Pseudoerythromycin derivatives

Details Pseudoerythromycin derivatives Pseudoerythromycin derivatives

2002-07-25

2004-05-11

Peselev, Elli (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S007300, C536S017200, C536S017500

Reexamination Certificate

active

06734292

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel pseudoerythromycin derivatives or salt thereof.
2. Description of Related Art
Erythromycin (hereinafter sometimes designates as EM) has been used for long time as 14-membered macrolide antibiotic for treatment of infectious disease caused by Gram-positive bacteria. During past ten and several years, erythromycin has known to improve long-term chronic inflammatory diseases such as diffuse panbronchiolitis and bronchial asthma, except for therapeutic action to bacterial infectious diseases. (Kudo, Shojli et al., Studies of clinical results on long term small administration of erythromycin for diffuse panbronchiolitis-Treatment results for 4 years, J. Japan. Thorac. Dis. Assoc., 25: 632-642, 1987).
Erythromycin is an antibiotic and has antibacterial action which is not always required for treatment of inflammatory diseases. Consequently, resistant bacteria are generated in patients who are administered antibiotics, as a result, it causes deterioration for treatment of infectious disease in the other occasion.
As described above, Kudo, Shoji et al. demonstrated that diffuse panbronchiolitis could be improved by long term small administration of erythromycin (Kudo, Shoji et al., Studies of clinical results on long term small administration of erythromycin for diffuse panbronchiolitis-Treatment results for 4 years, J. Japan. Thorac. Dis. Assoc., 25: 632-642, 1987).
SUMMARY AND OBJECT OF THE INVENTION
Recently, actions other than antibiotic activity of erythromycin is noted, as a result, usefulness other than pulmonary region, for example not limited in diffuse panbronchiolitis but for chronic sinusitis and Crohn's disease are reported. The mechanism of action of erythromycin for chronic disease such as diffuse panbronchiolitis is thought to be the result of original antibacterial action. Research studies are now ongoing, and indicate the antiinflammatory action mediated by immune inflammatory cells in the penumbral chronic respiratory tract inflammation.
For example, the studies indicate the regulation for migration of neutrophils to infectious region by direct action, and the regulation for migration of neutrophils or for release of active oxygen from neutrophils by indirect action through mediators or cytokines. Further, erythromycin has an action to lymphocytes, macrophages and mast cells to regulate their proliferation or cytokine production, or to induce differentiation. (Kudo, Shoji Ed., Supervisors: Shimizu, Kihachiro and Omura Satoshi “Inflammation, Immunity and Macrolides Up to Date”, Iyaku Journal Inc., Osaka, 1996)
As explained above, 14-membered macrolides are thought to cure chronic respiratory diseases as a result of exhibiting immune regulation and antiinflammatory action.
We have aimed at the promoting action of erythromycin for differentiation-induction frommonocyte to macrophage (N. Keicho, S. Kudoh, H. Yotsumoto, K. Akagawa, “Erythromycin promotes monocyte to macrophage differentiation”, J. Antibiotics, 47, 80-89, 1994), and tried to synthesize erythromycin derivatives for the purpose of creating the derivatives having disappeared antibacterial action and enhanced promoting action for differentiation-induction.
The present invention relates to a novel pseudoerythromycin derivative represented by the general formula [I],
wherein R
1
and R
2
are same or different and each represents H, alkyl, alkynyl, acyl, or sulfonyl, in which these groups may optionally have substituents, and Me indicates methyl.
Further, the present invention relates to a novel pseudoerythromycin derivative represented by the general formula [II],
wherein R is heterocyclic containing N which may optionally have substituents, and Me indicates methyl.
