United States Patent

[19]

[11 ] [45]

4,008,243 Feb. 15, 1977

Wikel et ale

""

. ........, .

[54] ANTIVIRAL THIAZOLINYL OR THIAZINYL BENZIMIDAZOLE ESTERS

[75] Inventors: James H. Wikel, Greenwood; Charles J. Paget, Indianapolis, both of Ind.

[73] Assignee: Eli Lilly and Company, Indianapolis, Ind.

..

[56] References Cited

UNITED STATES PATENTS

3 t 749, 71 7 7/1973 Haugwitz et at. .. 260/243 R

3,825,537 7/1974. Haugwitz et al. 260/306.7T

3,833,574 9/1974 Haugwitz et _at. 260/306.7 T

Primary Examiner Donald G. Daus

Assistant Examiner David E. Wheeler

Attorney, Agent, or Firm James L. Rowe; Everet _F. Smith

[22] Filed:

Nov. 19, 1975

[21 ] [52]

[51 ] [58]

AppL No.: 633,203

. "

u.s. Ct. . 260/306. 7 T; 2601243 R;

260/309.2; 260/454; 424/246; 424/27 B Int. CI.2 ••••••••••••••••••••••••••••••••••••••• C07D 417/04

Field of Search 260/306. 7 R, 306. 7 T,

260/243 R

[57]

ABSTRACT

•

Certain thiazolinyl or thiazinyl benzimidazole ester compounds are useful as antiviral agents.

15 Claims, No Drawings

h

..

4,008,243

. . ,

.

The incidence of viral upper respiratory disease is

immense. It has been estimated that nearly a billion cases annually appear in the United States alone. Stud-

ies performed in _ England (Tyrell and Bynoe, 1966 ) indicated that 74 percent of persons having colds were 10 infected with rhinoviruses, Because more than 80 strains of rhinoviruses are already identified, the development of a practical rhinovirus vaccine is not feasible.

In this, chemotherapy appears to the more desirable approach.

- ·-The abilityof chemical. compounds to. suppress the growth ofviruses irt vitro is .readily .demonstrated by using a virus. plaque-suppression · test s-imilar to that described. .by Siminoff, - Applied Microbiology, 9( 1 ),

66( 1961 )~ .'.:. . '~': ." _. - - _ _ -

• • I • • ••

It is an object of. this invention to provide - novel

• - • I •

thiazolinyl orthiazinyl benzimidazole esters which are

useful in suppressingthe growth of viruses, particularly Coxsackie, . echo, Mengo, .polio, rhinoviruses and, influ-

• 1_. I • •

,

enza. ., . ; .

I • I I . r 'I

Certain' thiazolinyl .orthiazinyl benzimidazole com-

I I .' • I. '-

pounds are disclosed :in the Jollowing .. references: .

U.S. Pat. No. .. 3;749,717 .disclo~esl-thiazolinyl- or I-thiaz;inyl .. 2-heterocy~~ic-benzirni~¥oles-·· useful . as

• I. I I -

anthelminic and. anti-inflammatory agen ts.. .

U.S. Pat~ No. 3,~25,537.d~scloses, .. l-thiazolinyl or I-thiazinyl-2-aniinobenzimjdazoles useful as an the 1-

• • . - I •• . .

mintic and anti-inflammatory age~ts.. . . .

.. .

U.S. Pat .. No. 3,833,574.discloses a method of pre-

paring I-thiazolinyl- or 1-~iazinylbenzimidazolin- 2-ones which are. anti-inflammatory agents. _

. .' • I.' • .

Derwent2619~W/16 discloses, l-thiazolinyl- or 1-

thiazinyl-2-phenylbenzimidazoles useful as anthelmin-

tic agents. .... .. _: .'. ...., . '. ..

. . ... , .

There is no. known prior art reference to .antiviral

, ..

activity of thiazolinyl or thiazinyl benzimidazole esters.

1

ANTIVIRAL THIAZOLINYL OR THIAZINYL BENZIMIDAZOLE ESTERS

BACKGROUND OF THE INVENTION

, .

SU-MMARY· OF:·THE ·INVENTION

'I' I

.. • I

+ .,'. • I :'1 I • ~ I

This invention concerns the pharmacologically useful

benzimidazole estercompounds. represeptedby . the

• 'I • • .1 •

formula .' . . , , . .. :.; '.

• I ••••• "

. ,

,.

M',. I

~ .' ..

. .. ",

... . . I I' I

- '1 ..

• • I,

,.

• • I •

. .

, ~

I . . •

, .

, ,.

I

• 1 •

,

.. .' " -:

.- I • I I

, ..

r . •

. .

,. '

. .,

,_ 1

1 ••

I. I:" • • .',!.

.. • - I ••

.. ,

. ,

r' :

. .

. ....

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..

. '. ' ...

. . I. •

. " _.,: .

,

. . ,

I~

, . ,

.. 1

• 1

, .

,

- .:

• - .. I ,. I I' ~

, I·

I.

1- '. 'I

". ... "I

, '

. • . . I:

. .,

. ..

.. •• : I I •••

.... • ;" I I· .... •

I • • ••••••• • ..

.: II

,. .

• I. • ", ~ • I .. ..

, . .

.. ,. ~ i.

: I . ... ~; .

I

. 1 .: ~ ~ :1. . _ :!.... -:. . 'I

I. .... ~ • I. I

I • I I I I

• rr- I • I •

"

.. . ..

., ,

,

I •••• • I I ••

- •• I :::"...... • .. • • I

.. .1.. ~ I

, ...

2

r'

N

3

I

5

o II ,

R30-C-' ..._.

I

N

, ..

, .

. '"

..

. ,.

. .~.-' ~

15

20

wherein, ,

., .

. R, is hydrogen, C1-Ca alkyl, benzyl or phenyl;

R2 is hydrogen, formyl, .a~etyl or propionyl; .

Rais C1--Cgalkyl, allyl, propargyl, C:rC7 cycloalkyl, . (C:rC7 cycloalkyl)methyl, 1.-(C:rC7 cycloalkyl)ethyl, benzyl, a-methylbenzyl or phenyl;

25

o

II RO~C-

3 .

; is at .the 5 .. or 6 position; and .

n is 2 or 3. .., '",' .

_' ~.. • ,I' • I. • • •

Thecompounds of the invention represented by the

30 aboveformula are especially effective in suppressing thegrowth of viruses selected from the. group consisting of Coxsackie, echo, Mengo, polio, rhinoviruses and influenza. An antivirally effective amount of a thiazoli-

• • I • • •

nyl or thiazinyl benzimidazole ester .represented by the

35 Formula lcan be administering ,to mammals susceptible to said virus infection including. humans ..

,

DETAILED DESCRIPTION AND 'PREFERRED

EMBODIMENT .... "

• • • • I.

40 -, The present invention relates' to novel thiazolinyland

thiazinyl benzimidazole ester compounds which are.

'I .". I • '. "

useful in suppressing ·the growth in mammals of certain

viruses including Coxsackie,echo~Mengo', polio, . and

. .

influenza, The novel ester compoundsprovided by this

45 invention are prepared, by reacting the 'salt (III) of a

r " I" I

. tautomeric .benzimidazole ester compound (II) with an

aliphatichaloalkylisothiocyanate.· (IV), ,X (CH2- )n " NCS,optionallysu~stituted . on the carbon chain with R, groups, wherein R., R2, R3 and n are as defined . 50 above and x is chloro or bromo, to yield a compound

" I I I" " " " ""

according to Formula V (Formula I above wherein R2

is hydrogen). ,

1 '

... .

• 1

"

H N

I

-

N

I

base

3

N

3

N.

III· (anion) " ,

" ..

