JPS59210071A - Antiviral compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] The present invention relates to a compound having antiviral activity.

In general, one aspect of the present invention is the following formula (1): (wherein each R
21- is independently H or σ lower alkyl group (having 6 or less carbon atoms);

Each R3σ is independently H-1: lower alkyl group.

RogeH is a lower alkyl group.

R1 and H are lower alkyl groups.

n represents the number 1 to 11.

Representation of the number y11' of m1n-2 to 2n.

Change the number of O or O.

The number of 2 and 1 is expressed, and then.

q represents a number from p to 2p.

Each of n + ffl + p and q is selected such that the SP3 bond trajectory of each carbon atom in each ring is satisfied. ) It relates to a compound having an antiviral effect in vivo and a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the antiviral compound of formula (1) 1/J 2-amino-4-oxo-5,6,7,8-
Tetrahydro-quinazoline; 2-amino-5,6,7,
8゜9-pentahydrocyclohebuta(d”lpyrimidin-4-ol; also(rgo2-amino-5,6,7,8
,9°10.11.12.1ro.14-decahydro-cyclododeca(d)pyrimidin-4-ol.

In another aspect, the present invention provides the following formula (2): (wherein, X1
j(C[4z)n, cii□ GH, CHzS or 汀C
)120 Beggar.

n represents the number from 1 to Otsu.

R4 represents a lower alkyl group, R3 and H1 lower alkyl groups, lower alkoxy groups (lower alkyl groups that also include oxygen atoms), nitrogen atoms, cm
Nitro group, amine group, i-class alkylamino group, lower dialkylamine group, lower alkyl-amino group, carboxyl group, lower alkoxycarbonyl group (containing 2 ester bonds)' f Table hL, 4-(iL , X is (C)h
) In the case of 2, it cannot be R3keh. 2-amino-4-oxo- 5,6,7-trihydrobenzocyclohebuta(5,6-d)-pyrimidine.

In another aspect, the present invention provides the following formula (3): (wherein, The present invention relates to a compound having an antiviral action and a pharmaceutically acceptable salt thereof.

One product was invented at Naka's production site, and a virus infection occurred.

Especially herpes infections, especially herpes simplex type 2 (herpes simplex type 2)
pes simplex type ll) antiviral effective amount of 2-amino-4-oxo-ro, 4.5.6-titrahydrobenzo(h') quinazoline and its pharmaceutically acceptable dosage. It relates to a method of treatment by administering salt.

This compound has two strong antiviral activities.

It is chemically stable, non-persistent to dancing mammals, and does not decompose inside the helmet. This compound is particularly useful in immunocompromised patients such as those infected with viruses, such as cancer patients.

It is particularly useful for patients at risk of infection with herpes simplex type 2 quills.

Other features and advantages of the present invention are mentioned below, which will become apparent from the preferred embodiments and the claims.
1, and the preferred compounds are as described above.

Compounds of the invention (all having an aminopyrimidone ring fused to a non-aromatic) may also have a third ring.

For (L compounds of formula (1), if no third ring is present, the non-aromatic ring can have up to 15 carbon atoms.

to the second fR if the third imaginary exists.

In general, it has fewer carbon atoms, i.e. 6 i or fewer carbon atoms, i.e. 1 in 71 and 2 if p is greater than 0.

In addition to the compound of the present invention, the scientifically measured volume of Shiurosalt is:
Administered alone and together with a carrier
-You can do something.

Examples of acceptable salts are hydrochloric acid, aqueous bromide, and succinic acid. 1 Salt with maleic acid and fumaric acid, or salt with potassium hydroxide, sodium hydroxide and dicyclohexylamine? For oral administration, K is included in the Kuwabata composition of the present invention.

5 Compositions, which may most conveniently be in the form of capsules or tablets; 1; Oral liquid formulations; 1; Compounds of the invention; It can also be provided in the form of creams, powders, and sprays.

