CA2087510A1 - Method of using m1-selective antimuscarinic pyridobenzodiazepiones in axial myopia therapy - Google Patents

Abstract

- i - 18651 TITLE OF THE INVENTION

PYRIDOBENZODIAZEPINONES IN AXIAL MYOPIA THERAPY

ABSTRACT OF THE INVENTION

Pyridobenzodiazepinones of the formula:

Description

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TITLE OF T~E INV$NTIOM

METHOD OF USING Ml-SELECTIVE ANTIMUSCARINIC
PYRIDOBENZODIAZEPINONES IN AXIAL M~O~PIA THERAPY

ACKGRO~ND ~F TEE INVENTION

Thi~ invention relates to control of ocular development in general and, more~particularly, to the : treatment of the eye to preve~t and/or arre~t the : deve:lopment of myopia (nearsightedne~
~: Myopia a~flicts approximately 25% of the : 25 world's population. In particular, myopia~af~lic~
15% to 75% of the youth of the world, depending ~pon race, geographic distrib~tion and level:of edacation.
Approximately one-hal~ o~ all cases are classifiable a~ axial myopia, where there is an e~ongation o~ the ~0 ~ye along the visual a~

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163FPGt - 2 - 18651 ~ t birth, the human eye is about two-thirds of the size o~ an adult eye. Thi~ i3 relatively ~hort in the directlon o the ~i~ual a~i~, or axial, direction. As a result, children tend to be far-sighted. Durin~ childhood, a~ the eye grows, therei8 a compensatory mechanism governing changes in the structure of the cornea and lens in response to increa~ing ocular lengt~ during childhood growth.
Often the proce~s is virtually perfect and no cor-rection is needed ~or sharp vision at a distance.However, when regulatory mechanisms fail, the eye tends to axially lengthen. As a result, di6tant image~ focus in front of the plane of the retina and the result for the patlent i~ axial myopia.
Myopia is ~ot a trivial maldevelopment of the eye. In its pathologic form, the ~clera cont;nues to grow as the retina stretches and degenerates sesulting in permanent blindnes6.
The ~urgical therapies attempted for this condi-tion are drastic and o~ten unsuccesE~ul.
Even in it8 milder forms, rnyopia has been shown to ha~e an effect on the self-image of a child during the critical s~ate o~ his development. Chil-dren who wear gla66es, ~ustly or not, are con~idered booki~h, i~troverted, and nonathletic (Curtin, 1985).
Because of the6e childhood memories, a parent that is ~ myopic i~ often particularly eager to inquire of the doctor about a therapy to limit the development o~
the myopia when it has been dia~no~ed in hi6 child. - :

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163FPG/ . - 3 - 186Sl Furthermore, the optical correctionR whic~
exist for myopia are neither ideal nor risk-free.
There are roughly 24 million contact lens weareræ
in the United States, and ~he number i~ expected to double in the next five years. No matter how well fitted or cared ~or, complications of contact lens wear range from allergic reaction~ to permanent loææ
of vi~ion due to corneal ulceration. The latter prob-lem was ~o serious that the Food and Drug Adminiætra-tion (FDA) reduced the recommended wearing time fore~tended wear contact lenses from 30 days to "one to 3even days". In 1988, over ~0,000 injuries related ~o contact lens wear were treated and reported by hospital emergency roome.
While eyeglasses eliminate most ~f the medical risks liæted above, they are not an acceptable option as evidenced by the contact lens wearer~ who tolerate the fruætration of contact lens wear. As a result, large efforts have been devoted to the correction o~ myopia by corneal surgery using conventional knives or e~cimer laæer~. Neither of these therapies are easily rever~ed or su~iciently predictable in their re~ult~. De3pite the risk of permanent visual impairment associated with the~e ~5 surgical the~apies, thousandæ of patient~ have undergone radial keratotomy in the ~nited Stateæ.
While the optical and surgical correction of ~yopia corrects the refractivt ætate of the eye, theæe therapies do not address the abnormal elongatlon of the eye during development. Survey~ indicate that 2~751~
1~3FPG/ - 4 - 18651 even low degrees of myopia (-1.00 to -5.00 diopter~) predispose patient~ to the development of glaucoma (Perkin~, 1982). In myop;a, the retina is stretohed and thinned, which predi~pose~ the eye to retinal S detachment. Consequently, ~everal studies have docu~
mented myopia as a risk faetor ~or the development of retinal detachment. All of the above highlight the need for a pharmacologic therapy to address the developmen~al abnormality of myopia.
lo Previously available therapies that relied on administration of drugs began with the use of cycloplegic agent~. Cycloplegics are topically administered drugs that relax the ciliary muscle of the eye, which is the muscle that focuses the eye by controlling lens dimensions.
The elassic cycloplegic drug i8 the belladonna alkaloid atropine, a~ailable for over a century. Atropine i6 a long-acting non-specific antimuscarinic agent that antagonizes the action of the neurotransmitter acetylcholine (ACh) at auto-nomic effector cells innervated by postganglionic cholinergic nerves of the parasympathetic nervous 8y8tem .
In 1971 Bedros3ian completed a t~o-year cros60ver study in 75 children with myopia. During the first year, the right eye wa~ treated with l~O~o atropine applled topically at bedtime. The left eye was treated during the ~econd year. As shown by Table 1, the progression of the myopia was halted in the treated eye (See Table 1).

