GB2258652A - Pharmaceutically useful azabicyclic oxime ethers - Google Patents

Abstract

A family of azabicyclic oxime ethers stimulate central muscarinic acetylcholine receptors and are therefore useful in the treatment of glaucoma; as well as neurological and mental illnesses, such as presenile and senile dementia, Huntingdon's chorea, tardive dyskinesia, hyperkinesia, mania and Tourette syndrome, whose clinical manifestations are attributable to cholinergic deficiency.

Description

Therapeutic Compounds The present invention relates to substituted oxime ethers which stimulate central muscarinic acetylcholine receptors and therefore are useful in the treatment of neurological and mental illnesses whose clinical manifestations are due to cholinergic deficiency. Such diseases include presenile and senile dementia (also known as Alzheimer's disease and senile dementia of the Alzheimer type respectively), Huntington's chorea, tardive dyskinesia, hyperkinesia, mania and Tourette syndrome. Alzheimer's disease, the most common dementing illness, is a slowly progressive neurological disorder characterised by marked deficits in cognitive functions including memory, attention, language and visual perception capabilities.

In addition, the compounds are useful in treating glaucoma. Glaucoma is an ocular disorder associated with elevated intraocular pressures which are too high for normal function and may result in irreversible loss of visual function. If untreated, glaucoma may eventually lead to blindness. Ocular hypertension, i.e. the condition of elevated intraocular pressure without optic nerve head damage or characteristic glaucomatous visual field defects, is now believed by many ophthalmologists to represent the earliest phase of glaucoma.

Many of the drugs formerly used to treat glaucoma proved not entirely satisfactory. Topical administration to the eye of agents such as pilocarpine may be used in order to improve the outflow of aqueous humour and reduce the intraocular pressure (see Drugs, 1979, vol 17, 38 and Drugs and Ther. Bull., 1989, vol 21, 85), but these have associated side effects such as emesis and myosis.

The compounds may lower intraocular pressure without exhibiting side effects to the extent associated with hitherto-known drugs used against glaucoma which act through cholinergic mechanisms.

Thus, the present invention provides a compound of formula (I), and salts and prodrugs thereof:

wherein m is 0 or 1; n is 1 or 2 (provided that when m is 1 then n is 1); and R is C16 alkyl.

The alkyl group may be straight, branched or cyclic, and may be saturated or unsaturated. Preferably, R is straight or branched, saturated C1-4 alkyl or allyl.

More preferably, R is methyl, ethyl, tert. butyl or allyl.

Preferably, m is 0. Also preferred is when n is 2.

It will be appreciated that the compounds may exist in different isomeric forms. For example, the -0atom may be syn or anti with respect to carbon atom 4 of the azabicyclic ring. All such isomers are encompassed within formula (I). Preferably, the compounds are in anti form.

Examples of compounds of formula (I) include: 3-tButoxyiminoquinuclidine; 3-Methoxyiminoquinuclidine; 3-Ethoxyiminoquinuclidine; 3-Allyloxyiminoquinuclidine; 3-Methoxyimino-l-azabicyclo2 .2. l]heptane; 3-Ethoxyimino-1-azabicyclo[2.2.1]heptane; 3-Allyloxyimino-l-azabicyclo[2.2.1]heptane; 2.2.1] heptane; and 3-tButoxyimino-l-azabicyclo[2.2.1]heptane; and salts and prodrugs thereof.

Also included within the scope of the present invention are salts of the compounds of formula (I). It will be appreciated that salts of the compound for use in medicine will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful for the preparation of the base or its non-toxic pharmaceutically acceptable salts. Acid addition salts, for example, may be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, oxalic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.

Preferred is the hydrochloride or hydrogen oxalate.

One group of prodrugs of compounds of this invention have a substituent ring which is convertible, e.g. hydrolysable in vivo to another group.

Groups which are hydrolysable in vivo to another amino group in the compounds of this invention may be readily ascertained by administering the compound to a human or animal and detecting, by conventional analytical techniques, the presence of the corresponding compound having another group in the urine of the human or animal.

This invention also provides a method of treating Alzheimer's disease, senile dementia of the Alzheimer type, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania or Tourette syndrome by the administration to a patient in need of such treatment of a pharmacologically effective amount of a compound of formula (I).

It may, where appropriate, be advantageous, in order to reduce unwanted peripherally mediated sideeffects, to incorporate into the composition a peripherally acting cholinergic antagonist (or antimuscarinic agent). Thus the compound of formula (I) may be administered together with a peripheral cholinergic antagonist such as N-methylscopolamine, N-methylatropine, propantheline, methantheline or glycopyrrolate.

It will be understood that any formulation may further comprise another active ingredient such as another antiglaucoma agent for example a topical carbonic anhydrase inhibitor.

The compound of formula (I) can be administered orally, parenterally or rectally at a daily dose of about 0.001 to 10 mg/kg of body weight, preferably about 0.01 to 1 mg/kg, and may be administered on a regimen of 1-4 times a day. When a cholinergic antagonist is administered, it is incorporated at its conventional dose.

