^-1

5- (6-Bromo-2-pyridyl- (5S) -5-hydoxypentanoic acid methyl ester and 5- (6-bromo-2- pyridyl) - (5R) -5-acetoxypentanoic acid methyl ester

7.5 g of methyl 5- (6-bromo-2-pyridyl- (5RS) -5-hydoxypentanoate are dissolved in 150 ml of vinyl acetate and 4.8 g of Lipase PS (Amano) are added. The mixture is stirred for 22 hours at 40 ° C. The enzyme is removed by filtration and the filtrate is evaporated to dryness in vacuo at 50 ° C. The residue is purified by chromatography on fine silica gel with hexane + 10% acetone as the eluent. 1.59 g of 5- (6 -Brom-2-pyridyl- (5R) -5-acetoxy-pentanoic acid methyl ester, [ ^α ] D = + 57.2 ° (c = 2.015 in CHCl₃) and 5.0 g 5- (6-bromo-2-pyridyl- (5S) -5- hydoxypentanoic acid methyl ester, [ ^α ] D = + 1.2 ° (c = 2.025 in CHCl₃). Since the latter compound still contains 13-15% of the undesired enantiomer according to HPLC, 4.7 g of this material are used again , after dissolving in 94 ml of vinyl acetate and adding 3 g of Lipase PS, the mixture is stirred for 44 hours at 40 ° C. Working up is carried out analogously to the first stage. 1 g of 5- (6-bromo-2-pyridyl- (5R ) -5-acetox methyl y-pentanoate, [ ^α ] D = + 49.8 ° (c = 2.030 in CHCl₃) and 2.2 g of methyl 5- (6-bromo-2-pyridyl- (5S) -5-hydoxypentanoate, [ ^α ] D = -3.0 ° (c = 2,030 in CHCl₃). The latter compound is 91% pure by HPLC and contains 1.4% of the wrong enantiomer (HPLC: Chiralcel OD, hexane / 2-propanol / ethanol = 900/15/25, 1 ml / min).

c) 5- (6-Bromo-2-pyridyl) - (5S) -5-acetoxypentanoic acid methyl ester

6 ml of acetic anhydride are added dropwise to a solution of 2.1 g of 5- (6-bromo-2-pyridyl) - (5S) -5-hydroxypentanoic acid methyl ester in 25 ml of pyridine with ice-cooling and the mixture is stirred at room temperature for 16 hours. The reaction mixture is mixed with methanol, concentrated and the residue is partitioned between water and ethyl acetate. The organic phase is shaken three times with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel with hexane / 0-25% ethyl acetate. 1.83 g of colorless crystals are obtained as a crude product. After recrystallization from n-hexane, 1.27 g of methyl 5- (6-bromo-2-pyridyl) - (5S) -5-acetoxypentanoate with a melting point of 70-71 ° C.
[ ^α ] D = -62.2 ° (c = 2.015 in chloroform), 99.5% ee (HPLC: Chiralpak AD, hexane / 2-propanol = 120/10, 0.5 ml / min). The S configuration of this connection is confirmed by an X-ray structure analysis.
IR (CHCHl₃): 2945, 1728, 1582, 1555, 1433, 1370, 1160, 1120, 985 cm ^-1 .

(5S) -5-acetoxy-5- {6 - [(1E) - (3R) -3-hydroxy-1-undecenyI] -2-pyridyl} - pentanoic acid methyl ester