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Table 1. Effect of 1.0% Atropine Upon Myopia (Bedro~æian, 1971) Cmean change in refractlon in diopters~
~ for hyperopla, - for myopia]
~i~h~ ~ye Le~t ~ye Year 1 +0.20 -0.85 ~ear 1 -1.05 +0.17 The result~ were ~ignificant a~ le~s than th@ 1% level.
A later study confirmed the findings of the first ~udy and indicated that the greatest ef~ect of atropine upon the ælowing of the rat~ of progre3sion of myopia wa~ Reen in children under nine year o$ age (See Table 2).

Table 2. Progression of Myopia (Brodstein, 1984) ~progression in diopters per year~
[+ for hyperopia, - for myopia~
Age of Onset Therapy with of ~hera~v 1.0% Ag~o~ine Control < 9 year~ -0.23 -0.69 '9-12 year~ -0.24 -0.48 > 13 yearR -0.20 -0.23 ', Atropine ha8 not been widely u~ed for ~lowi~g the progreasion of myopia due to drug effects includ~
ing glare from pupillary dilat~on, and inhibition of ocular focu~ing that impair hear vi6ual work like reading.In addition to the di comfort to the patient, there i~ evidence that long-term u~e of atropine or other long-term cycloplegies can harm the ret~a when it i8 exposed to bri~,ht light.

2087 ~10 Recently, ~elective-acting antimu~carinic agent~ were discovered to be u~eful in myopia therapy.
This di~covery was made possible by a new body of ~ubstantial evidence to link the po~terior part of the eye, ~pecifically the image quality region~ o~
the retina and hence an extension of the nervous system, to the postnatal regulation of ocular growth.
There i8 ~i~nificant e~idence of myopia re~ulting ln an eye that i6 subjected to retinal image degradation.
It has been shown that a~ial myopia can be experiment-al.ly induced, in either birds or primates, in an eye in which the retina i8 deprived of formed image6, e.g., by suturing the eyelid~ or wearing an image di~fusing goggle. The experimental myopia induced in birds or primates 6uch aB monkeys mlmics the co~mon axial myopia of humans.
Thus, the phenomenon of an animal's vision procesæ apparently contributes to the feedback ~ech-anism by which po3tnatal ocular growth is normally regulated and re~ractive error is de~ermined. This indicates that this mechanism i neural and likely originates in the retina. R. A. Stone, et al. have found a method of controlling the a~normal po6tnatal growth of the eye of a maturing ani~al, which com-25 pri8e8 controlling the presence of a neurochemical,it6 agonist or antagoni~t, which neurochemical i8 found to be changed under condition~ during matura-tion leading to abnormal axial length. Therein it i~ di~closed that in experimental animal~ such a6 chicks or monkeys ~ubjected to ocular image depriv-ation ordinarily leading to the de~elopment of myopia, the metabolism of certain retina~ neurochemicals ~

