United States Patent [19]
`Enz
`
`[54] PHENYL CARBAMATE
`
`[75]
`
`Inventor: Albert Enz, Basel, Switzerland
`
`[73] Assignee: Sandoz Ltd., Basel, Switzerland
`
`[21] Appl. No.: 466,502
`Jun. 6, 1995
`
`[22] Filed:
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`US005602176A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,602,176
`Feb. 11, 1997
`
`Int. Cl.6
`..................................................... A61K 31127
`[51]
`[52] U.S. Cl . ............................................. 514/490; 560/136
`[58] Field of Search .............................. 5601136; 514/490
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,469,700
`
`9/1984 Somers .................................... 424/265
`
`Related U.S. Application Data
`
`FOREIGN PATENT DOCUMENTS
`
`[63] Continuation of Ser. No. 353,848, Dec. 24, 1994, aban(cid:173)
`doned, which is a continuation of Ser. No. 110,622, Aug. 23,
`1993, abandoned, which is a continuation of Ser. No. 6,904,
`Jan. 21, 1993, abandoned, which is a continuation of Ser.
`No. 925,365, Aug. 4, 1992, abandoned, which is a continu(cid:173)
`ation of Ser. No. 859,171, Mar. 27, 1992, abandoned, which
`is a continuation of Ser. No. 750,334, Aug. 27, 1991,
`abandoned, which is a continuation of Ser. No. 664,189,
`Mar. 4, 1991, abandoned, which is a continuation of Ser. No.
`589,343, Sep. 27, 1990, abandoned, which is a continuation
`of Ser. No. 408,640, Sep. 18, 1989, abandoned, which is a
`continuation of Ser. No. 285,177, Dec. 15, 1988, abandoned,
`which is a continuation of Ser. No. 162,568, Mar. 1, 1988,
`abandoned.
`Foreign Application Priority Data
`
`[30]
`
`193926
`
`9/1986 European Pat. Off ..
`
`Primary Examiner-Michael L. Shippen
`Attorney, Agent, or Firm-Robert S. Honor; Melvyn M.
`Kassenoff; Thomas 0. McGovern
`
`[57]
`
`ABSTRACT
`
`(S)-N-ethyl-3-[(1-dimethylamino)ethyi]-N-methyl(cid:173)
`The
`phenylncarbamate in free base or acid addition salt form is
`useful as pharmaceutical, particularly for systemic transder(cid:173)
`mal administration.
`
`Mar. 4, 1987
`
`[DE] Germany .......................... 37 06 914.4
`
`12 Claims, No Drawings
`
`Page 1 of 6
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`

`1
`PHENYL CARBAMATE
`
`5,602,176
`
`5
`
`2
`prepared from the free base in known manner. These include
`e.g. the hydrogen tartrate.
`The compounds according to the invention exhibit phar(cid:173)
`macological activity as indicated in standard tests and are
`therefore useful as pharmaceuticals. They reach the central
`nervous system rapidly after s.c., i.p. or p.o. administration
`in rats. They exert a brain region-selective inhibition of
`acetylcholinesterase activity, hippocampal and cortical
`enzyme being more inhibited than acetylcholinesterase
`10 originating from striatum and pons/medulla. Furthermore
`they have a long duration of action.
`The following results, for example, illustrate the pharma(cid:173)
`cological profile of the compounds according to the inven(cid:173)
`tion as compared to the corresponding isomers and race-
`IS mates. Compound A is the compound of formula I in form
`of its hydrogen tartrate. Compound B is the optical isomer
`of said salt. C designates the racemic mixture of the com(cid:173)
`pound of formula I and its optical isomer, in form of the
`hydrochloride.
`
`In Vitro Assays
`
`This is a continuation of application Ser. No. 08/353,848
`filed Dec.12, 1994, which in tum is a continuation of
`application Ser. No. 08/110,622, filed Aug. 23,1993, which
`in tum is a continuation of application Ser. No. 08/006,904,
`filed Jan. 21, 1993, which in tum is a continuation of
`application Ser. No. 07/925,365, filed Aug. 4, 1992, which
`in tum is a continuation of application Ser. No. 07/859,171,
`filed Mar. 27,1992, which in tum is a continuation of
`application Ser. No. 07/750,334, filed Aug. 27,1991, which
`in turn is a continuation of application Ser. No. 07/664,189,
`filed Mar. 4, 1991 which in tum is a continuation of
`application Ser. No. 07/589,343, filed Sep. 27, 1990, which
`in turn is a continuation of application Ser. No. 07/408,640,
`filed Sep. 18, 1989, which in tum is a continuation of
`application Ser. No. 07/285,177, filed Dec. 15, 1988, which
`in tum is a continuation of application Ser. No. 07/162,568,
`filed Mar. 1, 1988, all now abandoned.
