AP236A - "3-substituted piperdine derivatives, pharmaceutical compositions containing them and their use in therapy". - Google Patents

"3-substituted piperdine derivatives, pharmaceutical compositions containing them and their use in therapy". Download PDF

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Publication number
AP236A
AP236A APAP/P/1991/000314A AP9100314A AP236A AP 236 A AP236 A AP 236A AP 9100314 A AP9100314 A AP 9100314A AP 236 A AP236 A AP 236A
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Prior art keywords
compound
pentylpiperidine
phenyl
compounds
pharmaceutically acceptable
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APAP/P/1991/000314A
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AP9100314A0 (en
Inventor
Thomas Henry Brown
David Gwyn Cooper
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Smithkline & French Laboratories Ltd
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Priority claimed from GB909017225A external-priority patent/GB9017225D0/en
Priority claimed from GB909021852A external-priority patent/GB9021852D0/en
Priority claimed from GB919107780A external-priority patent/GB9107780D0/en
Application filed by Smithkline & French Laboratories Ltd filed Critical Smithkline & French Laboratories Ltd
Publication of AP9100314A0 publication Critical patent/AP9100314A0/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to 3-substituted piperidine

Description

COMPOUNDS
The present invention relates to 3-substituted piperidine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
The present invention therefore provides, in a first aspect, compounds of structure (I):
N (I) in which
R is Cj.galkyl(phenyl)p, C2_8alkenyl(phenyl)p, C2_8alkynyl(phenyl)p, C3_8cycloalkyl or
Cj^.galkylC-j _gcycloalky 1;
p is 0 to 2; n is 0 to 6;
A is a bond, oxygen, sulphur or NR1;
R1 is hydrogen, C^.galkyl or phenylC^_^alkyl;
m is 0 to 3; and
Ar is aryl or heteroaryl, each of which may be optionally substituted, and salts thereof.
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Suitably, R is C^.galkyl(phenyl)p, C2_8alkenyl(phenyl)p, C2_galkvnyl(phenyl)p, C3_8cycloalkyl or C1_galkylC3_gcycloalkyl.
It will be understood that the alkylcycloalky1, alkylphenyl, alkenylphenyl and alkynylphenyl groups are linked to the piperidine nitrogen atom via the alkyl, alkenyl and alkynyl moieties respectively.
Preferably R is C1_8alkyl(phenyl)p in which p is 0 or
1, i.e. C^-galkyl, such as n-pentyl, cr phenylC^galkyl such as phenylpropy1, cr R is C2_8alkenyl(phenyl)p wherein p is 1, such as cinnanyl.
Suitably, n is 0 to 6; preferably n is 0 to 3; nest preferably n is 1.
Suitably, m is 0 to 3; preferably a is 0 or 1; most preferably a is 0.
Suitably, A is a bond, oxygen, sulphur or NR1; preferably A is oxygen or sulphur; most preferably A is oxygen. When A is oxygen n is preferably 1 and m is preferably 0.
Suitably, Ar is optionally substituted aryl or heteroaryl; preferably Ar is optionally substituted aryl.
Suitable aryl groups include, for example, unsaturated monocyclic and unsaturated or partially saturated bicyclic ring systems of up to 10 carbon atoms, such as, for example, phenyl, naphthyl and tetrahydronaphthyl. Preferred are optionally substituted phenyl rings.
AP 0 0 0 2 3 6
- 3 example, phenyl rings substituted by a C1_2alkylenedioxy group such as a 3,4-methylenedioxy group or by 1 to 3 substituents selected from halogen, Cy_4alkoxy, nitro, SC1_4alkyl, NR2R2 (in which each R2 group can be H or C1_4alkyl) , OCF3, C^galkyl, trifluoromethyl, CN, optionally substituted phenyl, optionally substituted phenylC1_4alkyl and optionally substituted phenylC1_4alkoxy. Preferred are phenyl rings substituted by one or two substituents, in particular, by a single halogen, trifluoromethyl, unsubstituted phenyl or unsubstituted phenylC1_4alkoxy group; or by two chloro atoms especially in the 3- and 4-positions of the phenyl ring.
