Field of the Invention

The present invention relates to a novel method for the treatment of disorders of the human eye, particularly glaucoma.

________D_____________D___D

Glaucoma is characterized by increased intraocular pressure resulting at least in part, from a diminished outflow of aqueous humor through the trabecular meshwor . Glaucoma is an eye disease which untreated can lead to blindness. The disease is one of the principal reasons to blindness in Europe and USA. The disease generally begins insidious without any trouble for the patient. Gradually the symptoms arise in the shape of loss of field of vision and sight degeneration which grow worse if the glaucoma is not treated. Normally the production and outflow of aqueous humor in the eye are in balance. Is this balance disturbed either by increase in aqueous humor production or, more usually, diminished outflow of aqueous humor the pressure in the eye is increased. The high intraocular pressure has an injurious effect on sight cells as well as on nerve- paths in the eye and leads to progressive lesions on these structures. The pressure can be decreased by increasing the outflow of aqueous humor.

Prigr_art

Heterocyclyl al k 1 sul fi nyl benzimi dazol es and heterocyclyl- al ky1 thiobeπzimi dazol es are known in the art, as are methods for using these compounds to reduce gastric acid secretion.

SUBSTITUTE SHEET

Outl τne_of_the_p_resent_inyention

According to the present invention it has been found that compounds of the general formula I as well as pharmaceuti¬ cally acceptable salts thereof are effective to decrease the intraocular pressure in eyes and are thus useful as medicals for the treatment of disorders of the human eye, particularly glaucoma.

The compounds of the formula I below are in most cases known. Compounds which are not known in the prior art can be prepared by methods known for analogous compounds.

The compounds of the invention are of the following formula I:

wherein

X is -S- or -SO-

and R , which are the same or different, are

(a) H

(b) alkyl containing 1-8, especially 1-6 carbon atoms

(c) alkoxy containing 1-8, especially 1-6 carbon atoms

(d) alkoxyalkyl containing 1-3 carbon atoms in each alkyl par

(e) alkoxyalkoxy containing 1-3 carbon atoms in each alkyl pa

(f) halogen

(g) -CM

( ) -CF ₃

(1) -N0 ₂

(j) -COR ¹⁰

(k) alkylthio containing 1-6 carbon atoms in the alkyl part

(1 ) alkylsulfinyl containing 1-7 carbon atoms in the alkyl part

( ) aryl-thio, -sulfinyl, -sulfonyl, -sul fonyloxy, -oxysul fonyl , -sulfonamido or -aminosulfonyl , whereby each aryl group optionally is substituted by 1-3 substi tuents , the same or different and selected from halogen, CF~ and (l-5C)alkoxy

(n) arylalkyl or arylalkoxy, containing 1-6 carbon atoms in the alkyl and alkoxy parts, respectively, whereby the aryl part optionally is substituted by 1-3 substituents , the same or different and selected from halogen, C ^, (l-δC)alkyl and (l-δC)alkoxy

(o) aryl or aryloxy, whereby each aryl group optionally is substituted by 1-3 subst tuents, the same or different and selected from halogen, CF,, (l-5C)alkyl and (l-δC)alkoxy

(p) haloalkoxy containing 1-6 carbon atoms and 1-11, especially 1-6 halogen atoms

(q) hydroxyalkyl containing 1-6 carbon atoms

1 2 2 3 3 4 (r) R and R , R and R or R and R together with the adjacent carbon atoms in the benzi i dazole ring form one or more

5-, 6- or 7-membered rings, which each may be saturated or unsaturated and may contain 0-3 hetero atoms selected from

N, S and 0, and whereby each ring may be optionally substituted with 1-10, suitably 1-6, or 1-4 substituents selected from alkyl groups with 1-3 carbon atoms and halogen or two or four of the mentioned substituents together form

1 2 2 one or two oxo groups (C=0), whereby if R and R , R and

3 3 4 R or R and R together with the adjacent carbon atoms in the benzimi dazole ring form two rings the rings may be condensed with each other;

SUBSTITUTE SHEET

R ⁶ is (a H (b alkyl containing 1-8, especially 1-6 carbon atoms (c alkoxy containing 1-8, especially 1-6 carbon atoms (d hal ogen

R ⁸ is (a H (ώ alkyl containing 1-8, especially 1-6 carbon atoms (c alkoxy containing 1-6 carbon atoms (d halogen arylalkyl containing 1-4 carbon atoms in the alkyl part

