الفهرس 
1. INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
ENGLISH SUMMARY
Ethyl 10H-Phenothiazine-10-yl acetate (2) [135-137] was obtained
by treating of phenothiazine (1) with ethyl choloroacetate in dry acetone
and anhydrous K2CO3 by refluxing in 88% yield. A solution of the
respective ester 2 in absolute ethanol and hydrazine hydrate was refluxed
for 3 h to afford 2-(10H-Phenothiazine-10-yl)acetohydrazide (3) as a pale
yellow powder in 88% yield (Scheme 1).
Amino acid ethyl ester hydrochlorides (5,10,15) were prepared by
treating of the corresponding amino acid with thionyl chloride in absolute
ethanol at -10oC followed by addition of absolute ethanol. The melting
points of the prepared ester were agreed with these in Aldrich fine
chemical catalog.
Methyl [(10Hphenothiazine-10-ylacetyl)amino]acetate (6) was
prepared by treating of the acid hydrazide 3 with AcOH and 1N HCl and
cooling at -5oC. Sodium nitrite (NaNO2) was added and the formed 10HPhenothiazine-
10-ylacetyl azide (4) was treated with glycine methyl ester
Summary
hydrochloride (5) in ethyl acetate containing Et3N at 0oC. The formed
product was purified by recrystallization from ethanol to afford the
corresponding peptide 6 in 78% yield.
A mixture of the above ester 6 and hydrazine hydrate (N2H4.H2O) in
ethanol was heated under reflux for 3 h to give N-(2-Hydrazinyl-2-oxoethyl)-
2-(10H-phenothiazine-10-yl)acetamide (7) in 88% yield (Scheme
2)
Summary
Methyl{{{[(10H-phenothiazin-10-ylacetyl)amino]acetyl}amino}}
acetate (9) was prepared by treating of the acid hydrazide 7 with AcOH
and 1N HCl and cooling at -5oC. Sodium nitrite (NaNO2) was added, and
the formed acid azide 8 was treated with glycine methyl ester
hydrochloride (5) in ethyl acetate containing Et3N at 0oC. The formed
product was purified by recrystallization from ethanol to afford the
corresponding peptide 9 in 70% yield (Scheme 3).
Methyl-2-[(10H-phenothiazin-10-ylacetyl)amino]-3-
sulfanylpropanoate (11) was prepared by treating of the acid hydrazide 3
with AcOH and 1N HCl and cooling at -5oC. Sodium nitrite (NaNO2)
was added, and the formed acid azide 4 was treated with cystin methyl
ester hydrochloride (10) in ethyl acetate containing Et3N at 0oC. The
formed product was purified by recrystallization from ethanol to afford
the corresponding peptide 11 in 75% yield (Scheme 4).
Summary
A mixture of the above ester 11 and hydrazine hydrate (N2H4.H2O)
in ethanol was heated under reflux for 3 h to give N-(1-hydrazinyl-1-oxo-
3-sulfanylpropan-2-yl)-2-(10H-phenothiazin-10-yl)acetamide (12)in 85%
yield (Scheme 5).
The peptide (14) was prepared by treating of the acid hydrazide 12
with AcOH and 1N HCl and cooling at -5oC. Sodium nitrite (NaNO2)
was added, and the formed acid azide 13 was treated with cystine methyl
ester hydrochloride (10) in ethyl acetate containing Et3N at 0oC. The
Summary
formed product was purified by recrystallization from ethanol to afford
peptide 14 in 78% yield (Scheme 6).
The peptide (16) was prepared by treating of the acid hydrazide 3
with AcOH and 1N HCl and cooling at -5oC. Sodium nitrite (NaNO2)
was added, and the formed acid azide 4 was treated with lysin methyl
ester hydrochloride (15) in ethyl acetate containing Et3N at 0oC. The
formed product was purified by recrystallization from ethanol to afford
the corresponding peptide 16 in 79% yield (Scheme 7).
Summary
A mixture of the above ester 16 and hydrazine hydrate (N2H4.H2O)
in ethanol was heated under reflux for 3 h to give acid hydrazide (17) in
88% yield (Scheme 8).