Let me explain based on the drawings: (Well, a flexible sheet 10 consisting of a fibrous absorbent star is impregnated with the antiviral compound of the above-mentioned invention diluted with a carrier, for example, distilled water, if desired. Clancy, U.S. Pat. No. 5,398,826, which is incorporated herein by reference.
Williams) U.S. Patent No. 3,057.4
It is folded and placed in a rectangular sealed gas-impermeable fading device 2 with a fused periphery 14 in a manner similar to that described in the '67 patent. For example, the technique disclosed in Bauer U.S. Pat. No. 5,786,615 (1).
(one of which is hereby incorporated by reference for reference).

Formula of the present invention +IJ, +2! Alternatively, (to prepare the compound represented by 31), the appropriate alpha-keto ester and guanidine carbonate may be passed through a mixed tube in xylene overnight, and the final product may then be collected from house to house for purification.

If this alpha-keto ester is not commercially available, it can be prepared by any method of godliness, such as reaction with a cyclic ketonon diethyl oxalate, followed by hot fraction j14j7:I.

Alternatively, a commercially available alpha-keto acid, such as camphorcarboxylic acid, may be esterified or bulked with diethyl carbonate and a suitable bath medium, such as evaporated alcohol, xylene, or toluene. It can be produced by reaction in the presence of m-guanidine salt at ambient temperature.

General references for the synthesis of alpha-ketoesters include ThePyrimid/Synthesis.
inar ') J + A, We + ssberg
er+ Ed.

Interscientcp,+New York+
196:2; J, Org.

Ghem, 3 [1, 1837 (1965): J.O.
rg.

Chpm, 63.4288 (1968);
t, Ghem.

7 * 197 (1970); J, Het, Ch
em, + 15 + 675 + 1976); Org,
Syn, 47.20 (1967), etc.

Another method for producing compounds of formulas (1), (2) and (3) is to combine bulk ketones and dicyandiamide in the presence or absence of a suitable bath medium, such as dimethylformamide, ethoxyethoxyethanol. 2.4-
Manufactured from diaminopyrimidine derivatives.

Then, one amine group is selectively hydrolyzed.

The following is an explanation of the production of specific compounds using examples. Example The compound of formula (1) is produced as follows.

2-Amino-4-oxo-5,6,7,8-tetrahydroquinazolineethyl-2-cyclohexanone carboxylate (2
, []y-) and guanidine carbonate (2,66F) in xylene (40 ml).

After cooling, the solid was collected by filtration, washed with water and methanol, and dried over Mg304. Touch point>6000C white solid 0.6? was recovered. This product was dissolved in concentrated hydrochloric acid, and the excess 1 (Cj) was removed and dried. The gummy residue was treated with methanol-ether to give colorless plates with 0.71%
'f got it.

Ethyl-2-cycloheptanone self-cutting lupoxylate) (
A mixture of 880 Ing) and carbon guanidine (950 ■) in xylene (20 rnl) was refluxed overnight. After cooling, a white solid was collected by filtration, washed with water, and dried.

The crude product was recrystallized from methanol. Mass Spect/
l/: 179 (mol, ion).

-4-All xylene 5Qm! , and ethyl-2-cyclododecanone carboxylate 4.0? and guanidine carbonate)
The mixture with 3.121 was refluxed overnight. After cooling, remove the white solid, wash with water, and recrystallize with ethanol to obtain 2.1
5? A white powder of 50 ml of xylene and ethyl-2 was obtained.
-cyclooctanonecarpogysylate 3.55' and guanidine carbonate) 3.82 Ljt was refluxed overnight. After cooling, a white isomorphic compound was washed, washed with water, and dried to obtain a 2.010 product, which was prepared as follows.

250m1 with dropping funnel and water-cooled condenser installed
(50% NaH under nitrogen atmosphere in a three-necked flask)
First, by adding 3.4fI-' mineral oil dispersion, 2
Preparation 2 of -ethoxycarbonyl-1-penzosuberone was carried out. The mineral oil was removed by washing several times with dry benzene, and the residue was removed with 64 ml of dry benzene;
did. Then 5.9 Pv (diethyl carbonate) was added at once. After reflux.