ι s (a H (b alkyl containing 1-7 carbon atoms (c alkoxy containing 1-7 carbon atoms (d alkoxyalkyl containing 1-3 carbon atoms in each alkyl part

(e) alkoxyalkoxy containing 1-3 carbon atoms in each alkyl part

(f) aryloxy, whereby the aryl group optionally is substituted by 1 or 2 substituents, the same or different and selected from halogen, CF-, (l-3C)alkyl or (l-3C)alkoxy

(g) arylalkyl or arylalkoxy containing 1-7 carbon atoms in the alkyl resp. alkoxy part, whereby the aryl part optionally is substituted by 1 or 2 substituents, the same or different and selected from halogen, CF.,, (l-3C)alkyl and (l-3C)alkoxy

(h) alkenyloxy containing 1-7 carbon atoms in the alkenyl part (i) alkynyloxy containing 1-7 carbon atoms in the alkenyl part ( ) alkylthio containing 1-7, preferably 1-3 carbon atoms in the alkyl part (k) arylthio or arylal kylthi o containing 1-3, preferably

1 carbon atom in the alkyl part (1) dialkylamino containing 1-7, preferably 1-3 carbon atoms in the alkyl parts (m) orpholino

(n) pi peri di no (o) N-methylpiperazino (p) pyrrol idi no

(q) fluoroalkoxy containing 2-5 carbon atoms and 1-9 fluorine atoms

6 7 7 8 or R and R , or R and R together with the adjacent carbon atoms in the pyridine ring form a 5- or 6-membered, saturated or unsaturated ring, which may optionally contain an oxygen, sulphur or an optionally alkylated nitrogen atom;

R is (a) alkyl containing 1-6 carbon atoms (b) alkoxy containing 1-6 carbon atoms (c ) aryl ;

as well as pharmaceutically acceptable salts thereof, especially alkali salts such as sodium and potassium salts.

Illustrative examples of the various radicals in the formula I are as follows. These illustrative examples will be applicable to the different radicals depending on the number of carbon atoms prescribed for each radical.

The group alkyl in the definitions of R ¹ , R ² , R ³ , R ⁴ , R ⁶ , R ⁷ ,

8 10 R , R are exemplified by methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl , t-butyl, n-pentyl , n-hexyl , cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl , cycl opentyl ethyl , cyclopentylethyl , and cyclohexylmethyl . Lower alkyl groups containing 1-4 carbon atoms are especially preferred.

The group alkoxy in the definitions of R , R , R , R , R , R ,

8 10

R and R are exemplified by methoxy, ethoxy, n--propoxy, iso-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentoxy, i-pentoxy, n-hexoxy, cycl opropoxy , cycl opentoxy, cyclohexoxy, cycl opropylmethoxy , cycl opentyl methoxy , cycl opeπtyl ethoxy, and cycl ohexyl ethox . Lower alkoxy groups are preferred, especially those containing 1-4 carbon atoms,

preferably a lower alkoxy group having especially preferred 1-3 carbon atoms, e.g. methoxy, ethoxy, n-propoxy or isopropoxy.

Halogen in the definitions of R 1 , R2 , R 3 and R 4 is chloro, bromo, fluoro and iodo, preferably chloro, bromo, and fluoro.

In R ,1 , R , R ^* R and R when representing alkylthio or alkylsulfinyl the alkyl is preferably a lower alkyl having especially preferred 1-4 carbon atoms, e.g. methylthio, methylsulfinyl , ethylthio, ethylsulf inyl , isopropylthio, n-butylsulfinyl or i sobutyl thio.

1 __ "~l A Η

The group aryl when present in R , R , R , R , R , R has preferably up to 10 carbon atoms, especially preferred up to 6 carbon atoms, e.g. a phenyl group.

1 2 3 4 7 R , R , R , R and R representing an aryloxy or arylthio group have preferably up to 10 carbon atoms, especially preferred up to 6 carbon atoms, e.g. a phenoxy or phenylthio group.

The groups arylalkyl, arylalkoxy, and aryl alkyl thi o, when 1 „2 _n 3 „4 „5 „7 „8 present in R , R R have preferably up to 10 carbon atoms in the aryl group. Especially preferred are 6 carbon atoms in the aryl group and 1-3 carbon atoms in the alkyl group or alkoxy group, respecti ely, e.g. phenylmethyl , phenylethyl, phenyl ethoxy, phenyl ethoxy, phenyl propyl , phenylisopropoxy, phenylmethylthi o, and phenylethyl hio.

