Med Chem 1985 28 601606
`
`601
`
`ously2 Male CD rats 180250
`were fed Purina certified rodent
`chow 5002 and water ad libitum 2025-Diazacholesterol
`was
`suspension 0.1% Tween 80/saline
`given intragastrically as
`at
`days Test compounds were ad-
`daily dose of mg/kg for
`ministered as suspensions intragastrically over the last
`days
`of the test Rats were killed
`after the last treatment the livers
`io
`were removed the microsomal
`fraction was prepared
`G/min and HMG CoA reductase activity was determined for
`control and treat group rats on the basis of conversion of
`HMG CoA to Cmevalonate.3
`All results are presented as
`percent reduction from concurrent controls Means were corn-
`pared to respective controls by Students
`test
`
`13
`
`Brown
`249 789 1874
`
`Dana and
`
`Goldstein
`
`Biol Chem
`
`Acknowledgment We are grateful to
`Damascus
`Zielinski and their staff
`for the spectroscopic and
`analytical results We are indebted to Williams and
`in the preparation of addi
`Lindberg for their assistance
`tional amounts of comnounds
`Registry No
`628-97-7 2d
`if
`Id 97-62-i
`627-90-7 lj
`52939-56-7 2f 52939-58-9 2j 52939-55-6 3b 52939-72-7 3c
`52939-71-6 3d 52939-65-8 3e 95249-30-2 3f 52939-68-1 3g
`95249-31-3 3h 95249-32-4 3j 52939-64-7 3k 95249-33-5 31
`95249-34-6 3m 95249-35-7 4a 73489-84-6 4b 72060-93-6 4c
`95249-36-8 4d 95249-37-9 4e 95249-38-0 4f 95249-39-i 4g
`95249-40-4 Sa 34695-32-4 Sb 95249-41-5 Sc 95249-42-6 Sd
`95249-29-9 7a 95249-44-8 7b 95249-45-9 8a
`95249-43-7
`95249-46-0 Sb 95249-47-1 Sc 95249-48-2 HMGR 9028-35-7 allyl
`bromide 106-956
`
`Effect of Structural Modification of the Hydantoin Ring on Anticonvulsant
`
`Activity
`
`Sergio Cortes Zeng-Kun Liao Darrell WatsonTh
`
`and Harold Kohnlc
`
`Department of Chemistry University of HoustonUniversity Park Houston Texas
`
`77004 Received February 15 1984
`
`13 examples 2-imidazolones
`15 examples 4-hydroxy-2-irnidazolidinones
`Selectively substituted hydantoins
`10 examples 2-imidazolidinones
`four examples vicinal diamines
`two examples and simple amino acid
`four examples have been prepared and evaluated in the maximal electroshock seizure MES
`derivatives
`seizure threshold sc Met and rotorod Tox tests The medium effective doses
`subcutaneous pentylenetetrazole
`ED5O and the medium toxic dose TD5O for the most active compounds are reported In general
`the most
`and protected amino acids Within each series of compounds
`pronounced activity was observed for hydantoins
`enhanced anticonvulsant activity was often noted for compounds containing an aromatic group one carbon removed
`from nitrogen atom Among the most active compounds
`observed were the amino acid derivative N-acetyl-DL-alanine
`benzylamide 6d and the two 2-imidazolones 4-methyl-1-phenylmethyl-13-dihydro-2H-imidazol-2-one
`3e and
`1-phenyl-13-dihydro-2H-imidazol-2-one 3g Compound Sd proved to be slightly more potent
`in the MES test
`than phenacemide
`
`Vicinal diamine based substrates form an important set
`Among the most im-
`of CNS-active medicinal agents.2
`portant members of this class of compounds are the hy-
`The effect of structural modification of the
`dantoins
`hydantoin ring system on biological activity has been
`Attention has been
`subject of considerable interest.3
`focused on the select replacement of the ring atoms and
`the alteration of the hydrogen bonding properties of the
`heterocycle.4
`
`R3N
`
`NR1
`
`Abstracted from Ph.D dissertation of this author Addi-
`tional structure proof discussion and experimental and spec-
`On leave from the
`tral data may be found in this reference
`University of Mary Hardin-Baylor Belton TX 76513 1982
`Camille and Henry Dreyfus TeacherScholar Grant Re-
`cipient 19771982
`For previous studies see Kohn
`Kohn
`Steenberg
`Med Chem 1977 20 158160 Ar
`Buckley
`Kohn
`ceneaux
`Steenberg
`Buckley
`Pharm Sci 1978 67 600-602
`For general discussion see Jones
`Vande
`Guiot
`Moustafa
`Med Chem 1984 27 7678 and references
`
`Woodbury
`
`Poupaert
`Dumont
`therein
`
`In this report we describe the syntheses physical
`properties and anticonvulsant activities of
`select series
`of hydantoins
`4-hydroxy-2-imidazolidinones
`imidazolones
`vicinal diamines
`2-imidazolidinones
`and amino acid derivatives
`This study differed con-
`siderably from previous reports in that
`the basic sequence
`of atoms NC--CNC present in hydantoins
`has been
`retained in almost all the substrates examined Differen
`tiation among the classes of compounds 16 evaluated
`however was achieved by altering the oxidation state
`basicity and lipophilicity of the compounds
`
`2-
`
`R3NNR
`
`R1
`
`4R1
`
`R33__-----
`
`Rs.__
`
`HO
`
`R5
`
`R4
`
`R5
`
`RNHCH2CHNHCH3
`
`ii
`
`RNHdCHNHR
`
`R5
`
`Selection of Compounds Hydantoins
`lai served as
`Within this
`the parent compounds
`in this study Table
`class of compounds we have systematically varied the R3
`from methyl to benzyl
`to phenyl and the R5
`substituent
`group from hydrogen to methyl
`to phenyl
`Identical
`substituent patterns were incorporated into the 4-
`
`Breckenridge Exhibit 1015
`0022-2623/85/1828-0601$01.50/O
`Breckenridge v. Research Corporation Technologies, Inc.