The peptide (19) was prepared by treating of the acid hydrazide 17
with AcOH and 1N HCl and cooling at -5oC. Sodium nitrite (NaNO2)
was added, and the formed acid azide 18 was treated with glycine methyl
Summary
ester hydrochloride (15) in ethyl acetate containing Et3N at 0oC. The
formed product was purified by recrystallization from ethanol to afford
19 in 78% yield (Scheme 9).
Ethyl [3-(10H-phenothiazin-10-ylmethyl)-1,2,4-oxadiazol-4(5 H)-
yl]acetate (21) was obtained by treating of 10-(4,5-dihydro-1,2,4-oxadiazol-
3-ylmethyl)-10H-phenothiazine (20) with ethyl choloroacetate in dry
acetone and anhydrous K2CO3 by refluxing in 88% yield.
A solution of the respective ester 21 in absolute ethanol and
hydrazine hydrate was refluxed for 3 h to afford 2-[3-(10H-phenothiazin-
10-ylmethyl)-1,2,4-oxadiazol-4(5H)-yl]acetohydrazide (22) as a pale
yellow powder in 88% yield (Scheme 10).
Summary
Methyl {[(3-(10H-phenothiazin-10-ylmethyl)-1,2,4-oxadiazol-4(5
H)-yl)acetyl]amino}acetate (24) was prepared by treating of the acid
hydrazide 22 with AcOH and 1N HCl and cooling at -5oC. Sodium nitrite
(NaNO2) was added, and the formed acid azide 23 was treated with
glycin methyl ester hydrochloride (5) in ethyl acetate containing Et3N at
0oC. The formed product was purified by recrystallization from ethanol to
afford the corresponding peptide 24 in 74% yield (Scheme 11).
Summary
A solution of the respective ester 24 in absolute ethanol and
hydrazine hydrate was refluxed for 3 h to afford N-(2-hydrazinyl-2-
oxoethyl)-2-[3-(10H-phenothiazin-10-ylmethyl)-1,2,4-oxadiazol-4(5 H)-
yl]acetamide (25) as a pale yellow powder in 88% yield (Scheme 12).
The peptide (27) was prepared by treating of the acid hydrazide 25
with AcOH and 1N HCl and cooling at -5oC. Sodium nitrite (NaNO2)
was added, and the formed acid azide 26 was treated with glycin methyl
ester hydrochloride (5) in ethyl acetate containing Et3N at 0oC. The
formed product was purified by recrystallization from ethanol to afford
the corresponding peptide 27 in 75% yield (Scheme 13).
The structure of 27 was elucidated by I.R and mass spectroscopy .
Summary
A solution of the respective ester 27 in absolute ethanol and
hydrazine hydrate was refluxed for 3 h to afford N-(2-hydrazinyl-2-
oxoethyl)-2-[3-(10H-phenothiazin-10-ylmethyl)-1,2,4-oxadiazol-4(5 H)-
yl]acetamide (28) as a pale yellow powder in 88% yield (Scheme 13).
The peptide (30) was prepared by treating of the acid hydrazide 28
with AcOH and 1N HCl and cooling at -5oC. Sodium nitrite (NaNO2)
was added, and the formed acid azide 29 was treated with glycin methyl
ester hydrochloride (5) in ethyl acetate containing Et3N at 0oC. The
formed product was purified by recrystallization from ethanol to afford
30 in 77% yield (Scheme 14).
Summary
The peptide (31) was prepared by treating of the acid hydrazide 22
with AcOH and 1N HCl and cooling at -5oC. Sodium nitrite (NaNO2)
was added, and the formed acid azide 23 was treated with cystin methyl
ester hydrochloride (10) in ethyl acetate containing Et3N at 0oC. The
formed product was purified by recrystallization from ethanol to afford
peptide 31 in 75% yield (Scheme 15).
Summary
A mixture of the above ester 31 and hydrazine hydrate (N2H4.H2O)
in ethanol was heated under reflux for 3 h to give acid hydrazide (32) in
85% yield (Scheme 16).
Summary
The peptide (34) was prepared by treating of the acid hydrazide 32
with AcOH and 1N HCl and cooling at -5oC. Sodium nitrite (NaNO2)
was added, and the formed acid azide 33 was treated with cystine methyl
ester hydrochloride (10) in ethyl acetate containing Et3N at 0oC. The
formed product was purified by recrystallization from ethanol to afford
the corresponding peptide 34 in 78% yield (Scheme 17).