A solution of 860 mg of 5- (6-bromo-2-pyridyl) - (5S) -5-hydroxypentanoic acid methyl ester in 7 ml of toluene is mixed with 1.31 g of (1E) -1- (tri-n-butylstannyl) -1- undecen- (3R) -3-ol (EP 0416.069) and 170 mg of 1,1'-bis- (diphenylphosphino) -ferrocene-palladium-II-chloride were added and the mixture was stirred for 5.5 hours at 100 ° C. (bath temperature) under an argon atmosphere . The reaction mixture is diluted with ethyl acetate, washed twice with saturated sodium chloride solution, the organic phase is dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel with hexane / 0-20% ethyl acetate. 575 mg (53% of theory) of (5S) -5-acetoxy-5- {6 - [(1E) - (3R) -3-hydroxy-1-undecenyl] -2-pyridyl} - entanoic acid methyl ester as received yellow oil.
[ ^α ] D = -51.0 ° (c = 0.5 in acetone), 96.4% ee (HPLC: Chiralcel OD, hexane / 2-propanol / ethanol = 900/15/25, 1 ml / min ).
IR (film): 3430 (wide), 2920, 2845, 1735, 1655, 1585, 1570, 1368, 1230, 1160, 970 cm ^-1 .

e) (5S) -5-Hydroxy- {6 - [(1E) - (3R) -3-hydroxy-1-undecenyl] -2-pyridyl} pentanoic acid

A solution of 120 mg (5S) -5-acetoxy-5- {6 - [(1E) - (3R) -3-hydroxy-1-undecenyl] -2-pyridyl} - methyl pentanoate in 6 ml of methynol is mixed with 3, 7 ml of 2N sodium hydroxide solution were added and the mixture was stirred at room temperature for 4 hours. The methanol is removed in vacuo, the residue is mixed with a little water, acidified to pH 4 with 2N sulfuric acid, extracted three times with ethyl acetate, the organic phase is dried over sodium sulfate and concentrated. 95 mg (5S) -5-hydroxy- {6- [(1E) - (3R) -3-hydroxy-1-undecenyl] -2-pyridyl} pentanoic acid are obtained as a yellow oil.
[ ^α ] D = -20.1 ° (c = 0.565 in acetone)
IR (film): 3360 (wide), 1710, 1590, 1572, 1455, 970 cm ^-1 .

Example 2 (SS) -5-Hydroxy-5- {6 - [(IE) - (3R) -3-hydroxy-1-undecenyl] -2-pyridyl} pentanoic acid methyl ester

A solution of 15 mg (5S) -5-acetoxy-5- {6 - [(1E) - (3R) -3-hydroxy-1-undecenyl] -2-pyridyl} - pentanoic acid methyl ester in 0.5 ml of absolute methanol treated with 6.5 mg of anhydrous potassium carbonate and stirred for 4 hours at room temperature. The reaction mixture is acidified to pH 4 with 2N sulfuric acid, diluted with water, extracted three times with ethyl acetate, the organic phase is dried over sodium sulfate and concentrated. 13 mg of the title compound are obtained as a yellow oil.
[ ^α ] D = -16.9 ° (c = 0.360 in acetone)
IR (CHCl₃): 3600, 3420 (broad), 2925, 2860, 1730, 1574, 1455, 1260, 1010 cm ^-1 .

Example 3 Preparative HPLC separation of (5RS) -5-hydroxy-5- {6 - [(1E) - (3RS) -3-hydroxy- 1-undecenyl] -2-pyridyl} -pentanoic acid methyl ester in the 4 enantiomers

• a) 137 mg (5RS) -5-hydroxy-5- {6 - [(1E) - (3RS) -3-hydroxy-1-undecenyl] -2-pyridyl} pentanoic acid Remethyl esters (WO 91/14676) are dissolved in 20 ml of eluent (hexane / chloroform / 2-propanol = 700/270/30) dissolved and in 4 ml injections on an HPLC system over a Kromasil column (100 Si, 250 mm × 4.6 mm, 10 µm) with an eluent flow of 16 ml / min and UV detection at 305 mm in the Diastereomers A and B separated. 68 mg of diastereomer A (retention time: 19.6 min) and 55 mg of diastereomer B (retention time: 24.8 min).
• b) 68 mg of diastereomer A are dissolved in 12 ml of eluent (hexane / ethanol = 800/200) and in 4 ml of Injections on an HPLC- # system using a Chiralcel OD column (500 mm × 20 mm, 20 µm) an eluent flow of 9 ml / min at 40 ° C and UV detection at 305 mm in the enantiomers A1 and A2 separated. 31 mg of enantiomer A1 (retention time: 9.2 min) and 33 mg of Enantiomer A2 (retention time: 11.8 min) was obtained.
• c) 55 mg of diastereomer B are dissolved in 10 ml of eluent (hexane / 2-propanol = 500/500) and in 1 ml injections on an HPLC system via a Chiralcel OF column (250 mm × 4.6 mm, 10 mm) separated into enantiomers B1 and B2 with a flow of 0.5 ml / min and UV detection at 305 mm. 23 mg of enantiomer B1 (retention time: 12.7 min) and 22 mg of enantiomer B2 (retention time, 19.1 min) are obtained.
  According to HPLC, the enantiomer B1 is identical to the (5S) -5-hydroxy-5- {6 - [(1E) - (3R) -3-hydroxy-1-undecenyl] -2-pyridyl} pentanoic acid methyl ester obtained according to Example 2 .