`
`1985 American Chemical Society
`
`

`
`602
`
`Journal of Medicinal Chemistry 1985 Vol 28 No
`
`Cortes et al
`
`Table
`
`Pharmacological
`
`Evaluation of 24-Imidazolidinediones Hydantoins
`
`3N
`
`H5
`
`R5
`
`CH3
`Ph
`
`CH3
`Ph
`
`R5
`
`MESb
`
`sc
`Met
`
`Tox5
`
`ASP
`
`results
`
`III
`
`III
`
`III
`
`III
`
`R1
`
`R3
`
`compound
`
`CH3
`CH3
`CH3
`Brie
`Bnt
`Bn
`Ph
`Ph
`Ph
`CH2Ph3-OCH3
`CH22Ph
`CH23Ph3-OCH3
`
`no
`
`la
`lb
`Ic
`
`Id
`
`le
`
`if
`
`ig
`ih
`
`ii
`
`ij
`1k
`
`11
`im
`in
`
`io
`
`CR3
`Ph
`CH3
`CH3
`CH3
`CH3
`Ph
`CH3
`CH3
`CH3
`The following code has been adopted
`noticeable activity at dose levels of 600 mg/kg
`no activity at dose levels of 600 mg/kg
`noticeable activity at dose levels of 300 mg/kg
`noticeable activity at dose levels of 100 mg/kg
`noticeable activity at dose levels
`bMES
`seizure test sc Met
`pentylenetetrazole Metrazol seizure test
`dTox
`of 30 mg/kg
`maximal electroshock
`subcutaneous
`toxicity the rotorod test ASP Results Classification Bn
`benzyl
`neurologic
`
`CH3
`CR3
`CR3
`
`III
`
`III
`
`III
`
`II
`
`III
`
`II
`
`Table II Pharmacological
`
`Evaluation of 3-Substituted 4-Hydroxy-2-imidazolidinones
`
`R3NN
`
`R5
`
`HO
`
`H5
`
`no
`
`R1
`
`compound
`
`R3
`
`R3
`
`R5
`
`MES5
`
`sc
`Met
`
`Toxd
`
`ASP
`
`results
`
`2a
`2b
`2c
`2d
`
`2e
`
`2f
`
`2g
`2h
`
`2i
`
`2j
`2k
`21
`
`2o
`
`CH3
`CH3
`CR3
`Bnt
`Bn
`Bnt
`Ph
`Ph
`Ph
`CH2Ph3-OCH3
`CH22Ph
`CH23Ph3-OCH3
`CH3
`CH3
`The following code has been adopted
`noticeable activity at dose levels of 600 mg/kg
`no activity at dose levels of 600 mg/kg
`noticeable activity at dose levels of 300 mg/kg
`noticeable activity at dose levels of 100 mg/kg
`noticeable activity at dose levels
`seizure test Tox
`bMES maximal electroshock
`seizure test Sc Met
`pentylenetetrazole Metrazol
`subcutaneous
`of 30 mg/kg
`toxicity the rotorod test ASP Results Classification Bn
`neurologic
`
`CH3
`Ph
`
`CH3
`Ph
`
`CH3
`Ph
`CH3
`CH3
`CH3
`CH3
`
`CR3
`CR3
`CH3
`
`benzyl
`
`III
`
`III
`
`II
`
`III
`
`II
`
`III
`
`III
`
`III
`
`III
`
`III
`
`III
`
`II
`
`III
`
`hydroxy-2-imidazolidinone 2ai Table II
`and 2-
`imidazolone 3ai Table III
`series We have also ex-
`amined the pharmacological activity of two carbon-5 mo-
`nosubstituted hydantoins im and
`Table
`the more
`complex N1N3C5- and N3C5C5-trisubstituted
`hydantoins
`lo and lii
`respectively Table
`and the corresponding
`4-hydroxy adducts 2o and 2j1 Table II as well as 2-
`imidazolone 3o Table III
`Included in our survey were
`the substituted imidazolidinones 4ae the vicinal diamines
`5a and 5b and the amino acid derivatives 6ad Table IV
`Of note the substituent patterns present in
`have been
`preserved in these structural derivatives
`
`The synthetic
`Chemistry
`procedures as well
`as
`lao56
`physical and spectral properties of hydantoins
`2al and
`2056
`4-hydroxy-2-imidazolidinones
`2-
`imidazolidinones 4bd6 and vicinal diamines 5a and 5b5
`have been previously reported All the carbon-5 mono
`as well as diamines 5a and 5b
`substituted hydantoins
`were racemic Pharmacological evaluation of 4-hydroxy-
`2-imidazolidinones 2b 2c 2e 2f 2h and 2i was conducted
`on the synthetic diastereomeric mixture
`
`________________________________________________
`Kohn
`Org Chem 1983 48 22462254
`Cortes
`Org Chem 1982 47 27872789
`Kohn
`Liao
`
`

`
`Anticonvulsant Activity of Hydantoins
`
`Journal of Medicinal Chemistry 1985 Vol 28 No
`
`603
`
`Table III Pharmacological Evaluation of 3-Substituted 2-Imidazolones
`
`no
`
`3a
`3b
`3c
`3d
`
`3e
`
`3f
`
`3g
`3h
`
`3i
`3o
`
`compound
`
`R1
`
`R3
`
`CH3
`CH3
`CH
`Bnt
`Bnt
`Bnt
`Ph
`Ph
`Ph
`CH3
`
`NS1
`R3N
`HR5
`
`R5
`
`CH3
`Ph
`
`CH3
`Ph
`
`MESb
`
`sc Metc
`
`Toxd
`
`ASPe
`
`resultsa
`
`III
`
`III
`
`III
`
`II
`
`III
`
`III
`
`II
`
`III
`
`CH2
`Ph
`CH3
`CH3
`The following code has been adopted