The peptide (35) was prepared by treating of the acid hydrazide 22
with AcOH and 1N HCl and cooling at -5oC. Sodium nitrite (NaNO2)
was added, and the formed acid azide 23 was treated with lysin methyl
ester hydrochloride (15) in ethyl acetate containing Et3N at 0oC. The
formed product was purified by recrystallization from ethanol to afford
35 in 79% yield (Scheme 18).
Summary
A mixture of the above ester 35 and hydrazine hydrate (N2H4.H2O)
in ethanol was heated under reflux for 3 h to give acid hydrazide (36) in
88% yield (Scheme 19).
The peptide (38) was prepared by treating of the acid hydrazide 36
with AcOH and 1N HCl and cooling at -5oC. Sodium nitrite (NaNO2)
was added, and the formed acid azide 37 was treated with lysin methyl
Summary
ester hydrochloride (15) in ethyl acetate containing Et3N at 0oC. The
formed product was purified by recrystallization from ethanol to afford
38 in 78% yield (Scheme 20).
5-(10H-phenothiazin-10-ylmethyl)pyrimidine-2,4(1 H,3H)-dione
(40) was obtained by treating of phenothiazine (1) with uracile (39) in the
presence of paraformaldehyde by refluxing in 68% yield (Scheme 21).
Summary
Ethyl[2,6-dioxo-5-(10H-phenothiazin-10-ylmethyl)-3,6-
dihydropyrimidin-1(2 H)-yl]acetate (41) was obtained by treating of 5-
(10H-phenothiazin-10-ylmethyl)pyrimidine-2,4(1 H,3H)-dione (40) with
ethyl choloroacetate in dry acetone and anhydrous K2CO3 by refluxing in
88% yield.
Asolution of the respective ester 41 in absolute ethanol and
hydrazine hydrate was refluxed for 3 h to afford 2-[2,6-dioxo-5-(10Hphenothiazin-
10-ylmethyl)-3,6-dihydropyrimidin-1(2H)-
yl]acetohydrazide (42) as a pale yellow powder in 88% yield(Scheme 22)
The peptide (44) was prepared by treating of the acid hydrazide 42
with AcOH and 1N HCl and cooling at -5oC. Sodium nitrite (NaNO2)
was added, and the formed acid azide 43 was treated with glycin methyl
ester hydrochloride (5) in ethyl acetate containing Et3N at 0oC. The
formed product was purified by recrystallization from ethanol to afford
44 in 74% yield (Scheme 23).
Summary
A solution of the respective ester 44 in absolute ethanol and
hydrazine hydrate was refluxed for 3 h to afford acid hydrazide (45) as a
pale yellow powder in 88% yield (Scheme 24).
Summary
The peptide (47) was prepared by treating of the acid hydrazide 45
with AcOH and 1N HCl and cooling at -5oC. Sodium nitrite (NaNO2)
was added, and the formed acid azide 46 was treated with glycin methyl
ester hydrochloride (5) in ethyl acetate containing Et3N at 0oC. The
formed product was purified by recrystallization from ethanol to afford
the corresponding peptide 47 in 75% yield (Scheme 25).
- 1 -
METHODS FOR THE PEPTIDE SYNTHESIS AND ANALYSIS
1. INTRODUCTION
Peptides as drugs show unique characteristics (high biological activity,
high specificity, and low toxicity) thereby making them particularly attractive
therapeutic agents [1]. However, the role of peptides in drug discovery has
suffered ups and downs during the last four decades. A first analysis of the new
chemical entities (NCEs) accepted by the Food and Drug Administration (FDA)
indicated that while 53 NCEs were introduced as drugs in 1996, only 17 were
introduced in 2002. This number increased to 31 in 2004, but decreased again in
2005 with just 18 new drugs, 17 in 2007, and a slight increase to 21 in 2008
(Figure 1.1) [2, 3]. An analysis of these 21 drugs approved in 2008 indicated
that almost 50% of the new drugs can be considered nonclassical, in the sense
that they are nonclassical small molecules.
Figure 1.1 Distribution by chemical structure of the newdrugs approved by the FDAin 2008.
(See insert for color representation of this figure.)