CA2049368C

CA2049368C - Treatment of cerebro-vascular disorders

Info

Publication number: CA2049368C
Application number: CA002049368A
Authority: CA
Inventors: Yoshiaki Tanaka; Naomi Kobayashi; Tadashi Kurimoto; Yugo Ikeda
Original assignee: H Lundbeck AS
Current assignee: H Lundbeck AS
Priority date: 1990-09-06
Filing date: 1991-08-16
Publication date: 2001-10-23
Anticipated expiration: 2011-08-16
Also published as: IL98968A0; HK21595A; DK213290D0; JPH085787B2; IL98968A; SG165594G; AU8259491A; EP0474580A3; EP0474580B1; IE912682A1; IE72160B1; CA2049368A1; DE69104314D1; DE69104314T2; EP0474580A2; ZA916187B; KR970002246B1; KR920005983A; DK0474580T3; ATE112166T1

Abstract

A method for the treatment of dementia and cerebrovascular disorders and for inhibiting platelet aggregation in patients in need thereof comprising the step of administering a therapeutically effective amount of a 1-(3-(dimethylamino)propyl)-1-phenylphthalane of the formula (see formula I) wherein R1 and R2 each are selected from the group consisting of halogen, trifluoromethyi, cyano and R-CO-, wherein R is an alkyl radical, or a pharmaceuti-cally-acceptable acid addition salt thereof, as well as medicaments or pharmaceutical compositions containing the same, and methods for the preparation thereof, are disclosed.

Description

TREATMENT OF CEREBROVASCULAR DISORDERS
The present invention relates to the use of a class of 1-[3-(dimethylamino)propylJ-1-phenylphthalanes for the treatment of dementia and cerebrovascular disorders and for inhibiting platelet aggregation and to the production of medicaments or pharmaceutical compositions containing the same for such purposes.
US patent No. 4,136,193 relates to 1-(3-(dimethylamino)propylJ-1-phenylphthalanes having the general formula /~3 ~H2CH2CH2N' Formula I
~3 R' wherein R~ and R2 each are selected from the group consisting of halogen, tri-fluoromethyl, cyano and R-CO-, wherein R is an alkyl radical with 1 to 4 C-atoms 1'S inclusive, and acid addition salts thereof with pharmaceutically-acceptable acids.
Said compounds are described to be selective, centrally-active serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors and accordingly to have antidepressant activities. One of the tests used to show such activities was inhibition of ~4C-5-HT
uptake in rabbit blood platelets in vifro . The compound of Formula I wherein R~ is a cyano group and R2 is a fluorine atom is the known antidepressant citalopram, the antidepressant activity of which has been reported in several publications, e.g., J.
Hyttel, Prog. Neuro-Psychopharmacol. & Biol. Psychiat., 1982, 6, 277-295 and A.
Gravem, Acta Psychiatr. Scand.,1987, 75, 478-486. A method for preparation of and intermediates for the preparation of citalopram are described in US Patent No.
4,650,884 and methods of preparing the individual enantiomers of citalopram are disclosed in US Patent No. 4,943,590.
Biochemical postmortem investigations of patients with Alzheimer's disease have shown hypofunction of the serotonin nervous system in the brain (D. M. Bowen et al., J. Neurochem., 1983, 41, 266-272). It is also known that depression is one of the major symptoms in Alzheimer's disease, and citalopram has been reported to be effective against depression associated with Alzheimer's disease (C. G. Gottfries, Psychopharmacology, 1988, 96, 45 (Suppl.)). A study of a group of patients with moderate dementia of Alzheimer's type (AD/SDAT) or multi-infarct dementia (MID) has shown significant improvements in emotional lability, motivation, confusion, fear-panic, irritation, reduced mood and restlessness, whereas citalopram did not appear to have effect on intellectual functions (Nyth, A.L. et al. "The effect of citalopram in dementia disorders", presentation at CINP, August 1988;
subsequently reported in Nyth, A.L and Gottfries, C.G., "The clinical efficacy of citalopram in treatment of emotional disturbances in dementia disorders. A nordic multicentre study." Br. J. Psychiat., 1990, 157, 894-901).
Later controlled studies showed that treatment with citalopram caused no significant improvement on emotional disturbances in patients with vascular dementia .(VD, inci.
MID) (Nyth, A.L. et al. "The efficacy of citalopram in treatment of emotional disturbances in dementia disorders", ECNP Abstract 1989, Sweden, 79).
it has also been descibed that certain 5-HT1A agonists show effect in the treatment of Apoplexia cerebri.
Cerebrovascular disorders, such as ischemia which are triggered by cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, subarachnoid hemorrhage, cerebral thrombosis, cerebral embolism, and other diseases 2a are of increasing importance among the population and there is a great demand for effective and safe drugs for the treatment of such disorders and the sequelae of such disorders. A particular problem is dementia not only caused by cerebrovascular disorders but also dementia of other genesis. Another particular problem is amnesia associated with ischemia.
Surprisingly, it has now been found that the compounds of the above Formula I effect improvement of cerebrovascular disorders, in particular ischemia, and the brain damage and the impairment of memory functions in connection therewith, and that they show inhibiting action on platelet aggregation. Furthermore, the compounds of the general Formula I have been found to have an anti-amnesic effect and to improve ~~r~~~~