`noticeable activity at dose levels of 600 mg/kg
`no activity at dose levels of 600 mg/kg
`activity at dose levels of 300 mg/kg
`noticeable activity at dose levels of 100 mg/kg
`noticeable activity at dose levels
`noticeable
`MES
`seizure test Sc Met
`Tox
`pentylenetetrazole Metrazol
`of 30 mg/kg
`maximal electroshock
`subcutaneous
`seizure test
`1Bn
`toxicity the rotorod test
`ASP Results Classification
`neurologic
`
`The
`were prepared by the acid-
`promoted dehydration of the 4-hydroxy-2-imidazolidinones
`Key physical and spectral properties for these corn-
`pounds are listed in Table
`Imidazolone 3c was selectively hydrogenated to give 4a
`by using palladium on activated carbon H2 40 psi 40
`in glacial acetic acid.2 The methodologies employed for
`the preparation of each of the racemic amino acid deny-
`atives 6ad were patterned after procedures common to
`peptide synthesis.1 DL-Phenylglycine methylamide 6a
`and DL-alanine benzylamide 6c were synthesized by
`treatment of the hydrochloride salt of the corresponding
`methyl ester4 with excess methylamine or benzylamine
`respectively Acetylation of 6a and 6c with
`slight excess
`of acetic anhydride gave 6b and 6d respectively as crys-
`talline solids
`The 48 substrates
`Pharmacological Evaluation
`prepared in this study were submitted to the National
`Institutes of Health Antiepileptic Drug Development
`Program for pharmacological evaluation Each compound
`was tested for anticonvulsant activity in mice by using the
`procedure described by Krall et al.5
`test results are summarized in Tables ITV
`The phase
`All compounds were administered in four dose levels 30
`100 300 and 600 mg The smallest dose that produced
`activity was noted for separate tests involving maximal
`convulsions MES subcutaneous
`electroshock-induced
`convulsions sc Met and
`Metrazol-induced
`toxicity test Tox The overall effect of the drug in these
`
`rotorod
`
`Leonard
`82188221
`WilkI
`NovakJ.J
`
`Wiemer
`
`Am Chem Soc 1976 98
`
`Org Chem 1950 15 10201022
`Close
`Collect Czech Chem Commun 1978 43
`
`10 Chupp
`Heterocyci Chem 1971
`11 Forrest
`Chen
`Dauphinee
`1974 52 27252729
`12 Duschinsky
`Dolan
`Randall
`Am Chem Soc 1947 69 3150
`13 Bodanszky
`Klausner
`Ondetti
`Synthesis 2nd ed Wiley New York 1976
`14 Barfield
`Hruby
`Al-Obeidi
`Am Chem Soc 1982 104 33023306
`15 Krall
`Penry
`White
`Kupferberg
`Epilepsia 1978 19 409428
`Swinyard
`
`557563
`Can
`
`C/rem
`
`Lehmann
`
`Peptide
`
`Walter
`
`benzyl
`
`three tests was then given by one of four different ratings
`ASP Results Classification IIV Compounds with rat-
`or II are considered promissory and were con-
`ings of
`sidered for phase II quantification testing Table VI
`This stage involved the same tests previously described
`except under more strict monitoring of dosages and ac
`It also included an evaluation of the
`tivity time spans
`median effective dose ED5O and the median toxic dose
`TD5O
`Evaluation of the composite set of results revealed sig
`trends First the level of CNS activity decreased
`nificant
`as the overall state of oxidation of the molecule was re
`duced For the six classes of compounds evaluated hy
`dantoins
`and amino acid derivatives
`were the most
`active followed by 4-hydroxy-2-imidazolidinones
`2-
`imidazolones
`and 2-imidazolidinones
`followed by
`Second enhanced anticonvulsant ac
`vicinal diamines
`tivity was often noted for compounds containing an aro
`matic group one carbon removed from an amino residue
`i.e ice in 2c 2e 3d 3e 3g 3i 4a 4b Ge and 6d
`Exceptions were observed i.e 1k 11 lo 21 Ample
`precedence exists for this structural pattern Many corn-
`pounds which exhibit pronounced CNS depressant activity
`contain an aromatic group one carbon removed from
`diamine linkage.6
`In view of these trends it was of interest to trace the