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163FPGt - - 7 - 18~51 altered leading to change6 in retinal concentrations thereof. Specifically, retinal concentration~ of dopamine were found to be reduced during such image deprivation and the ocular administration of a dopamine-related agent, e.g., apOmorphine, a dopamine agonl~t, wa~ found to inhibit or actually prevent the axial enlargement o~ the eye under conditions ordinarily leading to such enlargement.
There have ~een recent advances made in the understanding of the cholinergic nervous system.
Cholinergic receptors are proteins embedded in the wall of a cell that respond to ~he chemical acetyl-choline. The~e receptoræ are broadly broken down into nicotinic and muscarinic receptors. In this respect, it i~ now known that the ~uscarinic recept-ors are not all of one type. Recent ~indings show that there are at least ~ive, if not more, types ~f cholinergic ~uscarinic receptors (types Ml throug~
M5). Type Ml receptors are those pre~ent in abun-dance and thought to be enriched irl the brain neuraltiRæue and neural ganglla. Other receptors are con-. centrated in other tis~ues, such a~ in heart1 smooth :; muscle ti~ue, or glands. While many pharmacological agents interactin~ with muscarinic reCeptorB influe~ce 2~ several typeæ, ~ome agents are known to have a majoreffect on a single type of receptor with rela~ive selectivity and other agents ca~ have a relatively ~elective e~ect on a different 6ingle receptor.
Still other agents may have a ~ignificant e~fect on more than o~e or even all ~ypes o~ receptors. It is known, ~or example, that pirenzepine, (~astrozepin, LS ~19) 5,11-Dihydro~ 4-methyl-1-piperazinyl) ~7~

163FP&/ - ~ - 18651 acetyl3-6~-pyrido~2,3-b~1,4Jbenzodiazepin-6-one, and it~ dihydrochloride, are anticholinergic, antimuscarinic, and relatively selective ~or ~1 receptor~. It i~ al~o known that 4-DAMP S4-s diphenylacetoxy-N-methylpiperadine methiodide) is a relatively ~elective antagoni~t for mooth musc1e (ordinarily called M3 type but variouæly called type M2 or M3, as the current cla~sification of reCeptorB
i~ ~n flux). In contrast, it is believed that lo atropine, discussed above a~ a cycloplegic agent, i~ a non-~pecific antagoni~t for all types of cholinergic ~usearinic receptors.
- Pirenzepine, being primarily an Ml antagoni6t, inhibit~ a~ial elongation, but i8 ~ar le~s effective at pupil ~ilation than atropine or another cycloplegic agent. This ma~es it possible to suppress the development of myopia without dilating the pupil and paralyzing the accommodation activity of the ciliary body.
. Pirenzepine, however, has a disadvantage.
The admini~tration of a drug ~opically into the eye oP a developing child for a long period of ti~e make~
it desireable to have a minimal li~elihood o~ sensi-tization of the eye. Pirenzepine te~ts positive in æen~itization a66ay8. There i8 therefore a need in the art for a ~elective anti-muscarinic agent that can be ù~ed to treat myopia, which will not cau~e effects on pupil ~ize or accommodatlon of the ciliary body, and which will be les8 likely to cause ~ensitization than pirenzepine.

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SUMMARY OE T~E INvENTIQ~

The invention i~ a method of using a compound of the ~ormula:

~_R

10 ~;j H

and the pharmaceutically acceptable salt~ thereof, where R is piperidine substituted by Cl_5 alkyl, in the therapy of myopia by ocular administration of cUch a compound, which will prevent abnormal increases in the axial length of the eye.
Specifically, the compounds rispenzepine (ulenzepine) ,~N ~ CH9 ,~N~
O tl a~d nuvenzepine 2087~10 163FP~/ - 10 ~651 O~\N--~H3 S ~) N~

' 10 can be used .in the method of the pre~en~ invention, by their ocular administration to ~revent abnormal increa~es in the axial length of the eye and thus prevent progression of axial myopia.

DETAILED DESCRIPTION OF T~E INVENTXON

Compounds of formula I are prepared e~arting from compound3 of formula II, de~cribed in J~ Med Chem. 6, 255, 1963; Bull. Soc. Chim. Fran. 7, 2316, lg66; and German Pat. No. 1,179,943, by acylation with the acyl chlorides of formula III, according to the follo~ing ~cheme: -O~
H ~ R

CICOR ~

O H H
Il .