1-penzosuberone (4) was added to the mixture for 6 hours.
The mixture was treated by adding 100 ml of dry benzene (1ON) and continued fast flow for an additional 0.5 h. The mixture was cooled to a base, treated with 5M acetic acid and 17 hours of ice water to dissolve the solids, then the organic layer was washed several times with water and dried over MgSO3. After the bath salts were boiled, the remaining liquid was fractionally distilled to give a colorless oily product of 5.12Pη and 14F at 135-140°G and 10.3Hg.

2-Ethoxycanobonyl-1-penzosuberone 282
J and guanidine carbonate 2.62? A mixture of 5Qml of xylene and 5Qml of xylene was refluxed overnight. After cooling to room temperature, the obtained solid IF' was taken, washed with water, washed with ethanol, and then dried. The solid was dissolved in 22N HCl with heating and then cooled in a water bath. The white precipitate wtr was collected, washed with ether, and then dried to give 900 m2 of white powder. '! I got 1”.

250I with 10 drops and water cooling condenser installed
50% N under a nitrogen atmosphere in a three-bottle flask of Iu & Mushrooms.
aH mineral oil dispersion 4.65? Preparation 2 of 2-ethoxycarbonyl-1-tetralone was carried out. By washing several times with dry benzene.

Remove 1 part of the mineral oil and re-coat with 48m of dry benzene to make it cloudy, then add 8.1% of diethyl carbonate. were added all at once. After refluxing, the mixture was soaked with alpha-tetralone (5,01 dry benzene (1 m
J) Treat the mixture by adding bath liquid and further add 0
．． Reflux was continued for 2 hours for 5 hours. The mixture was cooled to room temperature and diluted with acetic acid.
The solid was dissolved by treatment with N and 23+ d of ice water, and the organic layer was then washed several times with water and dried over anhydrous Mg SO4. After evaporating the bath salts, separate the fish into the fish box, 151-1
At 57° C. and 10.2 msHg, 2.6 J of colorless oil was obtained.

A mixture of 0.651 2-ethoxycarbonyl-1-tetralone and 0.65 ii' of guanidine carbonate and 15-xylene was refluxed overnight. After cooling to room temperature, the resulting solid was removed, washed with water, washed with ethanol, and then dried to yield a brown solid with a melting point of 3 o p'c or higher (0.24 mm). Once the solid is obtained, dissolve it in hydrochloric acid, concentrate to dryness in vacuo, and add ethanol for use in mammals, eg, orally, intranasally, topically, parenterally.

When administered intravenously or as a suppository, this compound has antiviral effects, especially on the eyes, skin, and oral cavity.

This compound acts directly on the virus, as the in vivo test results are better than the in vitro test, which would be effective against the herpes simplex virus, which affects the genitals and upper respiratory tract. Rather, it is suggested that the mechanism of action is, for example, immune modulation and induction of interferon production.

This compound is expressed in mammals, for example, 25-30% compared to humans.
0 my/Kq/day, preferably 100-2[10■/
Referring again to the figure, it could be administered in an amount of kf/day. When an antiviral compound is desired for local use, the sealed envelope parent device 2 containing the impregnated towel strip 10 is torn open, the towel strip is taken out and used, and the wrapped and used towel strip is discarded.

Impregnated towel strips can be used to treat and prevent herpes simplex type 2 virus infections. For the treatment of skin lesions due to herpes, a piece of impregnated towel can be used to apply the antiviral compound to the lesion site and then discarded. To prevent herpes infections, a piece of impregnated towel can be used to apply to the area where the user has just been exposed to the herpes virus, such as the genitals during sexual intercourse.

Other embodiments are also within the scope of the invention. For example, other suitable lengths of material such as non-woven fabric may be used between the two impregnated sheets and the absorbent string. Instead of sticking one wet towel strip into a single package, it is also possible to put a number of impregnated sheets into one container, for example a jar, a tin or a tin can.