Suitable optionally substituted phenylCj_4alkyl groups include, for example benzyl. Suitable optionally substituted phenylC1_4alkoxy groups include, for example benzyloxy groups.
Suitable substituents for said optionally substituted phenyl, phenylC1_4alkyl and phenylC1-4alkoxy groups include for example halogen, C1_4alkyl, C1_4alkoxy, nitro and trifluoromethyl groups.
Suitable heteroaryl rings include, for example, unsaturated monocyclic and unsaturated or partially saturated bicyclic ring systems of up to 10 carbon atoms containing at least one heteroatom, such as pyridyl, thienyl, quinolinyl, tetrahydroguinolinyl and imidazolyl rings. The heteroaryl ring can be linked to the remainder of structure (I) via a carbon atom or via a hetero atom, e.g. a nitrogen atom.
Suitable substituents for said heteroaryl rings include, for example, 1 to 3 substituents selected from halogen, C1 4alkyl and C1 4alkoxy.
BAD ORIGINAL ft
Alkyl groups present in the compounds of structure (I), alone or as part of another group, can be straight or branched.
It will be appreciated that for use in medicine a salt of a compound (I) should be pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically acceptable inorganic or organic acid addition salts. Other nonpharmaceutically acceptable salts may be used for example as intermediates and are included within the scope of this invention.
Particular compounds of the invention include:
3-(4-fluorophenoxymethyl)-1-pentylpiperidine oxalate, 3-(3,4-methylenedioxyphenoxymethyl)-1-pentylpiperidine hydrochloride,
3-(3-trifluoromethylphenoxymethyl)-1-pentylpiperidine hydrochloride,
3-(3-phenylphenoxymethyl)-1-pentylpiperidine oxalate,
3-(2-phenylphenoxymethyl)-1-pentylpiperidine oxalate,
3-(4-phenylphenoxymethyl)-1-pentylpiperidine oxalate,
3-(2-benzylphenoxymethyl)-1-pentylpiperidine oxalate,
3-(4-benzylphenoxymethyl)-1-pentylpiperidine hydrochloride,
3-(4-benzyloxyphenoxymethyl)-1-pentylpiperidine hydrochloride, l-cinnamyl-3-(3,4-dichlorophenoxymethyl)piperidine oxalate,
3-(4-iso-propylphenoxymethyl)-1-pentylpiperidine hydrochloride, and
3-(3,4-dichlorophenylaminomethyl)-1-pentylpiperidine dihydrochloride.
It will be appreciated that the compounds of structure (I) may contain one or more asymmetric centres, in particular at the 3-position of the piperidine ring. Such compounds will exist as optical isomers (enantiomers). Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of
22039
AP 0 0 0 2 3 6
- 5 the two are included within the scope of the invention. Further, all diastereoneric forms possible (pure enantiomers and mixtures thereof) are within the scope of the invention.
The compounds of the present invention can be prepared by processes analogous to those known in the art. The present invention therefore provides in a further aspect, a process for the preparation of a compound of structure (I) which comprises:
(a) for compounds of structure (I) in which A is O, S or NR1, reaction cf a compound of structure (II) :
in which R and n are as described for structure (I) and Ax is O, S or NR1, with a compound of structure L(CH2)mAr in which m and Ar are as described for structure (I), and L is a leaving group;
(b) for compounds of structure (I) in which A is 0, S or
22039 \CH ) L 2 η (III) in which n and R are as described for structure (I) and 10 L1 is a group displaceable by a nucleophile, with a ccrpound of structure HA1 (CH2)mAr where m and Ar are as described fcr structure (I) and A1 is as described for structure (II); or
IS (c) fcr compounds of structure (I) in which A is NR1, reduction of a compound of structure (IV) :
(IV)
N
I
I
R m which R epresents the group ff ,
-(Ci-f^NfR^CfCH^^Ar cr - (CH2) n_1CN (R1) (CH2 ) ^Ar , and n, m, R and Ar are as described for structure (I (d) for compounds of structure (I) in wh reaction of a compound of structure (V) .ch A is a bond,
BAD ORIGINAL
AP 0 0 0 2 3 6
R (V) (wherein R, L1, m and n are as hereinbefore defined).