.,

3

4,008,243

4

-continued

N

3

I

N

•

v

•

.:

C:rC7 cycloalkyl alcohol refers to cyclopropanol, cyclobutanol, cyclopentanol, cyclohexanol andcycloheptanol. The term C:rC7 cycloalkylmethanol refers. to

methanol substituted on carbon with saturatedalicyclic rings of three to seven carbon atoms such ',as' cyclopropanemethanol, cyclobutanemethanol, cyclopen-

tanemethanol, cyclohexanemethanol,' and cyclohep-

_ tanemethanol. These C3-C7 alicyclic methanols are available from the corresponding Ca-C1 alicyclic car- 25 boxaldehydes by reduction. The term 1-(CrC.7 cy-

cloalkyl)ethanol refers to ethanol-which is substituted

substituent group at the 5-position of the benzene moi- on the carbon atom in the I position with saturated

ety has a corresponding tautomeric form with which it alicyclic rings of three to seven carbon atoms such as

is in equilibrium wherein the substituent resides alter- l-cyclopropaneethanol, l-cyclopentaneethahol, 1-

natively at the 6-position. The isomer mixture can be 30 cycloheptaneethanol and the like. These ethanols are

indicated by numbering the alternate positions as 5(6). available from the corresponding'l-(C:rC7 cycloalkyl)

As a consequence of such tautomerism, . the 5(6)-sub- methyl ketones by reduction. The term 1-(C:rC7cyclo-

stituted tautomeric benzimidazole salt (III) can react alkyl) ethyl refers to ethyl radicals substituted on the

on either nitrogen with the haloalkylisothiocyanate carbon atom in the I position with saturated alicyclic

(IV) to produce an isomeric mixture containing both 35 rings of three to seven carbon atoms. _ -.

the 5- or 6-substituted thiazolinyl or thiazinyl benzimid- The term thiazolinyl or thiazolin-2-yl refers to the NI

azole (V), named herein as 5(6)-substituted com- moiety of Formula I wherein n is 2 and indicates a

pounds. 4,S-dihydrothiazole radical attached at the 2-pbsition

The following definitions refer to the various terms which may have substituent groups (R1) in the _:4 :or 5

used throughout this disclosure. The term C1-Ca alkyl 40 positions. The term thiazinyl or thiazin-2-yl refers to

· refers to the straight and branched alkyl radicals of one the NI moiety wherein n is 3 and indicates a 'S,6-dihy-

to eight carbon atoms including methyl, ethyl, propyl, dro-4H-l,3-thiazine radical attached at the 2-position

isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, which may be substituted on the 4,5 or 6position's~by R, '

isoamyl, sec .. amyl sec-isoamyl (1 ,2-dimetbyJpropyl), groups. Illustrative of the thiazinyl or thiazolinylmoi-

tert-amyl (I, I-dimethylpropyl), neopentyl, hexyl, iso- 45 eties which are- included within the scope of this inven-

hexyl (4 .. methylpentyl), sec-hexyl (l-methylpentyl), tion are those which can be substituted in the 4,5 or

2~methylpentyl, 3-methylpentyl, 1, I-dimethylbutyl, 6positions with methyl, ethyl, propyl, benzyl or phenyl

2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbu- groups. ,

tyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1,1,2- The compounds of Formula V can be prepared by

., . trimethylpropyl, heptyl, isoheptyl (S-methylhexyl), 50 first converting the appropriately substituted benzimid-

sec-heptyl (l-methylhexyl), l-ethylpentyl, 2,2-dimeth- azole reactant (II) into its salt (III) by employing a .base

ylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2... such as metal hydrides; e.g., sodium hydride or potas-

dimethylpentyl, 1 ,3-dimethylphenyl, I ,4-dimethylpen- sium hydride; a metal amide; e.g., sodium amide; alkali

tyl, 1,2,3 .. trimethylbutyl, I ,1 ,2-trimethylbutyl, 1, 1 ,3.. metal alkoxides; e.g., sodium methoxide, potassium

trimethylbutyl, oetyl, isooctyl (6-methylheptyl), sec- 55 ethoxide or sodium butoxide and the like bases. Anion

oetyl ( I-methylheptyl), tert-oetyl ( I , 1 ,3, 3-tetramethyl- formation can be brought about in a variety of aprotic

butyl) and the like. The term C1-CS includes within its solvents such as aromatic hydrocarbons, e.g., benzene,

definition the tern) C1-Ca alkyl. toluene or xylene, or ethers such as ethyl ether, glyme

The tern. C:rC7 cycloalkyl refers to the saturated or . tetrahydrofuran at a temperature ranging from

alicyclic rings of three to seven carbon atoms such as 60 about 0° to about 1500 C. for periods of about 1 hour to

cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopen- 24 hours. A slight excess of the base is desirable; thus

tyl, cyclohexyl, 1-, 2-, 3-, or 4~methylcyclohexyl and the molar ratio of benzimidazole reactant to base can

cycloheptyl. The term C:rC7 cycloalkylmethyl refers to range from about I: I to 1 :2.

a methyl radical substituted with saturated alicyclic The benzimidazole anion (III) reacts with an ali-

rings Of three to seven carbon atoms as exemplified in 65 phatic haloalkylisothiocyanate (IV) to Yield a thiourea

the term ere7 cycloalkyl, SUCh as cyclopropylmethyl, intermediate in situ, which thiourea intermediate un-

cyclobutymethyl, cyclopentylmethyl, cyclohexyl- dergoes intramolecular alkylation on the SUlfur atom to

methyl, cycioheptyimethyl and the like. The term form a I-thiazolinyl- or I-thiazinylbenzimidazole prod ..

The tenn "tautomeric benzimidazole " refers, to a benzimidazole ester compound used as a starting material in the above reaction and which can be" substituted on either nitrogen atom with a hydrogen atom. The

benzimidazole reactant, unsubstituted on nitrogen and 20 bearing an

•

4,008,243

5

uct represented by Formula V. The molar ratio of the benzimidazole reactant ( II) to haloalkylisothiocyanate (IV) can range from 1 :.1 'to' 1: t. 5 and the reaction time can vary from about one to twenty-four hours at temperatures from about 25° to about 1500 c. The methods 5 and conditions for preparing the l-thiazolinyl- or 1- thiazinylbenzimidazole products are analogous to those disclosed in U.S. Pat. Nos. 3,749,717 and 3,825,537.

The thiazolinyl or thiazinyl benzimidazole product may be isolated by conventional methods such as filtration followed by concentration of the filtrate to induce crystallization, Alternatively the reaction mixture can

be evaporated to dryness and the residue treated with a suitable solvent such as acetone or methanol to separate and remove any insoluble material. The solution 15 containing the product is concentrated to crystallize the product or is evaporated to give a second residue, which is dissolved in methanol for example. The benzimidazole compound is recovered by filtration or centrifugation.

The reaction of the tau tomeric anion (III) with the haloalkylisothiocyanate generally provides a 1: 1 mixture of 5( 6 )-isomers of thiazolinyl or thiazinyl benzimidazole product. The 5 ( 6 )-isomers are separated by fractional crystallization or by column chromatogra- 25 phy. Usually the 6-isomer crystallizes first from a solution of the isomeric mixture. Individual isomers can be unambiguously characterized by their proton magnetic resonance spectra in the phenyl proton region (7.0 to 8.3 ppm).

The thiazolinyl or thiazinyl benzimidazole ester compounds represented by Formula I wherein R2 is formyl, acetyl or propionyl can be prepared by reacting the

l-thiazolinyl- or I-thiazinyl-2-aminobenzimidiazole esters (Formula V) with the anhydrides of acetic or 35 propionic acid or the mixed anhydride of fonnie acid and acetic acid.

The required benzimidazole reactants (II) can be prepared from the appropriate a-phenylenediamine esters by methods known to the benzimidazole art.

For example 3,4-dinitrobenzoic acid can be reacted with oxalyl chloride and pyridine in benzene to provide the corresponding 3,4-dinitrobenzoyl chloride. This, acid chloride is reacted with an appropriate carbinol; i.e., a straight or branched chain aliphatic alcohol of 45 one to eight carbon atoms, allyl alcohol, propargyJ alcohol, a Ca C7 cycloalkyl alcohol, a (C3-C7 cycloal .. kyl) methanol, a 1-( Ca--C7 cycloalkyl) ethanol, benzyl alcohol, a-methylbenzyl alcohol or phenol, in benzene with an acid scavenger such as pyridine to provide the corresponding ester. The appropriate 3,4-dinitrobenzoic acid ester is then hydrogenated at 60 psi in the presence of a catalyst such as Raney nickel or palladium-on-carbon to provide the corresponding 0- phenylenediamine ester. . Cyclization of an 0- 55 phenylenediamine ester thus obtained yields the 2-·

aminobenzimidazole esters (II). The cyclization is .carried out in the presence of cyanogen bromide as described by Buttle, et. aI., Bio Chern, J., 32, 110 I. ( 1938) and British Patent 551 ,524. The preparation of a variety ofbenzimidazoles is also well documented in Weissberger's The Chemistry of Heterocyclic Compounds, Imidazole and Its Derivatives (Interscience Publisher Co., New York, 1953). Ethyl 2-amino-5(6)-benzimidazole carboxylate is described by Paget, et aI., J. 65 Med. Chern. 12, 1010 (1969) ..

