CA2062094C - Method of treating mania - Google Patents

Abstract

Mania is treated by administering, to a patient in need thereof, galanthamine or a salt or derivative thereof or a functional equivalent of galanthamine, the functional equivalent being an acetylcholinesterase inhibitor which is active substantially selectively at nicotinic receptor sites.

Description

28~02 '92 20:14 $.l5 33 323825 Plou8manl'in6toPt ~002~0.10 The present invention relates to a novel and excellent method of treating or preventing mania in humans.
Mania is a severe affective disorder which almost disables the patient in the manic phases and which in most patients recurs with individual intervals.
The medication used in practice until now in the treatment of affective disorders is, with respect to depression, to augment the noradrenergic and/or serotonergic activity in the brain. With respect to mania, the rationale behind the medication used in practice until now seems rather to be directed against the symptomatic relief of the psychotic behaviour of the manic patient in general, rather than against the supposed mechanism of the disease.
Thus, mania is presently treated with, e.g. lithium salts and/or in certain cases benaodxazepines or neuroleptics.
Lithium is mostly used in the prophylaxis of mania but in some cases is also used in the acute treatment of mania.
The treatment with lithium salts has as the advantage that it prevent the outbreaks of the manic phases. However, lithium salts have a very slow onset of action, because they pass the blood-brain barrier only very slowly (2-4 days; Welner, Joseph et al., Psykiatri, 2nd edition, F.A.D.L., Copenhagen, 1985 (textbook)) and is therefore of limited use in the acute phases. Also, lithium salts have long term side effects, such as nephrotoxici.ty. Further-more, the lithium concentration in plasma has to be moni-tored closely to avoid intoxication: lithium ig exa~eted through the kidneys, and just a small deviation from the normal lithium clearance increases the risk of intoxica-3o tion; such small derriations can occur in connection with slimming diets, in combination with medication with diu-retics, and in connection with administration of NSAIb arid ACE inhibitors. Also, many patients feel that they are slowed down more than wanted both motoric and psychic and it could be due to a mental side effect of lithium.

28'02 'p2 20:15 $ 15 33 323825 Plouemant'inetoPt ~ 003!0 10 Benzodiazepines such as rivotril are riot used prophylacti-cally, and do not alleviate the basic condition, but only give a symptomatic damping of some of the symptoms in mania, such as the motor and verbal activity and the voice and noise level.
Neuroleptics such as haloperidol preparations are also used in the treatment of the acute phases of mania but some people are hypersensitive to neuroleptics and reveal extra-pyrimidal side etfects such as symptoms liJCe in ParlSirison's disease.
Janowsky DS., El-Yousef MK, Davis JM, et al. A CholinergiC
adrenergic hypothesis of mania and depression. Lancet 1972:2:6732-6735, proposed an adxenergic-cholinergic ba-i5 lance hypothesis of affective disorders, depression being a disease of cholinergic predominance, and mania being a disease of cholinergic deficiency. Janowsky et al. found that physostigmine, a centrally active cholinesterase inhibitor, rapidly converted mania to a syndrome consistent 2o with a psychomotor retardation. Having received physostig-mine, manics became significantly less talkative, euphoric, active, cheerful, happy, friendly or grandiose and showed a decrease in flight of ideas. Patients also reported that they felt drained, being without energy, becoming apathetic 25 and having no thoughts, Also, physostigmine has been found to cause a depressed mood in a group of euthymic bipolar patients maintained on lithium. Risch S. C. et al. (1983):
Psychopharmacol. Bull, 19:696-698, have shown that some normals become depressed after receiving physostigmine.
30 EP 311 303 discloses novel 4-aminopyridine derivatives which are stated to be acetylcholinesterase inhibitors and are stated to be active against Al2heimer's disease. It is also stated that the derivatives exhibit antidepressant activities.

28% 02 ' 92 20:15 $'d5 33 323825 Plougman~'instoft ~ 00.1% O.10 EP 413 667 discloses halogenalkylphenylalcohols, -ketones and their hydrates and states that these compounds show selective central acetylcholinesterase inhibiting effect on homogonizod rat brain ticcuo, and that, in ouch experiment, enzyme from various brain ragion9 are significantly in-hibited, whereas enzyme from peripheral organs is affected only to a small degree, and that one of the compounds, in this experiment, has a strong inhibiting effect vn Cortex, Hippncamruc, ~triatmm, ~r~r3 Pt~n!~/mt?t71~11a, wherpaa enzyme from the heart is not affected. It is stated that the compounds are useful as selective acetylcholinesterase inhibitors, e_g. for treatment of Alzheimer's disease, Huntingtons chorea, tardive pyskinesia, Hyperkinesia, mania, acute panic reactions, Down's syndrome, Myasthenia gravis, Friedrich's ataxia, and pain_ EP 383 318 discloses novel aralkylamine compounds and discloses that a number of the compounds show acetylcholin-esterase inhibitor activity in homogenated cerebral cortex from Wistar rats. It is stated that the compounds are z0 indicated for senile dementia, Alzheimer's disease, Hun-tington's chorea, hyperkinesia and mania.
EP 412 822 discloses novel 4,4-disubstituted piperidine derivatives which have central nervous system activity as shown by inhibition of tetrabenazine-induced catalepsy, z5 inhibition of pentylenetetrazole-induced seizure, and analgesic effect in mouse writhing tests. The compounds are stated to show an antidepressive effect which is higher than that of imipramine or nomifensine. The compounds are stated to have anticholinergic effect and are suggested for 30 treatment of psychotic disorders, such as insomnia, mania, agitation, depression, anxiety, eme~is, pains, and demen-tia.
According to the present invention, it has been found that mania in humans can be effectively txeated by administra-35 tion of galanthamine, and that galanthamine seems to not 28:02 '92 20:1d $.15 33 323825 Plou~manl'inBto~t ~ 0050.10 only mask the symptoms, but to provide real improvement and disappearance of symptoms faster than the usual treatment, without the severe side effects and disadvantages associa-ted with the above-mentioned lithium, benzodiazepine and neuroleptic treatment which are the hitherto used treat-ments in humans.
G~xlar~~laniirm is a well-known acatylcholinsstcrasa 3.nhibitor which is active substantially selectively at nicotinic receptor sites and has substantially no effect on muscari-nic receptor sides, is capable of passing the blood-brain barrier in humans, and presents no severe side effects in therapeutically necessary dosages.
Galanthamine and acid addition salts thereof have, fox many years, been known to have anticholinesterase properties.
Galanthamine, a tertiary alkaloid, has been isolated form the bulbs of the Caucasian snowdrops Galantanus woronowi (Proskurnina, N.F. and Yakoleva, A.P. 1952, Alkaloids of Galanthus woronowi. II. Isolation of a new alkaloid. (In Russian.) Zh. obschchei Khim. (J.Gen.Chem.) 22, 1899-1902.
Chem.abs. 47,6959, 1953. It has also been isolated from the common snowdrop Galanthus Nivalis (Boit, 1954).
Galanthamine has been used extensively as a curare reversal agent in anaesthetic practice in Eastern bloc countries (cf. review by Paskow, 1986) and also experimentally in the west (cf. Bretagne and valetta, 1965: Wislicki, 1967;
Conzanitis, 1971).
Pharmacokinetic studies have recently been made by Thomsen, T. and H. Kewitz. (selective Inhibition of Human Acetyl-cholinesterase by Galanthamine in vitro and in vivo. Life sciences, Vol 46, pp. 1553-1558 (1990), and, by the same authors, Galanthamine Hydrobromide in a Long-Term Treatment of Alzheimer's Disease. Dementia 1990, 1:46-51).