20~7~1 ~
163FPG/ ~ 18651 where R is defined as before, that is piperidille substituted by Cl_5 alkyl. The reaction iB carried out in polar solv~nts such as dimethylformamide and d-methylsulfo~ide in the presence of bases sueh a~
triethylamine, alkaline hydroxides and alkaline earbonate~ at temperatures ranging from room temperature to 150C, with reaction times ranging from 2 to 24 hours.
Representative pharmaceuticaily acceptable lo ~alts include, for e~ample, hydrochloride and maleate.
Salts are generally prepared as acid addition salts by combining the core compound with one-to-three equi~
valents of an appropriate acid in an inert solYent.
The ~alt i3 then recovered by solvent evaporation or by fYltra~ion if the ealt precipitates ~pontaneously, or by precipitation using a co-solvent or a non-~olar co-solvent followed by filtration.
The term "pharmacologically effective amount"
shall mean that amount of a drug or pharmaceutical agent that will elicit the ~iological or medical response of a tiæsue, sy tem or organ that iæ being sought by a veterinarian or phy6ician.
The term ~'alkyl~ ~hall mean linear ~traight .or branched chain alkane or alkene.
The term 't~ubætitutedi' shall be deemed to include multiple degrees o~ substitution by a named subætituent. : .
The compounds u~ed in the method of the invention can be prepared readily according to the ~ollowing detailed example~ using readily available stasting mater~als, reagents and conventional syn-thesiR procedure~. In the~e reactions, it i~ also 2 ~
163FPG/ ~ 18651 po~sible to ma~e use of variantæ whioh are themselves known to those o~ ordinary skill in this art, ~ut which are not mentioned in greater detail. Addi-tional background ;nformation is taught in U.S.
Patent No. 4,556,653, the entire disclosure of which is incorporated herein by reference.

~XAMPLE 1 ll-(l-Methylpiperidin-3-carbonyl~-5,11-dihydro-lo 6H-pYrido r 2.3-bl r 1~4lbenzodiaz~pin-6-one The chloride o~ l-methylpiperidine-3-carboxylic acid hydrochloride (4.7g) is added to a solution o~ 5,11-dihydro-6~-pyr;do[2,3-b]~1,4]
benzodiazepin-6-one (5g) and triethylamine ~7.5ml) in dimethylformamide (200ml). The reaction mixture is heated to 90C for 24 hour~.

EXAMP~$_~
ll-(l-Me~hylpiperidin-4-carbonyl)-5, ll-dihydro-6H-pvridor2.3-blrl.4l~nzodiaz~in-6-one The chloride of l-methylpiperidine-4-carboxylic acid hydrochloride ~4.7g) was added to a ~olutio~ of 5,11-dihydro-6~-pyrldo~2,3-b~[1,4~
benzodiazepin-6-o~e (5g) and triethylamine (7.5ml) in dimethylformamide (200ml). The reaction mixture wa6 heated to 90C for 24 hour~.
The ~olvent was evaporated under ~aeuum and 30 the re~idue was di~olved in lOZ acetic acid (150ml).
The æolution waæ repeatedly washed with methylene chloride, decolored wi~h charcoal, alkalinized to 2~7~

163FPG/ . - 13 - 18651 pH 8 with a ~aturated solution of æodium bicarbonate and extracted with methylene chloride (lOOml ~ 5).
The collected organic extracts were dried on ~odium sulphate and evaporated. The residue, cry~tallized from ethanol-ethylether, yielded 2.4g (30%) o 11-~l-methylpiperidin-4~carbonyl)-5,11-dihydro-6H-pyrido C2,3-b]~1,43benzodiazepin-6-one melting at 265-267C
dec.
The mu~carinic agents for u e in this invention are those relatively 3elective in blocking the Ml type receptors and which are relatively les~
selective for the type M3 smooth muscle receptor~.
Relative affinitie~ for Ml-M5 receptor~ were deter-mined using the following as~ay.
XAMPIJ~ ~