`biological activities of two series of compounds
`In the first
`set le 2e 3e 5b 6c and Gd each compound contained
`both N-benzyl moiety and methyl group attached to
`In the second group ic 2c
`the vicinal diamine linkage
`3c 4a 5a 6a and 6b the common structural
`features were
`phenyl moiety attached to the
`N-methyl group and
`diamine moiety All the compounds
`in the former set other
`than the basic diamine 5b exhibited significant activity
`Compounds ic and Gd were both assigned an ASP clas
`Protected amino acid 6d can be
`sification rating of
`viewed as the open-chain analogue of hydantoin ic.7 The
`
`16 For representative examples see Troupin
`Friel
`Levy
`Feigl
`Wilensky
`Moretti-Ojemann
`Neurology 1979 29 458460 Congdon
`Forsythe
`Ann
`Epilepsia 1980 21 97102 Griffith
`Karp
`493 Pinder
`Brogden
`Neurol 1980
`Speight
`Avery
`Drugs 1976 12 321361
`Ogata
`Med Chem 1977 20 776781
`Matsumoto
`Hirose
`
`

`
`604
`
`Journal of Medicinal Chemistry 1985 Vol 28 No
`
`Table IV Pharmacological
`Diamine Based Substratesa
`
`Evaluation of Additional Vicinal
`
`compd
`
`MESb
`
`sc Met
`
`Tox
`
`ASPe
`
`no
`
`4a
`
`OH3NNH
`
`Ph
`
`4b r6j5
`
`4c
`
`4d
`
`5a
`
`5b
`
`6a
`
`6c
`
`6d
`
`0H3N\
`
`OH3
`
`OH3
`
`CH3NHCH2HNHCH3
`
`BNNCH2HNHCH
`OH3
`
`CH3NHCCHPhNH2
`
`d/
`
`CH3NHCCHPhNHCOH3
`
`d/
`
`BnNHCCH
`
`CH3 NH2 dl
`
`BNH CC
`
`H3
`
`dl
`
`IT
`
`II
`
`III
`
`III
`
`III
`
`III
`
`III
`
`TV
`
`II
`
`no activity at dose
`following code has been adopted
`levels of 600 mg/kg
`levels of 600
`noticeable
`activity at dose
`activity at dose levels of 300 mg/kg
`mg/kg
`noticeable
`noticeable activity at dose levels of 100 mg/kg
`noticeable
`ac-
`MES
`tivity at dose levels of 30 mg/kg
`maximal electroshock
`sc Met
`pentylenetetrazole Metra
`subcutaneous
`seizure test
`zol seizure test dTox
`toxicity the rotorod test
`eASP Results Classification Bn
`benzyl
`
`neurologic
`
`results observed in the latter set were less straightforward
`for ic
`Significant pharmacological activity was detected
`2c and 4a while 3c 5a and 6a were inactive and the fully
`protected amino acid 6b gave inconsistent
`test results
`The pharmacological activities observed for compounds
`Ic id 1k in 3d 3e 3g and 6d warranted their further
`evaluation in phase II trails These data are summarized
`in Table VI along with similar information for several
`proven antiepileptic drugs.58 Promising results were
`obtained for compounds 3e 3g and 6d Compound 6d was
`in the MES test
`than
`found to be slightly more potent
`and equally as toxic Compounds 3e 3g and
`phenacemide
`6d are slated for additional screening at the National
`In-
`stitutes of Health
`
`Experimental Section
`General Methods Melting points were determined with
`Thomas-Hoover melting point apparatus and are uncorrected
`
`17 Although amino acid derivatives Gad structurally resei
`analogues the sequence of atoms in these two
`phenacemide
`classes of compounds differ
`18 Results obtained by Dr Gill
`Gladding ASP Project of the
`and Communicative Disor-
`National
`Institute of Neurological
`ders and Stroke at the National
`Institutes of Health private
`communication
`
`Cortes et al
`
`8.6
`
`so-
`
`4.35
`
`Infrared spectra IR were rur on
`Beckman IR-4250 spectro
`photometer and calibrated against the l.601-cm band of poly
`styrene Absorption values are expressed in wavenumbers cm
`NMR spectra were re
`Proton nuclear magnetic resonance
`corded on Varian Associates Models T-60 and FT-80A NMR
`spectrometers Carbon nuclear magnetic resonance 3c NMR
`spectra were run on Varian Associates Models FT-80A instru
`ment Chemical shifts are in parts per million
`values relative
`to Me4Si and coupling constants .J values are in hertz Mass
`spectral data were obtained at an ionizing voltage of 70 eV on
`Hewlett-Packard 5930 gas chromatographmass