28:02 '92 20:11 $a5 33 323825 PlougmaW'ingtoft ~ 008!Od0 2U~2094 The findings according to the present invention seem to be in accordance with the above-mentioned 1973 findings by Janowski et al., the only prior art reference reporting treatment, in that galanthamina is an acetylcholinesterase s inhibitor, such as is physostigmine, and thus counteracts cholinergic deficiency. On the other hand, physvstigmxne, used by Janowsky, has a profile of properties which is basically different from the profile of galanthamirie. Thus, physostigmine, contrary to galanthamine, has a considerable 1o effect at muscarinic receptor sites, and has a very fast onset of activity and a very short half life, of the order of minutes and at least less than an hour.
It is believed that the excellent and surprising effect against mania possessed by galanthamine is due to its specific profile of properties, the most important of the known ones of which can be summarized as follows:
- capability to pass the blood brain barrier in humans, - a high selectivity far acetylcholinesterase as opposed to butyrylcholinesterase (about 50-fold when measured by the in vitro method by Thomsen et al., see below), - a sufficient elimination half life to warrant duration of an effective concentration of at least 4 hours, z5 probably at least 6 hours, - a relatively low toxicity in therapeutical concentra-tions, - capability of being effective in doses which are 3o sufficiently low to keep peripheral side effects low Galanthamine must be considered as being a very desirable drug for the treatment according to the invention: The elimination half life of galanthamine hydrobromide is over four haurs; it shows a practically complete renal elimina-' 6 tion; its two metabolites, epigalanthamine and galanthamin-one are both probably inactive. A complete elimination~of metabolites and galanthamine takes place in 72 hours.
Galanthamine has been used in Eastern Block countries~since around 1958 as an anticurare agent in anesthesiology, and a considerably number of patients have been treated with galanthamine without any reported case of liver toxicity or serious side effects. Galanthamine hydrobromide, being a tertiary amine and lipid soluble, is absorbed rapidly from the gut and transverses the blood brain barrier easily. The common side effects, other than the ones related to cholin-ergic crisis, are either nausea or vomiting, and a slight headache. However, these side effects are rare, especially when care is taken to start medication in low doses such as mentioned above.
With most patients, mania is a recurring disease, starting with hypomanic stages develpping into mania, but it is difficult even within the same patient to predict the onset of a new hypomanic/manic phase or the duration thereof.
This means that it is of great importance to have a drug, like galanthamine, which has an onset of action of as little as a few minutes.
Accordingly, a central aspect of the present invention relates to use~of a pharmaceutically acceptable acetylcholin-esterase inhibitor which is active substantially selectively at nicotinic receptor sites, and which is capable of passing the blood-brain barrier in humans for the treatment of mania.
The galanthamine can suitably be administered.orally in the form of an acid addition salt, e.g. the hydrobromide, but other administration forms are possible and realistic, such as is described below.
The effective amount will normally be referred to as a therapeutically e:Efective amount, but the invention also comprises the cases where treatment is started before the symptoms have fully developed, e.g. prophylactically in 28: U2 ' 92 20:18 $.15 33 323825 Plougmanfingtoft ~ OU8: 0.10 hypomanic stages. "Prophylaxis" in the classical meaning of this term, e.g. such as lithium is administered for pxophy-lacting mania, would normally not come into consideration because galanthamine arid functional equivalents have a fast onset of action.
Because galanthamine has substantially no effect on the activity at muscarinic receptor sites, as apparent from its high selectivity for acetylcholi.nesterase as opposed to butyrylcholinesterase, it will not give rise to the often to severe side effects on the heart which are associated with cholinesterase inhibitors which have a low selectivity for acetylaholinesterase as opposed to butyrylaholinesterase.
Galanthamine has a selectivity for acetylcholinesterase opposed the effect on butyrylcholinesterase of 6o to 7..
The amount of galanthamine is preferably adjusted individu-ally based upon observation of the effect of initially very low dosages. There. is as considerable difference with respect to how sensitive individuals are to acetylcholin-esterase inhibitors. Thus, the amount of galanthamine is suitably adjusted by means of a r~gimcn starting at low dosages, e,g. 1 mg, preferably at 5 mg, per day, but, if dpprvpri~xLe, even as lvw a5 0.s iug per day, if the dosage is well tolerated by the patient within the first two hours the dosages i5 incrcasad to, e.g. 1o mg per dosage dosed 3 to 4 times per day or in some severe cases to 60 mg or more per day dosed over 3 or 4 times. The increase of the do-sages is suitably discontinued when the dosage of galan-thamine 1) positions the affective mood of the patient in a condition of at the most hypomania, that is, a score of at the most.l4 on sech~s Mania Scales described by Bech et al. Acts Scand. Psych. 1986, suppl. pp 29-3~., preferably at trie most ll, more preferably at the most ~.o, still more preferably at the most s, and most preferably at the most 5, 28~02 '92 20:19 $'.15 33 323825 PlougmanVingtoft C~009i0.10 2os~o9~
a 2) augments the quantity and quality of the sleep in the patient (an increase in the quality of the sleep is an increase in the proportion of REM sleep), but 3) still gives substantially no heart side effects, and 4) is lower than the amount which will give rise to a cholinergic crisis.
Decausa cholinergic cri3is, a lifer-thrcatcning dove-depen-dant side effect of all kinds of acetylcholinesterase inhibitors, should, by all means, be avoided, it is recom-mended to start with the low dosages as mentioned above and furthermore not to exceed 150 mg per day and preferably not to exceed dosages above 60 mc3 rPr day, unlace the patient shows a very low sensitivity to acetylcholinesterase in-hibitor, in which case higher doses, such as 200 mg per day, could be ust~d.
The effect of the galanthamine against the patient's mania is suitably measured by scoring the symptoms of the pa-tients in accordance with the guidelines in Bech~s mania Scales as described in Example 2. Referring to that scale, the patient's point score should preferably, where pos-sible, be reduced to at the most 14, which is the limit between manic and hypomanic stages, more preferably at the ~s most 5 which ire t.t~r l3.mi 1. l~Ht.wr-ee:em liypumani.c and normal stages.
2~t~c troatmont acr_~c,rrling rn tha i n~rAnt i nn chnn 1 r7 prPfPrAhl y be continued until the manic phase xs over. As a measure that the manic phase is over can be used the daily and later in the treatment weekly by scoring the patients according to Hech's mania Scale. When the pat~.ents have reached a score below 6, they are kept on galanthamine 28:02 '92 20:20 $d5 33 323825 PlougmanflngtoPt ~1010i0.10 medication for about another two months to be sure that the patient is properly treated.
As far ac i.~ l.nnwn, galant-hamine is the only acetylcholin-esterase inhibitor wiLlr Lhe ak~uv~s-~i~srimV ~rzurilc of ~rro-pertiee which has been tasted against mania in humans.
While galanthamine has, indeed, given remarkable results, such as ~tppedrs rrmn Llre clinical cluta given in the ex-amples, it is justified to presume that other acetylcholin-esterase inhibitors which are functional equivalents to galanthamine with respect to its combination of high selec-tivity with respect to nicotinic receptor sites and capa-bility of passing the blood brain barrier in humans in yiyo, will also show a useful combination of effect against mania arid acceptability in the clinic, although it cannot be ruled out that galanthamxne, galanthamine salts and galanthamine derivatives, due to the special conformation of the galanthamine ring system, have specific properties which are decisive for the remarkable effect on mania.
rn accordance with the above, compounds which are function-2o al equivalents of galanthamine are defined herein as com-pounds which a) possess an at least 10-fold Selectivity, preferably an at least 20-fold selectivity, more preferably an at least 40-fold selectivity, and most preferably an at least 50-60 fold selectivity, for acetylcholinesterase as opposed to butyrylcholinesterase, when measured by the ~ vitro method by Thomsen et al., see below, b) are capable of passing the blood brain barrier in humans 'fin, yivo.
3o A useful drug for the treatment of mania in accordance wil.l~ Llie FrreaenL 111VC11t1V11 has a pha~.~naceuticr~lly accep-table, low toxicity in therapeutical concentrations, and is capable of reducing the point score, on Bech's Mania Scales 28-U2 '02 20:21 $~15 33 323825 PlougmaW'ingtoft ~OlliUJO