An alternative. method for ,the preparation Of 0.phenylenediamine esters begins With 3-nitro-4-

6

chlorobenzoic acid instead of 3,4-dinitrobenzoic acid. Reaction of 3-nitro-4-chlorobenzoic acid as above with oxalyl chloride and pyridine yields 3-Nitro-4-chloro-

benzoyl chloride. The appropriate 3-nitro-4chlorobenzoic acid ester is then prepared from the acid chloride as previously described. The 3-nitro-4-~hlorobenzoic

acid ester is next reacted with dibenzylamine in dimethylformamide at elevated temperatures to give the cor-

•

res ponding 3 - n itro-4-di benzy lamina benzoic acid es ter.

1 0 At this point the nitro dibenzyl ~ster is hydrogenated catalytically with Raney nickel for example, with concomitant debenzylation and reduction of the nitro group tp provide the corresponding o-phenylenedia-

mine ester. As before, the o-phenylenediamine ester is cyclized by methods know to the benzimidazole art to provide the required benzimidazole reactants (II).

The required haloalkylisothiocyanate reactants optionally substituted with C1-C3 alkyl, benzyl or phenyl groups useful in synthesizing the compounds of this 20 invention are readily prepared from, the corresponding haloalkyl amines (V) and thiophosgene:

Additional routes for the preparation of haloalkylisothiocyanates (IV) are described in Houben-Weyl's

. .

Methoden Der Organischen Chemie, Vol. 9 (G. Thieme

30 Verlay Stuttgart, 1955. Examples of haloalkylisothiocyanates which can be employed herein include the following:

SCN(CH2)2Br, SCN(CH2)2C1,' SCNCH2CH(CH3)Cl,

. SCNCH2CH(CsHs)Br, SCN(CH2)aBr,

SCNCH(CH3)CH2CI, SCN(CH2)3C1,

SCNCH2CH( CH3)CH2Br, SCNCH2CH2CH( C6HS) Br, SCNCH2CH2CH(C6H5)CI, and the like.

It will be appreciated by those skilled in the art that advantageous chemical operations Can be performed at 40 optional stages of product synthesis. For example a I-thiazoliny 1- or 1- thiaziny Ibenzitnidazole compound can ,be prepared initially and then be modified chemically to provide the final desired product.. In those compounds represented by Formula I wherein R2 is formyl, acetyl or propionyl it is preferred that the acyl

function be introduced after the thiazoline or thiazine

moiety has been formed. ': .' .

The compounds of the invention exhibit a broad spectrum of antiviral activity. Not only are they espe-

50 cially effective in inhibiting the growth of echo virus, Mengo, Coxsackie, (A9,21,B5), polio (types I, II, III) or . rhinovirus (25 strains) but they also inhibit various types of influenza viruses including influenza strains

such as Ann Arbor; Maryland B, Massachusetts B, Hong Kong A, Pr-8a and Taylor C (types A,B). The ability of compounds coming within the scope of For-

mula I above to suppress the growth of different viruses in vitro is readily demonstrated by using a plaque suppression test similar to that described by Siminoff, Ap-

60 plied Microbiology, 9( 1), 66--72 (1961). The specific tests are described in detail hereinbelow .. The compounds of the invention were tested by the following methods.

TEST METHODS

. African green monkey kidney cells (BSC-l) or Hela cells (5,,3) were grown in 25 ce. Falcon flasks at 37 C. in medium 199 With 5 percent inactivated fetal bo-

4,008,243

7

vine serum (FBS), penicillin (150 units 1 ml.) and streptomycin (I 50 mcg./ml.). When confluent monolayers were formed, the supernatant growth medium was removed and 0.3 ml. of an appropriate dilution of

8'

2-amino- 5 ( 6 )-alkoxycarbonylbcnzimidazole. Colum ns 3-1 0 indicate the percentage virus plaque reduction at drug dilu tions from O. 7 5-1 00 micrograms per milliliter (mcg./ml. ).

Table I

..

Polio I Plaque Reduction of I-Thiazolinyl(Thiazinyl )w2~Amino- 5( 6 )-alkoxycarbonylbenzimidazoles

I-Substituent

5( 6 )-Substituent*

/

I _

,. .'

• <

-

_ Qrug_CpQcentration (mcg/mJ)

zzL d I!III ,

100

50

25 12 6 3

0.75 ,

I •• •

Percent Plague Reduction
Thiazolin-2-yl 6-m ethoxycarbony I 100 100 100 100 100 83 45 18 .,
Thiazolin-2-yl 5~ethoxycarbonyl 100 97 74 44 0 0 .0 0
. '
Thiazolin-2-yJ 6-ethoxycarbonyl 100 100 100 100 99 55 16 · 0
Thiazin-2-yl 5 .. ethoxycarbonyl 100 99 81 49 18 0 0 0
;. Thiazin-2-yl 6 -~ tho X ycarbon y I 100 100 100 100 98 66 31 0
( 5-methylthiazo)-
, ·in-2-yl) 5( 6 )-ethoxycarbonyl 100 100 100 87 34
! tox tox 100
. .
( 4 .. methylthiazol-
in-2-yl) .. 5( 6 )-ethoxycarboI1yl 100 100 100 100 100 100 70 51
( 4,5-dimethyl- .
thiazolin-2-yl) 5 ( 6 )-ethoxycarbon y I tox tox tox 100 100 100 100 76
,
*Number 5 or 6 indicates respective isomer; 5(6) indicates isomer mixture. virus (echo, Mengo, Coxsackie, polio or rhinovirus) was added to each flask. After absorption for one hour

at room temperature, the virus infected cell sheet was 25 overlaid with a medium comprising one part of 1 percent Ionager No.2 and one part double strength medium 199 with FBS, penicillin, and streptomycin which contains drug at concentrations of 100, 50, 25, 12, 6, 3,

1.5, and 0.75 micrograms per milliliter (mcg./ml.). The 30

•

flask containing no drug served as the control for the

test. The stock solutions of thiazolinyl or thiazinyl benzimidazole ester compounds were made up in dimethylsulfoxide at a concentration of 1 04 mcg./mg. The flasks were incubated for 72 hours at 3 7° C. for 35 polio, Coxsackie, echo, and Mengo virus and 120 at 32°

C. for rhinovirus. The influenza virus' strains such as, Ann Arbor, Maryland B, Massachusetts B, Hong Kong

A, Pr-8a or Taylor C (types A,B), were incubated for

72 hours at 37° C. using MDCK cells (Madin-Darby 40 canine kidney celis). Plaques were seen in those areas where the virus infected and reproduced in the cells. A solution of I 0 percent formalin and 2 percent sodium acetate was added to each flask to inactivate the virus and fix the cell sheet to the surface of the flask. The 45 virus plaques, irrespective of size, were counted after staining the surrounding cell areas with crystal violet. The plaque count was compared to the control count at each drug concentration. The activity of the test compound was expressed as percentage plaque reduction, 50 or percent inhibition. Alternatively, the drug concentration indicated by the symbol Iso which inhibits plaque formation by 50 percent can be used as a measure of activity.

Test results are expressed in terms of Polio virus type 55 I inhibition because the virus is easy to grow and consistent test results are obtained. However, the activity of the preferred compounds was confirmed against other virus cultures such as Coxsackie (A 9, A 21, B5), echovirus (strains 1-4), Mengo, rhinovirus (25 strains Polio 60 (type I, II, III), and influenza virus strains such as Ann Arbor, Maryland B, Massachusetts B, Hong Kong A, Pr-8A and Taylor C (types A, B). Test results for various thiazolinyl or thiazinyl benzimidazole compounds are summarized in Table I below. In the table, column 65

1 gives the name Of SUbstituent in the I-position and COlumn 2 gives the name Of SUbstituent in the 5(6)POSition Of the corresponding l-thiazolinyl (thiazinyl)-

The l-thiazolinyl- or I -thiazinylbenzimidazole ester compounds were tested both as pure compounds and as isomer mixtures. As can be seen -frorn Table I, both isomers inhibit virus growth, the 6-isomer generally being more active than the 5-isomer.

Compounds coming within the scope of the above formula are able to suppress the growth of several viruses when added to a medium in which the virus is growing. The compounds of the invention can therefore be used in aqueous solution, preferably with a surfactant, to decontaminate surfaces on which polio, Coxsackie, rhinovirus and influenza viruses are present, such surfaces including hospital glassware, hospital working surfaces, and similar areas in the preparation of food.

Furthermore, the compounds can be orally administered to warm-blooded animals and humans in a dose of I to 300 mg./kg. of animal body weight. The administration can be repeated periodically as needed. In accordance with general practice, the antiviral compound can be administered every four to six hours.

