throbber
(12) UK Patent Application
`
`(19) GB (11)
`
`(43) Application published 12 Oct 1988
`
`(51} INT CL'
`A61K 31/27 C07C 125/067
`
`(52} Domestic classification (Edition J}:
`ASB 170 423 42Y 430 431 43Y 541 544 54Y 566
`56Y 586 58Y 596 59Y 646 64Y 664 66Y HA LG
`C2C 220 227 22Y 29X 29Y 302 SOY 323 32Y 340
`34Y 627 71 Y KB
`U1S 2418 A5B C2C
`
`(56) Documents cited
`EP A2 0193926
`
`(58} Field of search
`ASB
`C2C
`Selected US specifications from IPC sub-class
`A61K
`
`(21) Application No 8804888
`
`(22) Date of filing 1 Mar 1988
`
`(30) Priority data
`(31) 3706914
`
`(32) 4 Mar 1987
`
`(33) DE
`
`(71) Applicant
`Sandoz Ltd
`
`(Incorporated in Switzerland)
`
`35 Uchtstrasse, CH-4002 Basle, Switzerland
`
`(72) Inventor
`Albert Enz
`
`(74) Agent and/or Address for Service
`B A Yorke & Co
`Coomb House, 7 St John's Road, lsleworth,
`Middlesex, TW7 6NH
`
`(54) Phenyl carbamates
`
`(57) Compositions for systemic transdermal administration contain the compounds:
`
`0
`
`ol.«(:~
`
`1'
`
`Rl {<·
`
`or
`
`tH3
`5
`where R1 is-H, alkyl, cyclohexyl, allyl or benzyl
`R2 is-H, -CH3 , -C2H5 or -C3H7
`R1 and R2 together with -N for a morpho line or piperidine group
`R3 is -H or alkyl
`R4 and R5 are alkyl, in their free base or acid addition salt form. The compositions particularly contain the novel
`compound (S)-N-ethyl-3-[1-dimethylamino}ethyi}-N-methyl-phenyl-carbamate and are used to treat Alzheimer's
`disease, mania etc.
`
`/'
`
`G)
`OJ
`I\.)
`1\)
`0
`(.,.)
`0
`~
`0
`)>
`
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`
`Page 1 of 23
`
`

`

`-t~
`
`? 0 r: l· r-·
`r-..: t:r \} \.·~·
`'-'
`
`-~
`~·-
`
`.....
`
`\..
`
`CASE 100-7041
`
`PHENYL CARBAMATE
`
`The present invention relates to a novel phenyl carbamate with
`anticholinesterase activity.
`
`More particularly the invention relates to the (S)-N-ethyl-
`3-[(1-dimethylamino)ethyl]-N-methyl-phenyl-carbamate of formula I
`
`(-)
`
`I
`
`in free base or acid addition salt form.
`
`As can be seen from this formula, in free base form the 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 rotation.
`
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`

`- 2 -
`
`100-7041
`
`The racemic mixture (±)-N-ethyl-3-[(1-dimethylamino)ethyl](cid:173)
`N-methyl-phenyl-carbamate in form of its hydrochloride 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 amidation of ~-m-hydroxyphenylethyldimethylamine with
`a corresponding carbamoyl halogenide. The resulting compound and
`its pharmacologically acceptable acid addition salts, which can
`be prepared from the free base in known manner, are disclosed as
`acetylcholinesterase inhibitors in the central nervous system.
`
`It has now surprisingly been found that the (-)-enantiomer of
`formula I and its pharmacologically acceptable acid addition
`salts, hereinafter referred to as compounds according 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 contains
`the optically active centre, is mainly responsible for the
`acetylcholinesterase inhibiting activity of the phenyl
`carbamates.
`
`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(cid:173)
`tartaric acid. The acid addition salts may be prepared from the
`free base in known manner. These include e.g. the hydrogen
`tartrate.
`
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`