(see below), to at the most 14, preferably at the most 5 in a randomly selected group of human mania patients in a double blind test, in doses which are sufficiently low to keep peripheral side~effects acceptably low and to avoid S cholinergic crisis.
As will be understood from the above definition, a compound can be subjected to well-defined and relatively short-lasting tests (see below) to determine whether it fulfills criterion a) above. Then, the likelihood whether the~cvm-1o round will pass t-.hR blond brain barrier in humans iIl v3vo (criterion b)) can be assessed in a model. one such model is a whole rat brain model in which rats are given the acetylcholine esterase in vi.yQ and are then killed where-upon homogenate of the rat brain is examined with respect to the acetylcholinesterase activity; the result is then compared to the acetylcholinesterase activity in rat brains not treated with acetylcholinesterase inhibitors. Another rat model could be the measurement and comparison of acet-ylcholinesterase activity in cerebrospinal fluid in vivo in the same rat before and after treatment. If the compound i:ulfills criterion a), and its likelihood of passing the blood brain barrir~r has h~Rn P~st~:ah1 i ahRrl i n c7ne of. the above-described rat brain models, it will be a candidate drug. An initial determination of toxicity is necessary in cases before ariy effect in humans can be assessed; such initial determination of toxicity can be performed by pharmacologic tests in a manner known per ~. After the pharmacological tests, the capability of the candidate drug of passing the blood brain barrier in humans ~ vivo can be determined by the method described below. If the candidate drug has been found to possess this capability, it can be passed to thA mania tPSt-.ing preppy. f~ptionally, the can-didate drug can be subjected to additional short-lasting tests, such as the ,~ vivo selectivity test described by Thomsen et al., and a test to determine whether it in-creases aortisol level in humans. Both of these tests give further indication of whether the candidate drug has a 28:02 '92 20:21 $.~5 33 323825 Plougman~'lngtoPt 1~0i2i0.t0 spectrum of properties equivalent to galanthamine with respect to what must be presumed to be essential proper-ties. Peripheral side effects will be assessable when tha erLect is tested clinically, which is acceptable from an experimental and ethical point of view, provided the toxi-city has first been assessed by the above-mentioned phar-macological tests. with respect to the final assessment of the candidate drug s effect on mania, it is evident that a rational and efficient design of the assessment will in-valve an initial test on one or a few patients and, pro-vided the initial test is positive, the above-mentioned conclusive double blind test. Because of the well-defined and brief character of all of the tests, and especially the we7.l~defined i~ vitro aharaetcr of the initial screening, the test series for identifying useful functional equiva-lents of galanthamine is a reasonable an not burdensome routine which is within the realm of the person skilled in the art.
Functional equivalents and derivatives of galanthami~ne which are useful in the method of the invention w~.ll be employed in the same manner as stated herein for galan-thamine. Whenever quantities of such a functional equiva-lent or derivative are referred to herein, the quantities are given as the equipotent quantity of galanthamxne hydro-bromide with respect to inhibition of acetylcholinesterase, that is, as the quantity of galanthamine hydrobromide which result in the same inhibition of acetylcholine esterase in the above-mentioned in vi o test according to Thomsen et al as does the functional derivative or derivative.
The selectivity of the acetylchalinesterase inhibitor for acetylcholinesterase as opposed to butyrylcholinesterase can be determined by ire t o and ~,n vivo tests as de-scribed by Thomsen and Kewitz in the above mentioned paper Selective Inhibition of Human Acetylcholinesterase by Galanthamine in vitro and in vivo, Life Sciences, Vol 4f>, pp. 1553-1558 (1990), and T. Thomsen, H. Kewitz arid O.