`The present invention relates to a novel phenyl carbam- 20
`ate with anticholinesterase activity.
`More particularly the invention relates to the (S)-N(cid:173)
`ethyl-3-[(1-dimethylamino)ethyl]-N-methyl-phenyl-car(cid:173)
`hamate of formula I
`
`I 25
`
`Electrically evoked 3H-acetylcholine release from rat hip(cid:173)
`pocampal slices
`Electrically evoked 3H-acetylcholine eH-ACh) release
`from rat hippocampal slices is a functional in vitro model to
`investigate presynaptic muscarinic autoreceptor agonists
`and antagonists. This model can also be used as an indirect
`method to evaluate drugs which inhibit acetylcholinesterase
`30 (AChE). Inhibition of AChE activity leads to the accumu(cid:173)
`lation of endogenous ACh which then interacts with presyn(cid:173)
`aptic muscarinic autoreceptors and inhibits further release of
`3H-ACh.
`Rat hippocampal slices (Wistar strain, 180-200 g) are
`prepared by chopping into cross sections whole hippocam(cid:173)
`pal slices at a distance of 0.3 mm with a Mcilwain tissue
`chopper. Hippocampal slices obtained from 3 rats are incu(cid:173)
`bated for 30 min. at 23° C. in 6 ml Krebs-Ringer containing
`0.1 uCi 3H-choline and transferred into the superfusion
`chamber and superfused with Kreb's medium containing 10
`f.lM hemicholinium-3 at a rate of 1.2 ml/min. at 30° C.
`Collection of 5 min. fractions of the superfusate begins after
`60 min. of superfusion. Two periods of electrical stimulation
`(2Hz rectangular pulses 2 msec, 10 rnA, 2 min.) are applied
`45 after 70 min. (S 1) and after 125 min. (S2 ) of superfusion.
`Test substances are added 30 min. before S2 and are present
`in the superfusion medium untill45 min. of superfusion. At
`the end of the experiments the slices are solubilized in cone.
`formic acid and tritium content is determined in the super(cid:173)
`fusate and the solubilized slices. Tritium outflow is
`expressed as the fractional rate of tritium outflow per min.
`Electrically evoked tritium outflow is calculated by subtrac(cid:173)
`tion of the extrapolated basal tritium outflow from the total
`tritium outflow during the two min. of electrical stimulation
`and the following 13 min. and is expressed as percent of the
`tritium content at the beginning of the sample collection.
`Drug effects on stimulation evoked tritium outflow are
`expressed as the ratios SiS 1 . All experiments are run in
`dublicates using a programmable 12 channel superfusion
`system. For the calculation a computer program is used.
`In this test compound A inhibits electrically evoked
`3H-ACh release from hippocampal slices by approximately
`40% (100 f.LM) while racemate C (100 f.LM) inhibits by
`approximately 25%. The inhibitory effects of compound A
`65 and racemate C can be antagonized by atropine. These
`results are compatible with an AChE-inhibiting activity.
`Compound B is inactive in this model.
`
`CH2-CH3
`
`I
`
`(-)
`
`CH3
`
`60-CO-N\CHJ
`
`CH-N/
`I
`\
`CH,
`CH,
`in free base or acid addition salt form.
`As can be seen from this formula, in free base form the 35
`sign of rotation of the compound of formula I is (-).
`However in acid addition salt form it may be ( +) or (-). For
`instance the sign of rotation of the hydrogen tartrate is (+).
`The present invention covers the free base form as well as
`the acid addition salt forms, independently of their sign of 40
`rotation.