The present invention further relates to a novel pseudo erythromycin derivative represented by the general formula [III],
wherein R
3
is O or NOH, and Me indicates methyl.
The invention further relates to a novel pseudoerythromycin derivative represented by the general formula [IV],
wherein R
1
and R
2
are same or different and each represents H or methyl, R
3
and R
4
represent H, hydroxyl or amino, and Me indicates methyl.
The present invention further relates to a novel pseudo erythromycin derivative represented by the general formula [V],
wherein R
1
and R
2
are same or different and each represents H or methyl, and Me indicates methyl.
Synthetic methods of various erythromycin derivatives are, for example, illustrated in the synthetic scheme as shown in FIG.
1
. Namely, erythromycin A is treated with ice-cold acetic acid according to the references: (a) I. O. Kibwage, R. Busson, G. Janssen, J. Hoogmartens, H. Vanderhaeghe, Translactonization of Erythromycins, J. Org. Chem., 52, 990-996, 1987, (b) H. A. Kirst, J. A. Wind, J. W. Paschal, Synthesis of Ring-Constracted Derivatives of Erythromycin, J. Org. Chem., 52, 4359-4362, 1987, introducing to erythromycin A enol ether (EM 201), subsequently refluxing in methanol with heating in the presence of potassium carbonate to introduce pseudoerythromycin A enol ether (EM701) (known compound).
The product was treated with iodine and sodium acetate according to the reference (L. A. Friberg, U.S. Pat. No. 3,725,385) to obtain de-N-methyl-pseudoerythromycin A enol ether (EM703) (known compound). The compound was further treated with iodine and sodium methoxide to obtain bis(de-N-methyl)-pseudo erythromycin A enol ether (EM721) (novel compound). Alkylation, acylation and sulfonylation using EM703 and EM721 resulted to synthesize various derivatives through bis-de(3′-N-methyl)-3′-N-ethyl-8,9-anhydro-pseudoerythromycin A 6,9-hemiketal (EM722).
The synthetic scheme of compounds of the present invention is illustrated in FIG.
1
. Namely, the compounds can be obtained by the synthetic route of: erythromycin A (EMA)→erythromycin A enol ether (EM201)→pseudoerythromycin A enol ether (EM701)→de-N-methyl-pseudoerythromycin A enol ether (EM703)→bis (de-N-methyl)-pseudoerythromycin A enol ether (EM721).
In order to confirm enhancing effect for differentiation-induction of the compounds of the present invention, the enhancing effect for differentiation-induction from human monocyte to macrophage was assayed. Method is performed as follows.
THP-1 cells were collected from cultured liquid by centrifugation, adjusted the concentration to 2×10
5
cells/ml using medium (RPMI 1640) and distributed into the 48-well plate at 500 &mgr;l/well. PMA solution 10 &mgr;l and sample solution 5 &mgr;l were added in each well, stirred with mild shaking and incubated at 37° C. for 72-96 hours under 5% CO
2
. Further MTT 0.5 mg/ml solution was added at 300 &mgr;l/well, and incubated at 37° C. for 3 hours under 5% CO
2
. Supernatant solution was suctioned using the injection tube, added DMSO 500 &mgr;l using automatic continuous injector to dissolve formazan completely and transferred each 100 &mgr;l to the 96-well plate. The optical absorption was measured using the plate-reader.
Results of the enhancing effect for differentiation-induction from human monocyte to macrophage measured by the above assay method are shown in Table 1.
TABLE 1
Structure cf EM703 analogous derivatives
and activities in THP-1/M&phgr; system
Others
Treated conc. (&mgr;M)
EM
R
1
R
2
0.3
1
3
10
30
ED
50
(&mgr;M)*
703
Me
H
+
+
+
+
/
0.3
721
H
H
NT
NT
−
+
/
10
722
Et
H
−
+
+
++
/
1
723
Et
Et
−
+
+
/
1
724
Allyl
H
−
+
+
++
/
1
725
Allyl
Allyl
NT
−
±
+
/
3
726
Ac
H
−
−
−
−
−
—
727
Ms
Me
−
+
+
+
/
1
728
CH
2
C≡CH
H
−
+
+
+
+
1
729
CH
2
C≡CH
CH
2
C≡CH
−
±
±
±
/
1
730
Pr
H
+
+
+
/
/
0.3
731
Pr
Pr
−
−
+
/
/
3
732
Bn
H
+
+
+
+
/
0.3
733
Bn
Bn
−
±
±
/
/
1

734
−
±

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