CA1095524A

CA1095524A - Antiinflammatory imidazothiazoles

Info

Publication number: CA1095524A
Application number: CA269,924A
Authority: CA
Inventors: Robert E. Moser; Larry J. Powers; Zaven S. Ariyan
Original assignee: Diamond Shamrock Corp
Current assignee: Diamond Shamrock Corp
Priority date: 1976-01-19
Filing date: 1977-01-18
Publication date: 1981-02-10
Also published as: CH634075A5; DE2701853A1; GB1556878A; FR2338281A1; AU2136277A; NL7700531A; AU516452B2; JPS52106893A; CH625249A5; IL59626A0; FR2338281B1; GB1556877A; IL59625A0

Abstract

ABSTRACT OF THE DISCLOSURE
Certain imidazothiazoles and thiazolopyrimidines have been found to prevent and inhibit the formation of granuloma tissue in animals. This result is accomplished by administering to the animal subject a therapeutically effective amount of a compound having the formula:

Description

S~
ANTlINFLAMM~TO~Y IMIDAZOTHIAZOLES
AND l~lIAZOIOPYRIMIDINES

, .
. , , - , . .

BACKGROUND OF THE INVENTION
Many compounds are known whlch exhlbit some degree of antiinfla~mat~ry activlty.
For example, British Patent 1,099,389 discloses certain 2,4-disubstituted thiazoles which are known to be antiinflammatory. However, these compounds suffer ~rom certain lnherent deficiencies which limit their utility as antiin~lammatory drugs. Also, in U.S. Patent 3,796,800 is d~sclose~ another group of thiazoles which exhibit antiin-flammatory properties. These compounds are generally ldentified by the formula:

~ N i ~
R"'~ S

wherein R is lower alkyl (e.g., -CH~), or N-amlnocarbamoyl, R"
and R"' are independently selected from the group consisting of hydrogen, lower alkyl (e.g.~ -CzH5) and lower acyl (e.g., -COCH3);
and R' is hydrogen, CONHRl or CONRzR9, wherein Rl is phenyl3 mono-d~- or tri-(lower) alkylphenyl, cyclohexyl, or amino; Rz is lower alkyl (C~-C9); R3 15 lower al~yl (C2 -C9) or phenyl; or Rz and R3 toeether with the nitrogen atom form a morpholino ring, and ph~rmaceutlcally acceptable acid addltion salts thereo~, sueh as the hydrochlorid~

- 2 -55 ~ ~

Wh$1e the above compounds evidence antiinflammatory properties~ they also exhiblt certain other properties which limit their utillty as such drugs.
From the Canadlan Journal of Chemistry (Vol. 42, pg 2847, 1969) certain [2,1-b] thlazoles and thiazolo [3,2-a~
pyrimidines are known as anthelmintics. 3-(Hydroxy- or methoxy)-phenyl-5,6-dihydroimidazo-[2,1-b~ thiazoles are known from U.S.
Patent 2,969,~69 to have a variety of pharmaceutical activities, including an antilnflammatory effect. Further, U.S. patent

3,860,718 describes the use of quaternary 7-substituted imidazo 12,1-b] thiazolium compounds as hypoglycemic agents (blood-sugar lowering agents), but no disclosure can be found therein which would indicate that such compounds have antiinflammatory properties.

. STATE~ENT OF THE INVENTION
A
Therefore, it is an object of the present invention to provide effective antiin~lammatory compositions containing as the active ingredients thereof certain imidazothiazoles and thiazolo-py.rimidines.
It is a further object of the present invention to provide a method for preventing and inhibiting the formation of granuloma tissue in animals employing certain imidazothiazoles and thiazolopyrimidines.
It is a still further ob~ect of the present invention to provide an imidazothiazole and certain hydrated precursors of imidazothiazoles and thiazolopyrimidines which have pharma-ceutical activity.
These and further ob~ects of the present invention will become app~rent to those skilled ln the art from the specification and claims which follow.

~ 5 2 ~

There has now been found a pharmaceutical preparation in dosage unit form, the active ingredient of whi~h consists of a nontoxic antiinflammatory amount of at least one compound of the formula:

R" R' wherein n is 2 or 3; R is h~drogen or methyl; R' is hydrogen, C ~-C3 alkyl or thioalkyl, phenyl, or carboxy methyl; and R" is C1-C4 alkyl, 2-benzofuranyl, naphthyl, phenyl, or mono- or disub-stituted phenyl, and acid addition and quaternary salts thereo~
Further in accordance with the ob~ects and practices of the present invention, there have been ~ound active antiinI~am-matory compounds and mixtures thereof and pharmaceutical preparations in nontoxic dosage unit form adapted for oral or parenteral administration comprised o~ compounds of the ~ormula:

~S
R~ - B ~ N
\ ~ .
~ S

~3 ~2 wherein B is ethylene, vinylene ( CH=CH-) or l',~'-cyclohexylene and when B is ethylene R2 is C l-C3 alkylsulfonyl or a group of the ~ormula where R7 and R~ are independently selected from hydrogen, monofluorophenyl, tri~luoromethylphenyl, or trimethylphenyl with the proviso that R7 and R~
can not simultaneously be hydrogen~ or R7 and R8 when taken together w~th the nitrogen atom to which they are attached form cis-dimethylpyrrolidine; R9 is C1-C4 alkyl (preferably methyl) or phenyl; R5 and R~ are each independently selected from hydrogen or Cl-C4 alkyl (preferably methyl); and when B is vinylene 0 R2 is hydrogen; R3 is hydrogen or ca-c4 alkyl; Rs and R6 are independently selected from hydrogen, pheny~ bromo- or nitrophenyl (preferably para - -substitu~ed) with the proviso that Rs and Rff can not simultaneously be hydrogen; and when B is 1~,2' cyclohexylene R2 is hydrogen and R3 is Cl-C4 alkyl (preferably methyl) or phenyl and R5 and R6 are each hydrogen with the proviso that when R3 is methyl the bond at the 2,3- position of the thiazole ring may be saturated :~ and the C-3 carbon atom thereof optionally substituted by a hydroxyl group;

and the pharmaceutically acceptable inorganic or organic acid addition and quaternary salts thereof.
A method of preventing and inhibiting the formation of granuloma tissue in an animal subject has further been found, which method comprises administering ~o said animal a nontoxic antiinfla~atory amount of at least one such compound or phar-maceutlcal preparation thereof.
: There have further been found 3-~2-benzofuranyl)-5,5-.) dihydro-4H-imidazo-[2,1-b] thiazole and certain hydrated pre-;: cursors o~ imidazothiazoles and thiazolopyrimidines having the ~ormula: .

.
.
,.,. .

i~9~i52~

~ N
(CH ~ ~

N , HO ~ - -Y R
wherein n is 2 or 3; R is H or CH3; and Y is phenyl or p-chloro-or p-methoxyphenyl. These compounds also have antiinflammatory effect and may be employed in the acid addition or quaternary salt form.
Thus, in accordance with the present teachings, a process is provided for the preparation of a compound of the general formula:

R - - B -- I

N S
L- ~

wherein B is ethylene or 1', 2'-cyclohexylene; and when B is ethylene, R3 is benzofuranyl and R2 is hydrogen; and when R2 is Cl-C3 alkylsulfonyl or a group of the formula ` . ~a~

where R7 and R8 are independently selected from hydrogen, monofluorophenyl, trifluoromethylphenyl, or trimethylphenyl with the proviso that R7 and R8 can not simultaneously be hydrogen, or R7 and R8 when taken together with the nitrogen atom to which they are attached form cis-dimethylpyrrolidine;
R3 is Cl-C4 al~yl or phenyl; R5 and R6 are each independently selected from h~drogen or Cl-C4 alkyl; and when B is 1', 2'-cyclohexylene, R2 is hydrogen and R3 is Cl-C4 alkyl or phenyl and R5 and R6 are each hydrogen or when R3 is methyl the bond of unsatura-tion at the 2,3-position of the thiazole ring is saturated and the C-3 carbon atom thereof optionally substituted by a hydroxyl group and R5 and R6 are each hydrogen;
which comprises (a) condensing at reflux an ~-haloketone of formula O Hal - . .

in which Hal represents a halo~en, with a 2-mercaptoimidazoline f the formula R6- N ~ ~
I SH
H

to obtain the desired, optionally substituted 5,6-dihydro-4H-imidazo-~2,1-b~-thiazole or (b) condensing said ~-haloketone with said ~-mercaptoimidazoline at a temperature lower than reflux to obtain the desired hydroxyl derivatives.

DESCRIPTION OF THE PREFERRED EMBODIMENTS
Compounds which are the active ingredients of the present invention fit the general formula:

E

i24 ~ N
(CHR
J~
R" R' In this formula, when n is 2, the compounds are designated generally as substituted 5,6-dihydro-4H-imidazo- 2,1-b thia-zoles. When n is 3, the cGmpounds are designated as substituted tetrahydrothiazolo- 3,2-a pyrimidines. The substituent R, of which 1 may be present on each methylen group, represents either hydrogen or methyl. The groups represented by R' include hydrogen, Cl-C3 alkyl (especially methyl and ethyl) and thio-alkyl (especially thiomethyl), carboxy methyl; and phenyl. The members fitting the definition for R" include Cl-C4 alkyl (especially methyl and tertiarybutyl), 2-benzofuranyl, naphthyl, phenyl, and mono- or disubstituted phenyl (especially wherein the substituents are electronegative and in the "para" position, -6b-1~355~4 such as Cl, Br, NO2, OCH3, and 3,4-dichloro- or dimethyl). A
preferred and novel compound at this time is 3-(2-benzofuranyl) -5,6-dihydro-4H-imidazo[2,1-b] thiazole (including salts there-of). Preferred and novel hydrated precursors of the above for-mula are those corresponding to the formula:

(CH ~ / ~

t HO
Y R
wherein n is 2 or 3; R is H or methyl; and Y is phenyl or p-chloro- or p-methoxyphenyl.
As exemplary specifically preferred compounds of the formula \ /\
N S

and salts thereof referred to above, there may be mentioned 2',4'j6'-trimethyl-3-methyl-5,6-dihydro-4H-imidazo-[2,1-b]
thiazole-2-carboxanilide, 2'-fluoro-3-methyl-5,6-dihydro-4II-imidazo~[2,1-b] thiazole-2-carboxanilide, 3'-trifluoro-methyl-3-methyl-5,6-dihydro-4H-imidazo-[2,1-b] thiazole-2-carboxanilide, 2',4',6'-trimethyl-3,4 (or 3,5)-dimethyl-5,6-dihydro-4H-imidazo-[2,1-bJ thiazole-2-carboxanilide, 2',4',6'-trimethyl-3-phenyl-5l6-dihydro-4~-imidazo-[2,1-b] thiazole-2-carboxanilide, cis-2',5'-dimethyl-3-methyl-5,6-dihydro-4H-imidazo-~2,1-b] thiazole-2-pyrrolidamide, 6-phenyl (or 6-phenyl-~3 ~

3-methyl)-4H-imidazo-~2,1-b] thiazole and the corresponding 7-(4"-chlorobenzyl) thiazolonium chlorides, 6-(4'-nitrophenyl)-4H-imidazo-~2,1-b~ thiazole, 6-(4'-bromophenyl)-4H-imidazo-2,1-b] thiazole and the correspondin~ 7 (2",4"-d~chlorobenzyl), (2"-chlorobenzyl) or (~"-propargyl) th~azolonium chlorides, ~ 3-methyl-4,5,5,7,8,9-hexahydrobenzimidazole thiazole, trans-3-methyl-4,5,6,7,8,9 hexahydrobenzimidazole thiazole, trans-3-methyl-~-hydroxy~2,~,4,5,6,7,8,9-octahydrobenzimidazole thiazole corresponding, respectively, to the structural formulas _ .. . . . _ and H OH
N

~ N ~ ~

as well as the stereoisomeric random mixtures thereof and the pharmaceutically acceptable inorganic and organic acid addition salts and quaternary salts of the foregoing such as, for instance the hydrochloride, hydrobromide, tartrate, phosphate or alkyl or aral~yl halides, i.e., propargyl bromide, mono- or dihalobenzyl chloride, and the like.
While the compounds themselves exhibit excellent antiinflammatOry acti~ity, they may be and often are employed in the form of pharmacolo~ically acceptable a~id addition or quaternary salts thereof. For example, one may employ acid halides, such as HBr or HCl, or tartaric acid, to form the addition salts or al~yl halides and the like, such as pro-pargyl bromide, ~or quaternization. The criteria for choosing and methods for preparing salts suitable for administration are well known to those skllled in the art.

~ S5 Z ~

In preparlng the pharmaceutlcal compositions of the present invention in unit dosage form, a nontoxic, antiinflam-matory amount of one or more of the compounds of the present lnvention is incorporated with the appropriate carriers and/or diluents. ~enerally, the amount ~or administration will be from about 10 to 500 milligrams ~ ilogram/day of ~ody weight, prefer-ably from about 50 to 300 mg/~g/day For example, ~n the case of a tablet, the composit~on w111 comprise, in addition to the active ingredient, fillers, binders, and diluents such as lactose, methylcellulose, talc, gum tragacanth, gum acacia, agar, polyvinylpyrrolidoneg stearic .
acld, and/or corn starch, etc. In the case of a liquid suspen~
sion for oral administration, the composition will comprise, in addition to the active ingredients, a filler such as sodium carboxymethylcellulose and/or syrup, e.g., a glycerine based syrup. In the case of a parenteral solution or suspension, the composition will comprise, in addition to the active ingredient, a suitable sol~ent or other liquid such as a saline solution.
In the case of a topical ointment, a vehicle such as petroleum Jelly or hydrophillic petroleum is suitable.
The compounds employed in the instant invention may be prepared by the condensation of an C~-haloketone with (1) 2-mercaptoimidazoline or a substituted derivative to yield the desired (substituted) 5,6-dihydro-4H-imidazo-[2,1-b] thiazole or (2) with 1,2,3,4-tetrahydro-2-pyrimidinethiol or a substi-tuted derivative to yield the desired (substituted) tetrahydro-thiazolo-~3~2-a.] pyrimidine. Reference to such standard prepa-rations is set forth in the Canadian Journal of Chemistry, Vol.
47 (1969) at page 2843.
The 2-carboxanilide deri~ati~es Or the inventlon may be synthesized by allowing the appropriate 2-mercaptoimidazole to react w~th a 2-chloro -acetoacetanilide in rerluxing alcohol.