Preferably, the compounds to be employed in accordance with the present invention are employed in combination with one or more adjuvants suited to the particular route of administration. Thus, in the case of oral administration, the compound is modified with pharmaceutical diluents or carriers such as lactose, sucrose, starch powder, cellulose, talc, magnesium stearate, magnesium oxide, calcium sulfate, acacia powder, gelatin, sodium alignate, sodium benzoate and stearic acid. Such compositions can be formulated as tablets or enclosed in capsules for convenient administration. In addition, the compounds can be administereed parenterally.

The compounds can also be mixed with a liquid and administered as nose drops or intranasal spray.

Among the preferred compounds of the invention are those wherein R2 is hydrogen and Ra is C1-Ca alkyl.

Illustrative of the thiazolinyl or thiazinyl benzimidazole ester compounds. included in the scope of this

invention are the following:, .

1-( thiazolin-2-yl )-2-propionamido-5 (6 )-me~oxycar-

bonylbenzimidazole, .,.

1- ( thiaz in - 2- Y I )-:- 2-ace tamido- 5 ( 6)-~thoxycarbon Y 1-

benzimidazole, . . .

•

4,008,243, ... '

9

10.·

1 ... ( thiazolin-2-yl )-2-formamido-5 (6)-propoxycar- .

bonylbenzimidazole, '.

1-( thiazin-z-yl )-2-amino-5 (6 )-butoxycarbonylben ...

zimidazole, , ., .

1-( thiazolin- 2- y I )- 2-prop ionamido- 5 ( 6 )-pen ty lox ...

ycarbon ylbenzimidazole , .." :. '. : .

1-( 4-propylthiazolin-2 ... yl) .. 2-acetamido-5( 6 ) .. hex-

yloxycarbonylbenzimidazole, . ' .

1-( 5-benzylthiazin-2-yl )- 2~formamido- 5 ( 6)- octylox-

ycarbonylb~nzimidazo]e, . ..... . •

1-( 6-methylthiazin-2-yl) - 2-propionamido-~ ( 6 I-pen-

tyloxycarbonylbenzimid~ole, " . .

1-( 4-pbenylthiazoliil-2-yl )~2-ace~~i90-~( 6 ) .. butox-

ycarbonylbenzimidazole, .' .... . · .

1-( thiazin- 2~ yl) .. 2 .. forrnamido- 5 ( 6 )-propoxycar-. :.

bonylbenzimidazole,. . : .

1-( 4-ethylthiazolin-2-yl.)-2-amino-5(6 )-ethoxycar- .

bonylbenzimidazoJe, .r •

1-( 4-ethylthiazin-2-propionamido-5( 9 )-methoxycar- '.

bonylbenzimidazole, '. ,..... ". 20

1-( thiazolin .. 2~yl }-2-,~cetamido~5 ( 6 )-ethoxycarbonyl ..

benzimidazole, . .." . . .' ."

1-( thiazin-2-yl)~~-formamido-5 (6 )-propoxycar-:- .

bonylbenzimidazole, . .

1-( S ... methylthiazolin-2-y 1)- 2-amino-5 ( 6 )-butoxycar- 25

bonylbenzirnidazole.. . ..' .

1-( 6-benzylthiazin ... 2-y~)-2-propionamido-5 (6)octyloxycarbonylbenzimidazole,. . .

1-( thiazolin- 2- yl )- 2-acetamido- 5 ( 6 )~ penty loxycar-

bonylbenzimidazole, . . .'

1-( 5-methylthiazin-2-yl ) .. 2-formamidp-5( 6 )-propox-

ycarbonylbenzimidazole, ..

1-( 4-benzylthiazolin-2-yl)-2-amino-5 (6 )-methox- ..

ycarbonylbenzirnidazol~, . , ..

1-( thiazin- 2-yJ )-2-propionamido-5 ( 6 )-ethoxycar-

bonylbenzimidazole, .... ,.' . <

1-(5-propythiazolin~2~yl)-2 .. acetamido-S(ej-pen ..

tyloxycarbonylhenzimidazple, ',' . . '.

1-(thiazin-2-yl)~2-formamido-5( 6 )~hexyloxyca(-

bonylbenzirnidazole, '.: .. '. 1-(thiazolin-2-yl)-2-amino-5( 6 )-methoxycarbonyl ...

benzimidazole, > • ., . ,'. . ,'.

1-( 5-phenylthi~in-2-yl)-2-propiqnamidQ-5 ( 6 )-

propoxycarbonylbenzimidazole, . :" . ".

1-( 4-phenylthiazolin-2-yl) -acetamido-St 6-octylox- 45

ycarbonylbenzimidazole" '..

1-( thiazin-2-yl ) ... 2-forma~ido-S ( 6 )-ethoxycarbonyl-

benzimidazole .. ; ;,. .

1-( 5-benzylthiazolin-2-yl )-2-aminow5(6 ) .. propox-

ycarbonylbenzimidazole" " .

1-( 4-propylthiazin-2-yl)-2-propionamido~S( 6 )-hex-

yloxycarbony Ibenzimidazole, .... .:': .' .: '. .

1-( thiazolin- 2- yl)- 2-acetamido-S ( 6 )-propoxycar-

bonylbenzimidazole, .' .

1-(thiazin-2-yl)-2-forrnamido ... S( 6 )-methoxycar-

bonylbenzimidazole, .

1-( 4-methylthiazolin-2-yl) .. 2-amino-5( 6 )-octylox ..

ycarhonylbenzimidazole, '. . .

t -(thiazin .. 2-yl)-2-prop~onamido-5( 6 j-ethoxycar- .

bonylbenzimidazole, . . .

1-(thiazo1in-2-yl)-2~acetamido-5( 6 ) .. butoxycar- .

bonylbenzimidazole, '. . . . :

1-( 4-propylthiazin-2-yl)-2~forlnamido-S( 6 )~octylox ...

ycarbonylb~nzimidazole, . . ..... .. ...

1-< S-benzylthiazolin-2-yl)-~-amino-S(6 )~heptyloJ{- .. 65 ycarbonylbenzi~idazole, . ..... ~ ... ; .. .: : .. : .. :. ..

1-( thiazin- 2- Y l)-2-propio namido-S ( 6 )- methoxycar- ....

bonylbenzimidazole, . . . . . .

1 .. ( thiazolin- 2"a~~tam ido-5( 6 )-propoxycarbonylben ..

zimidazole, .

1 .. ( 5~pr,?pylthjazin~2-fonnamido-S ( 6 )-ethoxycar-

bonylbenzimidazole, .

5 1-( 4-phenylthiazolin-2-y~)-2~amino-S( 6 )-heptylox-

- • • I.

ycarbonylbenzimidazole, '. .

1 .. ( thiazin-2-yl) .. 2-propionamido-S( 6 ) .. butoxycarbonylbenzimidazole, .,'.. ','. '"

1-( thiazolin-2-yl )-2 .. acetamido-Sf 6 )-ethoxycarbonyl-=

1 0 .' benzimidazole,' . ,.

1-( ~~propylthiazin-2-yl)-2-formamido-5( 6 )-propoxycarbon ylbenzimidazole, .

1 .. ( 5-:-benzylthiazolin-2-yl )-2-amino-S ( 6 )-hexylox-

ycarbonylbenzimidazole, .

. 15 1-(thiazin-2-yl)-2 .. propionamido-5( 6)-pentyloxycar- .

bonylbenzimidazole, 1-(thiazolin-2-yl)-2-acetamido-5( 6 )-heptyloxycarbony lbenzimidazole,

1-( 6--:methylthiazin-2-yl )-2-formamido-5( 6 )-methox-

ycarbonylbenzimidazole, .

1-( 5-methylthizaolin-2-amino-5( 6 )-heptyloxycar-

, ,

bonylbenzimidazole, .

1-( thiazin-2 .. yl )-2-propionamido-5( 6 )-octyloxycar- . bonylbenzimidazole, .

1 .. (5-ph~nylthiazolin-2-yl)-2-amino-5( 6 )-methox-

ycarhonylbenzimidazole., . ,~

1-( 4-benzylthiazolin-2-yl)-2-formamido-5( 6 )-butox-

ycarbonylbenzimidaZole, .

. .

1-( 5-propylthiazolin-2-yl )-2-acetamido-5 ( 6) ..

methoxycarbonylbenzimidazole,

1-( 4-methylthiazolin- 2-yl )-2-propionamido-5( 6)penty loxycarbonylbenzimidazole,.

, .