cognitive function in elderly depressed patients having concomitant dementia, i.e., not only dementia of cerebrovascular origin, but also dementia as a result of chronic organic reactions, such as neurodegenerative disorders.
Accordingly, the present invention relates to the use of a compound of the above Formula I for the prevention or treatment of senile dementia and of cerebrovascular disorders and for the inhibition of platelet aggregation, and for the manufacture of medicaments or pharmaceutical compositions for such uses.
Senile dementia may be senile dementia of any genesis such as neurodegenerative, traumatic, cerebrovascular, anoxic, etc., i.e.,dementia of Alzheimer's type, multi-infarct dementia, or vascular dementia, etc.
Cerebrovascular disorders are brain damages caused by cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, subarachnoid hemorrhage, cerebral thrombosis, cerebral embolism, or the like, e.g., ischemia, and the psychological and neurological sequelae of such damages.
The use of the optical isomers of the compounds of general Formula 1 and their mixtures, including racemic mixtures thereof, is embraced by the invention.
The compound of general Formula I may be used as the free base or as a pharmaco-logically-acceptable acid addition salt thereof. As acid addition salts such salts formed with organic or inorganic acids may be used. Exemplary of such organic salts are those with malefic, fumaric, benzoic, ascorbic, embonic, succinic, oxalic, bis-methyienesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzene sulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromo-theophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
An appropriate oral dose of the compound of general Formula I is 1-100 mg/day p.o..