Example 4 (5S) -5-Hydroxy-5- {6 - [(1E) - (3R) -3-hydroxy-1-undecenyl] -2-pyridyl} pentanoic acid

Under the conditions of Example 1e, 23 mg of the enantiomer B1 in 1 ml of methynol are saponified with 1 ml of sodium hydroxide solution and processed. 14 mg of the title compound are obtained as a yellow oil.
[ ^α ] D = -18.4 ° (c = 0.19 in acetone).

Example 5 (5R) -5-Hydroxy-5- {6 - [(1E) - (35) -3-hydroxy-1-undecenyl] -2-pyridyl} pentanoic acid

Under the conditions of Example 1e, 22 mg of the enantiomer B2 in 1 ml of methynol are saponified with 1 ml of sodium hydroxide solution and processed. 21 mg of the title compound are obtained as a yellow oil.
[ ^a ] D = + 17.2 ° (c = 0.51 in acetone).

Example 6 (5R or 5S) -5-hydroxy-5- {6 - [(1E) - (3R or 3S) -3-hydroxy-1-undecenyl] -2-pyridyl} - pentanoic acid

Under the conditions of Example 1e, 31 mg of enantiomer A1 are saponified in 1 ml of methanol and 1 ml of sodium hydroxide solution and processed. 16 mg of the title compound are obtained as a yellow oil.
[ ^α ] D = + 15.4 ° (c = 0.505 in acetone).

Example 7 (5R or 5S) -5-hydroxy-5- {6 - [(1E) - (3R or 3S) -3-hydroxy-1-undecenyl] -2-pyridyl} - pentanoic acid

33 mg of enantiomer A2 are saponified and processed in 1 ml of methanol and 1 ml of sodium hydroxide solution under the conditions of Example 1e. 26 mg of the title compound are obtained as a yellow oil.
[ ^α ] D = -13.1 ° (c = 0.51 in acetone).

Claims (3)

1. Optically active leukotriene B4 analogs of the general formula I, wherein R¹ is COOR³ with R³ in the meaning of a hydrogen atom or a (C1-C4) - alkyl group or R¹ is CH₂OH
R2 is a hydrogen atom or an acly radical with 1-4 C atoms
A is an alkylene group with 1-4 C atoms in the chain,
XN or CH,
mean a single or double bond, and optionally their salts with physiologically acceptable bases. 2. Pharmagenetic preparations, characterized by a content of leukotriene B₄ derivatives general formula I according to claim 1. 3. A process for the preparation of leukotriene B₄ derivatives of the general formula I according to claim 1,
characterized in that the racemate of the general formula II wherein R¹, A and X have the meanings given above and Z symbolizes a bromine atom or an iodine atom, in the presence of a lipase with vinyl acetate by means of kinetic resolution in the optically active compounds of the formula II and III wherein R¹, A, X and Z have the meanings given above and the optically active compounds of the formula II after esterification or the optically active compounds of the formula III directly with an optically active tin compound of the formula IV or V in the presence of a palladium catalyst.