When administered for the treatment of elevated intraocular pressure or glaucoma, the active compound is preferably administered topically to the eye, although systemic treatment is, as indicated, also possible. The dose administered can be from as little as 0.1 to 25 mg or more per day, singly, or preferably on a 2 to 4 dose per day regimen althougn a single dose per day is satisfactory.

This invention also provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier therefor. It further provides the use of a compound of formula (I) for the preparation of a medicament for the treatment of the illnesses mentioned hereinbefore.

When given systemically, the drug can be given by any route, although the oral route is preferred. In oral administration, the drug can be employed in any of the usual dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, or suppositories which forms are for oral, parenteral or rectal administration. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g.

conventional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of formula (I). When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills or capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids or mixtures of polymeric acids with such materials as shellac, acetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil and peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspension include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone and gelatin.

When given by the topical route, the active compound or an ophthalmologically acceptable salt thereof such as the hydrochloride salt is formulated into an ophthalmic preparation. In such formulations, from 0.0005% to 15% by weight can be employed. The objective is to administer a dose of from 0.1 to 1.0 mg per eye per day to the patient, with treatment continuing so long as the condition persists.

Thus, in an ophthalmic solution, insert, ointment or suspension for topical delivery, or a tablet, intramuscular or intravenous composition for systemic delivery, the active medicament or an equivalent amount of a salt thereof is employed, the remainder being carrier, excipients, preservatives and the like as are customarily used in such compositions.

The active drugs of this invention are most suitably administered in the form of ophthalmic pharmaceutical compositions adapted for topical administration to the eye such as a suspension, ointment, or as a solid insert. A preferred composition is eye drops. Formulations of these compounds may contain from 0.0005 to 15% and especially 0.05% to 2% of medicament.

Higher dosages as, for example, about 10% or lower dosages can be employed provided the dose is effective in reducing or controlling elevated intraocular pressure.

As a unit dosage from between 0.001 to 10.0 mg, preferably 0.005 to 2.0 mg, and especially 0.1 to 1.0 mg of the compound is generically applied to the human eye, generally on a daily basis in single or divided doses so long as the condition being treated exists.

This invention therefore further provides a pharmaceutical formulation adapted for topical administration to the eye which formulation comprises a compound of formula (I) and a carrier suitable for topical administration.

These hereinbefore described dosage values are believed accurate for human patients and are based on the known and presently understood pharmacology of the compounds, and the action of other similar entities in the human eye. As with all medications, dosage requirements are variable and must be individualized on the basis of the disease and the response of the patient.

For topical administration, pharmaceutically acceptable carriers are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or arylalkanols, vegetable oils, polyalkylene glycols, petroleum based jelly, ethyl cellulose, ethyl oleate, carboxymethylcellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally-employed non-toxic, pharmaceutically acceptable organic and inorganic carriers.The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents, bodying agents and the like, as for example, polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, phenylmercuric salts known to have cold sterilizing properties and which are non-injurious in use, thimerosal, methyl and propyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredients such as sodium chloride, sodium borate, sodium acetates, gluconate buffers, and other conventional ingredients such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine tetraacetic acid, and the like.

Additionally, suitable ophthalmic vehicles can be used as carrier media for the present purpose including conventional phosphate buffer vehicle systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles, isotonic sodium borate vehicles and the like.

The pharmaceutical formulation may also be in the form of a solid insert such as one which after dispensing the drug remains essentially intact, or a bioerodible insert that is soluble in lacrimal fluids or otherwise disintegrates.

The present invention therefore further provides a process for preparing a pharmaceutical composition according to the invention which process comprises bringing a compound of formula (I) into association with a carrier therefor, such as by mixing.

The compounds of formula (I) may be prepared by any process known to those skilled in the art for the preparation of oxime ethers. For example, by reacting a compound of formula (II) with a compound of formula(III) or salts thereof:

wherein m, n and R are as defined for formula (I).

Preferably, the hydrochloride salts of the intermediates are used. More preferably, the synthesis takes place with heating under reflux in a polar organic solvent such as ethanol.

Other methods are described, for example, in Advanced Organic Chemistry: Reactions, Mechanisms, and Structure by Jerry March (McGraw-Hill, pages 317, 327).

In any of the above reactions it may be necessary and/or desirable to protect any sensitive groups in the compounds. For example, if the reactants employed include amino, carboxy, keto, hydroxy or thiol groups, these may be protected in conventional manner.

Thus, suitable protecting groups for hydroxy groups include silyl groups such as trimethylsilyl or t-butyldimethylsilyl, and etherifying groups such as tetrahydropyranyl; and for amino groups include benzyloxycarbonyl and t-butoxycarbonyl. For tertiary amines such as the nitrogen of the azabicyclic ring, a suitable protecting group is borane. Particularly when using the alkylation method described by March (see above), it is necessary to protect the tertiary amine. Keto groups may be protected in the form of a ketal. Carboxy groups are preferably protected in a reduced form such as in the form of their corresponding protected alcohols, which may be subsequently oxidised to give the desired carboxy group. Thiol groups may be protected by disulphide formation, either with the thiol itself or with another thiol to form a mixed disulphide.The protecting groups may be removed at any convenient stage in the synthesis of the desired compound according to conventional techniques.