Due to the inhibition of platelet aggregation the medicaments obtained and used in accordance with the invention are useful in the treatment and/or prevention of microcirculation disturbances in the brain resulting from the above cerebral conditions or from venous or arterial thrombosis, or elsewhere in the body resulting from venous or arterial thrombosis or related conditions.
In view of the beneficial effects on cognitive function and on brain damages and of the platelet aggregation inhibiting effects now found as well as of the known effects on 5-HT uptake, the medicaments obtained and used in accordance with the present invention are useful in the treatment of senile dementia and cerebrovascular disorders, and the sequelae of cerebrovascular disorders such as psychiatric symptoms, e.g., anxiety, depression, loss of memory, hypobulia, restlessness, dementia, hallucinations, delusions, disturbances of consciousness, hypochondriac tendency; insomnia, excitation, garrulity, hyperkinesia, deliriums, and disturbances of orientation, neurological symptoms, e.g., alalia, and hypodynamia, and sub)ective symptoms, e.g., headache, dizziness, feeling of numbness, feeling of stiffness in the shoulder, feeling of exhaustion and heavy feeling in the head.
Additionally they have the further advantage of a very good safety profile.
A preferred compound of Formula 1 is citalopram.
The medicaments manufactured and used in accordance with the present invention are particularly useful in the treatment or prevention of ischemia in the brain and especially of dementia caused by ischemia.
Due to the pharmacological proble the medicaments manufactured and used in accordance with the present invention are especially useful in elderly patients.
Citalopram may be prepared by the methods disclosed in US patent No 4,650,884 and the other compounds used in accordance with the invention may be prepared analogueously or by the methods of US patent No. 4,136,193. The individual enantiomers of citalopram may be prepared as described in US patent No.
4,943,590 and enantiomers of the other compounds of Formula 1 may be prepared ~~'.~~L~LJ~
by similar methods.
The acid addition salts of the compounds may be prepared by methods known in the art. The base is reacted with either the calculated amount of acid in a water-miscible 5 solvent, such as acetone or ethanol,with subsequent isolation of the salt by concentra-tion and cooling or with an excess of the acid in a water-immiscible solvent, such as ethylether, ethylacetate,or dichloromethane, with the salt separating spontaneously.
The medicaments prepared and used in accordance with the invention may be administered in any suitable way and in any suitable form, for example orally in the form of tablets, capsules, powders or syrups, or parenterally in the form of usual sterile solutions for injection.
The pharmaceutical formulations of the invention may be prepared by conventional methods in the art. For example, tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently compressing the mixture in a conventional tabletting machine. F_xamples of adjuvants or diluents comprise: Corn starch, potato starch, talcum, magnesium stearate, gelatine, lactose, gums, and the like. Any other adjuvant or additive colourings, aroma, preservatives, etc., may be used provided that they are compatible with the active ingredients.
Solutions for injections may be prepared by dissolving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilization of the solution and filling in suitable ampules or vials. Any suitable additive conventionally used in the art may be added, such as tonicity agents, preservatives, antioxidants, etc.
The present compounds and their non-toxic acid addition salts may also be used in combination with other active ingredients, such as neuroleptics, thymoleptics, analge-tics, etc.

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~-~c~i.i~/t In toxicity studies male and female SD rats ranging in weight from 170 g to 200 g were used one day after fasting. Citalopram was dissolved in water and adminis-tered orally, Symptoms were observed for one week after citalopram administration.
Even when citalopram was administered at a dose of 350 mg/kg no deaths were observed and accordingly it was obvious that citalopram has a very good safety profile.
PHARMACOLOCWn TESTS
ISCHEMIA-INDUCED HIPPOCAMPAL DEATH IN GERBILS
The overall objective of the study was to investigate the effects of citalopram on hippocampal lesions induced by ischemia in Mongolian gerbils.
METHODS
Test compounds were administered intraperitoneally to Male Mongolian gerbils min before carotid occlusion. Carotid occlusion time was 5 min . Seven days after recovery, the animals were killed, brains removed, sectioned and surviving neurons were counted along CA1 in the hippocampus.
RESULTS
As is shown in Table 1, citalopram (20 mg/kg) had a weak but non-significant protective effect against neuronal lesions. The higher dose of this compound (40 mg/kg) showed a significant (p < 0.05 ) protective effect against neuronal lesions.
Ketamine (100 mg/kg) showed significant (p < 0.01 ) protective effect.

7 ~r.
r _:: c: ,..9 ~,, LJ

Effects on ischemia induced hippocampal neuronal damage in gerbils Drug Dose Gerbils Survival neurons/mm (mg/kg i.p.)used mean S.E. p Vehicle - 10 12.8 2.6 Citalopram20 12 38.0 18.5 N.S.

