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Publication numberUS3681351 A
Publication typeGrant
Publication dateAug 1, 1972
Filing dateApr 15, 1970
Priority dateApr 15, 1970
Publication numberUS 3681351 A, US 3681351A, US-A-3681351, US3681351 A, US3681351A
InventorsIan Wellings
Original AssigneeIan Wellings
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
CERTAIN 5,6,7,8-TETRAHYDRO-5,8-ETHANO-PYRIDINO{8 2,3-b{9 -THIENO{8 5,4-d{9 PYRIMIDINES
US 3681351 A
Abstract
This invention relates to a novel class of ethanopyridinothienopyrimidines which possess antiviral activity against viruses having a core of double stranded D.N.A. Specifically, the compounds of the invention exhibit antiviral activity against Herpes simplex/H4 virus, Herpes simplex/2 Ala./SM virus, pseudorabies virus, vaccinia virus, vesicular stomatis and adenovirus based on experimental data in warm-blooded animals and birds, (animals possessing the homeostatic mechanism).
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Description  (OCR text may contain errors)

United States Patent Wellings [is] 3,681,351 [451 Aug. 1, 1972 [54] CERTAIN 5.6.7,8-TETRAHYDRO-5,8- ETHANO-PYRIDINO[2,3-B]-THIENO[ 5 ,4-D]PYRIMIDINES [72] Inventor: Ian Wellings, 1713 Shadybrook Rd,

Wilmington, Del. 19803 [22] Filed: April 15, 1970 [21] Appl. No.: 28,959

[52] US. Cl. ..260/256.5 R, 260/2948 B, 424/251 Frobisher, Fundamentals of Microbiology, 8th Edition, Saunders, Page 234, 1968, QR 46 F 76 Carcinogenisis Abstracts Vol. 8, No. 1, July 1970, Item No. 0187, RC 261 Al C.3

Primary Examiner-Alan L. Rotman Attorney-Gerald A. Hapka [5 7] ABSTRACT This invention relates to a novel class of ethanopyridinothienopyrimidines which possess antiviral activity against viruses having a core of double stranded DNA. Specifically, the compounds of the invention exhibit antiviral activity against Herpes simplex/l-14 virus, Herpes simplex/2 Ala./SM virus, pseudorabies virus, vaccinia virus, vesicular stomatis and adenovirus based on experimental data in warmblooded animals and birds, (animals possessing the homeostatic mechanism).

3 Claims, No Drawings 3 ,68 1 ,3 1 1 2 CERTAIN 5,6,7,8-TETRAHYDRO-5,8-ETHANO- possess some antiviral activity against infections caused PYRIDINO [2,3 B]-THIENO [5,4-D] PYRIMIDINES by RNA type viruses, such as arbovirus.

Illustrative of the compounds of this invention are SUMMARY OF THE INVENTION the following: This invention relates to compounds of the formulas: 5 5,6,7,8-tetrahydro-5,8-ethanopyridino[2,3-b]thieno [5 ,4-d]pyrimidine-4-amine 5 if 5,6,7,S-tetrahydro-S,8-ethanopyridino[2,3-b]thieno 3 [5,4-d]-pyrimidine-4-ol O 5,6,7,8-tetrahydro-5,8-ethanopyridino[2,3-b1thieno L q J I [5,4-d]-pyrimidine-4-thiol i 1 N-methyl-S,6,7,8-tetrahydro-5,S-ethanopyridino whe re [2,3-b ]thieno-[ 5 ,4-d]pyrimidine-4-amine.

N-all 1-5 ,6,7,8-tetrah dro-5,8-ethano ridino[2,3- R1 hydmgen of b ]t hieno-[5,4-d]pyi' imidine-4-amin H N-propargyl-5,6,7,8-tetrahydro-5,8-ethanopyridino [2,3-b ]thieno- 5 ,4-d] pyrimidine-4-amine 5,6,7,8-tetrahydro-5,8-ethanopyridino[2,3-b]thieno wlhelre R is hydrlogen, alkyl of one to six carbon atoms, 5 i gjggggi g zi gspy p 3 b]thieno ayorpropargy;