`spectrometer
`High-resolution El mode mass spectra were performed by Dr
`James Hudson at the Department of Chemistry University of
`Texas at Austin on CEC21-1JOB double-focusing magnetic
`sector spectrometer at 70 eV Elemental analyses were obtained
`at Spang Microanalytical Laboratories Eagle Harbor MI
`The solvents and reactants were of the best commercial grade
`further purification unless noted
`avallable and were used without
`All anhydrous reactions were run under nitrogen and all glassware
`was dried before use
`General Procedure
`Preparation of 2-Imidazolones
`To
`6.115.8
`suspension of the 4-hydroxy-2-imidazolidinone
`mmol in CHCl 200 mL or CHC12MeOH 200 mL 10100/1
`v/v was added two drops of TFA and the mixture stirred 30
`mm at room temperature During this time interval the initially
`heterogeneous system became
`clear solution Evaporation of
`the solvent in vacuo afforded the desired 2-imidazolone Spectral
`NMR analyses
`and
`indicated that
`the material was
`essentially pure
`Purification was accomplished in the case of 3a by recrystal
`lization from dichioromethanehexanes 3b by sublimation 70
`0.1 torr 3c by recrystallization from EtOH 3d by recrys
`tallization from dichloromethanehexanes
`3e by recrystallization
`from benzenemethanol 3f by recrystallization from EtOH
`CH2C1 or sublimation 168
`0.14 torr and 3g and 3h by
`recrystallization from benzene
`Preparation of l-Methyl-4-phenyl-2-imidazolidinone 4a
`glacial HOAc solution 40 mL of 3c 1.70
`98 mmol in
`To
`thick-wall glass bottle was added PdC Pd content 1% 1.00
`The container was connected
`to medium-pressure hydro
`genation apparatus and the resulting mixture stirred under
`The catalyst was filtered with the aid of Celite
`40 psi for 40
`pad and the filtrate was neutralized pH
`with aqueous
`50 mL The organic
`NaOH and then extracted with CHC1
`layers were combined dried NaS04 and concentrated
`in vacuo
`Recrystallization from CHClhexanes gave 1.00 58% of 4a
`NMR CDCI
`JR CHC12 1715 cm-
`mp 134.5136.0
`7.4 8.6 Hz
`2.72
`3.12
`3.71
`7.4 8.8 Hz
`6.08 br
`13C NMR CDC1 30.5 53.6 56.1 126.0 128.0 128.8
`141.9 162.5 ppm mass spectrum m/e relative intensity 176
`100 175 37 104 28 Anal CH2NO
`DL-PheflylglyCifle Methylamide 6a 40% aqueous
`lution of methylamine 60 mL 0.70 mol was slowly added to
`44.7 mmol
`DL-phenylglycine methyl ester hydrochloride4 9.00
`The resulting solution was heated to reflux
`and then ex
`50 mL The organic layers were corn-
`tracted with CHC1
`bined dried NaS04 and concentrated in vacuo Purification
`of the oily residue by short-path distillation 100
`0.5 torr gave
`63% of 6a JR neat NaCl 3310 1665 1550 cm
`4.60
`NMR CDC1
`50 Hz
`2.64
`1.85
`NMR CDCI 25.9
`7.357.60 br
`7.26
`59.6 126.8 127.6 128.6 141.6 173.9 ppm mass spectrum CI
`Anal C9H2NO
`mode m/e 165
`Methylamide 6b Acetic
`N-Acetyl-DL-phenylglycine
`28 mmol was added dropwise to
`3.40
`anhydride 2.90
`20 mmol and the mixture allowed to stir at room temperature
`copious white precipitate formed This
`1.5
`During this time
`material was collected by filtration dried in vacuo and recrys
`49% of 6b mp
`tallized from absolute alcohol
`to give 2.00
`dec JR KBr 3310 1645 cm 1H NMR MeSO-d6
`232235
`4.6 Hz
`8.1 Hz
`1.89
`2.58
`8.1 Hz
`4.2 Hz
`8.18 hr
`NMR Me250-d6 22.4 25.5 56.3 127.1 127.8 128.1
`139.0 1689 170.3 ppm mass spectrum CI mode m/e 207
`Anal C1H4NO
`
`8.8 Hz
`
`7.31
`
`4.69
`
`7.35
`
`5.42
`
`8.47
`
`

`
`Anticonvulsant Activity of Hydantoins
`
`Journal of Medicinal Chemistry 1985 Vol 28 No
`
`605
`
`Table
`
`Summary of Selected Physical and Spectral Properties of 2-Imidazolone Derivatives
`
`NH
`
`yield
`
`R5
`
`mp
`
`IR data1
`
`CO
`
`NMR data
`C4
`
`3C NMR data
`_________________________
`C4
`
`CO
`
`no
`
`3a
`3b
`3c
`3d
`3e
`
`3f
`
`3g
`3h
`
`3i
`
`R3
`CH
`CH
`CH