Citalopram40 11 95.8 27.9 < 0.05 Ketamine 100 8 174.5 25.7 < 0.01 Statistical analysis was carried out according to Dunnett's t-tests vs vehicle group.
PASSIVE AVOIDANCE IN ISCHEMIC GERBILS
The test employed was step-down passive avoidance in gerbils treated with test compounds prior to occlusion of carotid arteries followed by acquisition trial (training phase).
METHODS
Test compounds were administered intraperitoneally to gerbils 30 min prior to carotid occlusion or ketamine was administered intraperitoneally 10 min prior to carotid occlusion. The gerbils were anesthetized with 2% halothane contained in a mixture of 70% nitrogen and 30% oxygen. The right and left common carotid arteries were occluded for 5 min. The gerbils were trained for 5 min in a step-down type passive avoidance chamber (16x16x20 cm) two days after induced ischemia.
Each gerbil was placed on a safety platform (6x16x20 cm) in the chamber and received a series of mild foot shocks (0.1 mA for 3 sec every 6 sec), when the gerbil stepped down to a floor made of metal rods. Gerbils were returned to the safety platform for testing 24 hrs later and their step-down latencies to the grid floor were recorded (max. 60 sec).

I

RESULTS
Ischemia did not alter step-down latency measured during the training phase.
Step-down latency during the training phase was not significantly modified in the gerbils treated with test compound.
Step-down latency in the testing phase was significantly decreased between ischemic control and sham operated gerbils. Citalopram (20 mg/kg) and ketamine (120 mg/kg) significantly increased the latency of ischemic gerbils. But the latency in indeloxazine (40 mg/kg) treated gerbils was not significantly different from that in ischemic control gerbils.

Effect on passive avoidance in ischemic gerbils Drug Dose Number Ischemic Step-down latency of (mg/kg of treatment [ log(sec) j i.p.) gerbils Mean S.E.

Saline (sham)- 15 - 1.471 0.075***

Saline (control)- 20 + 0.953 0.116 Citalopram20 7 + 1.386 0.083*"

Indeloxazine 40 6 + 1.085 0.244 Ketamine 120 9 + 1.348 0.100*

* : p<0.05, **: p<0:01, ***: p<0.001 (vs Saline control, by Student's t-test) BRAIN ISCNEMIA-INDUCED DEATH IN MICE
MATERIALS
Mate ICR MICE (Charles River) weighing 30 - 40 g were used after they were fasted for 1 day.

~~, !? ~~n~
!w v _;. .:' ,:J 3,,i METHOD
Test compounds were administered intraperitoneally to the mice 30 min prior to permanent ligation of bilateral common carotid arteries under conscious condition.
Surviving mice were observed over 4 hrs.
RESULTS
Citalopram (30 mg/kg) significantly prevented ischemia-induced death both 2 hrs and 4 hrs after bilateral carotid arterial ligation. Ifenprodil (30 mg/kg), however, did not significantly increase survival rate 4 hrs after ligation, although it showed signifi-cantly increased survival rate 2 hrs after the ligation.

Effect on ischemia-induced death in bilateral carotid arterial ligation (BCAL) in mice -______________________________________________________________________________ _____________.___________________ Drug Dose Number Survival rate (%) (mg/kg,p.o.) of mice 2 hr after BCAL 4 hr after BCAL
Saline - 30 23 17 Citalopram 30 30 50* 43*
Saline - 30 13 7 Ifenprodil 30 30 47** 20 * : p<0.05, ** : p<0.01 (Chi-square test vs each Saline) KCN-INDUCED COMA IN MICE
METHODS
Male mice (Crj:ICR) weighing 20-30 g were used. The mice were fasted for one day.
The drugs, dissolved in saline, were injected intraperitoneally. 30 min after the injection, KCN, dissolved in saline, was injected intravenously at a dose of 1.3 mg/kg. The duration of disappearance of righting reflex was measured as coma time.

.' w ,~ n, f? f) ~ _.. .. . ,:' i'.) RESULTS
Intraperitonal injection of citalopram significantly reduced coma time at a dose of 10 mg/kg. Indeioxazine at a dose of 20 mg/kg also significantly reduced the coma time.