1-( 5-ethylthiazolin .. 2-yl)-2-amino-5 (6 )-heptylox-

ycarbonylbenzimidazole, . .

35 1-( 4-phenylthiazo)e-2-yl)-2-propionamido ... 5( 6)- .'

ethoxycarbonylbenzimidazole, ..

1-( 5-.methylthiazol-2-yl)-2-acetamido-5( 6 )-butox- ", ycarbonylbenzimidazole, 1-( thiazolin- 2-y 1)- 2-formamido-5 ( 6 )-propoxycarbonylbenzimidazole,

40 1-( 4-methylthiazolin-2-yl)-2-amino.5( 6 )-pentylox- .' ycarbonylbenzimidazole,

1 .. ( 5-phenylthiazolin-2-yl )-2-propionamido-5 (6)- .

octyloxycarbonylbenzimidazole, .

1-( 4 .. ethylthiazolin)-2-acetamido-5( 6 ) .. ethoxycarbonylbenzimidazole,

1-( 5-propylthiazoIin ... 2 ... yl )-' 2-amino-5( 6 )-methox.-

ycarbonylbenzirnidazole,

1-( thiaz 0 Iin- 2-yl )-2-propionamido- 5 ( 6 )- hexyloxycarbonylbenzimidazole,

50 1 ( 4 .. propylthiazolin-2 ... yl)-2-amino-5 (6 )-octyloxycar ...

bony Ibenzimidazole,

1-( thiazolin-2-yl )-2-propionamido-5 (6 )-heptyloxycarbonylbenzimidazole; 1-( 5~benzylthiazolin-2- yl)- 2-acetamido-5 ( 6 )-octy loxycarbonylben ... zimidazole,

1-(thiazolin-2-yl)-2-formamido-5( 6 )-hexyloxycarbony Ibenzimidazole, 1-( 5-propy Ithiazolin- 2-yl) .. 2- . amino-5( 6 )--bQtoxycarbonylbenzimidazole,

t -( thiazolin ... 2-yl)-2 ... propionamido-S (6 ) ... ethoxycarbony lbenzimidazole,

1 .. ( 5 .. methylthiazolin- 2-yl )-2-acetamido-5 ( 6)-· methoxycarbonylbenzimidazole,

1-( thiazolin-2-formamido-S (6 )~propoxycarbonylbenzimidazole, .

1-( 4 .. ethylthiazolin-2-yl)-2-amino-S (6 )-pentyloxycarbonylbenzimidazote, ., .

1-< thiazclin-Z-yl )-2-propionamido-S (6 )-heptylox-

ycarbonYlbenzimidazole,... • . .

30

55

60

4,008,243

11

.1

1-( thiazin-2-yl)-2-acetamido-5 (6)-ethoxycarbonylbenzimidazole"

1-( 6-phenylthiazin~2-yl )-2-forlnamido-5(6 )-butox-

ycarbon y I benzimidazo Ie, .' .

1-( 4-methylthiazin-2-yl )~2-amino-5( 6 )-propoxycar-

bonylbenzimidazole; .

1-( 5-propylthiazin:2-yl )-2-propionamido-5( 6 )-pen-

. . tyloxycarbonylbenzimidazole, . . .

1-( 4-benzylthiazin-2-acetamido-5( 6 )-hexyloxycar. bonylbenzimidazole,

1-( thiazolin-2-yl )-2-formamido-5( 6 )-heptyloxycarbon y 1 benzimidazole,

1-( 5-propylthiazin-2-yl)- 2-amino-5 ( 6 )-octyloxycarbonylbenzimidazole,

1-( 4-ethylthiazin-2-yl)-2-propionamido-5( 6)methoxycarbonylbenzimidazole,

1- ( thiazin - 2- y I ) - 2-acetam ido- 5 ( 6 )- methoxycarbon y I-

. ' benzimidazole, '

1-( 6-methylthiazin-2-yl )-2-formamido-5( 6 )-propox-

ycarbonylbenzimidazole, 20

1-( 4-ethylthiazin-2-yl-2-amino-5( 6 )-pentyloxycar-

. bonylbenzimidazole,

1-( thiazolin-2-yl )-2-propionamido-5 (6 )-heptylox- .

ycarbonylbenzimidazole, .

1-( 5-propylthiazin-2-yl )-2-acetamido-5 (6 )-octyloxycarbon ylbenzimidazole,

1-( 4-propylthiazolin-2-yl )-2-formamido-5( 6 )-hexyloxycarbonylbenzimidazole, 1-( thiazolin-2-yl )-2- amino-5 (6 )-butoxycarbonylbenzimidazole,

1-( thiazin-2-y).)-2-propionamido-5( 6 )-ethoxycar ... bonylbenzimidazole, 1-(S-ethylthiazolin-2-yl)-2-acetamido .. 5(6)-heptyloxycarbonylbenzimidazole,

1-( 5-benzy lthiazin-2-yl)- 2-formamido- 5 ( 6 )-penty loxycarbonylbenzim idazole,

1-( thiazolin-2-yl )-2-amino-S ( 6 )-propoxycarbonyJbenzimidazole,

1-( 4-phenyIthiazin-2':'yl)~2-propionamido-5( 6)- , methoxycarbonylbenzimidazole,

1-( 5-methylthiazolin-2 ... y 1)- 2-acetamido .. 5 ( 6)octyloxycarbonylbenzimidazole,

1-( 4-propylthiazin-2-yl )-2-formamido-5( 6 )-hexyloxycarbonylbenzimidazole, .

- 1-(5-ethylthiazolin-2-yl)-2-propionamido-S( 6)-

butoxycarbonylbenzim idazole,

1-( thiazin .. 2- y I ) .. 2-acetam ido- 5 ( 6 )-etho xycarbon ylbenzimidazole,

1-( 4-benzylthiazolin-2-y 1 )-2-formamido-5( 6 )-heptyloxycarbonylbenzim idazole,

1-( 4-methylthiazin-2~yl) -2-amino-5 ( 6 ) -propoxycarbonylbenzimidazole,

1 .. ( thiazolin-2-yl)-2-propionamido-5( 6 )-pentyloxycarbonylbenzimidazole,

1-( 5 ... phenylthiazin-2-yl )-2-acetamido-5 (6 )-heptylox- 55. ycarbon ylbenzimidazole,

1-( 4-propy Ithiazolin-2-y I )-2-formamido .. 5 ( 6 j-hex .. yloxycarbonylbenzimidazole, 1-(thiazolin-2-yl)-2-forlnamido-5( 6 )-( l-cyclo ... propylethoxy )carbony Ibenzimidazole,

1-( 4-methylthiazoIin .. 2-yl )-2-amino-5( 6)cyclobutyloxycarbony Ibenzimidazole, 1-(5-phenylthiazolin ... 2-yl)-2-propionamido .. S( 6)cyclobutylmethoxycarbonylbenzimidazole, 1-< 4-ethYlthiazoJin-2"YI )-2-acetamido-5( 6 >-( 1- cyclobutylethoxy)carbonylbenzimidazole,

1 .. (5 - propy Ithiazolin - 2- Y 1)- 2-amino- 5 ( 6 j-cyclopentyloxycarbonylbenzimidazole,

5

10

15

25

30

35

40

'45

50

60

65

12

1-( thiazolin-2-yl )-2-propionamido-5 (6 )-cyclopentylmethoxycarbonylbenzimidazole,

1-( 4-propylthiazolin-2-yl )-2-amino-5( 6 )-( 1- cyclopenty lethoxy ) carbonyl benzim idazole,

1-( thiazolin-2-yl )-2-propionamido-5 (6 )-cyclohexy loxycarbon y I benzi midazo Ie, 1-(5-benzylthiazolin-2-yl )-2-acetamido-5( 6)cyclohexylmethoxycarbonylbenzimida~ole, .

1-( thiozoIin-2-yl )-2-formamido-2-formamido-5( 6)( l-cyclohexylethoxy ) carbonylbenzimidazole ,

1-( 5-propylthiazolin-2-yl )-2-amino-5 (6 j-cyclohep ..

tyJoxycarbonylbenzimidazole,

1-( thiazolin-2-yl )-2-propionamido-5 (6 )-cyclo,beptyl-

methoxycarbonylbenzimidazole,' '.

1-( 5-methylthiazolin-2-yl )-2-acetamido-5( 6 )-( 1- cycloheptylexthoxy)carbonylbenzimidazole, '.

1-( thiazolin-2-yl )-2-formamido-5( 6 )-cycloheptyJo~-

ycarbonylbenzimidazole, ...