Three radioligand binding assays were establi~hed in order to determine the affinitie~ of mu~carinic antagoni6ts for M~, M2 and M3 muscarinic receptor subtypes. Ml receptors in rat cerebral cortex were labeled with 3~-pirenzepine, 3~-AEDX-384 labeled M2 receptor~ in rat heart and M3 receptor~ in rabbit iris ~ ciliary body (minus ciliary processes which contain Ml receptor~ were labeled with 3~-QNB.
Scatchard analy~is revealed that one population o~
binding ~ites wa6 labeled in each ti~sue and t~e following Kd and Bmax values were obtained: cortex (2.36 nM, 1781 fmol/mg protein), heart ~5.77 nM~ 164 fmoltmg protein) and iris + ciliary body ~24.5 pM and 210 fmol/mg protein). Ki values in the three bind-ing a~say~ were obtained ~or atropine, rispenzepi~e, 2 0 ~

~63FPG/ - 14 - 18651 pirenzepine and nuvenzepine. The most potent of the agents at Ml binding æites was atropine with a Ki value o~ 0.13 nM. Pirenzepine, nuvenzepine and ri~penzepine posses~ed Ki value~ of 4.87 nM, 1.50 nM
and 2.61 ~M, respectively. Atropine was the mo~t potent of the antagonists at M2 receptors pos~eesing a Ki of 0.82 nM while pirenæepine (532 nM~, nuvenze-pine (248 nM) and ri~penzepine (226 nM) were much le~ effective. Atropine wa3 al~o the mo~t potent (0.37 nM)-at M3 binding sites be~ng followed by nuvenzepine (29.7 nM>, pirenzepine (37.2 nM) and rispenzepine (38.9 nM). In term~ of their ability to distingui6h between Ml and M3 receptors, atropine waæ
eæsentially devoid of selectivity while pirenzepine, nuvenzepine and ri~penzepine were re8pecti~ely 8-,.
20- and 15-~old more selective for Ml than for M3 receptors.

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2~7~0 Al~erna~ively, ~h~ affini~y and relative affinity of ~uscarinic antagoni~ts for Ml-M5 receptor~ can be determined by other means ~nown in the art. ~or example, ~ee Buckley, et al., Molecular Pharmacology, 35: 469-476 (1989) or Dorje, et al., J.
Pharmacol. Exp. Ther. 256:727-733 (1991) for detailed description~ of techniques known in the art for determining the a~tagoni~t binding properties o~ five cloned human muscarinic receptor~. Similarly, there are other ways in which to accomplish functional 6tudie~ to measure Ml ~en~itivity. For instance, one popular method at present is to u~e vas deferens of the guinea pi~ which has an Ml ~ensitivi~y. First it i8 ~et up so that its tension i~ measured and a known 6timulat~r such a~ the Ml agonist McNeil A343 i8 given to change ~Pnsion by a predictable amount.
Under this condition, the predicted effect of the agonist is first carefully plotted and then the degree to which one or another antalgoni~t block~
this agonist effect i~ measured.
. An in vivo animal model of myopia i~ avail-able for ~creening, which i~ de6cri~ed a~ follows.
Form-deprivation myopia i~ induced in day-old White Leghorn chick under aseptic condi-tion~ and other anesthesia by eyelid ~uture toone eye. The chicks are maintained on a 12 hour ~ight:dark cycle. The ~utured eyes are treated .
with nuvenzepine, rispenzepine and pirenzepine and saline solution as a eontrol. Drug i8 injected daily subconjunctivally during the light cyc~e. At two week~ of agc the animal~ ~re ~acrificed and axia~
and equatorial dimension~ o~ unfixed eyes are measured with vernier calipers independently by two ~7~

observers. Ri~penzepine and nuvenzepine, because of their ~omewhat greater potency at the Ml receptor relative to pirenzepine, would be expected to be at least as effective as pirenzepine in myopia ther~py.