The impregnated flakes can be used to treat or prevent other viruses, such as common infections. VC for cold treatment
For example, one could impregnate a facial F+1 tissue with an antiviral compound and apply this tissue to the area to provide VC antiviral compound qf/J.

[Brief explanation of drawings]

The drawing is a cutaway plan view of g1~ of a visual device containing a towel piece impregnated with the antiviral compound of the present invention. 10...Impregnated towel piece 12...Wrapping device 4...
・Fusion Peripheral Percentage Reading Applicant: Biomajor Incorporated J”” Agent: Patent Attorney Kyozo Yuasa (4 others) Engraving of drawings (no change in content) Procedural amendment (method) 1927 ≠Mr. Kazuo Wakasugi, Commissioner of the Japan Patent Office, 1, Indication of the incident, dated 1923, 31≠ No. 1,000 needles A +V
"A <j +fJ 'e 1117i4'A";'3
1'￥)3.Relationship with the case of the person making the amendment.Applicant's address/4.
Do 4, agent

Claims (1)

[Scope of Claims] (1) The following formula (1j: H' In the C formula, each H2 is independently a lower alkyl group (number of element atoms of 6 or less). H is a lower alkyl group. H is a lower alkyl group. H is a lower alkyl group. H is a p alkyl group. n is a number from 1 to 11. The number of 2n is expressed. The number of pil-1'O to 6 is expressed. 2 represents the number of 0-1:take 1, and. (Represents the number of 1 p to 2p. The number of n+m+p and q (2) The following formula (2): (2) The following formula (2): Medium, Xage(C)]2)., CHzO4(,CH
zS represents CHzO. An expression of the number of nge1 to otsu. R4 represents a lower alkyl group. R3HH, lower alkyl group, lower alkoxy group. Halogen atom, (,=N, nitro group, amino group, alkylamino group, dialkylamine group, arylamine group,
carboxyl group, lower alkoxycarbonyl, l
&'f expression, however, in case of n or 2. It can't be R3 and B. ) or a pharmaceutically acceptable salt thereof. (3) Following formula (3): In formula C, XH(C)I2)n,C)]]2-Cday,C]
2S straddle OH20 request. An expression of the number of nge1 to otsu. H4a represents a lower alkyl group. R3σH1 lower alkyl group, lower alkoxy group. Represents a halogen atom, CEN, nitro group, ami7 group, alkylamino group, dialkylamine group, arylamino group, carboxyl group, and lower alkoxycarbonyl group. )' or a pharmaceutically acceptable salt thereof. (4) n is 2, 1m is 4, p is O, and R
o is B, Hl is B, 2 is 0, and each R
2-amino-4-oxo-5,6,7,8 where 2 is H
-Tetrahydroquinazoline and its pharmaceutically acceptable salt. (5) n is 6, m is 6, p is 0, and R
o is H, R1 is H, 2 is 0, and each R2
is H, 2-amino-5,6,7,a,9-pentahydrocyclohezuc cd) pyrimidin-4-ol and its pharmaceutically acceptable salts Claim 1
Compounds described in Section. I6) 11 is 8, 1m is 16, p is 0, Ro is H, and E(2-amino-5, where 1 is H, 2 is 0, and each R2 is H, 6,7,8゜9
．． 10.11,12.13.14-Decahydrocyclodote(d) The compound according to claim 1, which is birimicin-4-ol or a pharmaceutically acceptable salt thereof. (7) n is 4, 1m is 8, p is 0, and R
O is H, R1 is H, 2 is D, and each R2
3. The compound according to claim 1, which is pyrimidin-4-ol. (8) X is (OH2) 3 and tn')Fl'' is H and h
The compound according to claim 2, which is 2-amino-4-oxo-5,6,7-)lihydrobenzocyclohebuta(5,6-d)pyrimidine. (9) An antiviral composition comprising an antiviral effective amount of the compound described in claims 1, 2 and 3 and a pharmaceutically acceptable carrier substance. 10. The composition of claim 9 which is a pill, capsule or tablet for oral administration of the active compound to a human patient for the treatment of Qlj viral infections.