`

`- 3 -
`
`100-7041
`
`The compounds according to the invention exhibit pharmacological
`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 originating from striatum and pons/(cid:173)
`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 invention as
`compared to the corresponding isomers and racemates. 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 compound of formula I and its optical
`isomer, in form of the hydrochloride.
`
`In vitro assays
`
`~~~~EE!~~~~~-~!~~~~-=~=~~~E~~~~~~!~~-E~!~~~~-!E~~-E~E-~!EE~~~E~!
`slices
`
`Electrically evoked 3a-acetylcholine (3H-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 (AChE). Inhibition of
`AChE activity leads to the accumulation of endogenous ACh which
`then interacts with presynaptic muscarinic autoreceptors and
`inhibits further release of 3H-ACh.
`
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`
`100-7041
`
`Rat hippocampal slices (~istar strain, 180 - 200 g) are prepared
`by chopping into cross sections whole hippocampal slices at a
`distance of 0.3 mm with a Mcilwain tissue chopper. Hippocampal
`slices obtained from 3 rats are incubated 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 ~M 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 (2 Hz rectangular pulses 2 msec, 10 rnA,
`2 min.) are applied aJter 70 min. (S1) and after 125 min. (S2) of
`superfusion. Test substances are added 30 min. before s2 and are
`present in the superfusion medium until 145 min. of superfusion.
`At the end of the experiments the slices are solubilized in cone.
`formic acid and tritium content is determined in the superfusate
`and the solubilized slices. Tritium outflow is expressed as the
`fractional rate of tritium outflow per min. Electrically evoked
`tritium outflow is calculated by subtraction 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 s2;s1. All experi(cid:173)
`ments 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 ~M)
`while racemate C (100 ~M) inhibits by approximately 25 %. The
`inhibitory effects of compound A and racemate C can be
`antagonized by atropine. These results are compatible with an
`AChE-inhibiting activity. Compound B is inactive in this model.
`
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`

`- 5 -
`
`100-7041
`
`AChE preparations of different rat brain regions (Cortex, hippo(cid:173)
`campus and striatum) are used in this test and the rc50
`(inhibitory concentrations in ~M) 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 different 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 1:
`
`TABLE 1
`
`ICSO
`
`Cortex
`
`Hippocampus
`
`Striatum
`
`Compound A
`Compound B
`Racemate G
`
`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.
`
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`

`- 6 -
`
`100-7041
`
`~~~!~!~~£!!~~~!~!~~~-!~!~!!!£~-~~-~!~£_!~-~!!!~!~~!_!~!-~!~!~
`!~~!£~~
`
`30 minutes after administration of different doses of 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 ~mol/kg p.o. in striatum, 4 ~mol/kg p.o. in hippocampus and
`2 ~mol/kg p.o. in cortex. The rc50 obtained after administration
`of the racemate C are for all examined regions about 2 - 3 times
`higher. Six hours after administration of compound A
`(10 ~mol/kg 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
`
`Male OFA rats (150 - 200 g) were used both for acute and sub(cid:173)
`chronic 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 GLOYINSKI 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-dihydroxyphenylacetic
`acid) and HVA (homovanillic acid) are determined in brain tissue
`extracts which are obtained by homogenisation of the stored brain
`tissue samples in 0.1 N HCl containing 0.05 mM ascorbic acid and
`subsequent centrifugation. Striatal and cortical tissues are
`used.
`
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`

`

`- 7 -
`
`100-7041
`
`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 YALDMEIER 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.
`
`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 accumulation provoked by
`said compounds). However compound A is more active than
`compound B and racemate C in enhancing the striatal dopamine
`metabolite concentration.
`
`Changes in the functional activity of the CNS are associated 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 regional glucose metabolism.
`
`Male Yistar rats (150 - 200 g) are used. Drugs are administered
`at various doses and by different routes (i.v., p.o., i.p.) to
`animals. [14C]-2-deoxyglucose (125 ~C/kg) is injected 45 min.
`before the animals are sacrificed. The brains are immediately
`excised, frozen at - 80 ° C and subsequently cut in slices with a
`thickness of 20 ~m. The optical densities of the radiographic
`
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`