The guinea pig magimlzation test is re~uired by the U.S. Food and Drug Administration of all drug~
lQ intended for ophthalmic admini~tration. The test population for nuvenzepine and ri~penzepine versus pirenzepine consisted of at least nine female Dunkin Hartley al~ino guinea pig~ between 300 and 500g, w.ith 10 control animal~. In Pha~e I, which i~ the induc-tion phase, o~ day 1 two intradermal injection~ atthe highe~t generally tvlerated coneentration of the test material were administered in the shaved ~ter-capsular area (0.lml of the test agent in a 50:50 mixture of Freund'æ complete ad juYant and distilled ~0 water). On day 7, approximately 400mg of a mixture of 10% ~odium laurel sul~ate in petrolatum wa6 applied to the ~haYed intercapsular area. On day 8, 400mg of a mixture of the te~t compound in petrolatum was -applied, on a 2 ~ 4 cm piece of Whatman paper to the 2s chaved intercapsular area, along with Blenderm tape.
I~ Phase II, which i8 the challenge phase, on ~ay 22, 200mg o~ petrolatum was applied ~o the sha~ed right flank, wh:ile 200mg of test compound at the highest non-irritant concentration (micronized in petrolatum~ wae applied to the ~haved le~t flank, with each application being occluded ~or 24 hours.

2 ~

Readings were taken on days 24 and 25, with grades assigned as follows:
O = no reaction 1 = scattere~ mild redne~
. 5 2 = moderate and diffused redne6s 3 = intense redneæs and æwelling Nuvenzepine and ri~penzepine bo~h ~howed O, no reaction in any test animal. Pirenzepine, however, showed a grade of"l"in ~ix of the animals and a lo grade o~ "2" in two of the animals, out o~ a ~otal population of nine animals.
Diagnosis and treatment, using the method of the invention, is well known to those of ordinary skill in tne art~ .
1~ The refractive state o~ the eye i~ ea~ily determined even in newborn in~ant~ by the use of a retinoscope, a handheld instrument. This objective mea~urement i~ performed after cycloplegia o~ the eye has been obtalned by topical administration of cyclopentolate or a~ropine. Furthermore, the axial length of the eye can easily be ~easured using ultrasonography.
Myopia become~ manifest as children reach the age of 7 to 12 year~. Once identified, the 2S myopia usually progre~se~ until the eye completes development after the age o~ 14.
Once identified, the progression of myopia can be documented by examination every 6 to 12 months. Risk ~actors for the development of high degrees of myopia include race and ~amily h~story.
Once the myopia has been documen~ed a~
progressing, pharmacolog~c therapy could be initiated ~7~

to reduce the rate of progre~sisn. Therapy would be continued until the ocular development is completed.
For most childre~, therapy would be initiated between the ~ges of 7 and 10 years and discontinued around the age of 14 years.
Therapy to inhibit axial-elongation myopia during maturation can be admin~ætered by the use of the agent in eye drops. Indeed, in the va~t majority of ca~es, treatment agents are adminiRtered to human eyes by the application of eye droRs. Eye drops are typically made up at a concentration of active agent between about O.S and 2 percent in the ophthalmic medium. A 1% ~olution o riæpenzepine or nuvenzepine in water would be a likely concentration for clinical lS use. Some constraint6 in formulation may e~i~t having to do with p~ and preæervative. A p~ of about 6.5 i8 expected to be acceptable a~ an ophthalmic drop and practical in terms o~ known solubility and stability of pyridobenzodiazepinones. Since pirenzepine ie known to form very acidic solutions in physiological saline, treatment with known compatible bases to bring the p~ up to about 4.5 to 7.5 ~preferably 6 or 6.5) is recommended. Phosphate buf~ering i8 al~o common for eye drop3 and i~ compatible with ri~penzepine and nuvenzepine. A common regimen for ~pplication of e~e dropæ i8 two to three time~ a day spaced eve~ly throughout waki~g hours. More e~fective agent6 may require fewer applications or enable the u6e of more dilute ~olution~.' Alternatively, ointment~ and ~olid in~erts are now coming into increased use in clinical practiee. They avoid problemæ o~ drug decompo~ition while deliverlng a def ined amount of drug. It i~, 2~7~