R is hydrogen, alkyl of one to four carbon atoms,

OH or and the pharmaceutically 5,6,7,8-tetrahydro-5,8-ethanopyr1d1no[2,3-b]th1eno ceptable salts of said compounds; and s4'dlpynml'dme'2'thlol N-ethyl-S,6,7,8-tetrahydro:5,8-ehtnaopyr1d1no[2,3- (II) NH b]th1eno-[5,4-d]pynm1d1ne-2-am1ne 5 4 H N-isopropyl-S ,6,7,8-tetrahydro-5,8-ethanopyridino sin. [2,3-b1thieno-[5,4-d]pyrimidine-2-amine l k 5 ,6,7,S-tetrahydro-Z-methyl-S,8-ethanopyridino[2,3 I N SAN/ R5 -b]thieno-[5,4-d]pyrimidine-4-amine s l 5,6,7,8-tetrahydro-5,8-ethanopyridino[2,3-b]thieno [5 ,4-d]-pyrimidine 2,4-diamine where 2-amino-5,6,7,8-tetrahydro-5,8-ethanopyridino[2,3- R, 1s alkyl of one to four carbon atoms, phenyl of b]thieno 5y4 d]pyrimidine 4 ol NH2 R5 15 hydrogen alkyl of one to four 4 amino-5,6,7,8-tetrahydro-5,8-ethanopyridino[2,3- atoms, 6 Where 6 18 b]thieno-[5,4-d]pyrimidine-2-ol hydmgen' alkyl of one SIX awms, allyl or 2-amino-5,6,7,8-tetrahydro-5,8-ethanopyridino[2,3- propargyl; and the pharmaceutically acceptable bhhieno [5,4 dlpyrimidine 4 thiol Salts fsa1d COmPOunds' 3,4,5,6,7,8-hexahydro-4-imino-3-methyl-5,8-

This invention also relates to a method for con- 40 ethanopyr1d1no-[5,4-d]th1eno[4,5-b]pyr1m1d1ne trolling virus infections of warm-blooded anlmals 3A56y7,g hexahydro 4 imino 3 phenyl 5,8

which comprises administering to said animal an antiviral effective amount of a compound of this invenethanopyndmo'[z3 bithieno[SAdlpynmldme tion prior to and/or during the period of exposure to i i said infection or after said animal has become infected. g gfi gg This invention further relates to harmaceutical compositions which contain an antiiliral effective 3 f dr Z amount of a compound of this invention in combinaethaxlopyndmol23'b]th1en0[5Adlpynmldme tion with suitable pharmaceutical adjuvants. 3amme 3,4,5,6,7,8-hexahydro-4-1m1no-3-methyl-5,8- DESCRIPTION OF THE INVENTION ethanopyridino-[2,3-b]thieno[5,4d]pyridinc-2-ol As summarized above, this invention relates to an- 7 f y -1m{n0-3-phenyl-5,8- tiviral active compounds of formulas (I) and (II) and ethaliopyndmol23b]thleno[54'd]pynmldme' the non-toxic acid addition salts of said compounds. Z'amme It will be understood that the term non-toxic acid adf dition salts includes those salts of the compounds of ethan Py ndm0[23'blthleno'l5Adlpynmldme formulas (I) and (II) which are suitable for administra- 23'd1amme tion to warm-blooded animals. Representative of such a y y salts are the hydrochloride, hydrobromide, sulfate, Q'PY l l lpy phosphate, acetate, nitrate, succinate, adipate, 2'amme propionate, tartrate, cyclohexylsulfamate, citrate, Ofthe above compounds the followmg are Preferred: bicarbonate and pamoate salts of said compounds. Of y PY these, the most preferred is the hydrochloride. lPy

The compounds of this invention are primarily active N methyl 5:677!8-tetrahydr0-5is ethanopyridino against infections caused by DNA type viruses such as [2,3-b]thien0-[5,4-d]pyrimidine-4-amine herpesvirus and poxvirus strains, although preliminary 3,4,5,6,7,8-hexahydro-4-imino-3-methyl-5,8-

tests indicate that the compounds of this invention also ethanopyridino-[2,3-b]thieno[5,4-d]pyrimidine It will be understood that the pharmaceutically acceptable salts of the above named compounds are also included within the scope of this invention. The term pharmaceutically acceptable salts as used herein means non-toxic acid addition salts of the compounds of this invention suitable for administration to warmblooded animals. Representative of such salts are the hydrochloride, hydrobromide, sulfate, phosphate, acetate, nitrate, succinate, adipate, propionate, tartrate, cyclohexylsulfamate, citrate, bicarbonate, and pamoate salts. Of these, the hydrochloride salt is preferred.