`

`- 8 -
`
`100-7041
`
`images are measured according to a modification of Sokoloff et
`al.
`
`After p.o. application of compounds A and B (7.5 ~mol/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.
`
`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-Energietechnik,
`Bremen). The brains are removed dissected according to Glowinski
`and Iversen (1966) and stored at - 70 ° C until analysis. The
`brain parts are homogenized in 0.1 M perchloric acid containing
`internal deuterated standards of ACh-d4 and Ch(choline)-d4. After
`centrifugation, endogenous ACh and Ch together with their
`deuterated variants are extracted with dipicrylamine
`(2,2',4,4',o,6'-hexanitrodiphenylamine) 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 mass(cid:173)
`fragmentography according to Jenden et al. Anal. Biochem., 55,
`438 - 448, (1973).
`
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`

`

`- 9 -
`
`100-7041
`
`A single application of 25 ~mol/kg p.o. increases ACh concen(cid:173)
`trations in striatum, cortex and hippocampus. The maximal effect
`is achieved about 30 min. after oral application 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 dependent. The influence of
`compound B is significantly weaker than that induced by
`racemate C, and the influence of racemate C is significantly
`weaker than that induced by compound A.
`
`Furthermore the compounds according to the invention are indi(cid:173)
`cated to be well tolerated and orally active, and they have a
`long duration of action, e.g. in the above and other standard
`tests.
`
`The compounds according to the invention are therefore useful for
`the treatment of senile dementia, Alzheimer's disease,
`Huntington's chorea, tardive dyskinesias, hyperkinesia, mania,
`acute confusion disorders, Down's syndrome and Friedrich's
`ataxia.
`
`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, together with solid or liquid carrier or diluents.
`
`In accordance with the foregoing, the present invention also
`provides a compound according to the invention, for use as a
`pharmaceutical, e.g. for the treatment of senile dementia,
`Alzheimer's disease, Huntington's chorea, tardive dyskinesias,
`hyperkinesia, mania, acute confusion disorders, Down's syndrome
`and Friedrich's ataxia.
`
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`

`

`- 10 -
`
`100-7041
`
`The present invention furthermore provides a pharmaceutical
`composition comprising a compound according to the invention in
`association with at least one pharmaceutical carrier or diluent.
`Such compositions may be manufactured in conventional manner.
`
`In the following example, the temperatures are uncorrected and
`are in degrees centigrade.
`
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`

`

`- 11
`
`100-7041
`
`EXAMPLE 1:
`
`(S)-N-ethyl-3-[(1-dimethylamino)ethyl]-N-methyl(cid:173)
`phenyl-carbamate
`
`130 g of (±)-N-ethyl-3-[(1-dimethylamino)ethyl]-N-methyl-phenyl(cid:173)
`carbamate and 210 g of (+)-di-0,0'-p-toluoyl tartaric acid mono(cid:173)
`hydrate are dissolved while heating in 1.3 liter of methanol/(cid:173)
`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 1 N NaOH and
`ether. [a]~O = - 32.1 ° (c = 5 in ethanol).
`
`The hydrogen tartrate of the title compound (from ethanol) melts
`at 123- 125 ° [a]~ 0 = + 4.7 ° (c = 5 in ethanol).
`
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`

`

`- 12 -
`
`100-7041
`
`The present invention furthermore provides the systemic
`transdermal application of the phenyl carbamates of formula I',
`
`I'
`
`wherein
`
`is hydrogen, lower alkyl, cyclohexyl, allyl or benzyl,
`is hydrogen, methyl, ethyl or propyl, or
`together with the nitrogen to which they are attached
`form a morpholino or piperidine radical,
`is hydrogen or lower alkyl,
`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 !' include for example the above defined
`compound A and racemate c.
`
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`