.
-The 2-chloro-acetoacetanilides can be conventionally prepared by chlorination of the corresponding acetoacetanilide with sul-furyl chloride in benzene. The acetoacetanilide starting materials can be obtained by heating ethyl acetoacetate with a substituted aniline.
Generally, the cis and trans isomers of 3-methyl-4 r 5 ~
6,7,8,9-hexahydrobenzimidazole thiazole can be obtained by the following stereospecific synthesis method. Commercially avail-able diaminocyclohexane (cls-trans mixture) is separated into the respective stereoisomers according to the procedure of R. Saito and Y. Kidani, Chemistry Letters, 123-126 (1976). The pure stereoisomers (cis or trans) are then allowed to react with carbon disulfide in ethanol-water. After treatment with concentrated HCl, 2-mercapto-4,5,6,7,8,9-hexahydrobenzimidazole is obtained. If the 2-mercaptobenzimidazole is allowed to re-act with chloroacetone at 25C, 3-methyl-3-hydroxy-octahydroben-zimidazo thiazoles are obtained. However, if the 2-mercapto-imidazole is allowed to react with chloroacetone in refluxing ethanol,3-methyl hexahydrobenzimidazo thiazoles are obtained.
Examples of the preparation of certain compounds of the instant invention follow.

To a refluxing solution of 3-benzoyl propionic acid~
(18 g) in CHC13 (100 ml) was added bromine (16.2 g) in CHC13 (100 ml). After 10 minutes of refluxing, the reaction mixture was cooled and the CHC13 removed in vacuo. 2-Mercapto-imida-æolidine (10.2 g) in absolute ethanol was added and the reaction mixture heated to reflux for 1 hour. The reaction mixture was cooled and the precipitate separated by filtration. The product was recrystallized from 95~ ethanol. The isolated product (5.5 g~ has a melting point of 258-263C and was found to be 3-phenyl-5,6-dihydro-4H-imidazo-C2,1-b] thiazo-2-yl-acetic acid hydrobromide.

~ 3~

EXAMPLE 1(a) Benzofuran-2-yl-methyl ketone (lOg, 0.062 moles) was dissolved in approximately 100 ml chloroform and the solution brominated using lOg (0.062 moles) bromine. The resultant brominated solution was heated to reflux for 2 hours, and the solvent stripped after cooling, to yield a solid.
To this was added 6.3g (0.062 moles) of 2-mercapto-imidazolidine in 100 ml. absolute ethanol and the mixture was refluxed for 3 hours. Upon cooling, a yellow precipitate formed which was filtered off and recrystallized from ethylacetate and methanol, yielding 16.5g of 3-(2-benzofuranyl)-5,6-dihydro-4H-imidazo-(2, l-b)- thiazole, as the hydrobromide salt.
Of course, benzofuran-2-yl-bromomethyl ketone may be employed to obtain the desired product in lieu of the brominated solution.

- lOA -:
" .~:,: . . :.

~35~

Similarly, for the preparation of 2-methylthio-3-t-butyl-5,6-dihydro-4H-imldazo-~2,1-b] th~azole hydrobromide~ the procedure of Example 1 was followed except l-methylthiopinacolone (10.7 ~) was brominated (11.4 g) for the desired intermediate.

Me Me Br Me-C-C0-CH2-S-Me ether ~ Me-C-C0-CH-S-Me Me Me EXAMPLE
A solution of 7 41 g (0.05 mole) of N-butyrophe~one and a trace of AlC13 in 15 ml anhydrous ethyl ether was bromi-nated using 8.o g (2.65 ml; 0.05 mole) of bromine The ether and the bromine were removed ln vacuo. The resulting oil was diluted to 100 ml with absolute ethanol and mixed with 5.809 g (0.05 mole) of 3,4,5,6-tetrahydro-2-pyrimidine thiol.
This material was refluxed for 8 hours. The crude product which ~ras obtained on cooling the reaction mixture was recrys-tallized from 95~ ethanol. Recovery was 8.og g (49.74~) of a white solid which was analyzed and found to be 2-ethyl-3-phenyl-

4~5~6~7~tetrahydrothiazole[3,2-a] pyrim~dine hydrobromide.
It should be noted that the intermediates, e.g., hydrated compounds, may be produced by well known variations of the foregoing general techniques. For example, they can be obtained by not refluxln~ but simply heating to a temperature of about 25C.

m-Trifluoromethyl anlline (~2.22 g) in benzene was dissolved ln benzene and diketene added slowly with mixing.
The reaction mixture was allowed to stand at 25c. The re-sulting solld product was recrystallized from ethanol to yield 3~ tri~luoromethyl acetoacetanilide.