PREPARATION The compounds of this invention can be prepared by treating 2-amino-4,5,6,7-tetrahydro-4,7- ethanothieno[2,3b]pyridine-3-carbonitrile with triethyl orthoformate to give Z-(ethoxymethyleneamino)-4,5,6,7-tetrahydro-4,7- ethanothieno[2,3b]pyridine-3-carbonitrile. The 2- (ethoxymethyleneamino)-4,5,6,7-tetrahydro-4,7- ethanothieno[2,3b]pyridine-3-carbonitrile is treated with ammonia or an appropriate secondary amine to obtain, respectively, 5,6,7,8-tetrahydro-5,8-ethano pyridino[ 2,3-b ]thieno-[ ,4-dlpyrimidine-4-amine or the corresponding 3-substituted 3,4,5,6,7,8-hexahydro- 4-imino-5,8-ethanopyridino[2,3-b]-thieno[5,4-d] pyrimidine.

Those compounds of this invention where R is hydroxy, can be prepared by treating an ester of 2- amino-4,5,6,7-tetrahydro-4,7-ethano[2,3-b]pyridine- 3-carboxylic acid first with triethylorthoformate and then with ammonia.

The 4-hydroxy derivatives may be converted to the corresponding 4-mercapto, 4-chloro and 4-alkylamino compounds by conventional chemical techniques known to the art.

The 4-alkylamino compounds can also be prepared by rearrangement of the 3-alkyl-3,4,5,6,7,8-hexahydro- 4-imino-5,8-ethanopyridino[2,3-b]thieno[5,4- dlpyrirnidines in aqueous solution.

The 2,4-diaminoand 2-amino-4-hydroxypyrimidines, respectively, can be prepared from the corresponding 2-amino-4,5,6,'7-tetrahydro-4,7- ethanothieno[2,3b]pyridine-B-carbonitrile or a 2- amino-4,5 ,6,7-tetrahydro-4,7-ethanothieno-[ 2,3-b] pyridine-3-carboxylate ester by treating said carbonitrile or ester with guanidine.

Treatment of the Z-amino-Lhydroxypyrimidine with phosphorous oxychloride followed by catalytic hydrogenation furnishes the 4,6,7,8-tetrahydro-5,8- ethanopyridino[2,3-b]-thieno[5,4-d]pyrirnidine-2- amine.

The 2-amino-4,5,6,7-tetrahydro-4,7-ethanothieno- [2,3-b]pyridine carbonitrile starting material can be prepared by reacting malonitrile, 3-quinuclidinone, sulfur and morpholine at a temperature of about 50 C. under a nitrogen atmosphere and can be isolated by conventional techniques.

The alkyl 2-amino-4,5,6,7-tetrahydro-4,7- ethanothieno[2,3b]pyridine3-carboxylate starting material can be prepared by reacting an alkyl cyanoacetate, 3-quinuclidinone, sulfur and morpholine at a temperature of about 40 C., cooling the reaction mixture, filtering and treating the filtrate with glacial acetic oxide to give a semi-solid product which can be purified if desired.

The following Examples are presented to illustrate the method of preparing the compounds of this inven tion.

EXANIPLE l 5,6,7,8-tetra.hydro-5,8-ethanopyridino[2,3-b1thieno [5 ,4-d ]-pyrirnidine-4-amine A solution of 0.1 mole of 2-amino-4,5,6,7- tetrahydro-4,7-ethanothieno[2,3-b]pyridine-3-carbonitrile in 200 ml. of triethyl orthoformate is refluxed for 4 hours under an atmosphere of nitrogen. The excess triethyl orthoformate is removed in vacuo to give a solid residue which is recrystallized from aqueous ethanol to yield 2-(ethoxymethylenearnino)-4,5,6,7- tetrahydro-4,7-ethanothieno[2,3-b1pyridine-3-carbonitrile, m.p. 99l 00C.

A solution of 0.1 mole of this carbonitrile in 200 ml. of ethanol is added with stirring to 300 ml. of ethanol saturated with ammonia gas. The reaction mixture is cooled to 10 C. and ammonia gas is bubbled through the solution for 30 minutes. The mixture is then allowed to stir overnight at room temperature. Removal of the ethanol in vacuo yields a solid residue which is recrystallized from DMF to give 5,6,7,8-tetrahydro- 5,8-ethanopyridino[2,3-b]thieno[5,4-d]pyrimidine-4- amine, m.p. 268-270 C.

The dihydrochloride of this compound is prepared by passing dry hydrogen chloride gas into an ethanolic solution of the base. The salt is recrystallized from ethanol/water to give 5,6,7,8-tetrahydro-5,8- ethanopyridino[2,3-b]thieno[5,4-d]pyrimi-dine-4- amine dihydrochlon'de, mp. 282284 C.