28~ 0,2 ' 92 20: 22 $d5 33 323825 Plougman~'instoft l~j 013 ; 0.10 pleul, J. Clan. Chem. Clin. Biochem. ~, 469--475 (X988).
This i~r viva test is the one referred to above in connec-tion with criterion a). Thus, with reference to this deter-mination mothod, a~ preferrad acetylchr~linA~tRra:~e inhibitor is one which in the in v' o method described has an at least 10-fold selectivity fox acetylcholinesterase as opposed to butyrylcholinesterase, such as an at least 20-fold selectivity for acetylcholinesterase as opposed to butyrylcholinesterase, e.g, an at least 4o-fold selectivity to for acetylcholinesterase as opposed to butyrylcholineste-rase. For galanthamine, these authors found a 50-fold to 60-fold selectivity for acetylcholinesterase as opposed to butyrylcholinesterase.
The capability to pass the blood brain barrier ,~ p'vo in humans can be assessed by either by a test which could be called "Auditory brain stem response" or by a test which is based on the measurement of CRH, ACTH and cortisol. The rationale behind these tests, and the way they ara per-formed, is explained in the following:
The auditory brain stem response test is based on the observation that mania-depressive patients are hypersensi-tive to criolinergic influences, vne umt~ir~station hereof being hypersensitivity to auditory signals as assessed by the increase of amplitude of auditory evoked potentials in the nuclei of the auditory system in the brain stem, i.e.
on the "brain side" of the blood brain barrier. This hyper-sensitivity manifeal.e itself in a lower amplitude than in normal humans when the person ~.a mut traated with a cholin-ergic agent such as acetylcholinesterase inhibitvr;~and a 3o vary ci7nifi~antly in~roacP c~f the amplitude when the person has received a cholinergic agent, provided, of Course, that the chollnergie agent is aLle to pass the blood brain barrier and thus enter the nuclei of the audi-tory system in the brain stem. See also example 3.
o~o~ncR n nn~ ~ ~ ~. r,..", .., .,o 28%Q2 '92 20:23 '$45 33 323825 PlougmanfingtoPt f~0ld% 0.10 The other test based on the measurement of cRH (cortico-tropic-hormone releasing hormone released from the hypotha-lamus in the brain, and which releases both ACTH from the adenohypophysis and cortisol from the adrenal medulla) and ACTH (corticotropic hormone, which releases cortisol from the adrenal medulla) is carried out by measuring the CRH, ACTH and cortisol concentration in the blood in healthy persons before and after medication with acetylcholineste-rase. If the concentration of all three hormone are in-creased after meaicatium ur aL ledbt CRH and cortisol are increased it is proven that the acetylcholi.nesterase has effect in the central nervous system, and since it is an _in vivo experiment it is further proven that the acetylcholin-esterase has passed the blood brain barrier.
As mentioned above, the selectivity of the acetylat,nlin-esterase inhibitor can, as an additional characterization, optionally be expressed with reference to the 'fir vivo determinations performed by Thomsen and Kewitz on ga7.an-thamine and described in the above-mentioned paper Selec-tive Inhibition of Human Acetylcholinesterase by Galan-thamine in vitro and in vivo, Life sc~.ences, Vol 46, pp.
1553-1558 (1990). With reference to this determination, a preferred acetylcholinesterase inhibitor is one which, upon administration in an amount of 10 mg to a healthy Z5 adult, results in inhibition of at least 40% of the acetyl-aholinesterase activity in erythrocytes from the adult within about 2-5 minutes and no substantial inhibition of butyrylcholinesterase therein, such as an acetylcholir~-esterase inhibitor which, when administered in an amount of 10 mg to a healthy adult, results in inhibition of at least 50% of the acetylcholinesterase activity in erythrocytes from the adult within about 2-5 minutes. For galanthamine, Thomsen and Kewitz found 65% inhibition of acetylcholin--esterase in the erythrocytes within 2 minutes after ad-ministration of 10 mg of galanthamine i.v. in a healthy volunteer, whereas no inhibition df butyrylcholinesterase in plasma was seen.

Compounds which ~tre c:vntempl~tLed Lv bts valuaLlts futtuLiuttal equivalents of galanthamine and useful in the treatment according to the invention care the galanthamino dorivativoc having the formula I (formula I also represent galanthamine itself ) OR, Hz0 I
J
~R

wherein Rl and RZ which may be the same or different each 20 represents a hydrogen atom or an aryl group, such as a lower alkanoyl group, e.g. an acetyl group or a straight-chained yr branched alkyl group, e.g. methyl, ethyl, propyl, or isopropyl; R3 is a straight or branched chain alkyl, alkenyl or alkaryl group which is optionally sub-stituted by a halogen atom or a cycloalkyl, hydroxy, alkoxy, nitro, amine, aminoalkyl, acylamino, heteroaryl, heteroaryl-alkyl, arvyl, aroylalkyl or cyano group; and R4 represents a hydrogen or halogen atom attached to at least one of the ring carbons of the tetracyclic skoleton, and 2o salts thereof, such as a hydrobromide, hydrochloride, methylsulfate or methiodide.
In the compounds of formula I, alkyl moieties preferably contain 1 to 8 carbon atoms, halogen atoms are preferably fluorine, chlorine, or bromine, especially fluorine or chlorine, aryl moieties are preferably phenyl, cyc7.oaJ.ky1 groups are preferably 3- tv 7-membered rings, especially cyclopropyl or cyclobutyl, and heteroaryl moieties are $29'7088A.001/A31/1~M2 U2 28 preferably 5- to 8-membered rings, e.g., thienyl, furyl, pyridyl, pyrrolyl, or pyrizanyl.
Among the compounds of the formula I are those described in EP-A-236684. The compounds of formula I may be prepared according to conventional techniques, including those described in EP-A-236684.
Other compounds which are contemplated to be valuable functional equivalents useful in the method of the inven-tion are galanthamine derivatives of the general formula II
R2 2 Ra ~ Ra io ~ - R

R~ ~ ~ 6 Rs i3 ~ .5 ~ Rs I I
~2~ \ _ys R4 i 9 v R

Ra Rs wherein the broken line represents an optionally present double bond between carbon atoms 3 and 4 . R1 and R2 are each selected independently from the group consisting of hydrogen, hydroxyl, amino or alkylamino, cyano, sulfhydryl, alkoxy of 1-6 carbon atoms, alkylthio, aryloxy, arylthio, R5-substituted aryloxy, R5-substituted arylthio, aralkoxy, an aliphatic or aryl carbamyl group wherein the aliphatic or aryl moiety may be R5 substituted or unsubstituted, aralkylthio, R5-substituted aralkoxy, R5-substituted aralkylthio, aryloxymethyl, R5-substituted aryloxymethyl, alkanoyloxy, hydroxy-substituted alkanoyl-oxy, benzoyloxy, R5-substituted benzoyloxy, aryloxycarbonyl and R5-substituted aryloxycarbonyl, R1 may also be alkyl of up to 14 carbon atoms, or hydroxymethyl, R2 may also be carboxymethyl, provided that at least one of R1 and R2 is hydroxy, amino or alkylamino unless Rg is hydroxy-methyl, .
829708BA.001/A31/1992 02 28 R3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, phenyl, R5-substituted phenyl, alkylphenyl, R5-substituted alkylphenyl, heterocyc-lyl selected from a- or p-furyl, a- or ~-thienyl, thenyl, pyridyl, pyrazinyl, and pyrimidyl, alkyl-heterocyclyl or R'-substituted heterocyclyl, where R' is alkyl or alkoxy, each R4 is independently selected from hydrogen, hydroxyl, sulfhydryl, alkyl, aryl, aralkyl, alkoxy, mercaptoalkyl, aryloxy, thiaryloxy, alkaryloxy, mercaptoalkaryl, nitro, amino, N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chloro, bromo, iodo, and trifluoromethyl, R5 is selected from the same groups as R4, R6 is hydrogen, halo, trifluoromethyl or alkyl of 1 to 4 carbon atoms.
Rg is hydrogen or hydroxymethyl, Rg is hydrogen or alkyl of 1 to 6 carbon atoms, or when R2 is hydroxyl, R9 may be a moiety of formula a wherein Rg is hydrogen and R2 is a linking bond; or R2 and R9 may jointly form semicarbazone, X is oxygen or NRS, Y is nitrogen or phosphorus, and methylenedioxy derivatives thereof with the proviso that when X is O, R3 is not methyl when R1 is methoxy, R2 is hydroxy, and all R4 are hydrogen, or a pharmaceutically acceptable acid addition salt thereof .
829708BA.001/A31/1992 02 28 28%02 '92 20:28 $.!5 33 323825 PlougmaW'instoft f~017~OdU