`

`- 13 -
`
`100-7041
`
`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 unexpectedly
`good skin penetration when administered percutaneously.
`
`The penetration through the skin of the compounds for admini(cid:173)
`stration 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 2098865 A and
`by T.J. Franz in J. Invest. Dermatol. (1975) 64, 194 - 195.
`Solutions containing the active agent in unlabelled 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 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 radioactivity.
`
`In this test using rat skin the following penetration rates, 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 administration of the
`compounds for administration according to the invention induces a
`long-lasting and constant inhibition of acetylcholinesterase
`activity as indicated in standard tests, with a slow onset of
`action, which is particularly advantageous with respect to the
`tolerability of these compounds.
`
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`

`

`- 14 -
`
`100-7041
`
`For example the acetylcholinesterase inhibition in different rat
`brain regions ex vivo has been measured after transdermal
`administration of the compounds for administration 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 ~1. 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 compound A, for
`example, induces a long-lasting, dose-dependent inhibition of
`AChE activity. In contrast to the rapid onset of the effect after
`either oral or subcutaneous application (max. 15 and 30 min.
`respectively), the AChE inhibition occurs slowly after this
`application route (max. > 2 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 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.
`
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`

`

`TABLE 2
`
`I
`
`I
`
`•
`!
`IT~•e after
`Treatment
`
`n
`
`.
`
`Cortex
`
`Transdermal
`30 )Jmollkg
`0.5 hours
`6
`hours
`24
`hours
`
`6 186.1
`6 142.4
`6 73.8
`
`± 5.7
`
`I
`6 121.0 ± 3.5
`6 165.3 ± 21.3
`6 99.2 ± 8.9
`
`I
`
`Oral
`10 )Jmol/kg
`I 0.5 hours
`I 6
`hours
`24
`hours
`-
`I
`I Subcutaneous!
`_
`I 8 )Jmollkg
`I
`I 0.5 hours
`I 6 116.8 ±
`I 6
`I 6 !85.1 ±
`hours
`124 _ ~~urs __l_!_j 93.8 ±
`
`2.0
`1.6
`5.9
`
`18.3 ± 3.1 1 28.2 ±
`81.4 ± 7.6 1 82.9 ±
`99.9 ± 9.9 1 91.o ±
`I
`
`I
`12.2 1
`2.8 I
`2.3
`
`I
`
`I
`2o.9 ± 2.9 I
`33.3 ± 5.6 1 17.4 ± 4.11
`87.1 ± 4.1 1
`51.o ± 17.9 1 79.5 ± 8.21
`98.7 ± 6.o 1
`65.7 ± 21.2 1105.7 ± 16.81
`I
`I
`I
`
`Control values (pmole/mg x min. ± SD o = 15):
`Cortex:
`3.67 ± 0.30
`Hippocampus: 4.42 ± 0.30
`Pons/Medulla: 7.98 ± 0.36
`Heart:
`2.27 ± 0.39
`
`Striatum:
`Blood:
`
`33.8 ± 3.08
`311.4 ± 44.2
`
`I
`AChE activity in % of controls ± SD
`!
`!
`!
`!
`I
`I
`I
`I
`Hippocampus I Striatum
`I
`I Pons/Medulla I Heart
`i
`i
`i
`I
`I
`I
`I
`I
`I
`I
`I
`± 5.6 I 86.7 ± 5.9 I 89.7 ± 8.4 I 91.5 ± 3.8 1109.0 ± 9.3 I 71.3 ± 12.31
`± 11.7 I 45.7 ± 15.0 I 65.9 ± 15.5 I 53.6 ± 13.3 I 52.0 ± 13.1 I 41.9 ± 13.11
`63.9 ± 12.5 I 78.1 ± 17.81
`80.4 ± 8.8 I 81.0 ± 8.2
`I
`I
`L_
`I
`I
`I
`I
`I
`I
`I
`I
`I
`l
`I
`I
`19.7 ± 3.8 I 32.9 ± 10.7 I 26.6 ± 4.0 I 71.2 ± 11.2 I 34.0 ± 2.01
`62.0 ± 15.4 I 87.5 ± 8.8 I 80.3 ± 9.2 1101.0 ± 7.0 I 77.2 ± 14.71
`94.2 ± 9.2 I 97.2 ± 13.81
`I
`I
`I
`I
`I
`I
`
`----------
`
`I
`
`Blood
`
`!
`I
`I
`
`I
`
`85.3 ± 4.2
`
`I
`I
`
`I
`
`97.2 ± 1.1 1 96.7 ± 3.3
`
`104.1 ± 6.8
`
`.....
`
`lJ1
`
`.....
`0
`0
`I
`-..J
`0
`.....
`-~=>­
`
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`