`Bnh
`Bn
`Bn
`Ph
`Ph
`Ph
`
`CH
`Ph
`
`CH
`Ph
`
`28
`
`24
`
`38
`
`51
`
`68
`
`32
`
`59
`
`17
`
`15
`
`268278 dec5
`134136
`158l6l
`247254 dect
`1361391
`
`6.16
`
`5.84
`698
`6.09
`
`5.77
`
`7.05
`
`6.41
`
`6.23
`
`6.86
`
`155.0
`
`155.1
`
`153.8
`
`155.0
`
`154.9
`
`153.7
`
`153.8
`
`153.7
`
`153.9
`
`108.3
`
`108.2
`
`109.5
`
`108.8
`
`106.9
`
`108.4
`
`109.7
`
`106.5
`
`106.3
`
`112.6
`
`117.9
`
`120.3
`
`111.2
`
`118.4
`
`120.9
`
`111.0
`
`119.5
`
`124.0
`
`1670
`1680
`1690
`1680
`1670
`1690
`1680
`CH
`1680
`169_1721
`180182
`Ph
`1690
`in cm NMR spectra
`detail description of the physical properties of 3m 1Infrared were taken in KBr disks
`See reference
`for
`dLit.7 mp 139140
`were taken in CDC13 or MeSO-d6 in
`sample Elemental composition verified by high-resolution
`eHygroscopic
`Lit mp 162165
`benzyl Lit mp 133135
`1Lit mp 170
`mp 275278
`hBn
`kLit.11 mp 123
`mass spectroscopy
`O3 mLit.iO mp 215216
`
`no
`
`ic
`id
`1k
`ln
`3d
`3e
`
`Table VI Summary of Phase II Evaluation
`MES
`Tox
`TD5OD
`ED5OD
`75 6088
`271 223326
`65 5382
`224 179288
`243 212268
`110 90-131
`399 341472
`156 129183
`83 7194
`190 176203
`90 8398
`268 229309
`211 194239
`124 103141
`3g
`77 6789
`454 417501
`Gd
`phenytoin
`66
`mephenytoin
`154
`31
`61
`116 71150
`87 74100
`421 337549
`phenacemidee
`1The
`are 95% confidence
`Numbers in parentheses
`intervals
`ED5O value was not computed for this substrate Reference 18
`Not effective
`Reference
`15
`
`sc Met
`ED5O
`26 1636
`114 88149
`130 101154
`109 85137
`90 53158
`
`173 156195
`
`10
`
`1.34
`
`4.42
`
`1.58
`
`7.27
`
`3.51
`
`7.39
`
`177
`
`DL-Alanine Benzylamide 6c Benzylamine 30.68
`0.29
`mol was added dropwise to
`stirred solution of DL-alanine methyl
`0.14 mol in methanol 50 mL The
`ester hydrochloride 20.00
`and concentrated in vacuo
`mixture was heated to reflux
`50 mL The
`and the residue was triturated with CHC1
`remaining solid was dissolved in aqueous 5% NaOH and extracted
`50 mL All the organic layers were combined
`with CHC1
`dried NaS04 concentrated in vacuo and distilled twice by
`short-path distillation apparatus 100
`using
`0.5 torr to yield
`5.50 22% of product JR neat NaCl 3300 1655 1525 cm
`NMR CDC13
`7.0 Hz
`7.0 Hz
`5.9 Hz
`NMR CDC1 21.8 43.1 50.8 127.4 127.7 128.7
`br
`138.6 175.6 ppm mass spectrum CI mode m/e 179
`mass spectrum m/e relative intensity 179
`178
`106 29 91 100 65 20 Anal CH4No
`N-Acetyl-DL-alanine Benzylamide 6d Acetic anhydride
`0.022 mol was slowly added to CHCl solution 30 mL
`2.20
`0.021 mol and allowed to stir at room temperature
`of 6c 3.80
`The mixture was then successively washed with H2o 15
`mL 1% aqueous NaOH 15 mL and HO 15 mL dried
`NaS04 and concentrated in vacuo The residue was recrys-
`tallized from CHCl to yield 2.50
`54% of 6d mp 239241
`JR CHC1 3440 3300 3005 1660 1515 cm NMR
`MeSO-d5
`7.1 Hz
`4.044.50
`7.3 Hz
`8.11 br
`8.42 br
`NMR MeSO-d6 182 22.4 41.9 48.2 126.5
`Hz
`126.9 128.1 139.4 168.9 172.4 ppm mass spectrum CI mode
`220.1208 calcd for C2H6NO 220.1212
`m/e 221
`Each compound listed in Tables IIV was
`Pharmacology
`tested for anticonvulsant activity phase
`evaluation with use
`of male Carworth Farms No mice All compounds were given
`in four dose levels 30 100 300 and 600 mg Seizures were then
`induced by either electroshock or pentylenetetrazole
`
`1.22
`
`7.26
`
`1.84
`
`artificially
`
`seizures MES are elicited with 60-cycle
`Maximal electroshock
`alternating current of 50-mA intensity 57 times that necessary
`to elicit minimal electroshock seizures delivered for 0.2
`via
`drop of 0.9% saline is instilled in the eye
`corneal electrodes
`prior to application of the electrodes so as to prevent
`the death
`of the animal Protection in this test
`is defined as the abolition
`of the hind limb tonic extension component of the seizure The