Examples of subclasses and specific compounds of the for-mula zz are given in Wo 8s/o87o8, which also discloses methods for preparing the compounds II.
Galanthamine, galanthamine derivatives and galanthamine functional equivalents, when suited therefor, may be ad-ministered orally at a dosage of e.g. 5-150 mg per day, such as 10-60 mg per day, e.g. 10-50 mg, such as 10-40 mg, per day, the dosage being adapted to the patient and the patient's response. As mentioned above, the treatment should often be started with a low dosage and then in-creased until the suitable dosage has been established.
The dosage of galanthamine functional equivalents is ex-pressed as the equipotent amount of galanthamine hydro--bromide, the reference basis being the capability of in-hibiting acetylaholinesterase in the Thomsen et al. ,~
v' o test mentioned above.
For the oral administration, galanthamine or a galanthamine salt or derivative or a functional equivalent may be formu-lated, for example, as an aqueous suspension or a solution in aqueous ethanol or as a solid composition such as a tablet or capsule. Suspensions or solutions for oral ad-ministration are typically of a concenl.raLiur~ oL 1-50 mg/ml, more commonly 5-4o mg/ml, for example, so-4o~mg/ml, typically 20-3o mg/ml of galanthamine. Divided doses int he range 0,1-3 mg/kg body weight per day may prove useful.
Typically, one might administer a dosage of 2o-zoo mg per day to a patient of a body weight of 40-100 kg, although in appropriate cases such dosages may prove useful for pa-tients having a body weight outside this range. In other oases, dosages as low as 10 mg and as high as 200 mg may be appropriate for persons in this body weight range.
Galanthamine and its acid addition salts form crystals.
They are generally only sparingly soluble in water at room temperature; therefore, injectable compositions axe normal-28-02 '92 2U:2i $45 33 323825 PlougmanflnBtoPt ~I018~Od0 ~y in the form of an actueous suspension. If necessary, pharmaceutically-acceptable suspension aids may be emp-loyed. Typically, such a suspension will be employed at a concentration of 0.1-30 mg/ml, more commonly 1-30 mg/ml, for example, 5-30 mg/ml, such as 10-30 mg/ml of galantha-mine. As mentioned above, typical dosage rates when ad-ministering galanthamxne by injection are the range 0.01-20 mg per day depending upon the patient. For example, divided doses in the range 0,5-5 mg/kg body weight per day to may prove useful. Typically, one might administer a dosage of 5-50, mg per day to a patient of a body weight of 40-100 kg, although in appropriate cases such dosages may prove useful for patients having a body wPic3hi-. ~ui~si~3~a this range. zn other cases, dosages as low as 5 mg and as high as 200 mg per day may be appropriate for persons in this body weight range.
Galanthami.ne and its pharmaceutically acceptable acid addition salts, and its derivatives and functional equi-valents, when suited therefor-, may be administered by subcutaneous, intravenous or intramuscular injection.
The parenteral dosage rate of galanthamine can also be expressed by reference to the body weight of the patient;
in this case, a normal dosage rate will often be 0.1 to 4 mg/kg body weight. Depot compositons will often deliver a dosage rate of 0.01 to 5.0 mg/kg per day.
In preparing tablets or capsules, standard tablet or cap-sule-making techniques may be employed. If desired, a pharmaceutically acceptable caxrier such as starch ar lactose may be used in preparing galanthamine or galan-3o thamine equivalent tablets. Capsules may be prepared using soft gelatine as the encapsulating agent. If desired, such capsules may be in the form of sustained release capsules wherein the main capsule contains microcapsules of galan-thamine or functional equivalents thereof which release the contents over a period of several hours thereby maintaining L8%UL NL YU:L7 $~S 33 :fYS~L3 YlouBmanvingtoft ~JUla~u-~U

a constant level of galanthamine or its functional equi-valent in the patient''s blood.
The following specific formulations may find use in the treatment of mania:
Tablets or capsules containing 0.1, 1, 2, 5, 10 and 25 mg galantahamine hydrobromide or functional equivalent to be tal.~n four times a day, or a austainad-release preparation delivering an equivalent daily d0eo.
Liquid formulation for oral administration available in 5 mg/ml and 25 mg/ml concentration.
Other interesting administration forms of galanthamine and functional equivalents are suppositories, a slow-release plaster, and other depot compositions.
All of the above-mentioned administration forms axe pre-pared in manners known per ~e.
Although galanthamine must be considered as having a high degree of safety, there have been certain side effects in a few of the patients treated. These have been slight nausea in about 30% of the cases (the nausea, however, disappear-ing after about one week of treatment), vomiting and dizzi-ness in 5-10% of the patients (also disappearing after about one week of treatment in most cases), and more severe side effects in 4-6% of the patients. These more severe stid~ aff4cts must be consid~r~d ae~r_.~lt.ablA in viEew e-~f thei effect of the drug; however, in patients who are suspected of developing arrhythmia, it should be considered to ad-minister, e.g., atropin in combination with the treatment according to the invention.
ThA invention also relates to a nharmar_.eutiral rnmp~sitinn in dosage unit form suitable for oral or parenteral ad-ministration for the treatment of mania, which comprises za~u~ az ~u:zn ~.ts ;f~ ~z;t~~5 rlougmaw ingtoit ~ u~u~udu 20 2U6~U94 as active ingredient an effective amount of an acetyl-cholinesterase inhibitor which is active substantially at nicotinic receptor sites, and which is capable of passing the blood brain barrier in humans 'fir vby,~, in admixture with a pharmaceutically acceptable carrier or excipient, as well as to a process for preparing an agent for treating mania, characterized in that an acetylcholinesterase in-hibitor which is active substantially selectively at nico-tinic receptor sites, and which is capable of passing the blood brain barrier in humans ',fit vivo, is used as active ingredient in the agent.