] -( 4-ethy lthiazolin- 2- y I )- 2-amino- 5 ( 6 )-cyclobepty 1-

methoxycarbonylbenzimidazole, 1-( thiazolin -2 ...

y I )- 2- propionamido- 5 ( 6 )-( l-cyclohepty lethoxy )-

carbonylbenzimidazole, , ,

1-(thiazin~2-yl)~2-acetamido-5( 6 )-cyclopropylox-

ycarbonylbenzimidazoJe, "

1-( 6-phenylthiazin-2-yl)-2 ... formamido-5( 6 )~cyclo-

propy Imethoxycarbonylbenzimidazole, , ..

1-( 4-:methylthiazin-2-yl )-2-amino-5 (6 ) ... ( I-cyclo. propylethoxy)carbonylbenzimidazole,

1-( 5-propylthiazin~2- yl )-2-propionamido-5(6)cyclobutyloxycarbonylbenzimidazole, .

1-( 4-benzylthiazin .. 2-yl)-2-acetamido-5(6)-: · cyclo butyl methoxycarbonylbenzimidazole, ...

1-( thiazolin-2-yl )-2-formamido-5( 6 )-( l-cyclobutyle-

thoxy)carbonylbenzimidazole, .

1-( 5-propylthiazin-2-yl )-2-amino-5( 6 ) ... cyclopen-

tyloxycarbonylbenzimidazole, , . _ .

1-( 4-ethylthiazin-2-yl )-2-propionamido-5( 6 )"<- . .'.,,'., ' eye lopentylmethoxycarbonylbenzimidazole, 1-(thiazin-2-yl)-2-acetamido-5( 6 )-( l-cyclopentyle-

thoxy)carbonylbenzimidazole, ; .

1-( 6-methylthiazin-2-yl)-2-formamido-5( 6)-'

cyclohexyloxycarbonylbenzimidazole, '.;

1-( 4-ethylthiazin-2-yl )-2-amino-5( 6)-cyclohexyJtne- ·

thoxycarbonylbenzimidazole, .: . .:

1-( thiazolin-2-yl )-2-propionamido-5 (6 )-( 1- ... " .

cyclohexylethoxy)carbonylbenzimidazole, . ~

1-( 5-propylthiazin-2- yl )~2·acetamido-5( 6 }-cyclo- .. propy loxycarbonylbenzimidazole,

1-( 4-propylthiazolin-2-yl )-2~forlnamido-5( 6 )-cyclp-

. .

propylmethoxycarbonylbenzimidazole, ,,'

, r.

1-( thiazolin- 2- yl )- 2-amino-5 ( 6 ) .. cyclopropyloxycar-

bonylbenzimidazole, .'

,.1-(thiazin-2-yl)-2-propionamido-S( 6 )-cyclopropyl-

methoxycarbonylbenzimidazole, "-,, ,. '.

.1-( 5-ethylthiazolin-2-yl)-2-acetamido-S( 6 )-( l-cyclopropy lethoxy ) carbo nylbenzimidazole,

1 (5-benzylthiazin-2-yl )-2-formamido-5( 6)- .. cyclo butyloxycarbonylbenzimidazole,

1-( thiazolin-2 .. yl )-2-amino-5( 6 )-cyclobutylmethoxycarbonylbenzimidazole,

1-( 4-phenylthiazin-2-yl )-2-propionamido-5( 6)cyclopentylmethoxycarbonylbenzimidazole, ,5-methylthiazolin-2 .. yl )-2-acetamido-5 ( 6 } .. ( 1)cyclo butylethoxy )carbonylbenzimidazoie,

1-< 4-propylthiazin-2-yl)-2-forlnamido-S( 6)cyclo pentyloxycarbonylbenzimidazole ,

1-( 5-ethylthiz30Iin-2-yl)-2-propionamido-S( 6)'"

cyclopentylmethoxycarbonylbenzimidazole, 1-

..

4,008,243

(thiazin- 2-yl ).;2.;acetamido~5 ( 6 )-l-cyclopentylethoxy)carbonylbenzimidazoIe,

1-( 4-benzylthiazolin~2.;yl )-2~formamido-5 ... ( 6)~

eye lohex y loxycarbon y Ibenzim idazol e,

1-( 4- meth ylthiazin- 2-am ino- 5 ( 6 )-cyclo hexylmethox-

.' ,

ycarbonylbenzimidazole, .

1-( thiazolin-2-yl )-2-propionamido-5( 6 j-J-cyclohex-

ylethoxy)carbonylbenzimidazoIe, .

1-(5-phenylthiazin-2-yl)-2-acetamido-S (6)- .

. .

cycloheptoxycarbon y I benzimidazole,

1-( 4-propylthiazolin-2-yl)-2-formamido-5( 6)-

cyclohepty lmethoxycarbon y lbenzim idazole, 1-

(thiazolin-2-yl)- 2-acetamido-5 ( 6-( l-cycloheptylethoxy )carhonylbenzim idazole,

1-( 6-propylthiazin-2-yl)-2-formamido-5( 6)cyclo bu ty loxycarbon y I benzimidazole,

1-( 5-benzy lthiazolin- 2-y 1)- 2-amino-5 ( 6 )-cyclopentylmethoxycarbonylbenzimidazole,

1-( thiazin-2-yl )-2-propionamido-5( 6 )-( l-cyclohexy lethoxy )-carbon y lbenzimidazole,

1-( thiazolin-2-yl )-2-acetamido-5( 6 )-cycloheptylox-

.

ycarbon y Ibenimidazol e,

1-( 6-methylthiazin-2-yl)-2-formamido .. 5( 6)-( 1- cyclohepy lethoxy )carbony lbenzimidazole, 1-( 5-methylthiazolin-2-yl )-2 .. amino-5( 6)-

cyclobu ty loxycarbon y lbenzim idazole,

1-( thiazin - 2- yl ) - 2-propio namido-5 ( 6 ) - t-bu ty loxycarbony Ibenzimidazole,

1-( 5-phenylthiazolin-2-yl)-2-amino-5( 6 )-t-butyloxycarbon y Ibenzimidazo Ie,

1-( 4-benzylthiazolin-2-yl )-2-formamido-5( 6 )-tbutyloxycarbonylbenzimidazole,

1-( 5-propylthiazolin-2-yl )-2-acetamido-5( 6 )-t ... butyloxycarbonylbenzimidazole,

1-( 4-methylthiazolin-2-y I )-2-propionamido-5 ( 6 )isobutyloxycarbonylbenzimidazole,

1-( 5-ethylthiazolin-2-yl) -2-amino-5-( 6 )-s-butylox-· ycarbon ylbenzimidazole,

1-( 4-phenylthiazole-2-yl )-2-propionamido-5( 6 )-tbutyloxycarbonylbenzimidazole, 1-(5-methylthiazol-2-yl)-2~acetamido-5(6)-t· butyloxycarbonylbenzimidazole,

1-( thiazin- 2-yl )-2-amino-5 ( 6 )-propoxycarbonylbenzimidazole,

1-( thiazoIin-2-yl )-2-propionamido-5-( 6 )-methoxycarbonylbenzimidazole,

1-( 6-methylthiazin-2-yl )-2-acetamido-5( 6 )-ethoxycarbonylbenzimidazole,

1-( 5-benzylthiazolin-2-formamido-5( 6 )-butoxycarbonylbenzimidazole,

1-( 5-methylthiazin-2-yl)-2-amino-5( 6 )-hexyloxycar .. bonylbenzimidazole,

1-( 4-ethylthiazolin-2-yl )-2-propionamido-5( 6 )-hep .. tyloxycarbonylbenzimidazole,

1-( thiazin-2-yl )-2-acetamido-5( 6 )-octyloxycarbonyl-

benzimidazole, 60

1-5-propylthiazolin-2-yl)-2-forlnamido-5( 6butoxylcarbonyl, and

1-( 4-phenylthiazin-2~yl)-~-amino-5( 6 )-methoxycarbonylbenzimidazole.

The following examples illustrate further the .preparation Of starting materials; intermedia tes, and compounds Of the invention.

. 13

14

EXAMPLES 1-4

1- Thiazolinyl( thiazinyl )-2-amino-5 (6 )-ethoxycarbonylbenzimidazoles (General Procedure).