`

`- 16 -
`
`100-7041
`
`Thus in another aspect the present invention provides a pharma(cid:173)
`ceutical composition for systemic transdermal administration
`comprising a compound of formula I' in free base or pharma(cid:173)
`ceutically acceptable acid addition salt form, in association
`with a pharmaceutical carrier or diluent suitable for systemic
`transdermal administration.
`
`In yet a further aspect the present invention provides the use of
`a compound of formula I' in free base or pharmaceutically
`acceptable acid addition salt form as active agent in the manu-
`..
`facture of a pharmaceutical composition suitable for systemic
`transdermal administration.
`
`The active agents may be administered in any conventional liquid
`or solid transdermal pharmaceutical composition, e.g. as
`described in Remington's Pharmaceutical Sciences 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.
`
`Noven Ex. 1002
`
`Page 17 of 23
`
`

`

`- 17 -
`
`100-7041
`
`The pharmaceutical compositions for transdermal administration
`may be used for the same indications as for oral or intravenous
`administration. The amount of pharmaceutically active agent to be
`administered will individually depend on the drug release
`characteristics of the pharmaceutical compositions, 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 be determined by routine
`bioavailability tests comparing the blood levels of active agents
`after administration of the 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 therapeutically effective dose of the pharma(cid:173)
`cologically 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 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 compared with the oral daily dose,
`since the first pass effect will be avoided. On the other hand,
`generally a maximum of only approximately SO % of the drug in the
`matrix is released through the skin in a 3 day period.
`
`Noven Ex. 1002
`
`Page 18 of 23
`
`

`

`- 18 -
`
`100-7041
`
`The pharmaceutical compositions of the invention in general have
`for example an effective contact area of drug reservoir on the
`skin of from about 1 to about 50 square centimetres, preferably
`about 2 to 20 square centimetres, 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
`2
`a patch of ca. 10 em , once every three days.
`
`The following example illustrates the invention.
`
`Noven Ex. 1002
`
`Page 19 of 23
`
`

`

`- 19 -
`
`100-7041
`
`EXAMPLE 2: Preparation of a transdermal composition containing
`a hydrophilic polymer
`
`20%
`Compound of formula I', e.g. compound A
`30 %
`Hydrophilic polymer, e.g. Eudragit E 100*
`Non swellable acrylate polymer, e.g. Durotack 280 - 2416** 44 %
`6 %
`Plasticizer, e.g. Brij 97***
`
`*
`
`**
`
`Registered Trade Mark, available from Rohm, Darmstadt,
`Y. Germany
`Registered Trade Mark, available from Delft National Chemie
`Zutphen, Netherlands
`***: Registered Trade Mark, available from Atlas Chemie,
`V. Germany
`
`The components are added to acetone or ethanol or another
`appropriate volatile organic solvent and mixed to give a viscous
`~ass. 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 temperature over 4 to 6 hours. The aluminium foil is then
`cut up into patches about 10 sq em in area.
`
`Noven Ex. 1002
`
`Page 20 of 23
`
`