1 2 3 4 7 '

R , R , R , R and R representing an alkoxyalkyl or alkoxyalkoxy group are exemplified by methoxymethyl , methoxyethyl , methoxypropyl , ethoxy ethyl , ethoxyethyl, propoxyethyl , methoxymethoxy, methoxyethoxy, ethoxypropoxy, ethoxyethoxy and propoxyethoxy.

R representing an alkenyloxy or alkynyloxy group has preferably 2-7 carbon atoms, especially preferred 3-4 carbon, atoms, e.g. allyloxy, propargyloxy, 2-butenyloxy and 2-butynyloxy.

1 2 2 Illustrative examples of ring structures formed by R and R , R and

R ³ and R ³ and R ⁴ are -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, -CH ₂ C(CH- ) ₂ CH ₂ -,

-CH ₂ ) ₅ -, -CH=CH-CH=CH-, -CHgCOCHg-, -OCHgO-, -0CH ₂ CH ₂ 0-,

-0CH ₂ CH ₂ CH ₂ 0-, -0CH ₂ CH ₂ -, -CH ₂ CH ₂ H-, -CH=CH-CH=N-, -C0CH ₂ C0-,

-SCH ₂ CH ₂ -, -SCH ₂ S-, -SCH ₂ CH ₂ S-, -C(CH ₃ ) ₂ -C0-C(CH3 ) _£ - , -OCFgO-,

-0CF ₂ CHF0-, -0CF ₂ CHF0-, -0CF ₂ CF ₂ 0-, and -0CF ₂ CFC10-.

6 7 7 8 R and R , or R and R representing a 5- or 6-membered saturated or unsaturated ring is preferably a saturated carbocyclic ring or a saturated ring containing an oxygen or a sulphur atom in the 4-position in the pyridine ring, e.g.

-CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ CH ₂ CH ₂ -, -0-CH ₂ CH ₂ -, -0-CH ₂ CH ₂ CH ₂ -,

-SCH ₂ CH ₂ -, or SCH ₂ CH ₂ CH ₂ -.

R , R , R and R when representing haloalkoxy is preferably a lower haloalkoxy. Especially preferred are lower fluoroalkoxy, or f1 uorochl oroal koxy groups, e.g. 0CF ₃ , 0CHF ₂ , 0CF ₂ CHF ₂ , 0CF ₂ CF ₃ , 0CF-CF ₃ , 0CF ₂ C1, 0CH ₂ CF ₃ .

R when representing alkoxy is exemplified by 0CH ₂ CF ₃ , 0CH ₂ CF ₂ CF ₃ and 0CH ₂ CF ₂ CHF ₂ .

1 2 3 4 R , R , R and R representing hydroxyalkyl is exemplified by

CH ₂ 0H, CH ₂ CH ₂ 0H, CH ₂ CH ₂ CH ₂ 0H, and (CH ₂ ) ₄ 0H.

R when representing a dialkylamino group is preferably -N(CH ₃ ) ₂ , or -N(C ₂ H ₅ ) ₂ .

Examples of pyridine radicals are those which are 3,5-di- methyl-4-methoxy-, 3-methyl -4-methoxy, 5-ethyl-4-methoxy-, 4-methoxy-, 4-ethoxy-, 4-i sopropoxy- , 3, 5-dimethyl - , 3,4-di- methoxy-,4,5-dimethoxy-, 3-meth l-4-(2,2,2-trifluoro)ethoxy-, 3,4-dimethoxy-, 4, 5-dimethoxy- , 3-methyl -4-ethyl thio-, 3-methy1-4, 5-dimethoxy.-, 3,4, 5-trimethy1 -, 3-ethyl-4-methoxy-, 3-n-propyl-4-methoxy-, 3-i sopropyl -4-methoxy-, 3-t-butyl-4_ methoxy-substi tuted.

Of special interest is the compound 2-[[(4-methoxy-3, 5-di - methyl-2-pyridinyl )-methyl]-sulfinyl]-5-methoxy-lH^benz- imidazole (omeprazole).

For the compounds with the general formula I containing an asymmetric centre, both the pure enantio ers and the racemic mixtures are within the scope of the present invention.

Accordingly, the invention relates to

- a method for the treatment of the ailment above by adminis¬ tering to a host in need thereof of a therapeutically effec¬ tive amount of a compound of the formula I

- a pharmaceutical preparation for use in the treatment of the ailment above comprising a compound of the formula I as active ingredient

- a compound of the formula I for use in the manufacture of a medicament for the treatment of the ailment above

Pharmacological test

In order to evaluate the intraocular pressure lowering effect the following method was used.