5 Fifty-four grams (0.265 mole) of 2-amino-5(6)-

ethoxycarbonyIbenzimidazole:. were suspended in 500 mL of ethylene glycol dimethyl ether (dimethoxyethane, DME). Thirteen grams (0.27 mole) of sodium hydride as a 50 percent mineral oil suspension was

1 0 added to the stirred reaction mixture in portions to generate the benzimidazole anion. A solution of 33 g. (0.27 mole) of p-chloroethylisot~iocyanate in 50 mI. of dimethoxyethane was added dropwise to the reaction mixture with ice bath cooling to moderate the exother-

15 mic reaction. The reaction mixture was stirred overnight at room temperature. The precipitated product··· . was filtered and washed successively with DME, water and ether. After dying the crude yield of product as an isomeric mixture was 52 g (67.5 percent yield). The

20 product was dissolved in 2 liters of 2B ethanol and

filtered. The filtrate was concentrated by boiling and the product isomers were isolated by fractional crystallization. The yield of 1-(thiazolin-2-yl)-2-amino-5-

25 ethoxycarbonylbenzimidazole was 12 g. The yield of 1--

-( thiazolin-2-yl)-2-amino~6-ethoxycarbonylben- .

zimidazole was 22.4 g. . .

Analysis C13H14N402S MW 290. Calcd: C, 53.78; H, 30 4.86; N, ~ 9.30; Found: 5-isomer:.C,. 53.85; H, 5.02; N, . 19.07. 6-lsomer: C, 53.62; H, 4 .. 64; N, 19.07.

The following compounds. were prepared by the method described above using '. 2-amino-5( 6 )-ethoxycarbonylbenzimidazole and·· 2-chloro-l-methyle- 35 thylisothicyanate (Ex. 2), 2-chloropropylisothiocyante (Ex 3), and 3 .. chloropropylisothiocyanate (Ex. 4).

1-( 4 ... methylthiazolin-2-yl)-2-amino-5( 6 )-ethoxycarbonylbenzimidazole as an isomeric mixture, yield 5.S g (52 percent) from 7.2 g. (0.035 mole) of benzimid-

40 azole est~r. . . .

Analysis C14H15N402S MW 303; Calcd: C, 55.43; H, 4.98; N; 18.47. Found: C, 55.47; H. 5.14; N, 18.81. 1-( 5-methylthiazolin-2-yl )-2-amino-5( 6 )-ethoxycarbonylbenzimidazole as an isomeric mixture, yeild 4.5 g 45 (42 percent) from 7.2 g (0.035 mole) of benzimidazole ester.

Analysis C14H15N2S MW 303; Calcd: C, 55.43; H, 4.98; H, 18.47. Found: C, 55.06;~H; 5.22; N, 18.16. 1-( thiazin-2-yl )-2-amino-S ( 6 j-ethoxycarbonylben- 50 zimidazole ~rom 7.2 g (0.035 ~mol~.) of benz~midazole ester. The Isomers were fractionally crystallized from

ethyl acetate.. ..

Analysis C14H16N402S MW 304; .: Calcd: C; 55.25; H, 5.30; N, 18.41. Found: 5-isomer: C, 55.40; H, 5.16; N,

55 18.19. 6-isomer: C, 55.02; H~ 5.23; N, 18.13.

The yield of 5-isomer, mp l,57°-160° C, was 0.9 g.

The yield of 6-isomer, mp 163°-166° C, was 2.3 g.

EXAMPLE 5

l-(Thiazolin- 2- yl)- 2-amino-6- metho xycarbon ylbenzimidazole

1-( thiazolin-2-yl)-2-amino-6-( l-imidazolylcarbonyl)benzimidazole was prepared from 1-(thiazolin- 2 ... yI) .. 2-amino-6-benzimidazole carboxylic acid and 1;

65 1 '-carbonylbisimidazole. One and three-tenths grams ( 4.2 mmole) Of 1-.( thiazolin .. 2-YI )-2 .. amino-ti-t 1 ... imidazolylcarboDyl)benzirnidazole were heated on the steam bath With 25 ml Of methanol and 15 mi. Of di ..

15

'4,008,243

and, filtered.' The ethyl' acetate .solution , was evaporated in vacuo to yield t 6 b .. (7~3. percent yield .based on cyanogen bromide) of ·2-amino'-5J. 6 )-;cyclol1exyloxycarbonylbenzimidazole ~s an· oil. _ < : ,;', ,

5 _', ,( P), ~ -(Th,i,~oIiQ-2~yl )~4~amino-6 .. cyclohexyloxycar-

bonylbenzimidazole " ., . ", ' , "

.Seven and eight-tenths grams,'·(Q.03 mole) of 2- amino-Sf 6)~cyclohexyloxy~arbo~'ylbentitpjdaz6Ie, 1 00 ml. of demethoxyethane (glyme) ~ '1.5 'g. of sodium

, ' 10 hydride as a 50 "percent mineral dispersion ~ "arid 3. 7 g.

1-(Thiazolin-2-yl )-2-Amino-6-Cyclohexyloxyc:irbQl1yI- (0.03 mole )of J3-chloroethylisothiocyanate were re-

"

. benzimidazole acted bythe method of Example 1 to yield 1.2 g. of

I . r.

,', ', (A)Cy clohexyl 3 _ nitro-4-chlorobenzoate ',', , 1-( t~i~ol~i1- 2:. y 1)- ~~am i~o~6-~yclohex yloxycarbony 1-

,Ten grams (0.05 mole) of3':'nitro-4-chlorobenzoic benzlmld.azole, mp 231- -232 C (methanol).

'~~jd"50ml. of benzene, 13g (0.1 mole) of oxalylchlor- '15 Analysis C17H20N402S ,MW 344; Calcd- C, 59.28; H,

,.' ide and, 3 drops of pyridine were stirred at room tem- 5.85; N, ..16.27. Found: C, 59.06; H, 5.72; N, 16.47 .

. , perature for about 1 hour. The mixture was warmedto ' :";'_' Examples 7-9

, 55° C to-obtain a homogeneous solution. The reaction ',' .

:. .mixturc was evaporated in vacuo to yield an oil. - Under 1-(Thiazolin- 2-yl )-:2-amino-5 ( 6 )-isopropyloxycar-

vacuum the oil crystallized to yield 12 g.of 3-nitro-4- 20 bopy,lbC!n~imidazolewas prepared from 2-amino-5(6)-

chlorobenzoyl chloride. isopropyl oxycarbonylbenzimidazole, via isopropy 3-

,.Twelve grams (0.055 mole) of crude-3-nitro-4- nitro-4-chloro~enzoate by the method of Example 6.

chlorobenzoyl chloride were dissoved in 200 ml. of Six and six-tenths grams (0.03 mole) of the benzirnid-

benzene. Eight milliliters of pyridine were added to the azole above, 109 ml. of dimethoxyethane, 1.5 g. of 50

reaction mixture. Six milliliters of cyclohexanol were 25 percent sodium' hydride and 3. 7 g. of f3-chloroethyliso-

dissolved, in 50 ml. of benzene and the solution was thiocyanate were reacted to yield J g. of 1;;.(thiazolin-2-

.". added dropwise to the acid chloride-pyridine mixture. yl)-2-amino~5(6)-isopropyloxycarbonylbenzimidazole.

,-' The reaction mixture was refluxed for 4 hours and Analysis C14HisN402S MW 304; Calcd.C, ,55.25; H,

filtered. The benzene filtrate was washed successively 5~30;N,J8,,41. Found: C', 55.05; H, 5.23; N,18.37.

" · " with dilute acidvdilute base and water. The benzene 30 1-(Thiazolin-2-yl)-2-amino-6-neopentyloxycarbonyl-

solution was dried and evaporated in vacuo to yield benzimidazole was. prepared by reacting 9.9 g. (40

12.5 g. (88 percent) of cyclohexyl 3-nitro-4-chloroben- mmole) of 2-amino-5( 6 )-neopentyloxycarbonylben-

zoate, mp 57°-58° C. zimidazole (via: .neopentyl 3-nitro-4-chlorobenzoate),

, Analysis C13H24CIN04 MW,283.5; Calcd: C, 5-5~04; 35 2.0 g. of 50 percent sodiumhydride, 200 ml, of dimeth-

H, 4.97; n, 4.91. Found: C, 54.90; H, 5.15; N, 5.14. oxyethaneand 4.9 g. of l3~chloroethylisothiocyanate by

(B)Cyclohexyl 3-nitro-4-dibenzylaminobenzoate the method of Example 6 to ,yield 1.54 g.of the6-iso-

Two and. eight-tenths grams (0.01 mole) of cyclo- mer, mp '. ,23?o-8° C,_(dec). ' '

hexyl 3-nitro-4-chlorobenzoate, 4.4 ml. (0.022 mole). Analysis C15H20N~02S ~W 332; Calcd: (_;, 57.83; H,

of dibenzylamine and 20 ml. of dimethylformamide 40 6.02; N~ 16.~,6. Found: ~~ 57.75; H., 5.85; N, 16.82.

