Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2000-07-31
2002-01-22
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
active
06340755
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the area of organic chemistry and medicine, specifically to barbituric acids and their derivatives, and is designed for use as substances having antiviral, antichlamydic, immunomodulating and antitumoral activity.
DESCRIPTION OF PRIOR ART
Many derivatives of barbituric acid are biologically active substances. The derivatives of pyrimidine are nucleic bases (uracil, thymine, cytosine), vitamins (thiamine, phosphothiamine), coenzymes (cocarboxylase), and they are utilized as pharmaceuticals having soporific, anticonvulsive (barbiturates, hexamidine, benzonal), diuretic (mercusal), antiinflammatory (pentoxil, methyluracil), and antithyroidal (methylthiouracil) actions; they are synthetic analogs of vitamins (“bephothiamine”), anabolic (orotic acid), anti-inflammatory and antibacterial (sulfazin, sulfadimethazin, sulfamonomethoxin, sulfadimethoxin, bactrim, salazodimethoxin), antimalarial (chloridin), anticarcinogenic (dopan, phosphamide, ethimidide, fluorouracil, fluorofur, cytarabin) substances [1, 2].
In recent decades, systems in which the pyrimidine ring is condensed with other heterocycles have received considerable attention. Such heterocycles are frequently analogs of natural, biologically active substances. They include purines, which occur in natural and synthetic biologically active substances: nucleic acids (adenine, guanine), ATP, substances that excite the central nervous system (caffeine, theobromine, theophylline, “nihexine,” diprophylline, xanthinol nictoninate), substances used in suppressing tissue incompatibility in organ transplants (azathioprine) (cytostatic and immumodepressive effect), and substances having an anabolic (inosine) or antileukemic effect (mercaptopurine), pyrazolo[3,4-d]pyrimidines used to treat diseases accompanied by hyperuremia (allopurinol); pteridines, used as diuretics (triamterene), vitamins (riboflavin, folic acid), anticarcinogenic drugs (methotrexate); pyrimido[5,4-d]pyrimidines having vasodilational properties (dipyridamole [1, 2].
Data on the biological activity of the most varied derivatives of 5-ylidenebarbituric acids have been summarized in a review [3] which notes the anticoma, antimicrobial, spasmolytic, antipyretic and antitumor activity of these substances. Data has also been obtained on the biological activity of certain 5-arylidenebarbituric acids [4-11], 5-aminomethylenebarbituric acids [12], products of the reaction of barbituric acids with isocyanates, isothiocynates - 5-arylcarbamoylbarbituric acids [13-16], pyrazolo[3,4-d]pyrimidines obtained by the condensation of 6-hydrainouracils with iso(thio)cyanates [17], 5-deazaflavins [18-20], condensation products of 6-aminouracils with nitrosobenzene-10-alkyl(halogenophenyl)-3-methylflavins [21, 22], derivatives of pyrrolo[2,3-d]pyrimidines [23], 7-methyl-5-hexyl-1H-pyrazolo-[3,4-d]-pyrimidino-4,6(5H,7H)-dion obtained by the action of Wilsmeyer's reagent on the corresponding 6-hydrazinouracil [24], pyrano[2,3-d]pyrimidines [25-27], 5-(3-nitrophenyl)-4-oxo-2-thioxo-1,3,7-triphenyl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidines [28-33],pyrimido[5,4-e][1,2,4]triazino-5,7(1H,6H)-dions [34], 5-dialkylaminomethylpyridines [35, 36], and pyrimido[4,5-c] pyridazines [37]. The foregoing compounds have pesticidal, antitumor, antimicrobial, immunosuppressive, nootropic and antihypertensive and antiallergic activity.
Only a few examples are known of the formation of the pyrano[2,3-d ]6,5-d′]dipyridimine system by the interaction of barbituric acids with 3-acylchromones [38, 39]. There is no information as to their biological activity. At the same time, available information on the biological activity of 5-substituted barbituric acids and condensed systems containing the pyrimidine ion fragment, as stated above, indicates that they have varying degrees of biological activity. The effectiveness of many of the substances that have been studied, however, is not satisfactorily high, and many of them are toxic and cause side-effects. Furthermore, bacteria, viruses and tumor cells rapidly develop resistance to the existing drugs, making their employment inefficient [40-46].