Formulation of tablets containing gtalantha Composition of 1 tablet containina 1 mc~ aal mine Galanthamine hydrobromide 0.001 g Calcium phosphate 0.032 g Lactose 0.005 g Wheat Starch 0.0056 g Microcrystalline Cellulose 0.015 g Talc 0.0007 g Magnesium stearate 0.0007 g Compo ition of 1 tablet conta,ning 5 m~z aalanthamine Galanthami.ne hydrobromidc 0.005 g Calcium phosphate 0.024 g Laotose 0.004 g Wheat Starch 0.004 g Microcrystalline cellulose 0.04 g Talc 0.002 g Magnesium Stearate 0.001 g 38.'0: '03 30:20 $.ts as a3a8~o Plougmnn~'ingtoft X021; Oa0 ~os~o9~

Galantharnine hydrobromide 0.010 g Lactose 0.040 g Wheat Starch 0.0234 g Microcrystalline Cellulose 0.0374 g Talc 0.0036 g Magnesium Stearate 0.0012 g Gelat~.n 0.0044 g All the tablets ars prepared according to routine tablett-ing procedures.

Clinical trials of the eff ct of aalanthamine on mania patients.
Methods and mater'als l~ruq Nivalin tablets containing 5 mg galanthamine, obtained from Waldheim Ltd., Vienna, Austria, were used in Lliid ~axamplc.
patients 5 persons suffering from mania with a score above 5 on the Bech~s Mania Scale for whom the symptoms could not be ascribed to any disease of organic origin.
Bech's Mania scale To evaluate the stage of mania in the patient to be treated Bech~s Mania Scale was used.

28~02 '92 20:29 $.15 33 323825 Plougman~'ingtoft ~ 022: 0.10 ZZ
All caws were evaluated before, under and after Nivalin treatment.
Bech's Mania Scale consists of 11 items:
1. Activity (motor), score from 0 (normal activity) up to 4 (constantly active, restlessly energetic. Even if urged the patient cannot sit still).
2. Activity (verbal), score from ZO 0 (normal verbal activity) up to 4 (impossible to interrupt, dominates completely the conversation).
3. Flights of thoughts, score from o (no flight of thoughts) up to 4 (it is difficult to impossible to follow the pa-tient's line or thoughts as the pa4ienl. c;umtamtly jumps from one topic to another).
4. Voice/Noise level, score from 0 (natural volume of voice) up to 4 (shouting, screaming, or using other sources of noise due to hoarseness).
5. Hostility/Destructiveness, score from o (no signs of impatience or hostility) up to 4 (overt physical violence, physically destructive).

6. Mood (feeling of well-being), score from 0 (neutral mood) up to 4 (extremely elevated mood, quite irrelevant to situa-tion) .
Self-Esteem, score from 0 (normal self-esteem) up to 4 (grandiose ideas which cannot be corrected).

2802 'U2 2U:3U '$.15 33 323825 PlougmaW'inBtoPt ~ 023.~OdU
2U6~U94 s. contact (intrusiveness), score from 0 (normal contact) up to 4 (extremely dominating and manipulating without context with the setting).
9. Sleep (average of last 3 nights), score from o (habitual duration of sleep) up to 4 (no s7 eep) .
10. Sexual interest, score from to o (normal sexual interest and activity) up to 4 (completely and inadequately occupied by sexuality).
11. Work, A At first rating of the patient, score from o (normal work activity, up to 4 (the patient is or ought to bs hospitalized and unable to participate in ward act~.vities).
b At weekly ratings, score from o (the patient has resumed work at his/hers normal activity level, up to 4 (the pat~.ent is still fully hospitalized and gene-rally unable to participate in ward activities).
The criteria for mania scored in the Bech's Mania scale are:
- A total scale score of o-g means that the patient is not manic.
- A total scale score of 6-14 means that the patient is hypomanic.
- A total scale score of 15 or more means that the patient is definitely suffering from mania.

28 ~ 02 ' 92 20 : 31 $d5 33 323825 Plougmant'ingtoPt ~ 02.1: O.10 Laboratory tests Blood samples from all patients were examined before the start of the treatment with respect to:
Haemoglobin concentration (Hgl) White cell count (WCo) Differentiated white cell count (DWCc) Mean corpuscular volume (MCV) Mean corpuscular haemoglobin concentration (MCHC) Packed red cells volume per 100 ml blood (PCV) Platelets ERS
Electrolytes (Na+, K+, C1-, Ca++, Phos++) Liver tests (bilirubin, ALT (alan~.nami~ru Liamaminase) , AsT
(aspartatamino transaminase), and GOT (glutamine-axala-acetic transaminase) Se-glucose so-craatine Thyroidstimulating hormone (TSH) Thyroids hormones (T3 and T4) zo These tests were performed before the treatment to exclude patients with mania-like symptoms caused by a disease of organic cx~.gin from the treatment with galanthamisre and were also performed during the treatment in order to docu-ment any alterations of the parameters during the treatment with Nivalin.
Q~h,~r measurem~rntm Blood pressure and EcG were measured before the start of the treatment and regularly during the treatment.
Results WILL Lt3~i~7CCt t0 the blood measurements and the blood pre3-28~02 '92 20:31 '$dS 33 323825 Plougman~'ingtott X025~'0.10 as sure and ECG, no observable changes in the results ware found during the treatment.
The following case examples are demonstrative of the ef-fects of Nivalin on mania symptoms.
Case No, l:
HO, a 74 year old woman with a bipolar affective disorder for ovex 3o years. She was hospitalized from 1988 six times. For the last year she was hospitalized three times with initially depression that evolved in three months to 1o mania. The mania was at least of degree II according to Carbon et al. 1973. She was given T. Haldol and evolved a malignant neuroleptic syndrome in the spring 7.990. (with a total white cell count over 28.00 x 7.0 9/1, temperature over 40 C, muscle rigidity, elevated Creative kinase.) i5 With the cessation of the neuroleptic drug she recovered and became euthymic for a short while and them became d~pr~~~ive ayainr. Later that yeas;, 1990, when she evolved into a manic state again the only possible medication was a benzodiazepine in high doses. She became heavily sedated 20 without a diminution of her manic symptoms. She had to be guarded day and night and there was also the danger of this frail woman to break her leg as she became very unsteady on hex feet.
Her manic symptoms lasted usually about three months and at 25 the time of this case her mania had lasted about three weeks and was steadily increasing, at that time definitely manic w7.th 29 points on the Bech's Mania Score. It was decided to give her T. Nivalin !5 mr~ ini.t.ially in thc~ marr-ing. She tolerated well the first 5 mg and was given T.
n Nivalin 5 mg x 2 in the afternoon. An hour after she had taken 10 mg of T. Nivalin her behaviors had markedly c:hay~d to Gv~zybody's surprise. Tht next deny shy had 14 points on the scale, i.e. slightly hypomanic.