with a compound of structure X^-Ar in which Ar is as described for structure (I), and X1 is an alkali metal;
(e) introduction of the group R into a compound of formula (VI) :
(CH ) A(CH ) Ar 2 n 2 m
(VI) by reaction with a compound RL2, wherein L2 is a leaving group;
(f) Reduction of a compound of formula (VII) :
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COR' (VII) wherein R5 is C1_7alkyl(phenyl)p, C2_7alkenyl(phenyl)p, 10 C2_7alkynyl(phenyl)p or C1_7alkyIC3_8cycloalkyl;
(g) Reduction of a compound cf structure (VIII):
(VIII) wherein R, A, Ar m and n are as hereinbefore defined and X© is a counter ion;
and optionally thereafter forming a salt.
In process (a) the reaction, between a compound of structure (II) and a compound can take place under conditions which depend on the nature of the
3C group L. Fcr example, when L is halogen or a sulphonic acid residue such as a tosylate cr mesylate, the reaction is carried out under standard conditions in a solvent, optionally in the presence of a base. When a fluoro-substituted aryl compound F-Ar is employed in
BAD ORIGINAL
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AP 0 0 0 2 3 6 process (a), the reaction is effected in the presence of a strong base such as sodium hydride, and in an inert organic solvent such as dimethylformamide. Preferably the aryl group is substituted by an activating group such as CF3 or N02·
The reaction between a compound of structure (III) and a compound of structure HA1 (CI^JjjjAr can take place under conditions which depend on the nature of L1 and A. For example when L2 is hydroxy, m is 0 and
A1 is oxygen or sulphur the reaction is carried out in the presence cf diethyl acccicarboxylate and triphenyl phosphine. Such a reaction is known as the hitsunobu reaction (as described in Synthesis 1931, 1).
Alternatively the leaving group L1 nay be for example a halogen atom or a sulphonyioxy group eg. methanesulphonyloxy or p-toluene sulphonyioxy. In this case the reaction may be effected in the presence or absence of solvent and at temperature in the range 0 to 2GOCC.
The reduction of a compound of structure (IV) can be effected by methods known in the art, for example using a reducing agent such as lithium aluminium hydride. Conveniently a compound cf structure (IV) can be prepared (for example as described below) and reduced in a 'one-pot' reaction, without isolation of compound (IV) itself .
The reaction between a compound of structure (V) and a compound of structure X^Ar can take place under standard conditions known to these skilled in the art for the formation of carton-carbon bonds.
The reaction cf a compound of structure (VI) with
RL2 according to process (e) may be effected in conventional manner, for example in an organic solvent, such as dimethyl fermamide. The leaving group L2 may be for example a halide such as bromide or chloride, an acyloxy group such as acetoxy or chloroacetoxy or a
BAD ORIGINAL Ά
2039
- 10 sulphonyloxy group such as methanesulphonyloxy or p-toluenesulphonyioxy. When L2 is a halide the reaction is preferably carried out in the presence of a weak base such as potassium carbonate, and when L2 is sulphonyloxy, a strong base such as sodium hydride or potassium t-butcxide may be employed.
Reduction of a compound of formula (VII) may be effected using standard reducing agents such as lithium aluminium hydride.
Reduction of a compound of formula (VIII) may be effected for example by hydrogenation, using a noble metal catalyst such as platinum, palladium or platinum oxide, suitably in a solvent such as an alcohol eg. ethanol.
The compounds of structure (II) can be prepared from the corresponding compounds in which R is hydrogen, by alkylation under standard conditions. For example, compounds cf structure (II) in which R is n-pentyl can be prepared from the corresponding precursor in which R is hydrogen by reaction with an n-pentylhalide such as n-pentyl bromide in a suitable solvent, such as methyl ethyl ketene, or a C1_4alkanol such as ethanol, in the presence of a base, such as potassium carbonate, or dimethvlformamide in the presence of an iodoalkane.