of cour~e, also possible to administer the above-described active agent~ in therapeutically effective amounts and dosages in pill~, capsults, or other preparatio~s of sy~temic admini~tration.
In experiments in animals, such a~ tho~e mentioned hereinabo~e in which axial myopia has been experimentally induced by depriving the retina o~ formed images, it has been noted by other~ in primates that amblyopia waB al60 e~perimentally and coincidentally induced. Amblyopia i8 evidenced by poor vi~ual acuity in the eye re~ultlng in poor vi3ual performance. Nor~ally, visual acuity improves during maturation. It i8 known that amblyopia may occur in humans from unknown causes or a~ part of ætrabismus. It iæ po~ible that adminiEtration of therapeutically effective amounts and doæages o.~ the muscarinic antagonist6 relatively selective in block-ing the Ml cholinergic receptors, but les~ ~elective in blocking cholinergic receptors in smooth muscle cells, e.g. rispenzepine and nuvenzepine, might prevent or inhibit the development of permanent or persistent amblyopia in maturing human~ with decreased likelihood of ~ensitizat~on of the eye.
It is al~o possible t~at humans who have already developed amblyopia from other or even unk.nown causes might be aided by similar therapeutic treatmen`t with the aforementioned agent~.
. In addition to rispenzepine and nuvenzepine, o~her selective antimu~carinic pyridobenzodiaze-pinone6 within the scope of the invention includethe following.

~$ 7 ~ ~ ~
163FPG/ - 21 - lB651 ~ N,~-Dime:thyl-4-t[~,ll-dihydro-6-o~o-~-pyrido~2,3-b~[lm4~benzodiazepin~ yl~carbonyl~
piperldinium iodide ~ N~Jf ~
O H

ll-C(l-ethylpiperidirl-4-yI)carbonyl~-6,11-dihydro-5-oxo-~-pyridotl,2-b~[1,5]benzodia~epine lS .

~ N
: O H
3-Methyl-4-Z(l-methylpiperidin-4-yl) carbony~]-4,9-dihydro-10-oxo-10~-thicno[3,4-b~
tl,~]benzodiazepine 0~

~N~
.~ N
O H

~0~7~ 1 ~
163FPG/ 22 - lB651 4- ~ ( 1 methylpiper 1 d in-4-yl 3 carbonyl ~ -3-methyl-4, 9-dihydro-10 oxo-lOH-pyrido~3, 2-b]~thieno [3 9 4-e~ ~1, 5~diazepiJIe ~ .
~

S~N~

O H

Claims (12)

1. A method of preventing abnormal increase in eye axial length in an animal in need thereof, comprising the step of ocularly administering to said animal a pharmacologically effective amount of a compound of the formula:

wherein R is piperidine substituted by C1-C5 alkyl.

2. A method of preventing abnormal increase in eye axial length in an animal in need thereof, comprising the step of ocularly administering to said animal a pharmacologically effective amount of a compound of the formula:

3. A method of preventing abnormal increase in eye axial length in an animal in need thereof, comprising the step of ocularly administering to said animal a pharmacologically effective amount of a compound of the formula:

4. A method of preventing progression of axial myopia in an animal in need thereof, comprising the step of ocularly adminstering to said animal a pharmacologically effective amount of a compound of the formula:

where R is piperidine substituted by C1-5 alkyl.

5. A method of preventing progression of axial myopia in an animal in need thereof, comprising the step of ocularly administering to said animal a pharmacologically effective amount of a compound of the formula:

6. A method of preventing progression of axial myopia in an animal in need thereof, comprising the step of ocularly administering to said animal a pharmacologically effective amount of a compound of the formula:

7. A compound of the formula defined in claim 1, 2 or 3, or a pharmaceutically acceptable salt thereof, for use in preventing abnormal increase in eye axial length in an animal.

8. A compound of the formula defined in claim 4, 5 or 6, or a pharmaceutically acceptable salt thereof, for use in preventing progression of axial myopia in an animal.

9. An ophthalmological pharmaceutical composi-tion comprising an amount of a compound of the formula defined in claim 1, 2 or 3, or a pharmaceutically acceptable salt thereof, effective in preventing abnormal increase in eye axial length in an animal, in association with an ophthalmologically acceptable carrier.

10. An ophthalmological pharmaceutical composi-tion comprising an amount of a compound of the formula defined in claim 4, 5 or 6, or a pharmaceutically acceptable salt thereof, effective in preventing progression of axial myopia in an animal, in associa-tion with a pharmaceutically acceptable carrier.

11. Use of a compound of the formula defined in claim 1, 2 or 3 in the manufacture of a medicament for the prevention of abnormal increase in eye axial length in an animal.

12. Use of a compound of the formula defined in claim 4, 5 or 6 as an agent for preventing progression of axial myopia in an animal.