(DMF) were refluxed for 6 hours. The reaction mixture 1-(Thlazohn-2-yl)-2-amlno~6-phenoxycarbonylben-

was evaporated in vacuo and the residue was diluted zimidazole ,~as prepar~d 'by reacting 10.2 g. (90

with 500 ml. of water. The aqueous mixture was ex- ~m?Ies) ,o! 2-amln~..;.5(6)-phenoxycarbonylben-

tracted with ethyl acetate. The ethyl acetate solution zlmldaz~le (via phenyl 3~nltro-4-chlorobenzoate, 170 '

was dried and evaporated in vacuo to give an oil. The 45 ml. ~f dimethoxyethane, 2.0 g~ of 5? pe~cent sodium

oil was taken up in ether and filtered. The solution was hydnde and 4.9 g. of .B-chloroethyhsothlocyanate by

evaporated in vacuo to yield 4.2 g. (95 percent) of the met~odoofExample 6 to yield 3.2 g. of the 6-isomer,

cyclohexyl 3-nitro-4-dibenzylaminobenzo3:~e as an oil. mp 225:6 C (dec). ,

(C) 2-Amino-5( 6 )-cyclohexyloxycarbonylben- Analysis ,C'17H14N402S MW',338; Calcd: C, 60.34; H,

zimidazole ' " ": ' , 50 4.17; N, 16.56. Found: C, 60.13; H, 4.22; N, 16.30.

One hundred grams (0.386 mole) of cyclohexyl 3- EXAMPLE 10

nitro-4-dibenzylaminobenza;ate were hydrogenated at 60° C for 22 hours with 25 g: of palladium-on .. carbon in 875 rnl, of 2B ethanol. The catalyst was filtered and the filtrate was evaporated in vacuo to leave an oil. The oil 55 was taken up in ethyl acetate and filtered. Anhydrous Hel gas was passed over the surface of the ethyl acetate solution with stirring. The precipitated o-phenylenediamine hydrochloride salt was collected and washed with anhydrous ether to yield 24.3 g. of product. The saIt was dissolved in water and the pH of the aqueous solution was adjusted to 7.00 with IN sodium hydroxide (130 mI.). Forty milliliters of methanol and 9 g. (0.0845 mole) of cyanogen bromide were added to the aqueous solution. The reaction mixture was stirred 65 OVernight. The aqueous mixture was basified in IN SOdium, hydroxide and extracted 'With ethyl acetate. The ethyl acetate extract was decolorized With carbon

methylformamide until the solution became homogenous. The reaction mixture was evaporated in vacuo to leave a residue. Water was added to the residue and the " insoluble product was filtered to, yield' 700 mg. of 1- (thiazolin- 2- yl )-2-amino-6-methoxycarbonylben~, .: '

zimidazole, mp 209°-211 0 C. " '.,' : , ' .

Analysis C12H12N402S MW 276; Calcd:C, ,52 . .1 6;H, 4.38; N, 20.28. Found: C, 51.99; H, 4.16;, N, 20.08. ',,,

EXAMPLE 6

.

1 :,(Th.azolin-2-yl)-2-J\mino~6-t-Butyloxycarbonylben-

. zimidazole

(A)t-Butyl 3,4-Dinitrobenzoate

Fifty-three grams (0.25 mole) of 3,4-dinitrobenzoic acid, 500 ml.. of benzene, 65 g. (0.51 mole) of oxalyl chloride and 1 mt. of pyridine were reacted according to Example 6 (A), first ,paragraph, to provide 3,4-dini-

60 trobenzoyl chloride as a crude oil. ,',

,", , The crude 3,4-dinitrobenzoyl chloride, 500' ml. of 'benzene, 25 ml. of pyridine and 22 g.(O:3()of t-butyl alcohol were reacted as in, Example: 6 '(A),second paragraph, to provide 33 g.;' (49 percent yield) of t-

butyl 3,4-dinitrobenzoate. :, · , , , ,

Analysis CllH12N206'MW 268;, Calcd; C,- 49·.26;. H, 4.51; N;,10.44. Found:C,48.9S;H, 4.30;'N, 10.14. (B)2-Affiino-S(6)-t-Butyloxycarbonylbenzimidazole

•

4,008,243

Four and two-tenths grams (0.02 mole) of t-butyl 3,4-dinitrobenzoate were hydrogenated in 95 ml. of ethanol with 19. of 5 percent palladium-on-carbon for one hour at room temperature. The exothermic reac- 5 tion reached a maximum temperature of 45° C with a

hydrogen uptake which was 85' percent of theoretical. The catalyst, was filtered and the filtrate was evaporated in vacuo to a residual oil. The crude t-butyl 3 ,4- diaminobenzoate product (0.017 mole) was taken up in a mixture of 20 ml. of methanol and 200 ml. of water. Cyanogen bromide, 1.8 g. (0.017 mole), was reacted with the diamine ester according to the method

of Example 6(C) to yield 1.5 g. (38 percent) of 2- amino-5( 6 ) .. t-butyloxycarbonylbenzimidazole.

(C) 1 .. (Thiazolin-2-yl )-2-Amino-6-t-Butyloxycarbony lbenzimidazole

Three grams (13 mmole) of 2-amino-5(6)-t-butyloxycarbonylbenzimidazole, I 00 mI. of dimethoxyethane, O. 7 g. of 50 percent sodium hydride, and 1.8 g of {3- chlorethylisothiocyanate were reacted by the method

of Example 1 to yield 300 mg. of the 6-isomer, 1- ( thiazolin- 2- yl)- 2-amino-6-t-butyloxycar bony Ibenzimidazole, mp, 218°-219° C.

Analysis ClsHlSN402S MW 318; Calcd: C, 56.58; H. 5.70; N, 17.60. Found: C, 56.80; H, S.92;N, 17.61.

17

We claim:

1. A compound of the formula

N

3

1

N

wherein

R, is hydrogen or C1-CS alkyl;

R2 is hydrogen, formyl, acetyl or propionyl;

•

18

Ra is C1-CS alkyl, Ca-C7 cycloalkyl, (ere7 cycloalkyl)methyl, 1-(C:rC7 cycloalkyl)ethyl, benzyl or a-methylbenzyl;

o II

R30-C-

is at the 5 or 6 position; and It is 20r 3.

1 0 2. A compound of claim 1 wherein R, is hydrogen or

methyl, R2 is hydrogen, R3 is C1-CS alkyl or Ca-C7 cycloalky I, and n is 2.

3. The compound of claim 2 which is 1-(thiazolin-2- yl)- 2-amino- 5 ( 6 )-ethoxycarbonylbenzimidazole.

15 4. The compound of claim 2 which is 1-(thiazolin .. 2- y 1)- 2-amino-5 ( 6 ) -isopropoxycarbon y lbenzimidazole.

S. The compound of claim 2 which is I -( 4-methylthiazolin- 2- yl)- 2-amino-5 ( 6 )-ethoxycarbon y Ibenzimidazole.

20 6. The compound of claim 2 which is 1 (5-metbyl- .

thiazolin- 2- yl-5 ( 6 )-etho xycarbony Ibenzimidazo Ie.

7. The compound of claim 2 which is 1-(thiazolin-2- yl )-2-amino-5( 6 )-t-butyloxycarbonylbenzirnidazole.

8. The compound of claim 2 which is 1-(thiazolin-2- 25 y 1)- 2-ami no- 5 ( 6 )-neopen tyloxycarbon y Ibenzimidazole.

9. The compound of claim 2 which is 1-(thiazolin-2- yJ )-2-amino-5( 6 )-cyclobutyloxycarbonylbenzimidazole.

30 10. A compound of claim 2 wherein

•

35

is at the 6 position.

11. The compound of claim 10 which is l-Ithiazolin- 2-yl )-2-amino-6-ethoxycarbonylbenzimidazole.

12. The compound of claim 10 which is 1-(thiazolin- 40 2-yl)-2-amino.;.6-isopropoxycarbonylbenzimidazole.

13. The compound of claim 1 0 which is 1 -( thiazolin- 2-yl)-2-amino-6-t-butyloxycarbonylbenzimidazole.

14. The compound of claim 10 which is l-(thiazolin- 2-yl )-2-amino-6-neopentylcarbonylbenzimidazole.

45 15. The compound of claim 10 which is l-(thiazolin- 2-yl )-2-amino-6-cyclobutyloxycarbonylbenzimidazole.

* * * * *

50

55

60

65