EXAMPLE 2 5 ,6,7,8-tetrahydro-5 ,8-ethanopyridino[ 2,3-b thieno [5,4-d]pyrimi-dine-4-ol A solution of 0.1 mole of ethyl 2-arnino-4,5,6,7- tetrahydro-4, 7-ethano[ 2,3-b] pyridine-3-carboxylate in 200 ml. of triethyl orthoformate is refluxed for 4 hours under an atmosphere of nitrogen. The excess triethyl orthoformate is removed in vacuo to yield ethyl 2- (ethoxymethyleneamino )-4,5 ,6,7-tetra-hydro-4,7- ethanothieno[2,3b]pyridine-3-carboxylate.

A solution of 0.1 mole of this ester in 200 ml. of ethanol is added with stirring to 300 ml. of ethanol saturated with ammonia gas. The reaction mixture is cooled to l0 C. and ammonia gas is bubbled through the solution for 30 minutes. The mixture is then allowed to stir overnight at room temperature. Removal of the ethanol in vacuo yields 5,6,7,8-tetrahydro-5,8- ethanopyridino[2,3-b]thieno[5,4-d1pyrimidine-4-ol.

EXAMPLE 3 N-isopropyl-S,6,7,8-tetrahydro-5,8-ethanopyridino [2,3-b ]thieno-{ 5 ,4-d1pyrimidine-4-arnine A mixture of 0.1 mole of 5,6,7,8-tetrahydro-5,8- ethanopyridine[2,3-b]thieno[4,5-b]pyrimidine-4-ol in 100 ml. of phosphorus oxychloride is warmed at 40 C. for 3 hours. The clear solution is cooled and poured into 400 ml. of ice and water, and the resulting solution is made basic with concentrated ammonium hydroxide solution to give a solid precipitate. The solid material is EXAMPLES 4-6 The procedure of Example 3 is repeated, substituting the indicated amine for the isopropylarnine of Example 3 to obtain the indicated product.

Example Amine Product 4 ethylamine N-ethyl-S ,6,7,8-tetrahydro-5 ,8-

ethanopyridino[2,3-b]thieno- [5,4-d1pyrimidine-4-amine.

N-hexyl-5,6,7,8-tetrahydro-5 ,8- ethanopyridino[ 2,3-b1thieno- [5,4-d]pyrimidine4-amine N-allyl-S,6,7,8-tetrahydro-5,8-

ethanopyridino[ 2,3-b1thieno- [5 ,4-d ]pyrimidine4-amine 5 hexylamine 6 allylamine EXAMPLE 7 5,6,7,8-tetrahydro-5,8-ethanopyridino[2,3-b]thieno [5 ,4-d]-pyrimidine-4-thiol A mixture of 0.1 mole of 5,6,7,8-tetrahydro-5,8- ethano-pyridino[2,3-b]thieno[4,5-b]pyrirnidine-4ol and 20.0 gm. of phosphorus pentasulfide in 250 m1. of xylene is stirred vigorously and refluxed for 2 hours. The mixture is then cooled in an ice-bath and an excess of 10 percent sodium hydroxide solution is added dropwise. The mixture is stirred for an additional minutes and then filtered to give a residue of 5,6,7,8- tetrahydro-5,8-ethanopyridino[2,3-b]thieno[5,4- d]pyrimidine-4-thiol.

EXAMPLE 8 5,6,7,8-tetrahydro-2-methyl-5,8-ethanopyridino[2,3-b ]thieno-[5,4-d]pyrimidine-4-amine A solution of 0.1 mole of 2-amine-4,5,6,7- tetrahydro-4,7-ethanothieno[2,3-b]pyridine-3-carbonitrile in 200 ml. of triethyl orthoacetate is refluxed for 4 hours under an atmosphere of nitrogen. The excess triethyl orthoacetate is removed in vacuo to give a solid residue which is recrystallized from pentane to yield 2-( l-ethoxyethyleneamino)-4,5,6,7-tetra-hydro- 4,7-ethanothieno[2,3-b]pyridine-3-carbonitrile, m.p. 87-88C.

A solution of 0.1 mole of this carbonitrile in 200 ml. of ethanol is added with stirring to 300 ml. of ethanol saturated with ammonia. The reaction mixture is cooled to 10C. and ammonia gas is bubbled through the solution for 30 minutes. The mixture is then allowed to stir overnight at room temperature. Removal of the ethanol in vacuo yields a solid residue which is recrystallized from DMF to give 5,6,7,8-tetrahydro-2- methyl-5,8-ethanopyridino[2,3-b]thieno[5,4-d] pyrimidine-4-amine, m.p. 26 l -262C.

The dihydrochloride of this compound is prepared by passing dry hydrogen chloride gas into an ethanolic solution of the base. The salt is recrystallized from ethanol/water to given 5,6,7,8tetrahydro-2-methyl-5,8- etahnopyridino[2,3-b]thieno-[5,4-d]pyrimidine-4- amine dihydrochloride, m.p. 279280C.