28:0» 'Q2 20:32 $15 33 323825 Plougman~'instoft ~ 02di0a0 The biggest change was in activity (motor and verbal), and =llgnz or thoughts. her sleep improves sllgntxy. sub wt~a~
was remarked mostly was her change in concentration. she was able to look at TV and read. Also she managed an hour long game of chess, which, incidentally, she won. Hut she had not been able to perform a sustained activity of any sort for days. Two days later the Nivalin treatment was stopped and she practically immediately became psychotic again.
so Once started an Nivalin treatment 30 mg per day she became visibly more manageable and resumed a more normal behaviour although according td the nurses slightly hyrcmanin. This was repeated once again with the same result. It was de-cided that she should continue on T. Nivalin 3o mg a day and the benaodiazepine treatment was stopped.
Ho continued on T. Nivalin 5 mg x 3 for three months; then the medication was stopped and she could manage her affairs at home. A month later she developed her usual depressive episode and was then hospitalized in a depressive mood.
Case No. 2:
HAS a 47 year old woman who had been hospitalized seven time since 1984. She was mostly hospitalized when she was in a manic state but Could stay at her home while depressed which always preceded her mania. she had taken an overdose Z5 of lithium just prior to her stay at the hospital and was in a lithium intoxioatdd state with nyetagmue and ataxia.
It was considered that she would not tolerate neuroleptic medication and was put on T. Nivalin 5 mg z x 3 a day. She stayed in the hospital for a month arid left practically 3o euthymic. On the Mania scale she dropped from initially 24 to 10 points in two days. Her activity and flight of ideas normalized the most. She was also clearly more able to 28-02 '92 20:33 $:~5 33 323825 Plougmant'ingtoft ~ 027: 0.10 206~09~4 2~
concentrate and sustain a commenced activity than before the medication.
Case No. 3:
SA a 33 year old woman which had been hospitalized fourteen time since 1982 with the diagnosis bipolar affective disor-der. Last winter she had been hospitalized because of a heavy depression. And in the spring she left hospital slightly hypomanic and stayed that way most of the last summer. Last December she was hospitalized with state III
mania or with the maxima. score on the Mania Scale which is 44 points. She was considered very sensitive to neuroleptic medication and developed always very soon extrapyramidal signs that took weeks to disappear after medication.
She was conseyu~ntly vary lur~Lila; to tlxts u~urxl uwcdi4ativn s5 in her manic state. She was given T. Nivalin 5 mg 2 x 3, and the next day she was slightly hypomanic with 11 points on the Mania scale. This was considered as a dramatic reduction in her manic symptoms, especially by her husband that knew her well, and it was decided to try to treat her at home especially that she had developed a very hostile attitude towards the hospital and its staff and to hospi-talize her would have demanded a legal step to be taken, which her husband was against. She went to her home and stayed there for over a month always slightly hypomanic.
She started to neglect her medication arid was later hospi-talized with her will. She was given a more conventional therapy and left the hospital two months later slightly hypomanic but on lithium and a weak neuroleptic.
3o The initial effect was without doubt no psychomotor retar dation nor anergy, but a substantial alleviation of her manic symptoms.

28: 0~2 ' 92 20: 3.~ ~d5 33 323825 PlougmaW'ingtoPt ~ 028i0d0 Case No. 4:
Bs a 4z year old male that had been hospitalized since 1981 over fourteen times. He had rece~.ved the diagnosis bipolar affective disorder, but also schizoaffective disorder. He was constantly on some neuroleptic medication. In his last hospitalization he did develop some simile of a manic episode arid was put on T. Nivalin 5 mg 2 x 3 or 30 mg a day. His behaviour normalized quickly and he became visibly quite euthymic. He had been rated with s7 points on the mania scale and became within normal range as mentioned. He told the nurses that he was afraid that Nivalin made him tvo noxmal and that his social assistance would therefore be withdrawn. He was somewhat reluctant to continue the medication when he left hospital.
Case No. 5:
KS six times hospitalized since 1988 because of bipolar affectivQ disordar. From February to May 1990 he had been hospitalized because of depression. Tn the spring he de-veloped a hypomanic state that lasted practically all summer 1990. He refused to be hospitalised and in Nov~mbcar 1990 was he by police forced to be internalized then in a highly manic state arid a constant embarrassment to his environment. He was given T. Haldol and T. Rivotxil and developed rapidly extrapyramidal signs, a Morbus Parkinson-z5 like mimic and stance even with low doses of the neurolep-tic and accompanied with T. Artane (benzhexol). Then the neuroleptic was totally withdrawn and he was given 30 mg of T. Nivalin a day. He maintained that T. Nivalin made him a little bit depressive and empty in the head. The manic symptoms were manageable. He told the nurses later that the energy and augmented depression disappeared later although hA r-nnt-; n,~c~rl r,n the Ni va 1 i n trPatmPnt:. p,nd h~ fel.t that the Nivalin treatment improved his memory which he had felt were failing him.

28~U2 '92 2n:3d $d5 33 323825 PlougmaW'ingtoPt ~ U29~Oa0 2oszo94 Conclusion The above-mentioned five cases are all chronically ill patients with advanced affective disorder. The cease show the value of Ltm ~reatmemt ur galanthamine in manic pa-s tients.

Auditvxv brain stem rc~~p Methods Electrical potentials caused by click-stimulation in the ears are measured with electrodes positioned outside on the head of the examined parson. In the configuration of the potentials are components from the brain stem and the brain.
Persons i5 A patient suffering from bipolar manio-depression in the ci~spr~essivG state and a healthy person, respectively.
D-rue Tablet containing 1o mg galanthamine itesults Figures lA, 18, 2A and zH show the potentials from a de-pressive patient and a healthy person, both treated and untreated.
Figures 1A, and 2A show that in the depressed patient, the auditory brain stem response without treatment has a much smaller, almost half, amplitude of the potential compared to the amplitude of the untreated healthy person.

28:02 '92 20:35 '$.15 33 323825 Plougman\'ingtoft ~030:O.IU
zoszo94 Furthermore, figures lA and 1B show a dramatically increase of the amplitude in the treated depressive patient compared to untreated persons.
Also, from figures 2A and 2B it is seen that the potentials 5 do not change from the untreated person to the treated person.
con lusion.
From the results in the depressed person it is seen that the potentials change after treatment with galanthamine, 10 such as explained above. This means that galanthamine must be able to cross the blood-brain barrier, since it is possible to inhibit in synapsis in the brain stem, which is positioned on the "brain side's of the blood-brain barrier.
hEGENDS Td FIGURES
15 Fig. 1 A shows tha auditory evo3ced respons~r of a ~lPrr. RRS~PC3 patient (a manio depressed patient in the depressed state) without treatment with galanthamine.
Fig. 1 B shows the auditory evoked response of a depressed patient (the same as in fig. 1 A) z hours after treatment 2o with 10 mg of galanthamine.
Fig. z A shows the auditory evoked response of a healthy person without treatment with galanthamine.
Fig. 2 B shows the auditory evoked response of a healthy person (the same as in fig. 2 A) 2 hours after treatment 25 with 10 mg of galanthamine.