._ 3S~4 3~-Trlfluoromethyl acetoacetanilide (28.45 g) obtained ln Example 4 was dissolved in warm benzene. Sulfuryl chlorlde (9.4 ml, .116 m) was added slowly and the reaction allo~ed to stand at 25C for about 2 hours. The solvent was removed and the residual oil was dissolved in ethanol (absolute-100 ml) and ethylene thiourea (11 8 g-.116 m) added. The mixture was then refluxed for 2 hours and the solid which separated on cooling was filtered, dried and recrystallized from absolute ethanol lC to yield 36.2 g o~ 3-methyl-~'-trifluoromethyl-5,6-dihydro-4H-~midazo-[2,1-b] thiazole-2-carboxanilide hydrochloride (m.p.
~71-275C).

2',4',6'-Trimethylbenzoylacetanilide (17.5 g-.o62 m) was slurried in 250 ml hot benzene and 8.4 g of sulfuryl chloride slowly added to the solution. Upon standing for approximately 2 hours~ the reaction mixture yielded a heavy white precipitate which was removed by filtration and dried. 17 g (.05~ m) of the precipitate was then reacted with ethylene thiourea (5.4 g) 2' in 350 ml absolute ethanol and allowed to reflux for about 25 hours. The sol~ent was stripped, yielding a yellow white solid which was recrystallized from ethyl acetate/methanol to give 9.9 g of the product 3-phenyl-2',4',6'-trimethyl-5,6-dihydro 4H-lmidazo-[2,1-b] thiazole 2-carboxanilide hydrochloride (m.p. 270-271C~.

Trans-diaminocyclohexane (20 g) in ethanol-water (50 ml; 50~) was heated to 60C. Carbon disulfide (16 ml) was then added dropwise over a 1 hour period. After refluxing ~or 3~ 1 hour, concentrated HCl (1.5 ml) was added and the mixture s35SZ~

refluxed for 18 hours. The hot reactlon mixture was poured ~nto an Erlenmeyer flask and cooled to 5C for 2 hours. The resulting precipate was separated by filtration and wash~d with 50~ ethanol-water. The residue was dried to yield 16.74 g, m.p. l96-lg7oc. The mother liquor was concentrated to yield another crop of crystals (m.p. 190-5C, 1.9 g) identified as trans-2-mercapto-4,5,6,7,8,9-hexahydrobenzimidazole.

Trans-2-mercapto-4,5,6,7,8,g-hexahydrobenzimidazole (2.0 g) obtained in Example 7 and chloroacetone (1.05 ml) were slurried in ethanol and the mixture heated to reflux for 18 hours. The reaction mixture was cooled and concentrated to about 20 ml. Diethylether (60 ml) was added to give a white precipitate. This was separated, washed with diethylether and dried to yield 2.~1 ~ (78~), m.p.212-14~, of trans-~-mPthy1-4,5,6,7,8,9-hexahydrobenzimidazole thiazole hydrochloride.

Trans-2-mercapto-4,5,6,7,8,9-hexahydrobenzimidazole (2.0 g) and chloroacetone w~re stirred in ethanol (40 ml) at - 20 25C for 18 hours. ~iethylether (60 ml) was added to the reaction mixture and the resulting suspension cooled to 5C.
The solid was separated, dried and washed with diethylether to yield 2.54 g (80~) of trans -~-methyl-3 -hydroxy-2,3,4,5, 6,7,8,9-octahydrobenzimidazole thiazole.

The compounds of the present in~ention have pharma-ceutical activity as antiinflammatory agents, effective in the prevention and inhibition o~ granuloma tissue formatlon. The actiYity is demonstratedlby a test whlch invol~es the diminution o~ experimental edema lnduced in the hind paw o~ a rat by the ; ln~ection of carrageenin.

The procedure used for measuring the lnhibition of carrageenin-induced edema is a slight modification of the method o~ Winter et al., Proc. Soc. Exptl. Biol. ~ed~ 544 (1962).
The device used for measurement of the paw volume is an adapta-tion of the ~ater displacem~nt procedure described by AdamXiewicz et al., Can. J. Biochem. Physiol. 33:332 (1955). The above compounds were studied for their effectiveness in preventing the edema caused by the intraplantar ~njection Or 0.05 ml c~
a sterile 1.0~ solution of carrageenin. Compounds were ad- -ministered orally, except when indicated as intraperitoneally (l.p.), one hour prior to the injection o~ the carrageenin into the left hind paw of rats. At peak s~relling time (3 hours) the volume of edema was calculated by differential paw volumes.
Table I (in which Ph = phenyl) sets forth resultsobtained at the indicated dosages with compounds (or their salts) of the formula:
~ N
(C~

S5Z~

~ t~ ~ ~ ~ In o ~ ~D oD OD ~ ~r cn ::~ ~ N N '~ t'~ ~ I` ll-) ~r U7 ~r It~ N ~ Lt~
~`

a)~ O~ ==O== S -====
O ~ ~

aJ

~ h _~ 5~

Ul h ~ ~1 ~ ! h h m - = = = : : U H O m u m m m m m m ~ m m m m ~I
m~
= ~ ~ ~ P~
~ I m ,I s~ m ~ m :c er U ~ U O ~ ~
,~ ~ ~ ,C I e I ~ ~: I ~ ~ m ~ ::
P~ ~ U ~ ~ ~ C~ U C~ ,~ U