`The racemic mixture (±)-N-ethyl-3-[(1-dimethylarnino(cid:173)
`)ethyl]-N-methyl-phenyl-carbamate in form of its hydro(cid:173)
`chloride is known from the European patent application
`193,926 where it is identified as RA7 HCL
`According to this disclosure the racemate in free base
`form is obtained by arnidation of a-m-hydroxyphenyleth(cid:173)
`yldimethylamine with a corresponding carbamoyl halo(cid:173)
`genide. The resulting compound and its pharmacologically
`acceptable acid addition salts, which can be prepared from 50
`the free base in known manner, are disclosed as acetylcho(cid:173)
`linesterase inhibitors in the central nervous system.
`It has now surprisingly been found that the (-)-enanti(cid:173)
`omer of formula I and its pharmacologically acceptable acid
`addition salts, hereinafter referred to as compounds accord- 55
`ing to the invention, exhibit a particularly marked and
`selective inhibition of the acetylcholinesterase.
`These findings are unexpected, particularly since it is not
`believed that the dialkylaminoalkyl side chain, which con(cid:173)
`tains the optically active centre, is mainly responsible for the 60
`acetylcholinesterase inhibiting activity of the phenyl car(cid:173)
`bamates.
`The compounds according to the invention have never
`been specifically disclosed in the literature. The free base
`may be prepared from the racemate by separation of the
`enantiomers in accordance with known methods, e.g. using
`di-0,0'-p-toluyl-taratric acid. The acid addition salts may be
`
`Page 2 of 6
`
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`
`

`

`5,602,176
`
`3
`Acetylcholinesterase inhibition in different rat brain regions
`AChE preparations of different rat brain regions (Cortex,
`hippocampus and striatum) are used in this test and the IC50
`(inhibitory concentrations in ~) are determined. The
`enzyme preparations are preincubated with the inhibitor 15
`minutes before the determination.
`The AChE activity is measured according to the method
`described by Ellman (Arch. Biochem. Biophys. 82, 70,
`1959). Rat brain tissue is homogenized in cold phosphate
`buffer pH 7.3 (0.25 mM) containing 0.1% of Triton X -100.
`After centrifugation aliquots of the clear supernatant is used
`as enzyme source. The enzyme is preincubated with differ(cid:173)
`ent concentrations of the inhibitor. After different times,
`substrate (acetylthiocholinjodide 0.5 mM) is added and the
`remaining activity determined.
`The results are given in the following table I:
`
`TABLE 1
`
`ICsa
`
`Compound A
`Compound B
`Racemate C
`
`Cortex
`
`Hippocampus
`
`Striatum
`
`2.8
`16.1
`3.2
`
`3.7
`14.5
`3.9
`
`3.0
`13.8
`3.2
`
`As can be seen from this table the AChE inhibition with
`compound A is slightly superior than that with racemate C,
`whereas compound B is significantly less active.
`Acetylcholinesterase inhibition ex vivo in different rat brain
`regions
`30 minutes after administration of different doses of 30
`compound A, the AChE activity in different rat brain regions
`is measured ex vivo. The method is as disclosed above. The
`IC50 values found are 7 !liilOllkg p.o. in striatum, 4 !liilOI/kg
`p.o. in hippocampus and 2 !liilOllkg p.o. in cortex. The IC50
`obtained after administration of the racemate C are for all 35
`examined regions about 2-3 times higher. Six hours after
`administration of compound A (10 !liilOllkg p.o.) the AChE
`in striatum is still inhibited by 16%, whereas at the same
`time the activities in cortex and hippocampus are inhibited
`by 39% and 44% respectively.
`
`In Vivo Assays
`
`Influence on dopamine metabolism
`Male OFA rats (150-200 g) were used both for acute and
`subchronic experiments. The animals are maintained under
`12 hour periods of light and dark. The animals are sacrificed
`always between 11.00 and 13.00 h. The brains are excised
`immediately, dissected on ice according to the method of
`GLOWINSKI and IVERSEN, J. Neurochem. 13, 655
`(1966), frozen on dry ice and the tissue samples stored at
`-80° C. until analysis.
`Dopamine and its metabolites DOPAC (3,4-dihydrox(cid:173)
`yphenylacetic acid) and HVA (homovanillic acid) are deter(cid:173)
`mined in brain tissue extracts which are obtained by
`homogenisation of the stored brain tissue samples in 0.1N
`HCl containing 0.05 mM ascorbic acid and subsequent
`centrifugation. Striatal and cortical tissues are used.