EXAMPLE 9 5,6,7,8-tetrahydro-5,8-ethanopyridino[2,3-b]thieno [5,4-d]-pyrimidine-2,4-diamine A solution of sodium methoxide in methanol is prepared by dissolving 0.10 g-atom of sodium in 150 ml. methanol. To this solution is added 0.11 mole of guanidine hydrochloride and the mixture is refluxed for 30 minutes. The mixture is filtered and 0.03 mole of 2- amino-4,5,6,7-tetrahydro-4,7-ethanothieno-[2,3-b] pyridine-3-carbonitrile is added to the filtrate and the mixture is then refluxed for 30 minutes. On cooling, a precipitate is formed which is removed by filtration and dried to yield 5,6,7,8-tetrahydro-5,8-ethanopyridino[ 2,3-b]thieno[5,4-d]-pyrimidine-2,4-diamine.

EXAMPLE l0 2-amino-5,6,7,8-tetrahydro-5,8-ethanopyridino[2,3-b ]thieno-[5,4-d]pyrimidine-4-ol By substituting ethyl 2-amino-4,5,6,7-tetrahydro-4,7 -ethano[2,3]-b]pyridine-3 carboxylate for the 2- amino-4,5,6,7-tetrahydro-4,7-ethano[2,3-b]pyridine- 3-carbonitrile employed in Example 9, the corresponding 2-amino-5 ,6,7,8-tetrahydro-5 ,8- ethanopyridino[2,3-b]thieno[5,4-d]pyrimidine-4-ol is obtained.

EXAMPLE 1 l 5,6,7,8-tetrahydro-5,8-ethanopyridino[2,3-b]thieno [5,4-d]-pyrimidine-2-amine A mixture of 0.1 mole of 2-amino-5,6,7,8- tetrahydro-S ,8-ethanopyridino 2,3-b]thieno[ 5 ,4-d] pyrimidine-4-ol in ml. of phosphorus oxychloride is warmed at 40 C. for 3 hours. The clear solution is cooled and poured into 400 ml. of ice and water, and the resulting solution is made basic with concentrated ammonium hydroxide solution to give a solid precipitate. This solid material is removed by filtration and dried to give 4-chloro-5,6,7,8-tetrahydro-S,8- ethanopyridino[2,3-b]thieno-[5,4-d]pyrimidine-2- amine.

To a solution of 0.1 mole of this chloro compound in 400 ml. of methanol is added 10.0 gm. of potassium hydroxide, 5.0 gm. of 5 percent palladium -oncalcium carbonate catalyst and a trace of 5 percent palladium oncarbon catalyst. This mixture is hydrogenated at 40 psi. for 2 hours, the catalysts are removed by filtration and the filtrate is concentrated to a volume of 100 ml. The addition of 50 ml. of water precipitates a solid which is removed by filtration and dried to give 5,6,7,8- tetrahydro-5,8-ethanopyridino[2,3-b]thieno[2,3-b]- thieno[5,4-d]pyrimidine-2-amine.

EXAMPLE A solution of 0.1 mole of 2-(ethoxymethyleneamino)-4,5,6,7-tetrahydro-4,7- ethanothieno[2,3b]pyridine-3-carbonitrile in 200 ml. of ethanol is added with stirring to 300 ml. of ethanol saturated with methylarnine gas. The reaction mixture is cooled to 10 C. and methylamine gas is bubbled through the solution for 30 minutes. The mixture is then allowed to stir overnight at room temperature. Removal of the ethanol in vacuo yields a solid residue which is recrystallized from acetonitrile to give 3,4,5,6,7,8-hexahydro-4-imino-3-methyl-5,8- ethanopyridino{2,3-b]thieno[5,4-d]pyrimidine, m.p. 178-180C.

EXAMPLE 13 3 ,4,5 ,6 ,7,8-hexahydro-4-imino-3-phenyl-5 ,8- ethanopyridino[2,3-b]-thieno[5,4-d]pyrimidine By substituting aniline for the methylarnine employed in Example 12, the corresponding 3,4,5,6,7,8- hexahydro-4-imino-3-phenyl-5,8-ethanopyridino[2,3- b]thieno[ ,4-d ]pyrimidine is obtained.