Claims (18)

1. Use of a pharmaceutically acceptable acetylcholinesterase inhibitor which is active substantially selectively at nicotinic receptor sites, and which is capable of passing the blood-brain barrier in humans for the treatment of mania.

2. The use according to claim 1, in which the acetylcholinesterase inhibitor is one which has an at least 10-fold selectivity for acetylcholinesterase as opposed to butyryl-cholinesterase.

3. The use according to claim 2, in which the acetylcholinesterase inhibitor is one which has an at least 20-fold selectivity for acetylcholinesterase as opposed to butyryl-cholinesterase.

4. The use according to claim 2, in which the acetylcholinesterase inhibitor is one which has an at least 40-fold selectivity for acetylcholinesterase as opposed to butyrylcholinesterase.

5. The use according to claim 1, in which the acetylcholinesterase inhibitor is one which, upon administration in an amount of 10 mg to a healthy adult, results in inhibition of at least 40% of the acetylcholinesterase activity in erythrocytes from the adult and no substantial inhibition of butyrylcholinesterase therein.

6. The use according to claim 5, in which the acetylcholinesterase inhibitor is one which, when administered in an amount of 10 mg to an adult, results in inhibition of at least 50% of the acetylcholinesterase activity in erythrocytes from the adult.

7. The use according to claim 1, in which the cholinesterase inhibitor is one which, upon administration to a healthy human, increases the cortisol level in the human.

8. The use according to claim 1, in which the cholinesterase inhibitor is galanthamine, or a galanthamine salt, or a galanthamine derivative.

9. The use according to claim 8, in which the compound is a compound of the formula I

wherein R1 and R2 which may be the same or different each represents a hydrogen atom or an acyl group, such as a lower alkanoyl group, e.g. an acetyl group or a straight-chained or branched alkyl group, e.g. methyl, ethyl, propyl, or isopropyl; R3 is a straight or branched chain alkyl, alkenyl or alkaryl group which is optionally substituted by a halogen atom or a cycloalkyl, hydroxy, alkoxy, nitro, amino, aminoalkyl, acylamino, heteroaryl, heteroaryl-alkyl, aroyl, aroylalkyl or cyano group; and R4 represents a hydrogen or halogen atom attached to at least one of the ring carbons of the tetracyclic skeleton, or a salt thereof, such as a hydrobromide, hydrochloride, methylsulfate or methiodide.

10. The use according to claim 8, in which the compound is a galanthamine derivative of the general formula II

33~

wherein the broken line represents an optionally present double bond between carbon atoms 3 and 4, R1 and R2 are each selected independently from the group consisting of hydrogen, hydroxyl, amino or alkylamino, cyano, sulfhydryl, alkoxy of 1-6 carbons atoms, alkylthio, aryloxy, arylthio, R5-substituted aryloxy, R5-substituted arylthio, aralkoxy, an aliphatic or aryl carbamyl group wherein the aliphatic or aryl moiety may be R5 substituted or unsubstituted, aralkylthio, R5-substituted aralkoxy, R5-substituted aralkylthio, aryloxymethyl, R5-substituted aryloxymethyl, alkanoyloxy, hydroxy-substituted alkanoyloxy, benzoyloxy, R5-substituted benzoyloxy, aryloxycarbonyl and R5-substituted aryloxycarbonyl, R1 may also be alkyl of up to 14 carbon atoms, or hydroxymethyl, R2 may also be carboxymethyl, provided that at least one of R1 and R2 is hydroxy, amino or alkylamino unless R8 is hydroxy-methyl, R3 is hydrogen, straight or branched chain alkyl of 1-6 carbon atoms, cycloalkylmethyl, phenyl, R5-substituted phenyl, alkylphenyl, R5-substituted alkylphenyl, heterocyclyl selected from .alpha.- or .beta.-furyl, .alpha.- or .beta.-thienyl or thenyl, pyridyl, pyrazinyl, and pyrimidyl, alkyl-hetero-cyclyl or R'-substituted heterocyclyl, where R' is alkyl or alkoxy, each R4 is independently selected from hydrogen, hydroxyl, sulfhydryl, alkyl,,aryl, aralkyl, alkoxy, mercaptoalkyl, aryloxy, thiaryloxy, alkaryloxy, mercarptoalkaryl, vitro, amino, N-alkylamino, N-arylamino, N-alkarylamino, fluoro, chloro, bromo, iodo, and trifluoromethyl, R5 is selected from the same groups as R4, R6 is hydrogen, halo, trifluoromethyl or alkyl of 1 to 4 carbon atoms;
R8 is hydrogen or hydroxymethyl, R9 is hydrogen or alkyl of 1 to 6 carbon atoms, or when R2 is hydroxyl, R9 may be a moiety of formula II wherein R9 is hydrogen and R2 is a linking bond; or R2 and R9 may jointly form semicarbazone, X is oxygen or NR5, Y is nitrogen or phosphorus, and methylendioxy derivatives thereof with the proviso that when X is O, R3 is not methyl when R1 is methoxy, R2 is hydroxy, and all R4 are hydrogen, or a pharmaceutically acceptable acid addition salts thereof.

11. The use of galanthamine or a salt thereof for the treatment of mania.

12. The use according to claim 11, wherein the salt is galanthamine hydrobromide.

13. A pharmaceutical composition in dosage unit form suitable for oral or parenteral administration for the treatment of mania, which comprises as active ingredient an effective amount of an acetylcholinesterase inhibitor which is active substantially selectively at nicotinic receptor sites, and which is capable of passing the blood brain barrier in humans in vivo, in admixture with a pharmaceutically acceptable carrier or excipient.

14. A pharmaceutical composition according to claim 13, wherein the acetylcholinesterase inhibitor is an acetylcholinesterase inhibitor as characeterized in any of claims 2-10.

15. A process for preparing an agent for treating mania, characterized in that an acetylcholinesterase inhibitor which is active substantially selectively at nicotinic receptor sites, and which is capable of passing the blood brain barrier in humans in vivo, is used as active ingredient in the agent.

16. A process according to claim 15, wherein the acetylcholinesterase inhibitor is an acetylcholinesterase inhibitor as characeterized in any of claims 2-10.

17. A pharmaceutical composition in dosage unit form suitable for oral or parenteral administration for the treatment of mania, which comprises as active ingredient an effective amount of galanthamine or a salt thereof, in admixture with a pharmaceutically acceptable carrier or excipient.

18. A process for preparing an agent for treating mania, characterized in that galanthamine or a salt thereof is used as active ingredient in the agent.