Effects of intraperitoneal injection of citalopram on KCN-induced coma in mice Drug Dose Number Coma time (sec) 10 (mg/kg, of mice Mean S.E.
i.p.) Vehicle - 16 55.9 8.8 Citalopram 1.25 15 38.5 4.2 Citalopram 2.5 15 33.2 10.0 Citalopram5 16 35.0 8.2 Citalopram 10 16 27.4 6.9*

Indeloxazine 20 17 13.8 3.7**

* : P<0.05, ** : P<0.01, Significantly different from values of vehicle control (Dunnett's t-test).
CARBON DIOXIDE-INDUCED AMNESIA IN RATS (PASSIVE AVOIDANCE TEST) The test employed was a one-trial passive avoidance test in rats, using carbon dioxide asphyxiation to induce amnesia.
METHODS
Female Sprague-Dawley (CD) rats (A. Tick & Son Ltd.) in the body weight range 160-180g were used for the study.
The one-trial passive avoidance apparatus consisted of a 32 x 32 x 32 cm chamber with opaque walls and a metal grid floor. A 6 cm wide , 25 cm long runway protru-ded from the front wall of the chamber. The runway was illuminated while the chamber was dark. When placed on the runway, a rat could enter the chamber c', ,~ ~, ~. y ,t° f3 ~w '~,';~ '.i ~~~ ,.!~ :;' 4.:9 through a 6 x 6 cm opening. A scrambled footshock could be delivered through the metal grid floor of the chamber.
On the first day of the experiment, the rats received three pre-treatment training trials, during which each animal was placed on the end of the runway and the time taken to enter the chamber (the 'step-through' latency) was determined.
On the second day of the experiment, groups of 10 animals were treated p.o.
with test compound dissolved in saline or with saline.
One hour after administration, an acquisition trial was performed. This was similar to a training trial, except that the rats received a footshock of 1.0 mA for 10 sec.
commencing 10 sec after entering the chamber. Immediately after the application of the footshock the animals were subjected to amnesic treatment.
Amnesic treatment consisted of placing the rats in a box filled with carbon dioxide until respiratory arrest occurred; the rats were then revived by artificial respiration.
24 Hours after the acquisition trial, a single retrieval trial was given to each rat and the time taken to enter the chamber ('step-through' latency) was recorded for each animal.
If a rat did not enter the chamber within 180 seconds it was taken from the runway.
RESULTS
There were no significant differences between the time of entry ('step-through' latency) of rats dosed with either vehicle, citalopram or piracetam, thus indicating that at oral doses of 40 or 1000 mg/kg, these compounds did not induce marked muscle incoordination of CNS effects of sufficient magnitude to modify entry times.
The amnesic effect of carbon dioxide has been clearly demonstrated in this study.
In those rats receiving footshock, but no drug treatment, treatment with carbon dioxide asphyxiation caused a decrase in 'step-through' latency.
Oral administration of citalopram at all doses tested caused dose-related increa ses in the group mean 'step-through' times, which in mast cases were statistically significant when compared to the saline-treated control group using Student's t-test.
At the 2 highest doses tested (i.e.,20 and 40 mg/kg), a marked and highly signifi-cant increase in time was observed.
As expected, piracetam treatment gave statistically significantly longer 'step-through' latencies.

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Effects of oral administration of citalopram on carbon dioxide-induced amnesia in rats.
Drug Dose C02 Number Latency (mg/kg; p.o.) Treatment of animals (sec) Saline - 10 110.6***

Saline + 10 0.8 Citalopram 5 + 10 31.2 Citalopram 10 + 10 77.2**

Citalopram 20 + 10 114.3***

Piracetam 300 + 10 108.8***

___________________________________________________.__ ___________________________ _______________________________ ** : p<0.01,*** : p<0.001, significantly f relevant control different from values o group (Students t-test).

IN VITRO PLATELET AGGREGATION
iVIETHODS
The test was performed with fresh human platelets. The drugs were diluted in physiological saline to give a solution at a concentration ten times that of the final concentration. The drug was added to the platelets and incubated at 37 °C for 15 min. and then platelet aggregation was induced by the addition of collagen (10 microgram/ml).
RESULTS
Citalopram at a final concentration of 100 microgram/ml inhibited the aggregation of human platelet induced by collagen by 58%. The same concentration of indeloxa-zine revealed weaker inhibitory effect (8%) than citalopram did on the aggregation by collagen.