EXAMPLE 14 3,4,5,6,7,8-hexahydro-4-imino-5,8-ethanopyridino[2,3 -b] thieno-[ 5 ,4-d] pyrimidine-3-amine A solution of 0.1 mole of ymethyleneamino )-4,5 ,6,7-tetrahydro-4,7- ethanothieno[2,3blpyridine-3-carbo-nitrile in 200 ml. of ethanol is added with stirring to 20 ml. of 95 percent hydrazine hydrate. After minutes a precipitate is formed and the mixture is stirred for two hours at room temperature.

The precipitate is removed by filtration and recrystallized from ethanol to give 3,4,5,6,7,8-hexahydro-4-imino-5,8-ethanopyridino[2,3-b]thieno[5,4- d]pyrimidine-3-amine, mp. 202204C.

EXAMPLE l5 N-methyl-S,6,7,8-tetrahydro-5,8-ethanopyridino[2,3- b]thieno-[5,4-d]pyrimidine-4-amine A solution of 0.1 mole of 3,4,5,6,7,8-hexahydro-4- imino-3-methyl-5,8-ethanopyridino[2,3-b]thieno[5,4- d]pyrimidine in 250 ml. of water is stirred and refluxed for 2 hours. After this time, a white precipitate has formed. The solid product is removed is removed by filtration and recrystallized from acetonitrile to give N- methyl-S ,6, 7 ,8-tetrahydro-5 ,8-ethanopyridino[ 2,3-b] thieno[5 ,4-d]pyrimidine-4-amine, mp. 21 1-2 l 2 C.

EXAMPLE 16 2-(ethox- 2-( l ethox- EXAMPLE t7 3,4,5,6,7,8-hexahydro-4-imino-3-methyl-5,8- ethanopyridino[2,3-b]-thieno[5,4-d]pyrimidine-2-ol A solution of 0.1 mole of 2-amino-4,5,6,7- tetrahydro-4,7-ethanothieno[ 2,3-b1pyridine-3-carbonitrile in 200 ml. of pyridine is treated with a solution of 0.1 mole of methyl isocyanate in 20 ml. of pyridine. After stirring overnight at room temperature, the reaction mixture is poured into 500 ml. of water to give a solid product which is removed by filtration and dried to yield 2-( 3-methyIureido)-4,5,6,7-tetrahydro-4,7- ethanothieno[2,3-b]pyridine-3-carbonitrile, mp. 219- 221 C.

A solution of 0.1 mole of this nitrile anO.l mole of sodium methoxide in 300 ml. of dimethylformamide is heated at C. for 1 hour. The reaction mixture is then concentrated and treated with 200 ml. of water to give a solid product. This material is recrystallized from aqueous dimethylformamide to yield 3,4,5,6,7,8-hexahydro-4-irnino-3-methyl-5 ,8-ethanopyridino-[ 2,3- b]thieno[5,4-d]pyiimidine-2-ol.

EXAMPLE 1 8 N-ethyl-3 ,4,5 ,6,7,8-hexahydro-4-imino-3-methyl-5 ,8- ethanopyridino-[ 2, 3-b] thieno[ 5 ,4-d]pyrimidine-2- amine A mixture of 3,4,5,6,7,8-hexahydro-4-imino-3- methyl-5,8-ethanopyridino[ 2,3-b]thieno[ 5,4- b]pyrimidine-2-ol in 100 ml. of phosphorus oxychloxide is warmed at 40 C. for 3 hours. The clear solution is cooled and poured into 400 ml. of ice and water, and the resulting solution is made basic with concentrated ammonium hydroxide solution to give a solid precipitate. This material is removed by filtration and dried to give 2-chloro-3,4,5,6,7,8-hexahydro-4- imino-3-methyl-5 ,8-ethanopyridino-[ 2,3-b] -thieno [5 ,4-d ]pyrimidine.

A solution of 0.1 mole of this chloro compound and 0.1 mole of ethylamine in ml. of toluene is refluxed for 6 hours. After cooling, the precipitate is removed by filtration, dissolved in the minimum amount of water and the solution made basic with concentrated potassium carbonate to give a precipitate. This product is filtered off, dried and dissolved in ethanol and the solution saturated with dry hydrogen chloride gas to give N- ethyl-3,4,5,6,7,8-hexahydro-4-imino-3-methyl-5,8- ethanopyridino-2,3-b ]thieno[ 5 ,4-d]pyrimidine-2- amine dihydrochloride.

The compounds of formulas (I) and (II) can be employed in pharmaceutical compositions according to the present invention in dosage forms suitable for oral, parenteral or topical administration.

in such compositions, the active ingredient will ordinarily always be present in an amount of at least 0.5 percent by weight based on the total weight of the composition and not more than 90 percent by weight. in addition to the active ingredient the antiviral compositions of this invention will contain a solid or liquid nontoxic carrier for the active ingredient and where applicable suitable pharmaceutical adjuvents or modifiers.