`

`- 20 -
`
`100-7041
`
`WAT YE CLAIM IS:
`
`1. A process for the production of the (S)-N-ethyl-3-[(1-di(cid:173)
`methylamino)ethyl]-N-methyl-phenyl-carbamate of formula I
`
`(-)
`
`I
`
`in free base or acid addition salt form, which includes the
`step of separating the enantiomers from the corresponding
`racemate and recovering the resultant compound of formula I
`in free base or acid addition salt form.
`
`2. A process for the production of the compound of formula I in
`free base or acid addition salt form, substantially as
`hereinbefore described with reference to the example.
`
`3. A compound of formula I in free base or acid addition salt
`form, as defined in claim 1.
`
`4. A compound of claim 3 which is the hydrogen tartrate of the
`(S)-N-ethyl-3-[(1-dimethylamino)ethyl]-N-methyl-phenyl(cid:173)
`carbamate.
`
`S. A compound of claim 3 or 4 in pharmaceutically acceptable
`form for use as a pharmaceutical.
`
`6. A compound of claim 3 or 4 in pharmaceutically acceptable
`form for use in the treatment of senile dementia.
`
`Noven Ex. 1002
`
`Page 21 of 23
`
`

`

`- 21 -
`
`100-7041
`
`7. A compound of claim 3 or 4 in pharmaceutically acceptable
`form for use in the treatment of Alzheimer's disease.
`
`8. A compound of claim 3 or 4 in pharmaceutically acceptable
`form for use in the treatment of Huntington's.chorea,
`tardive dyskinesias, hyperkinesia, mania, acute confusion
`disorders, Down's syndrome or Friedrich's ataxia.
`
`9. A pharmaceutical composition comprising a compound according
`to claim 3 or 4 in pharmaceutically acceptable form, in
`association with a pharmaceutical carrier or diluent.
`
`10. A pharmaceutical composition for systemic transdermal
`administration, comprising a compound of formula I',
`
`0
`H R
`o-c-«( 1
`R2
`
`I'
`
`wherein
`R1
`
`R2
`R1 and R2
`
`R3
`
`is hydrogen, lower alkyl, cyclohexyl, allyl or
`benzyl,
`is hydrogen, methyl, ethyl or propyl, or
`together with the nitrogen to which they are
`attached form a morpholino or piperidino radical,
`is hydrogen or lower alkyl,
`
`Noven Ex. 1002
`
`Page 22 of 23
`
`

`

`- 22 -
`
`100-7041
`
`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 a_cid addition
`salt form, in association with a pharmaceutical carrier or
`diluent suitable for systemic transdermal administration.
`
`11. A pharmaceutical composition according to claim 10 wherein
`the compound of formula I' is the (S)-N-ethyl-3-[(1-di(cid:173)
`methylamino)-ethyl]-N-methyl-phenyl-carbamate in free base
`or pharmaceutically acceptable acid addition salt form.
`
`12. A pharmaceutical composition according to claim 10 wherein
`the compound of formula I' is the (S)-N-ethyl-3-[(1-di(cid:173)
`methylamino)-ethyl]-N-methyl-phenyl-carbamate in hydrogen
`tartrate form.
`
`13. A pharmaceutical composition according to claim 10 wherein
`the compound of formula I' is the N-ethyl-3-[(1-dimethyl(cid:173)
`amino)ethyl]-N-methyl-phenyl-carbamate in free base or
`pharmaceutically acceptable acid addition salt form.
`
`14. The use of a compound of formula I' as defined in claim 10
`in free base or pharmaceutically acceptable acid addition
`salt form as active agent in the manufacture of a pharma(cid:173)
`ceutical composition suitable for systemic transdermal
`application.
`
`Noven Ex. 1002
`
`Page 23 of 23
`
`

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