C! :"~ ,9 ~'? r, f~ f7 :: a.7 ~l/

EX VIVO PLATELET AGGREGATION
Effect on collagen-induced platelet aggregation using blood of rats administered orally with citalopram was investigated.
MATERIALS
Male Wistar rats (Charles River) in the body weight range 350-400 g were used.
METHODS
One hour after oral dosing the rats were lightly anesthetized with ether and blood was collected by cardiac puncture. Nine ml of the blood was mixed with 1 ml of 3.8% sodium citrate and platelet rich plasma (300000 platelets/cmm) was prepared.
At the end of the incubation period at 37 °C for 2 min. effects of addition of 10 micro-gram/ml collagen on platelet aggregation were determined.
RESULTS
A moderate inhibition of collagen-induced aggregation was noted following citalo-pram at 30 mg/kg (60.4%). At doses of 10 mg/kg only slight inhibition of collagen--induced aggregation was noticed (16.7%).

Effect on platelet aggregation ex vivo in rats.
Drug Dose Number Mean S.D. [% Change (mg/kg, of rats (%) (%) from control]
p.o.) Vehicle - 12 54.6 27.3 [ - j Citalopram 10 8 45.5 16.0 [-16.7]

Citalopram30 8 21.6 21.6** [-60.4]

S.D.: Standard deviation.
Statistical significance using analysis of variance of treatment groups as compared to vehicle treated groups, ** : P<0.01.

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It appears from the foregoing Ischemia Induced Hippocampal Death Test that the compound according to the invention tested shows improving effect on neuronal lesion. The Passive Avoidance Test in Ischemic gerbils indicates improving effect on memory following ischemic attach, the Brain Ischemia-Induced Death Test in mice indicate effect on survival rate following ischemic attack, the KCN-induced Coma test in mice indicates improving effect following anoxia, and the Carbondioxide-Induced Amnesia Test in rats show positive effect on amnesia.
The results of the in vitro and the in vivo Platelet Aggregation Tests show inhibiting effects on platelet aggregation.
CLINICAL TEST
In a group of depressed patients having concomitant dementia, it was observed that cognitive functions improved after treatment with compounds of the general Formula 1 but not after treatment with placebo. Accordingly, compounds of general Formula I clinically have memory improving effect in patients having dementia which may not only be of cerebrovascular origin but also may result from chronic organic reactions such as neurodegenerative disorders. This is in contradiction to the earlier study of Nyth et al. mentioned above (Nyth, A.L. et al. " The effect of citalopram in dementia disorders", presentation at CINP, August 1988).
FORMULATION EXAMPLES
The following examples show typical formulations of the medicaments manufac-tured in accordance with the invention 1 ) Tablets containing 0.5 milligram of citalopram calculated as the free base:

h ;-~ ? f~~ n t~ ~
~ ~l '.!. ,: ~,Y ',l i:7 Cltalopram 100 mg Lactose 18 mg Potato starch 27 mg Saccharose 58 mg 5 Sorbitol 3 mg Talcum 5 mg Gelatine 2 mg Povidone 1 mg Magnesium stearate 0.5 mg 2) Tablets containing 1 milligram of citalopram calculated as the free base:
Citalopram 50 mg Lactose 16 mg Potato starch 45 mg Sacc'harose 106 mg Sorbitol 6 mg Talcum g mg Gelatine 4 mg Povidone 3 mg Magnesium stearate 0.6 mg 3) Syrup containing per milliliter:
Citalopram 5.0 mg Sorbitol 500 mg Tragacanth 7 mg Glycerol 50 mg Methyl-paraben 1 mg Propyl-paraben 0.1 mg Ethanol 0.005 ml Water ad 1 ml ~~ ~ ~ ~ r' O
'll ;. cs p ~.) (J