`pentylenetetrazole Metrazol seizure threshold test
`subcutaneous
`sc Met entailed the administration of 85 mg/kg of pentylene
`0.5% solution subcutaneously
`in the posterior
`tetrazole as
`midline This amount of pentylenetetrazole is expected to produce
`seizures in greater than 95% of mice The animal is observed
`for 30 mm Protection is defined as the failure to observe even
`threshold seizure
`single episode of clonic spasms of at least
`5-s duration The effects of the compounds on forced and
`spontaneous motor activity were evaluated
`in mice by the rotorod
`test Tox The animal is placed on an 1-in-diameter knurled
`plastic rod rotating at
`rpm after the administration of the drug
`Normal mice can remain on
`rod rotating at this speed indefi
`nitely Neurologic toxicity is defined as the failure of the animal
`to remain on the rod for mm The MES and sc Met
`tests were
`on single animals while four mice were utilized for the
`
`conducted
`Tox test
`The overall effect of the drug in these three tests is then given
`ratings ASP Results Classification IIV
`by one of four different
`The number
`indicated anticonvulsant activity at 100 mg/kg or
`less II designated activity at doses greater than 100 mg/kg III
`denoted no anticonvulsant activity at doses up to and including
`300 mg/kg and IV indicated that anticonvulsant activity and
`toxicity or toxicity alone was demonstrated at 30 mg/kg or that
`anticonvulsant activity was displayed at 100 mg/kg or less but
`that the test results were not consistent
`Compounds with ratings of
`and II are considered promissory
`and were considered for phase II quantification
`testing The
`doseeffect behavior of the eight substrates listed in Table VI
`was evaluated by using the previously described procedures by
`the administration of varying dose levels of each compound
`treating normally eight mice at each dose
`to Dr Gill
`We are grateful
`Acknowledgment
`Gladding and the Anticonvulsant Screening Project ASP
`of the National Institute of Neurological and Communi
`cative Disorders and Stroke at the National
`Institutes of
`Health for kindly performing all
`the pharmacological
`studies Funds for this project were provided by the Na-
`tional Institutes of Health
`Registry No la 6843-45-4 lb 74310-97-7 ic 93860-68-5
`id 2301-40-8 le 93781-89-6 if 93781-90-9 ig 2221-13-8 lh
`93781-91-0 Ii 93781-92-1 lj 81572-14-7 1k 93781-93-2 11
`81572-15-8 im 67337-69-3 in 27534-86-7 lo 93781-94-3 2a
`85369-76-2 2b 93781-95-4 2c 93781-96-5 2d 85369-80-8 2e
`92764-01-7 2f 93781-97-6 2g 85369-84-2 2h 93781-98-7 2i
`
`

`
`606
`
`Med Chem 1985 28 606612
`
`93781-99-8 2j 81572-18-1 2k 93782-00-4 21 81572-19-2 2o
`93782-01-5 3a 39799-77-4 3b 93782-02-6 3c 93782-03-7 3d
`67909-04-0 3e 33542-53-9 3f 93782-04-8 3g 53995-06-5 3h
`24631-04-7 31 2032-07-7 3o 24138-94-1 4a 93782-05-9 4b
`
`81572-20-5 4c 81583-49-5 4d 81572-22-7 5a 93860-69-6 5b
`93782-06-0 6a 93782-08-2 6b 93782-08-2 6c 93860-70-9 6d
`93782-09-3 DL-phenylglycine methyl ester hydrochloride
`15028-40-7 DL-alanine methyl ester hydrochloride 13515-97-4
`
`1- Diarylamino propylpiperidines and Related Compounds Potential
`Antipsychotic Agents with Low Cataleptogenic Profiles
`
`Lawrence Wiset
`Ian
`Ivan
`Sandra
`Lobbestael
`
`Pattisont Donald
`Nordin
`
`DeWaldt Edward
`But1er Horace
`Poschel1 and Linda
`Coughenour1
`
`Lewist
`
`of Chemistry and Pharmacology Warner-Lambert/Parke-Davis Pharmaceutical Research Ann Arbor
`Departments
`Michigan
`48105 Received June 21 1984
`
`series of 1-
`On the basis of
`structural model of the postsynaptic dopaminergic antagonist pharmacophore
`and related compounds was synthesized and evaluated for potential antipsychotic
`diarylaminopropylpiperidines
`rapid measure of activity the target compounds were initially
`activity For