Il I
m m m P:i U N N m tc m m ~n u c~ ~ m ~ ~ m P: ~q m u ~4 m m m ~ ~ m m ' ~ = ' ~ = 5 ~) m m ~, 1 N : : = = = : = : e O ~I N 1"1 ~r 15~ ~ 1~ 0 ) CS~ O _I ~`1 1~ ~r n --15_ 1~3Si5Z4 O CO OD ~ ~ ~ 0 ~r ~ o c~

~ ~ o = .~
U~ ~ U~ o o o o ~ o o o o o o Ln o o L~l o o m v 1,l m ~ V
U ~ ~ ~ h d I N Q) ~2~ a) ~rC O ~ ~
~1 h 1~ h h ~ O h 0 U ~ ~ 0 ~1 ~ m m m m ~ ~ o 5~ o h m ~ -tn P~ r R 1~
_ ., ~
~`
O ~
~_ ,1 ~ V O ~1 H ~ ,1 1~ 11 ~ O
~ o z; ~ m ~ Q
m ~

g Il U U~
m m m m m u m m m m m m m m m u m I C~ tq U ~ = C

Il I

', ~0 ~ r- OD ~ O ~1 ~ ~ ~r Lr) ~ 1- a:~ ~ o U
.

`. : : . :

S~:4 CO o . ~

i Y o U~ o ~r ~ ~1 .

h ,1 m .
U~ .
i..
. ~
:: ~

H ~ U

.
.~ .
, P: 0:
~ ' U X U

.i ''I

~ ' - 16a - ~

~g~

All compounds show a posltive effect, which may be increased by the use of larger dosages.

EXhMPLE 11 Following the procedure set forth in Example 10, hydrated compounds according to the following formula were e~aluated ~or antiinflammatory e~fect with the results shown in Table II:
.
~ _N
(CH~n , . ., -- - -- - - ~ S

. HO _ l Y R

. _, 1~95~Zfl~

~ ~ O ~ ~ N

0~
o O ~ o o O

.

~I h ~11 ~ = ~
I :C , H¦
m ,.~ .
o C~
~

.
~1 ;

~1 o ~ ..~ ~ ,_ oc) o~

. .

~t~'3S~24 Followlng the procedure set forth in Example 10~
compounds according to the followlng formula were evaluated for anti~nflammatory effect with the results shown ln Table II-A:
Rc~ N
, \,/1~
. ~4 1 ~ A X

' l\

~3~5;~

~ ."
_,~ ,, ~ ~ ~

P;

a E o O

X ~ V ~ I
¢ X

H¦ ~ G
~1 E~ p;

æ

m -' S
~ .

- 2 ~

.

1~35S;~

~_ ~
:~--:: ~;
_ ~ N N

~ ¢ P~ ' I
~ C~ I W W :~ ~

jW ~ W
.~ , ~

æ ~ ~ ~J ~3 ~ o . C~ =O ~ O
~ 0 1~
.. ~
~. ~

; ~

.. . ~ ~ 2 l ~
.

~iS~

.,, ~ ~ C~ ~
~: .

a) o o o o o o o ~ o ~q ~ O ~ O O U~ Lr~ -' N U~
E~I N CU r-l l l l l l l X I ~1 ~ h ~ 1 ~1 1 v m ~ v m ~ u . , I ~;
_ ~

C~ d I ~
V 1~ V V
~: ~ ~ ~~1 1 H V C' ~, T ~~
H P~ O P. ~3 C`J
~1 . . .
~ ~ ~ ' C C

~; Z; ~

~r ~ u~ '. .

!' ' .~

~ .

- 2? _ ~3~SZ~

Slmilarly, the following 1',2'-cyclohexylene derivatives were evaluated relative to their antiinflammatory erfects .

,TABLE II-B
Dose Reduction Compound _ ~mg~k~
H

~HBr 10 46 N ~ 25. 76 lC ~ ~ CH~ 25 57 HCl 50 80 H

HCl , ! ~ HBr 29 N

H

:

5~4 TABLE II-B (cont'd2 Dose Reduction ComPound (mg/kg) (%) N ~ S~
H

As ~s evident from the data in Table II-B, each of the respective cis and trans stereoisomers of compounds con- -taining a 1',2'-cyclohexylene moiety display excellent anti-lnflammatory activity. Likewise, those compounds comprised of random mixtures of each of the cis and trans stereoisomers are also active antiinflammatory agents. While the pure trans isomers appear to possess slightly greater antiinflammatory activity than the pure cis compounds or the random stereoisomeric mixtures based upon comparative dose-response relationships, preferential selection of a particular compound or stereoisomer will depend, of course, upon the mode of administration and dosage regimen contemplated, the severity of the lnflammatory condition to be treated, dosage related adverse effects, if any, observed and analogous considerations.