The corresponding compounds of structure (II) in which R is hydrogen are available commercially, known in the literature or can be prepared by standard techniques; for example by reduction of the corresponding 3-hydroxyalkylpyridine.
Alternatively, the compounds of structure (II) in which A1 is oxygen can be prepared by reduction of a compound of structure (IX):
BAD ORIGINAL &
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AP 0 0 0 2 3 6
)
R (IX)
Θ
X in which R and n are as described for structure (I) and
X” is a counter ion.
Compounds of structure (III) wherein L1 is OH can be prepared as described fcr compounds of structure (II), and compounds of structure (III) wherein L1 is a halogen atom, or a mesyloxy or tosyloxy group can be prepared from the corresponding alcohol in conventional manner.
Compounds of structure (IV) wherein R4 is a group
0 ι H
-(CH2)nN(R1)C(CH2)m-iAr can be prepared by reacting a compound of structure (II) wherein A1 represents NR1 with an acylating agent corresponding to the group -(CH2)_,Ar, for example an acid chloride
C10C(CH2)E1_1Ar.
Compounds of structure (IV) wherein R4 is a group 0
1' 1
-(CH2)(R1)(CH2)_Ar may be prepared for example by reaction of a corresponding compound wherein R4 represents -(CK2)n_1CO2H or an activated derivative thereof such as an acid halide, ester or anhydride, with an amine of formula HN (R1) (CH2)m Ar. It will be appreciated that when the acid itself is employed, reaction with the amine should be effected in
BAD ORIGINAL ft
22039
- 12 the presence of a coupling agent. The carboxylic acid may itself te prepared for example by oxidation of the corresponding alcohol, ie. a compound of structure (II) wherein is oxygen.
Compounds of structure (V) may be prepared in analogous manner to compounds of structure (III); where necessary the chain length may be increased using methods well known in the art.
Compounds of structure (VI) may be prepared for example according to any of processes (a) to (d) above, using intermediates analogous to structures (II) to (IV) wherein R is replaced by an N-protecting group, which is subsequently removed by methods well known in the art.
Suitable protecting groups include aralkyl groups such as benzyl, diphenylmethyl or triphenyImethyl and acyl groups such as acetyl, trifluoroacetyl, benzoyl, methcxycarbony1, ethoxycarbonyl, or benzyloxycarbonyl.
An aralkyl group such as benzyl may be cleaved by hydrogenolysis, and an acyl group such as benzoyl may be cleaved by hydrolysis. It will be appreciated that where the N-protecting group is aralkyl, the compound is of structure (I) and this reaction sequence thus provides a means of converting one compound of formula (I) into a different compound of formula (I).
A compound of formula (VII) may be prepared by reaction of a compound of formula (VI) with an appropriate acid derivative for example an acid chloride, or anhydride.
A compound cf structure (VIII) may be prepared using the general methods described in processes (a) to (e) above.
BAD ORIGINAL Λ
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AP 0 0 0 2 3 6
- 13 When compounds of structure (I) are obtained as mixtures of enantiomers, these may be separated by conventional methods such as crystallisation in the presence of a resolving agent, or chromatography, for example using a chiral HPLC column.
The compounds of the invention have been found to exhibit high calcium influx blocking activity and as such are expected to be of use in therapy in treating conditions and diseases related to an accumulation of calcium in the brain cells of mammals, in particular humans. For example, the compounds are expected to be of use in the treatment of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, and drug addiction withdrawal such as ethanol addiction withdrawal.
In a further aspect of the invention there is therefore provided a method of treatment of conditions or diseases caused or exacerbated by the accumulation of calcium in the brain cells of mammals which comprises administering to a subject in need thereof an effective amount of a compound of structure (I) or a pharmaceutically acceptable salt thereof. In addition, the present invention also provides a method of treatment bad original $ of anoxia, ischaemia including for example stroke, migraine, epilepsy, traumatic head injury, AIDS-related dementia, neurodegenerative diseases such as Alzheimer's disease and age-related memory disorders, and drug addiction withdrawal such as ethanol addiction withdrawal, which comprises administering to a subject in need thereof, an effective amount of a compound of structure (I) or a pharmaceutically acceptable salt thereof.