`The determination of the metabolites is performed using
`either
`the gas chromatography/mass fragmentography
`(GCMS) technique as described by KAROUM et al., J.
`Neurochem. 25, 653 (1975) and CATABENI et al., Science
`178, 166 (1972) or the fluorometric method as described by
`WALDMEIER and MAITRE, Analyt. Biochem. 51, 474
`(1973). For the GCMS method, tissue extracts are prepared
`by adding known amounts of deuterated monoamines and
`their respective metabolites as internal standards.
`
`10
`
`20
`
`4
`Dopamine metabolism in striatum is increased following
`the administration of compounds A and B and racemate C
`(This property is a consequence of the acetylcholine accu(cid:173)
`mulation provoked by said compounds). However com-
`5 pound A is more active than compound B and racemate C in
`enhancing the striatal dopamine metabolite concentration.
`Muscarinic and nicotinic effects on brain glucose utilisation
`Changes in the functional activity of the CNS are asso(cid:173)
`ciated with altered deoxyglucose (DOG) utilisation in the
`brain which can be visualised simultaneously in several
`brain regions using the autoradiographic method of Sokoloff
`et al., J. Neurochem. 28, 897 (1977). The administration of
`cholinergic drugs either direct (muscarinic agonists) or
`indirect (accumulation of acetylcholine) induces in this
`model a characteristic "fingerprint" pattern by modifying the
`15 regional glucose metabolism.
`Male Wistar rats (150-200 g) are used. Drugs are admin(cid:173)
`istered at various doses and by different routes (i. v., p.o., i.p.)
`to animals. [14C]-2-deoxyglucose (125 j.tC/kg) is injected 45
`min. before the animals are sacrificed. The brains are imme(cid:173)
`diately excised, frozen at -80° C. and subsequently cut in
`slices with a thickness of 20 jlffi. The optical densities of the
`radiographic images are measured according to a modifica(cid:173)
`tion of Sokoloff et al.
`After p.o. application of compounds A and B (7.5 !liilOll
`25 kg) significant changes in DOG utilisation in various rat
`brain regions are observed. The effect of compound A is
`more potent than that of compound B during the initial 30
`minutes. The most marked changes are found in the visual
`regions and the anteroventral thalamus and also in the lateral
`habenula mucleus.
`Acetylcholine levels in different rat brain regions
`The effects of compounds A and B and racemate C as
`AChE inhibitors in vivo is determined by measuring the
`levels of ACh in different regions of rat brain at various
`times after drug administration.
`OFA rats (200-230 g) are used. The animals are killed by
`microwave irradiation focused on the head (6 kW operating
`power 2450 Mhz exposure 1. 7 sec., Pueschner Mikrowellen(cid:173)
`Energietechnik, Bremen). The brains are removed dissected
`40 according to Glowinski and Iversen (1966) and stored at
`-70° C. until analysis. The brain parts are homogenized in
`0.1M perchloric acid containing internal deuterated stan(cid:173)
`dards of ACh-d4 and Ch(choline)-d4 • After centrifugation,
`endogenous ACh and Ch together with their deuterated
`45 variants are extracted with dipicrylamine (2,2',4,4',6,6'-hex(cid:173)
`anitrodiphenylarnine) in dichlormethane as ion pairs. The
`Ch moities are derivatized with propionyl chloride and the
`resulting mixture of ACh and propyl choline derivatives are
`demethylated with sodiumbenzenethiolate and analyzed by
`50 mass-fragmentography according to Jenden et al. Anal.
`Biochem., 55, 438-448, (1973).
`A single application of 25 !liilollkg p.o. increases ACh
`concentrations in striatum, cortex and hippocampus. The
`maximal effect is achieved about 30 min. after oral appli-
`55 cation and declines during the next 3-4 hours. In cortex and
`hippocampus the ACh levels are still significantly higher at
`4 hours compared to controls. The effects are dose depen(cid:173)
`dent. The influence of compound B is significantly weaker
`than that induced by racemate C, and the influence of
`60 racemate C is significantly weaker than that induced by
`compound A.
`Furthermore the compounds according to the invention
`are indicated to be well tolerated and orally active, and they
`have a long duration of action, e.g. in the above and other
`65 standard tests.