4) Solution for injection containing per milliliter:
Citalopram 50 mg Acetic acid 17.9 mg Sterile water ad 1 ml 5) Solution for injection containing per milliliter:
Citalopram 10 mg Sorbitol 42.9 mg Acetic acid 0.63 mg Sodium hydroxide 22 mg Sterile water ad 1 ml

Claims

1. Use of a 1-[3-(dimethylamino)propyl]-1-phenylphthalane of the formula:
wherein R1 and R2 each are selected from the group consisting of halogen, trifluoromethyl, cyano and R-CO-, wherein R is an alkyl radical with 1 to 4 C-atoms inclusive, or a pharmaceutically-acceptable acid addition salt thereof, for the manufacture of a medicament for the treatment of cognitive disorders or amnesia associated with dementia and of cerebrovascular disorders.

2. Use according to claim 1, wherein the medicament is for the treatment of cerebrovascular disorder caused by cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, subarachnoid hemorrhage, cerebral thrombosis, or cerebral embolism.

3. Use according to claim 2, wherein the medicament is for the treatment of ischemia.

4. Use according to claim 3, wherein the medicament is for the treatment of amnesia associated with ischemia.

5. Use according to claim 1, wherein the medicament is for the treatment of vascular or multi-infarct dementia.

6. Use according to claim l, wherein the dementia is a dementia of the Alzheimer's type.

7. Use according to any one of claims 1 to 6, wherein the compound of Formula I is citalopram or a pharmaceutically-acceptable acid addition salt thereof.

8. A pharmaceutical composition or medicament for the treatment of dementia and cerebrovascular disorders comprising an amount of a 1-[3-dimethylamino)propyl]-1-phenylphthalane of the formula:
wherein R1 and R2 each are selected from the group consisting of halogen, trifluoromethyl, cyano and R-CO~;
wherein R is an alkyl radical with 1 to 4 C-atoms inclusive, or a pharmaceutically-acceptable acid addition salt thereof, which is effective for such purpose, and a pharmaceutically-acceptable diluent or carrier.

9. Composition according to claim 8, which is for the treatment of cerebrovascular disorders caused by cerebral infraction, cerebral hemorrhage, cerebral arteriosclerosis, subarachnoid hemorrhage, cerebral thrombosis, or cerebral embolism.

10. Composition according to claim 9, which is for the treatment of ischemia.

11. Composition according to claim 9, which is for the treatment of amnesia associated with ischemia.

12. Composition according to claim 9, which is for the treatment of vascular or mufti-infarct dementia.

13. Composition according to claim 8, which is for the treatment of dementia of the Alzheimer's type.

14. Composition according to claim 8, wherein the compound of Formula I is citalopram or a pharmaceutically-acceptable acid addition salt thereof.

15. A method for the production of a pharmaceutical preparation useful in the treatment of dementia and cerebrovascular disorders in a patient in need thereof comprising the step of admixing an amount of a 1-[3-(dimethylamino)propyl]-1-phenylphthalane of the formula:
wherein R1 and R2 each are selected from the group consisting of halogen, trifluoromethyl, cyano and R-CO-, wherein R is an alkyl radical with 1 to 4 C-atoms inclusive, or a pharmaceutically-acceptable acid addition salt thereof, which is effective for such purpose, with a pharmaceutally-acceptable carrier or diluent.

16. A method according to claim 15, wherein the preparation is for the treatment of cerebrovascular disorders caused by cerebral infarction, cerebral hemorrhage, cerebral arteriosclerosis, subarachnoid hemorrhage, cerebral thrombosis, or cerebral embolism.

17. A method according to claim 16, wherein the preparation is for the treatment of ischemia.

18. A method according to claim 16, wherein the preparation is for the treatment of amnesia associated with ischemia.

19. A method according to claim 16, wherein the preparation is for the treatment of vascular or multi-infarct dementia.

20. A method according to claim 15, wherein the preparation is for the treatment of dementia of the Alzheimer's type.

21. A method according to claim 15, wherein the compound of Formula I is citalopram or a pharmaceutically-acceptable acid addition salt thereof.