A stock solution of 100 M of the test compound was made up in a mixture of 4.5 ml of DMSO and 0.5 ml of 0.1 H phosphate buffer at pH 7.3. One hundred μl of the test compound stock solution was added to 1.9 ml of balanced salt solution to make a final concentration of 5 mM. This 5 mM solution of the test compound was used in the experimental eye. The control sol¬ ution was composed of 100 μl of the DMSO-phosphate buffer solution added to balanced salt solution.

Twenty pigmented rabbits weighing 2 kg were used as the exper¬ imental animals. Pre-experi meπt eye examinations were per¬ formed on the rabbits and intraocular pressures were measured

using a pneumotonometer (Digilab model 30R). The pneumotonome- ter was calibrated prior to each series of measurements. Pro- paracaine hydrochl ori de 1/2 % was used as a local anaesthetic prior to each intraocular pressure measurement. Pre-treatment intraocular pressure measurements were done, then 50 μl of the experimental solution was placed on the right eye and 50 μl of the control solution was placed on the left eye of each rabbit.

Post-treatment intraocular pressures were performed on both eyes of each rabbit every 15 minutes for the first two hours, then v ry two hours for the next four hours, and a final intraocular pressure measurement was performed 24 hours following treatment.

The intraocular pressures of the experimental right eye were compared to the control fellow eye of each rabbit. Also comparisons were made between pre- and post-treatment intraocular pressures of each eye.

Results

The compound 2-[[( 4-methoxy-3, 5-dimethyl -2-pyri di nyl )-methyl] sul finyl]-5-methoxy-lH-benzimidazole was tested.

No evidence of ocular irritation was found in either exper¬ imental or control eyes of all 20 rabbits. The intraocular pressures in both experimental and control eyes decreased following treatment. Table 1 shows that this decrease in intraocular pressure was maximal at 2-4 hours following drug application and that the intraocular pressures returned to pre-treatment levels by 24 hours. There appeared to be a slightly greater decrease in intraocular pressure in the control eye when compared to the experimental eye, but this difference is not statistically significant. The maximum decrease in intraocular pressure was approximately 4 mm Hg or about 14 % of the pre-treatment intraocular pressure.

Table 1. Effect of topical administration on the intraocular pressure in the rabbit.

Pressure, mm Hg

Left eye Right eye

Administration

For clinical use the compounds can be administered suitably either topically to the eye or by miero1nject1on Into the trabecular meshwork". For topical adm.fn1 stration, the compound can be administered in solution or by another suitable vehicle -such--as oinment, together with a pharmaceutically acceptable carrier substance, e.g., physiological saline or ointment base. For compounds having limited water solubility the liquid carrier medium can contain an organic solvent, e.g., 3 % methyl cellulose. Methyl cellulose provides, by its high viscosity, increased contact time between the compound and the eye surface, and therefore increased corneal penetration. Corneal penetration can also be increased by administering the compound mixed with an agent which slightly disrupts the corneal membrane, e.g., 0.025 % benzal koni urn chloride.

Administration can made by periodically (e.g., one time per week to ten times per day). When using a solution of the active substance, drops of the compound in solution can be administered using an eye dropper, such that an effective amount of the compound is delivered through the cornea to the trabecular meshwork. The amount of the compound to be delivered in one administration will depend on individual patient characte istics, e.g., severity of disease. A typical administration may be 1-100 drops to each eye per day and each drop may contain 25-100 microliters of a 1-25 M solution of the compound, so that 0.0025 to 25 m oles of the compound are delivered to each eye per day.

Direct icroi njecti on of the solubilized compound into the trabecular meshwork offers the advantage of concentrating the compound in the location where it is needed, while avoiding the possibility of side effects resulting from generalized exposure of the eye to the compound. icroinjecti on also pro¬ vides the advantages of permitting infrequent periodic admin¬ istration, e.g., every few weeks, months, or even years, in contrast to the more frequent administrations required 1n the case of topical administration. Also, direct micro1nject1on

may promote the washing out of the trabecular meshwork of extracellular material interferring with fluid outflow. Dosage for microinjection, like that for topical administration, varies with the above-mentioned parameters. Typically, microinjection dosage is such that a final concentration of the compound within the trabecular meshwork of 0.001 - 0.1 mM is reached.

The compounds of the formula I can also be administered orally, rectally, parenterally or by other modes of administration, suitably in combination with a pharmaceutically acceptable carrier. The effect of the compounds of the formula I in the eye can be achieved by direct application or by using the systemic effect of the compounds.