`The compounds according to the invention are therefore
`useful for the treatment of senile dementia, Alzheimer's
`
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`
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`
`

`

`5,602,176
`
`6
`
`5
`disease, Huntington's chorea, tardive dyskinesias, hyperki(cid:173)
`nesia, mania, acute confusion disorders, Down's syndrome
`and Friedrich's ataxia.
`For these indications, the appropriate dosage will, of
`course, vary depending upon, for example, the compound 5
`according to the invention employed, the host, the mode of
`administration and the nature and severity of the condition
`being treated. However, in general, satisfactory results in
`animals are indicated to be obtained at daily dosages from
`about 0.01 to about 10 mg/kg, e.g. about 0.1 to about 5 10
`mg/kg animal body weight. In larger mammals, for example
`humans, an indicated daily dosage is in the range from about
`0.1 to about 25 mg, e.g. about 0.1 to about 5 mg of a
`compound according to the invention, conveniently admin(cid:173)
`istered, for example, in divided doses up to four times a day. 15
`The compounds according to the invention may be admin(cid:173)
`istered by any conventional route, in particular enterally,
`preferably orally, e.g. in the form of tablets or capsules, or
`parenterally, e.g. in the form of injectable solutions or
`suspensions.
`The above mentioned compound A is the preferred com(cid:173)
`pound for the above mentioned indications. The preferred
`indication is senile dementia.
`The present invention also provides pharmaceutical com(cid:173)
`positions comprising a compound according to the invention
`in association with at least one pharmaceutical carrier or
`diluent. Such compositions may be manufactured in con(cid:173)
`ventional manner. Unit dosage forms contain, for example,
`from about0.025 to about 12.5 mg of a compound according
`to the invention. Conveniently an acid addition salt form is
`used. The preferred salt form is compound A, especially for
`orally administrable forms, e.g. from the point of view of
`stability.
`In the following example, the temperatures are uncor(cid:173)
`rected and are in degrees centigrade.
`
`20
`
`25
`
`wherein
`R 1 is hydrogen, lower alkyl, cyclohexyl, allyl or benzyl,
`R2 is hydrogen, methyl, ethyl or propyl, or
`R 1 and R2 together with the nitrogen to which they are
`attached form a morpholino or piperidino radical,
`R3 is hydrogen or lower alkyl,
`R4 and R5 are the same or different and each is a lower
`alkyl, and the dialkylaminoalkyl group is in the meta,
`ortho or para position,
`in free base or pharmaceutically acceptable acid addition salt
`form.
`The compounds of formula I' and their pharmaceutically
`acceptable acid addition salts as well as their preparation and
`their use as acetylcholinesterase inhibitors are known from
`the above mentioned European patent application 193,926.
`The compounds of formula I' include for example the
`above defined compound A and racemate C.
`It has now surprisingly been found that the compounds of
`formula I' in free base or pharmaceutically acceptable acid
`addition salt form, hereinafter referred to as compounds for
`administration according to the invention, exhibit unexpect(cid:173)
`edly good skin penetration when administered percutane(cid:173)
`ously.
`The penetration through the skin of the compounds for
`administration according to the invention may be observed
`in standard in vitro or in vivo tests.
`One in vitro test is the well known diffusion test which
`may be effected according to the principles set out in GB
`30 2098865 A and by T. J. Franz in J. Invest. Dermatol. (1975)
`64, 194-195. Solutions containing the active agent in unla(cid:173)
`belled or radioactively labelled form are applied to one side
`of isolated pieces of intact human skin or hairless rat skin
`about 2 cm2 in area. The other side of the skin is in contact
`35 with physiological saline. The amount of active agent in the
`saline is measured in conventional manner, e.g. by HPLC or
`spectrophotometric techniques, or by determining the radio(cid:173)
`activity.
`In this test using rat skin the following penetration rates,
`40 for example, have been found:
`Above defined compound A: 23.6±14.9%
`Compound of formula I in free base form: 28.0±8.2%
`Moreover it has been found that transdermal administra(cid:173)
`tion of the compounds for administration according to the
`invention induces a long-lasting and constant inhibition of
`acety ]cholinesterase activity as indicated in standard tests,
`with a slow onset of action, which is particularly advanta(cid:173)
`geous with respect to the tolerability of these compounds.