`screened in vitro for inhibition of
`binding and in vivo in
`test of locomotor activity Behavioral efficacy of compounds identified
`screens was more accurately measured in rats by using
`from the initial
`suppression of high base-line medial forebrain
`bundle self-stimulation test model The propensity of these compounds for causing extrapyramidal side effects
`rat catalepsy method On the basis of these test models we have shown that the methine
`was evaluated by using
`carbon of the 1-44-diarylbutylpiperidines
`can be advantageously replaced with
`1-44-diarylbutylpiperidines The compounds
`than the corresponding
`arylaminopropylpiperidines were less cataleptic
`efficacious dose and cataleptic
`with the widest separation between
`1-
`propyl-1-phenyl-138-triazaspiro
`13-dihydro-2H-benzimidazol-2-one 11 1-
`pyridinyl -1 3-dihydro-2H-benzimidazol-2-one 22 and 1-
`phenylpiperazine 26
`
`dose are8-
`
`nitrogen atom The 1-
`
`1236-tetrahydro-4-
`2-methoxy-
`
`In the past 25 years the advent of antipsychotic drugs
`revolution in the treatment of
`has resulted in
`virtual
`schizophrenia Although these agents have proven ben-
`
`Scheme
`
`eficial their therapeutic effects are accompanied by dis- NH
`
`ZCH2COZ
`__________
`
`jCCHzCH2.
`
`OTS
`
`including extrapyramidal side effects
`tinct disadvantages
`EPS and tardive dyskinesia TD.2 At one time in fact
`EPS was actually considered by many investigators
`as
`evidence of therapeutic efficacy With the discovery of
`newer agents sometimes described as atypical antipsy
`chotic drugs it has been suggested
`that the side effects
`EPS and TD could be separated from the therapeutic
`For example the atypical antipsychotic agent
`effects.3
`clozapine has been reported to be both effective and free
`of EPS in clinical studies although other problems have
`it from the market place.4
`kept
`compound for
`the
`Therefore the development of
`treatment of schizophrenia with minimal EPS would
`therapeutic improvement over ex
`represent
`significant
`isting drugs This report summarizes some of the efforts
`from our laboratories directed toward this goal
`Studies of the structural features of the various classes
`of postsynaptic dopamine receptor antagonists used as
`agents have led investigators to identify
`antipsychotic
`common pharmacophore responsible for their activities
`Two series of compounds incorporating this pharmaco-
`
`and
`and the phenothiazines
`typified by pimozide
`On the basis of
`chlorpromazine
`the
`respectively
`structural features of these two series of compounds we
`became interested in the structureactivity relationships
`SAR of the
`and -piper-
`azines 627 which may be thought of as arising through
`replacement of the methine carbon atom of the
`either
`structure with
`1-44-diarylbutylpiperidine
`tertiary ni-
`
`tDepartment of Chemistry
`Department
`of Pharmacology
`
`phore are the1- New York 1983
`
`______
`
`CH2C
`
`6-27
`
`trogen atom or elimination of the bridged sulfur atom from
`the phenothiazine moiety The goal was to identify com
`
`Moloney
`Pavkovic
`Linden
`Janicak
`Davis
`and Clinical
`Neurochernical Behavioral
`Neutroleptics
`Eds Raven Press
`Enna
`Perspectives Coyle
`15
`Diagnosis and Treatment of
`Davis
`Klein
`Psychiatric Disorders Williams Wilkins Baltimore 1969
`Handbook of Psychopharmacology Iversen
`Crane
`Eds Plenum Press New
`Iversen
`Snyder
`York 1978 Vol 10 Chapter
`Psychopharmacologia
`Gerlach
`Thorsen
`Gray
`1975 40 341
`Voineskos
`Guirguis
`Curr Ther Res 1977 21 707
`Schlieman
`Gerlach
`Psychopharmacology 1978 59 105
`Simmelsgaard
`Leon
`Acta Psychiatr Scand 197959 471
`Tamminga
`Behavioral and
`Neuroleptics
`Neurochernical
`Eds Raven
`Enna
`Clinical Perspectives Coyle
`Press New York 1983
`281
`
`Fog
`
`0022-2623/85/ 1828-0606$01.50/0
`
`1985 American Chemical Society