It will be understood that phramaceutical compositions for oral administration include divided powders, tablets, capsules, pills, solutions, emulsions, suspensions and the like.

It will be understood that pharmaceutical compositions for parenteral administration include sterile solutions, suspensions, powders for solution or suspension, pellets for implantation and the like.

It will be understood that pharmacuetical compositions for topical application include solutions, suspensions, ointments, jellies and the like.

One embodiment of a pharmaceutical composition of this invention is a gelatin capsule for oral adminstration containing from about 1-50 percent of a compound of this invention, such as 5,6,7,8-tetrahydro-5,8- ethanopyridino 2,3-b thieno-[ ,4-d ]pyrimidine-4- amine, and from about 99-50 percent of a suitable pharmaceutical carrier. In another embodiment, the active ingredient is tableted with or without adjuvants. In yet another embodiment, the active ingredient is formulated as a divided powder and employed. In these capsules, tablets and powders, the active ingredient will generally constitute from about 5 percent to about 99 percent by weight and preferably from percent to 90 percent by weight of the finished formulation.

Another embodiment of a pharmaceutical composition of this invention is a sterile solution for parenteral administration containing from 0.05 percent to 10 percent by weight, and preferably from 0.1 to 1 percent by weight of a compound of this invention such as 5,6,7,8- tetrahydro-S,8-ethanopyridino[2,3-b]-thieno[5,4- d]pyrimidine-4-amine hydrochloride dissolved in sterile water. Alternatively, the pharmaceutical carrier can be a sterile oil such as peanut oil, soybean oil, mineral oil, sesame oil and the like.

In general, water, saline, aqueous dextrose and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are the preferred liquid carriers for injectable solutions when the salts of the active ingredient are to be administered When a parenteral dosage form of the free base, especially those compounds of this invention that do not readily form pharmaceutically acceptable salts, is desired, those oils hereinbefore enumerated are the most preferred pharmaceutical carriers.

The active ingredient can be prepared for oral administration in a suitable suspension or syrup, in which the active ingredient ordinarily will constitute from about 0.5 percent to 10 percent and preferably 2 percent to 10 percent by weight. The pharmaceutical carrier in such composition can be a watery vehicle such as an aromatic water, a syrup or a pharmaceutical mucilage.

The active ingredient can be prepared for topical ad ministration in a suitable solution, suspension, liquid emulsion, ointment, paste or jelly in which the active ingredient ordinarily will constitute from about 0.5 to 10 percent by weight. The pharmaceutical carrier in such topical compositions can be water; an organic solvent such as glycerin; a suitable emulsion or a suitable ointment base such as petrolatum, hydrophilic ointment, a jelly or the like.

Suitable pharmaceutical carriers are described in Remington Pharmaceutical Sciences" by E. W. Martin, a well known reference text in this field.

In addition to the exemplary illustrations above, the following examples further explain one aspect of the present invention.

EXAMPLE19 A large number of unit capsules are prepared for oral administration by filling standard two-piece hard gelatin capsules with 50 milligrams of powdered N- allyl-5,6,7,8-tetrahydro-5,8-ethanopyridino[2,3- b]thieno[5,4-d]pyrimidine-4-amine hydrochloride, 125 milligrams of lactose and l milligram of Cab-osil finely divided silica.

EXAMPLE 20 A large number of compressed tablets are prepared by conventional procedures so that the dosage unit is 5 milligrams of 3,4,5,6,7,8-hexahydro-4-imino-3-methyl- 5,8-ethano-pyridino[2,3-b]thieno[5,4-d]pyrimidine, 5 milligrams of gelatin, 1.5 milligrams of magnesium stearate and milligrams of lactose.

EXAMPLE 21 A parenteral composition suitable for administration by injection is prepared by mixing 0.25 percent by weight of N-propargyl-S ,6,7,8-tetrahydro-5 ,8- ethanopyridino[2,3-b]thieno[5,4-d]pyrimid-dine-4- amine with sterile soybean oil.

EXAMPLE 22 A composition for topical application is prepared by triturating 10 percent by weight of 5,6,7,8-tetrahydro- 5,8-ethanopyridino[2,3-b]thieno[5,4-d]pyrimidine-4- amine in hydrophilic ointment, U.S.P.

A large variety of compositions according to this invention can thus readily be made by substituting other compounds of this invention, and including specifically but not limited to compounds of this invention that have specifically been named hereinbefore. The compounds will be used in the amounts indicated in accordance with procedures well known and described in the Martin text mentioned above.