, EXAMPLE 13 Certain of the compounds of the invention were further tested to determine their EDso values. The EDso value is defined as that dose which reduced edema formation by about 25~ or more compared with the mean control response (parallel run) in 50~ of ~he animals. Typical results of these tests appear in Table III.
.' s~z~

TABLE III
EDso vs. CARRAGEENIN ASSAY
. Dose ED O Confidence ComPound (mg~k~)(m~ ~ g) ~imits-9 1 ~5, 75, 100, 150 25 18-~2 9 25, 50, 75, 100 20 . 16-24 Next, certa~n of the compounds were sub~ected to a secondary screen designated the adrenalectomized assay. In _0 this series of tests, the method used was identical to that - described above, except that the animals used were adrenalec-tomized several days prior to assay. Since the results in the nonadrenalec~omized animals were similarOto those obtained in . the adrenalectomized animals, it can be inferred that the anti-~n~lammatory act~vity of the test compounds was not caused by the release of endogeneous adrenocortical steriods.
,j .
The results o~ this test are given in Table IV.

TABLE IV
i Adrenalectomized S~ra~e Dawley ~ale Rats (Charles River) ComPound ~ Reduction Dose at mg/k~

4 ~1 25 . 5 15 . 25

6 19 25 . 8 23 25 . 10 18 50 ;. 16 1~ 50 ,-~D 17 60 . 50 29 18 ~ 25 . . _.

- ~5 -EXAMP~E 15 Selected compounds were further subjected to advanced evaluations. Specifically, in view of the interesting activity of compounds l and 9, those compounds were further subjected to the adjuvant-induced arthritis test. This test requires one mon~h (from day O to day 31). In the first seventeen days tO-17), the disease is in a developing stage, while for the re-mainder of the month (18-31) the disease is fully developed.
The results of this testl given in terms of percent reduction of swelling in the hind paw of the rat are shown in Table V.
The method is essentially that of Newbould, Brit. ~.
Pharmacol. 21: 127, 1963. The test compounds were studied in the developing ar~hritis state and in the established arthritic state. Separate groups of twelve rats were administered the compounds orally using methylcellulose as the vehicle. In the study on the developing disease, administration of the test compounds begins on day 1 and on day 2 each animal is injected :
with .05 ml/kg of a 0.5% suspension of heat-killed Mycobacterium ~; tuberculosis into the plantar surface of the left hind paw.
Foot volumes were measured by a water displacement device on the day of administration of the Mycobacterium and again on days 3, lO and 17. The test compounds were administered once daily. Body weights were recorded daily and the animals were examined for the spread of the inflammation and the degree of secondary lesions. For study in the established disease, another group of rats are~injected witht~le Mycobacterium and foot volumes are measured. After twenty days volumes are again measured and administration of the test compounds begins and continues for eleven days. Foot volume measurements are re-peated on day 27 and day 31. The extent of the spread of the inflammation and the degree of lesions are ~ 3~

recorded daily as are the body weights. The ef~ect of the test compounds is measured by the percentage reduction in left hind paw volumes as compared to the hind paw volumes of the control groups.

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In addition to the reduction in inflammation indicated in Table V, a lessening in the degree of secondary lesions was observed.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process of preparing a compound of general formula:

wherein B is ethylene or 1', 2'-cyclohexylene; and when B is ethylene, R3 is benzofuranyl and R2 is hydrogen; and when R2 is C1-C3 alkylsulfonyl or a group of the formula where R7 and R8 are independently selected from hydrogen, monofluorophenyl, trifluoromethylphenyl, or trimethylphenyl with the proviso that R7 and R8 can not simultaneously be hydrogen, or R7 and R8 when taken together with the nitrogen atom to which they are attached form cis-dimethylpyrrolidine;
R3 is C1-C4 alkyl or phenyl; R5 and R6 are each independently selected from hydrogen or C1-C4 alkyl; and when B is 1', 2'-cyclohexylene, R2 is hydrogen and R3 is C1-C4 alkyl or phenyl and R5 and R6 are each hydrogen or when R3 is methyl the bond of unsaturation at the 2,3-position of the thiazole ring is saturated and the C-3 carbon atom thereof optionally substituted by a hydroxyl group and R5 and R6 are each hydrogen;
which comprises (a) condensing at reflux an .alpha.-haloketone of formula:

in which Hal represents a halogen, with a 2-mercaptoimidazoline of the formula:

to obtain the desired, optionally substituted 5,6-dihydro-4H-imidazo-[2,1-b]-thiazole or (b) condensing said .alpha.-haloketone with said .alpha.-mercaptoimidazoline at a temperature lower than reflux to obtain the desired hydroxyl derivatives.