The 1-azabicyclic moiety may be introduced into the molecules concerned by methods known from the art, in particular by methods analogous to those described in EP A-0239309 or EP-A-0307142.

The following Examples illustrate the preparation and use of compound (I). In the Examples, all temperatures are in C; THF is tetrahydrofuran; and ether is diethyl ether.

EXAMPLE 1 3-tButoxyiminoquinuclidine Hydrochloride: A solution of 3quinuclidinone hydrochloride (11.5g) and 0tbutylhydroxylamine hydrochloride (9g) in ethanol (400ml) was heated under reflux for 5 hours. The reaction was cooled, concentrated under reduced pressure, and the resulting solid crystallised from ethyl acetate/methanol to give the title compound (13g), mp 117-119 C. (Found: C, 56.74; H, 9.26; N, 11.75. CllH20N2O.HCl requires C, 56.76; H, 9.09; N, 12.04). A single crystal X-ray structure determination assigned the double bond geometry of the oxime ether to be in the Z configuration.

The following examples were prepared in the same way using the appropriate O-alkylhydroxylamine hydrochloride instead of O-tbutylhydroxylamine hydrochloride.

EXAMPLE 2 3-Methoxyiininoquinuclidine Hydrochloride: mp 216-218 C (decomp.) (propan-2-ol). (Found: C, 49.93; H, 8.00; N, 14.20.

C8H14N2O.HCl.0.25H2O requires C, 49.80; H, 7.97; N, 14.52).

EXAMPLE 3 3-Etho-yiminosuinuclidine Hydrochloride: mp 181-183 C (ethyl acetate/methanol). (Found: C, 52.80; H, 8.64; N, 13.25.

C9H16N2O.HCl requires C, 52.81; H, 8.37; N, 13.69).

EXAMPLE 4 3-Auyloxviminoquinuclidine Hydrochloride: mp 123-125"C (ethyl acetate/methanol). (Found: C, 54.80; H, 8.11; N, 12.67.

C10H16N2O.HCl requires C, 54.85; H, 7.94; N, 12.79).

The following examples were prepared by the methods detailed above using 1-azabicyclo[2.2.1]heptan-3-one hydrochloride instead of 3 -quinuclidinone hydrochloride.

EXAMPLE 5 3-Methoxyimino-1-azabicyclo [2.2.1]heptane Hydrogen Oxalate: In this example the free base was obtained from the hydrochloride salt by partitioning between dichloromethane and aqueous potassium carbonate. The dichloromethane solution was dried (Na2SO4), concentrated and treated with oxalic acid in propan-2-ol. Crystallisation from this solution gave the title compound, mp 147-148 C. (Found: C, 46.62; H, 6.03; N, 11.79.

C7H12N2O.(COOH)2 requires C, 46.95; H, 6.13; N, 12.17).

EXAMPLE 6 3-Ethoxxvimino-1-azabicyclo[2.2.1]heptane Hydrochloride: mp 154-156"C (ethyl acetate/methanol). (Found: C, 48.05; H, 7.85; N, 13.98. C8H14N2o.HCl.0.5H2o requires C, 48.12; H, 8.08; N, 14.03).

EXAMPLE 7 3-Allyloxyimino-1-azabicyclo[2.2.1]heptane Hydrochloride: mp 140-1420C (ethyl acetate/methanol).

EXAMPLE 8 3-tButoxyimino-1-azabicyclo[2.2.1]heptane Hydrochloride: mp > 2300C (decomp.) (ethyl acetate/methanol). (Found: C, 55.01; H, 9.08; N, 12.62. C10H18N2O.HCl requires C, 54.91; H, 8.76; N, 12.81).

1-azabicyclo[2.2.1]heptan-3-one was prepared by the method described in the European Patent Application EP 307142A.

PHARMACEUTICAL EXAMPLES 1. Tablets containing 1 - 25 mg of compound (I) Amount - mg Compound (I) 1.0 2.0 25.0 Microcrystalline cellulose 49.25 48.75 37.25 Modified food corn starch 49.25 48.75 37.25 Magnesium stearate 0.50 0.50 0.50 2. Tablets containing 26 - 100 mg of compound (I) Amount - mg Compound (I) 26.0 50.0 100.0 Microcrystalline cellulose 52.0 100.0 200.0 Modified food corn starch 2.21 4.25 8.5 Magnesium stearate 0.39 0.75 1.5 Compound (I), lactose, and a portion of the corn starch are mixed together and granulated to a 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 1.0 mg, 2.0 mg, 25.0 mg, 26.0 mg, 50.0 mg and 100.0 mg of compound (I) per tablet.

Eye Drops The pharmaceutically acceptable salt of the active compound 0.5% Benzalkonium chloride solution 0.02% v/v Disodium edetate 0.05% NaCl 0.8% Water for injections to 100% The formulation is sterilised by autoclaving.

Claims (1)

1. CLAIM:

   1. A compound of formula (I), or a salt or prodrug thereof:

   wherein m is 0 or 1; n is 1 or 2 (provided that when m is 1 then n is 1); and R is C1-6 alkyl.