`For example the acetylcholinesterase inhibition in differ-
`50 ent rat brain regions ex vivo has been measured after
`transdermal administration of the compounds for adminis(cid:173)
`tration according to the invention, and compared to the
`inhibition obtained after administration via different routes.
`The compounds are dissolved in or diluted with n-heptane
`to a concentration of 1 or 3 mg/20 Ill· Male rats (OFA strain,
`ca. 250 g) are shaved in the neck region and the solution is
`applied with a micropipette on the skin. The application
`place is immediately covered using a thin plastic film and a
`plaster. The animal has no access to the plaster. Various
`times after the administration the animals are killed by
`decapitation and the remaining AChE activity is measured.
`Transdermal administration of the above defined com(cid:173)
`pound A, for example, induces a long-lasting, dose-depen(cid:173)
`dent inhibition of AChE activity. In contrast to the rapid
`65 onset of the effect after either oral or subcutaneous appli(cid:173)
`cation (max. 15 and 30 min. respectively), the AChE inhi(cid:173)
`bition occurs slowly after this application route (max.>2
`
`EXAMPLE 1
`
`(S)-N-ethyl-3-[(1-dimethylarnino )ethyl](cid:173)
`N-methyl-phenyl-carbamate
`
`130 g of (±)-N-ethyl-3-[(1-dimethylarnino)ethyl]-N-me(cid:173)
`thyl-phenylcarbamate and 210 g of (+)-di-0,0'-p-toluoyl
`tartaric acid monohydrate are dissolved while heating in 1.3
`liter of methanol/water (2: 1 ). The salt precipitated after
`cooling is filtered and recrystallised 3 times from methanol/
`water (2:1). The (S)-enantiomer is released by partitioning
`between lN NaOH and ether. [a]DD20=-32.1 o (c=5 in
`ethanol).
`The hydrogen tartrate of the title compound (from etha(cid:173)
`nol) melts at 123°-125°. [a)n20=+4.7° (c=5 in ethanol).
`The present invention furthermore provides the systemic
`transdermal application of the phenyl carbamates of formula
`I',
`
`R,
`
`0
`/
`II
`0-C-N'\Rz
`
`I'
`
`~
`
`RJ
`/
`I
`C-N
`I
`'\
`CH3
`Rs
`
`45
`
`55
`
`60
`
`Page 4 of 6
`
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`
`

`

`5,602,176
`
`7
`hours) without affecting the brain region selective AChE
`inhibition.
`The results are shown in the following table 2. Twenty
`four hours after transdermal application, the AChE activity
`is still inhibited in central and peripheral regions. After the 5
`same time, orally applied compound A has no effect on the
`enzyme, whereas after the s.c. application only the enzyme
`in the heart is significantly inhibited.
`
`8
`intravenous administration. The amount of pharmaceutically
`active agent to be administered will individually depend on
`the drug release characteristics of the pharmaceutical com(cid:173)
`positions, the drug penetration rate observed in in vitro and
`in vivo tests, the potency of active agent, the size of the skin
`contact area, the part of the body to which the unit is stuck,
`and the duration of action required. The amount of active
`agent and area of the pharmaceutical composition etc. may
`
`TABLE 2
`
`AChE activity in % of controls ± SD
`
`n Cortex
`
`Hippocampus
`
`Striatum
`
`Pons/Medulla
`
`Heart
`
`Blood
`
`6 86.1 ± 5.6
`6 42.4 ± 11.7
`6 73.8 ± 5.7
`
`86.7 ± 5.9
`45.7 ± 15.0
`80.4 ± 8.8
`
`89.7 ± 8.4
`65.9 ± 15.5
`81.0 ± 8.2
`
`91.5 ± 3.8
`53.6 ± 13.3
`85.3 ± 4.2
`
`109.0 ± 9.3
`52.0 ± 13.1
`63.9 ± 12.5
`
`71.3 ± 12.3
`41.9 ± 13.1
`78.1 ± 17.8
`
`6 21.0 ± 3.5
`6 65.3 ± 21.3
`6 99.2 ± 8.9
`
`19.7 ± 3.8
`62.0 ± 15.4
`97.2± 7.1
`
`32.9 ± 10.7
`87.5 ± 8.8
`96.7 ± 3.3
`
`26.6 ± 4.0
`80.3 ± 9.2
`104.1 ± 6.8
`
`71.2 ± 11.2
`101.0 ± 7.0
`94.2 ± 9.2
`
`34.0 ± 2.0
`77.2 ± 14.7
`97.2 ± 13.8
`
`Time after
`Treatment
`
`Transdermal
`30 JliiiOI/kg
`
`0.5 hours
`6 hours
`24 hours
`Oral