The material above suggests the potential usefulness of conducting a scientific search in the area of the synthesis of effective new biological substances by condensing barbituric acids with carbonyl compounds, producing, specifically, derivatives of pyrano[2,3-d:6,5-d′]dipyrimidine. The prototype of the invention, i.e., the substance closest in chemical nature to the claimed substance, is 1,3,7,9-tetramethyl-5-(3-chromonyl)-5H-pyrano[2,3-d:6,5-d′]dipyrimidino-2,4,6,8(1H,3H,7H,9H)-tetraon [38]. It is obtained by heating 1,3-dimethylbarbituric acid with 3-chromoncarbaldehyde, first in a mixture with pyridine and triethylamine, and then in acetic acid containing sulfur. As noted above, available sources contain no information on its biological activity.
OBJECT OF THE INVENTION
The object of the invention is to create new substances having antimicrobial, antiviral immunomodulating and antitumor activities.
ESSENCE OF THE INVENTION
The object of the invention is achieved by the synthesis of novel compounds—derivatives of pyrano[2,3-d:6,5-d′]dipyrimidine of general formula:
where:
R
1
is selected from the group HYDROXY GROUP, MERCAPTO GROUP, HALOGEN,
R
2
is selected from the group HYDROXY GROUP, ALKOXY GROUP, HALOGEN,
R
3
is selected from the group HYDROGEN, ARYL.
The best variants of the claimed substances are when
R
1
= R
2
= OH, R
3
= 4-O
2
NC
6
H
4
(I),
R
1
= R
2
= Cl, R
3
= C
6
H
5
(II),
R
1
= R
2
= OH, R
3
= 4-IC
5
H
4
(III),
R
1
= R
2
= OH, R
3
= H
(IV),
R
1
= OH, R
2
= OCH
3
, R
3
= 4-O
2
NC
6
H
4
(V),
R
1
= R
2
= OH, R
3
= 4-ClC
6
H
4
(VI),
R
1
= R
2
= OH, R
3
= 4-BrC
6
H
4
(VII),
R
1
= SH, R
2
= OH, R
3
= 4-ClC
6
H
4
(VIII),
R
1
= SH, R
2
= OH, R
3
= 4-O
2
NC
6
H
4
(IX).
It should be noted at once that the use of other representatives of the alkoxy group, the mercapto group, halogens and aryls does not differ in principal in the synthesis process or in the biological activities of the substances obtained, i.e., it is not the specific elements in the R
1
, R
2
and R
3
radicals that are of importance, but that they belong to the groups cited in the general formula.
The proposed best variants are listed in the table that follows for clarity.
Variant
R
1
R
2
R
3
I
OH
OH
4-O
2
NC
6
H
4
II
Cl
Cl
C
6
H
5
III
OH
OH
4-IC
5
H
4
IV
OH
OH
H
V
OH
OCH
3
4-O
2
NC
6
H
4
VI
OH
OH
4-ClC
6
H
4
VII
OH
OH
4-BrC
6
H
4
VIII
SH
OH
4-ClC
6
H
4
IX
SH
OH
4-O
2
NC
6
H
4
The general formula of the claimed substances and all of the variants of specific compounds listed above are new, and are not known to us from available sources of information. Furthermore, their synthesis and the existence of marked biological activity in them does not follow obviously from the current level of technology, i.e., they are not obvious to one skilled in the art.
REFERENCES:
patent: 4272534 (1981-06-01), Blythin
patent: 1952179 (1996-01-01), None
patent: 0541404 (1993-12-01), None
Moskvin, A. V.; Sibgatullina, A. A.; Ivin, B. A., Russian J. Gen. Chem., 65(12) 1995, 1878-1882.*
Moskvin, A.V. et al., “Azoles and Azines: CVII. Synthesis of 5H-Pyrano[3-d:6,5-d]-dipyrimidine-2,4,6,8(1H,3H,7H,9H)-tetraones and Their 2,8-Dithio Analogs,”Russian Journal of General Chemistry:1300-1305 (1998).
Gibbons, Del Deo, Doan, Griffinger & Vecchione
McKenzie Thomas C
Natural Drug Sciences LLC
Shah Mukund J.
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