The compounds of this invention have been found to possess antiviral activity against viruses having a core of double-stranded DNA. Specifically, the compounds exhibit antiviral activity against virus types such as herpes virus infections, poxvirus infections and adenovirus infections.

The compounds of this invention can be used for the prevention, treatment of mitigation of virus infections of warm-blooded animals such as caused by Herpes simplex/H4 virus, Herpes simplex/Z/Ala/SM virus, pseudorabies virus, vaccinia virus, vesicular stomatitis and adenovirus.

It will be understood that a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.

The compounds of this invention can be administered in the antiviral treatment according to this invention by any means that effects contact of the active ingredient compound with the site of virus infection in the body of a warm-blooded animal. It will be understood that this includes the site prior to infection setting in as well as after. For example, administration can be by the parenteral, topical or oral route.

The antiviral effectiveness of the compounds of this invention can be demonstrated against Herpes virus when a medium containing at least meg/ml. of 5,6,7,8-tetrarhydro-5,8-ethanopyridino[2,3-b1thieno [5,4-d]pyrimidine-4-amine is applied to rabbit kidney cells which have been infected with 200 plaque forming units of Herpes simplex/H4/virus with the result that complete inhibition of the cytophathic effect of the virus is noted.

In another test for antiviral activity, chick embryo cells were grown to confluency 24 hours). The growth media above the monolayer was removed and replaced with 5 ml. of new media containing 60 mcg/ml of 5,6,7,8-tetrahydro-5,8-ethano-pyridino[2,3- b]thieno[5,4-d]pyrimidine-4-amine. This preparation was incubated for 24 hours, after which 200 plaque forming units of vesicular stomatitis virus are added. The media containing virus and compound is stirred moderately and incubated an additional 72 hours. At the conclusion of the incubation period, monolayers in the presence of test compound plus virus appear completely normal, while the monolayers incubated with virus but with no test compound present, appear totally destroyed by virus. The result demonstrates that the test compound effectively inhibits the cytopathic effect of the virus on chick embryo cells.

In yet another test for antiviral activity, it has been observed that guinea pigs infected subcutaneously with herpes virus hominis develop skin lesions. It has also been observed that the number of lesions is significantly lowered when ethanopyridino[2,3-b]thieno[5,4-d]-pyrimidine-4- 5,6,7,8-tetrahydro-5,8- 3O amine is applied topically once a day for four days after infection when compared to the number of lesions observed in similarly infected guinea pigs which received no drug.

I claim:

1. A compound of the formula R is hydrogen, OH, SH, or -NHR where R is hydrogen, alkyl of one through six carbon atoms, allyl or propargyl;

R is hydrogen, alkyl of one through four carbon atoms, -OH, SH or NH and the pharmaceutically acceptable salts of said compounds.

2. The compound of claim 1 which is 5,6,7,8- tetrahydro-S ,8-ethanopyridino[ 2,3-b]thieno[ 5 ,4- d]pyrimidine-4-amine and a pharmaceutically acceptable salt of said compound.

3. The compound of claim 1 which is N-methyl- 5,6,7,8-tetrahydro-5,8-ethanopyridino[2,3-b]thieno [5,4-d]pyrirnidine-4-amine and a pharmaceutically acceptabie salt of said compound.

Non-Patent Citations
Reference
1 *Carcinogenisis Abstracts Vol. 8, No. 1, July 1970, Item No. 0187, RC 261 Al C.3
2 *Frobisher, Fundamentals of Microbiology, 8th Edition, Saunders, Page 234, 1968, QR 46 F 76
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4174396 *Apr 3, 1978Nov 13, 1979Laboratories Made, S.A.Reacting 3-thienylmagnesium bromide and n-methylpyridinium iodide, acidification, analgesics
US6849638Apr 29, 2002Feb 1, 2005Bayer Pharmaceuticals CorporationPhosphodiesterase enzyme 7b (pde7b) inhibitors; treating osteoporosis, osteopenia and asthma
US6951878May 28, 2002Oct 4, 2005Novo Nordisk A/SBenzo[b]thiophenyl or tetrahydro-benzo[b]thiophenyl modulators of protein tyrosine phosphatases (PTPases)
WO1996019482A1 *Dec 20, 1995Jun 27, 1996Richard Lewis JarvestThienoxazinone derivatives useful as antiviral agents
WO1997027200A1 *Jan 22, 1997Jul 31, 1997Richard Lewis JarvestThienoxazinone derivatives useful as antiviral agents
Classifications
U.S. Classification544/247, 546/80
International ClassificationC07D495/22
Cooperative ClassificationC07D495/22
European ClassificationC07D495/22