`JQ JliiiOI/kg
`
`0.5 hours
`6 hours
`24 hours
`Subcutaneous
`8 JliiiOI/kg
`
`0.5 hours
`6 hours
`24 hours
`
`6 16.8 ± 2.0
`6 85.1 ± 1.6
`6 93.8 ± 5.9
`
`18.3 ± 3.1
`81.4 ± 7.6
`99.9 ± 9.9
`
`28.2 ± 12.2
`82.9 ± 2.8
`91.0 ± 2.3
`
`20.9 ± 2.9
`87.1 ± 4.1
`98.7 ± 6.0
`
`33.3 ± 5.6
`51.0 ± 17.9
`65.7 ± 21.2
`
`17.4 ± 4.1
`79.5 ± 8.2
`105.7 ± 16.8
`
`Control values (pmole/mg x min. ± SD n = 15):
`Cortex: 3.67 ± 0.30
`Hippocampus: 4.42 ± 0.30
`Striatum: 33.8 ± 3.08
`Pons/Medulla: 7.98 ± 0.36
`Heart: 2.27 ± 0.39
`Blood: 311.4 ± 44.2
`
`Thus in another aspect the present invention provides a
`pharmaceutical composition for systemic
`transdermal
`administration incorporating as an active agent a compound
`of formula I' in free base or pharmaceutically acceptable
`acid addition salt form.
`In a further aspect the present invention provides a
`method of systemically administering an active agent of
`formula I' in free base or pharmaceutically acceptable acid 45
`addition salt form which comprises administering the active
`agent to the skin.
`The active agents may be administered in any conven(cid:173)
`tional liquid or solid transdermal pharmaceutical composi(cid:173)
`tion, e.g. as described in Remington's Pharmaceutical Sci(cid:173)
`ences 16th Edition Mack; Sucker, Fuchs and Spieser,
`Pharmazeutische Technologie 1st Edition, Springer and in
`GB 2098865 A or DOS 3212053 the contents of which are
`incorporated herein by reference.
`Conveniently the composition is in the form of a viscous
`liquid, ointment or solid reservoir or matrix. For example the
`active agent is dispersed throughout a solid reservoir or
`matrix made of a gel or a solid polymer, e.g. a hydrophilic
`polymer as described in European Patent Application No.
`155,229.
`The active agent may be incorporated in a plaster.
`The compositions for transdermal administration may
`contain from about 1 to about 20% by weight of active agent
`of formula I' in free base or pharmaceutically acceptable
`acid addition salt form.
`The pharmaceutical compositions for transdermal admin(cid:173)
`istration may be used for the same indications as for oral or
`
`be determined by routine bioavailability tests comparing the
`blood levels of active agents after administration of the
`40 active agent in a pharmaceutical composition according to
`the invention to intact skin and blood levels of active agent
`observed after oral or intravenous administration of a thera(cid:173)
`peutically effective dose of the pharmacologically active
`agent.
`Given the daily dose of a drug for oral administration, the
`choice of a suitable quantity of drug to be incorporated in a
`transdermal composition according to the invention will
`depend upon the pharmacokinetic properties of the active
`agent, including the first pass effect; the amount of drug
`50 which can be absorbed through the skin from the matrix in
`question for a given area of application and in a given time;
`and the time for which the composition is to be applied.
`Thus, a drug with a high first pass effect may require a
`relatively low quantity in the transdermal composition when
`55 compared with the oral daily dose, since the first pass effect
`will be avoided. On the other hand, generally a maximum of
`only approximately 50% of the drug in the matrix is released
`through the skin in a 3 day period.
`The pharmaceutical compositions of the invention in
`60 general have for example an effective contact area of drug
`reservoir on the skin of from about 1 to about 50 square
`centimeters, preferably about 2 to 20 square centimeters, and
`are intended to be applied for from 1-7 days, preferably 1-3
`days.
`Compound A may for example be administered at a dose
`of 10 mg in a patch of ca. 10 cm2
`, once every three days.