2. A process of preparing trans-3-methyl-4,5,6,7,8,9-hexahydrobenzimidazole thiazole hydrochloride which comprises treating trans-diaminocyclohexane with carbon disulphide under acidic conditions and separating the trans-2-mercapto-4,5,6,7, 8,9 hexahydrobenzimidazole so formed, followed by reacting the trans-2-mercapto-4,5,6,7,8,9-hexahydrobenzimidazole with chloroacetone and recovering the trans-3-methy1-4,5,6,7,8,9-hexahydrobenzimidazole thiazole hydrochloride so formed.

3. A process of preparing cis-3-methyl-4,5,6,7,8,9-hexahydrobenzimidazole thiazole hydrochloride which comprises treating cis-diaminocyclohexane with carbon disulphide under acidic conditions and separating the cis-2-mercapto-4,5,6,7,8, 9 hexahydrobenzimidazole so formed, followed by reacting the cis-2-mercapto-4,5,6,7,8,9-hexahydrobenzimidazole with chloro-acetone and recovering the cis-3-methyl-4,5,6,7,8,9-hexahydro-benzimidazole thiazole hydrochloride so formed.

4. A process for preparing trans-3-methyl-3 hydroxy-2,3,4,5,6,7,8,9-octahydrobenzimidazole thiazole hydrochloride which comprises treating trans-diaminocyclohexane with carbon disulphide under acidic conditions and separating the trans-2-mercapto-3 hydroxy-2,3,4,5,6,7,8,9-octahydrobenzimidazole so formed, followed by reacting the trans-2-mercapto-3 hydroxy-2, 3,4,5,6,7,8,9-octahydrobenzimidazole with chloroacetone and recovering the trans-3-methyl-3 hydroxy-2,3,4,5,6,7,8,9-octahy-drobenzimidazole thiazole hydrochloride so formed.

5. A process of preparing 3-(2-benzofuranyl)-5,6-dihydro-4H-imidazo-[2,1-b]-thiazole hydrobromide which comprises brominating benzofuran-2-yl-methyl ketone, reacting the bromin-ated product so formed with 2-mercaptoimidazoline and recover-ing the 3-(2-benzofuranyl)-5,6-dihydro-4H-imidazo-[2,1-b]-thiazole hydrobromide so formed.

6. The process of claim 1 wherein B is ethylene.

7. The process of claim 1 wherein R2 is the group

8. A compound selected from the group consisting of compounds of the formula:

wherein B is ethylene, or 1',2'-cyclohexylene; and when B is ethylene, R3 is benzofuranyl and R2 is hydrogen; and when R2 is C1-C3 alkylsulfonyl or a group of the formula where R7 and R8 are independently selected from hydrogen, monofluorophenyl, trifluoromethylphenyl, or trimethylphenyl with the proviso that R7 and R8 can not simultaneously be hydrogen, or R7 and R8 when taken together with the nitrogen atom to which they are attached form cis-dimethylpyrrolidine; R3 is C1-C4 alkyl or phenyl;
R5 and R6 are each independently selected from hydrogen or C1-C4 alkyl; and when B is 1',2'-cyclohexylene, R2 is hydrogen and R3 is C1-C4 alkyl or phenyl and R5 and R6 are each hydrogen or when R2 is methyl the bond of unsaturation at the 2,3-position of the thiazole ring is saturated and the C-3 carbon atom thereof optionally substituted by a hydroxyl group and R5 and R6 are each hydrogen;
and the pharmaceutically acceptable inorganic or organic acid addition and quaternary salts thereof whenever prepared or produced by the process of claim 1 or by their obvious chemical equivalents.

9. The compound as defined in claim 8 wherein B is ethylene whenever prepared or produced by the process of claim 6 or by any obvious chemical equivalent thereof.

10. The compound as defined in claim 8 wherein R2 is the group whenever prepared or produced by the process of claim 7 or by any obvious chemical equivalent there-of.

11. Trans-3-methyl-4,5,6,7,8,9-hexahydrobenzimidazole thiazole, pharmaceutically acceptable salts or stereoisomeric mixtures thereof whenever prepared or produced by the process of claim 2 or by their obvious chemical equivalents.

12. Cis-3-methyl-4,5,6,7,8,9-hexahydrobenzimidazole thiazole, pharmaceutically acceptable salts or stereoisomeric mixtures thereof whenever prepared or produced by the process of claim 3 or by their obvious chemical equivalents.

13. Trans-3-methyl-3 hydroxy-2,3,4,5,6,7,8,9-octahydrobenzimidazole thiazole, pharmaceutically acceptable salts or stereoisomeric mixtures thereof whenever prepared or produced by the process of claim 4 or by their obvious chemical equivalents.

14. 3-(2-Benzofuranyl)-5,6-dihydro-4H-imidazo-[2,1-b]-thiazole, and pharmaceutically acceptable salts whenever pre-pared by the process of claim 5 or by their obvious chemical equivalents.