`The following example illustrates the invention.
`
`65
`
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`

`

`5,602,176
`
`9
`EXAMPLE 2
`
`Preparation of a Transdermal Composition
`Containing a Hydrophilic Polymer
`
`Composition
`
`Compound of formula !', e.g. compound A
`Hydrophilic polymer, e.g. Eudragit E 100*
`Non swellable acrylate polymer, e.g. Durotack 280-2416**
`Plasticizer, e.g. Brij 97***
`
`20%
`30%
`44%
`6%
`
`*Registered Trade Mark, available from Robm, Darmstadt, W. Germany
`**Registered Trade Mark, available from Delft National Cbemie Zutphen,
`Netherlands
`***Registered Trade Mark, available from Atlas Cbemie, W. Germany
`
`The components are added to acetone or ethanol or
`another appropriate volatile organic solvent and mixed to
`give a viscous mass. The mass is spread on top of an
`aluminised polyester foil (thickness 23 microns) using a
`conventional apparatus, to produce a film of thickness 0.2
`mm when wet. The film is allowed to dry at room tempera(cid:173)
`ture over 4 to 6 hours. The aluminium foil is then cut up into
`patches about 10 sq em in area.
`What we claim is:
`1. The (S)-[N-ethyl-3-[(1-dimethylarnino)ethyl]-N-me(cid:173)
`thyl-phenyl-carbamate] enantiomer of formula I substan(cid:173)
`tially free of its (R) isomer
`
`25
`
`10
`4. A method of treating senile dementia, which comprises
`administering a therapeutically effective amount of a com(cid:173)
`pound of claim 1 in free base or pharmacologically accept(cid:173)
`able acid addition salt form to a subject in need of such
`treatment.
`5. A method of treating Alzheimer's disease, which com(cid:173)
`prises administering a therapeutically effective amount of a
`compound of claim 1 in free base or pharmacologically
`acceptable acid addition salt form to a subject in need of
`10 such treatment.
`6. A method of treating Huntington's chorea, tardive
`dyskinesias, hyperkinesia, mania, acute confusion disorders,
`Down's syndrome or Friedrich's ataxia, which comprises
`administering a therapeutically effective amount of a com-
`!5 pound of claim 1 in free base or pharmacologically accept(cid:173)
`able acid addition salt form to a subject in need of such
`treatment.
`7. A method of systemically administering a compound of
`claim 1 in free base or pharmaceutically acceptable acid
`20 addition salt form, which comprises administering the active
`agent transdermally through the skin.
`8. A systemic transdermal pharmaceutical composition
`according to claim 3 comprising a therapeutically effective
`amount of (S)-N-ethyl-3-[(1-dimethyl-amino)ethyl]-N-me-
`thyl-phenyl-carbamate in free base or pharmaceutically
`acceptable acid addition salt form, and a pharmaceutically
`acceptable carrier therefor suitable for systemic transdermal
`administration.
`9. A systemic transdermal pharmaceutical composition
`according to claim 3 comprising a therapeutically effective
`amount of the hydrogen tartrate salt of (S)-N-ethyl-3-[(1-
`dimethyl-amino)ethyl]-N-methyl-phenyl-carbamate, and a
`pharmaceutically acceptable carrier therefor suitable for
`systemic transdermal administration.
`10. A systemic transdermal pharmaceutical composition
`according to claim 8 in which the (S)-N-ethyl-3-[(1-dim(cid:173)
`ethyl-arnino)ethyl]-N-methyl-phenyl-carbamate is in free
`base form.
`11. A systemic transdermal pharmaceutical composition
`40 according to claim 8 in which the pharmaceutically accept(cid:173)
`able carrier is a transdermal patch.
`12. A method according to claim 7 in which the compound
`is in free base form.
`
`I 30
`
`35
`
`CH3
`in free base or acid addition form.
`2. The compound of claim 1 which is the hydrogen tartrate
`salt of (S)-N-ethyl-3-[(1-dimethylarnino)ethyl]-N-methyl(cid:173)
`phenylcarbamate.
`3. A pharmaceutical composition which comprises a com(cid:173)
`pound of claim 1 in free base or pharmaceutically acceptable
`acid addition salt form, in association with a pharmaceutical
`carrier or diluent.
`
`* * * * *
`
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`Noven Exh. 1024
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