In therapeutic use, the compounds of the present invention are usually administered in a standard pharmaceutical composition. The present invention therefore provides in a further aspect pharmaceutical compositions comprising a compound of structure (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
The compounds of structure (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent.
A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
Examples of such carriers include magnesium stearate,
AP 0 0 0 2 3 6
- 15 starch, lactose, sucrose and cellulose.
A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
Compounds of the invention may also be administered parenterally, by bolus injection or continuous infusion. Typical parenteral compositions consist of a solution or suspension of the compound or pharmaceutically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
Preferably the composition is in unit dose form such as a tablet or capsule.
Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 60 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
The daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, eg. 5 to 200 mg or an
22039
- 16 between 0.1 mg and 100 mg, preferably between 0.1 mg and 60 mg, eg. 1 to 40 mg of the compound of the formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day. Alternatively the compounds of the invention may be administered by continuous intravenous infusion, preferably at a dose of up to lOOmg per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.
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AP 0 0 0 2 3 6
- 17 DATA
Ca2 + Current Measurement
Cell preparations
Sensory neurons from dorsal root ganglia were dissociated from 1 day old rat pups (Forda et al, Developmental Brain Research, 22 (1985), 55-65). Cells were plated out onto glass coverslips and used within 3 days to permit effective voltage clamp of Ca2+ currents.
Solutions
The pipette (internal solution) contained in mM: CsCl, 130; HEPES, 10; EGTA, 10; MgCl2, 4; ATP, 2;
buffered to pH 7.2 with CsOH.
Cells were bathed in a normal. Tyrodes solution before establishment of whole cell recording when the bathing solution was changed to one allowing isolation of
Ca2+ currents.
The external solution for recording Ca2+ channel currents contained in mM: BaCl2, 10; TEA-CI, 130; glucose, 10; HEPES, 10; MgCl2, 1; buffered to pH 7.3 with TEA-OH. Barium was used as the charge carrier as this assists in current isolation and calcium dependent inactivation of current is avoided.
Compounds were dissolved in DMSO to make a 20 mM stock solution. At the drug concentration used the vehicle (0.1%) had no significant effect on Ca2 + currents.
All experiments were performed at 21 to 24°C.
5 Whole cell currents were recorded using List EPC-7 amplifiers and stored, digitised for later analysis using
-7,-,7 q
ONS ive
Compound of structure (I)
Sodium hydroxice/hydrochioric acid cclvethviene civcoi
;..e , -j
0.1 - 60 mg to pH ca 7 0 - 30 mi 0-30 mi 0 - 10 ml ctcre (1)
0.1 - 60 me sodium hydro:ice or hydrochloric acid polyethylene glycol 31 c c h. c 1 to pH ca 7 0 - 2.5 ml 0 - 2.5 ml water to 5 ml
A toxicity adjusting agent eg. sedium chloride, dextrose or -annitol may also he added.
»’ «-re ·· ·“·· ro ·»- 3 +30
22039
AP ο 0 0 2 3 6
- 18 PC based software similar to that described previously (Benham & Tsien, Journal of Physiology (1988), 404. 767-784) .
RESULTS
Ca2+ currents
Peak voltage gated Ca2+ channel currents of up to 10 nA from dorsal root ganglion neurons were recorded using 10 mM Ba2+ as charge carrier. Currents were evoked from a holding potential of -80 mV to a test potential of 0 or +10 mV every 15 seconds. This test potential was at the peak of the current voltage relationship and assessing block at this point reduced any errors due to drifting holding potential. Some cells showed slow rundown of current as is commonly seen when recording Ca2+ currents. The rundown rate was measured in control conditions and extrapolated through the time of drug application to derive a control value to relate the drug affected current to. Block by 20 μΜ drug was assessed 3 minutes after drug application.
Compounds of the invention gave percentage inhibition of plateau Ca2+ current in the range 30 to
100%.
BAD ORIGINAL
22039
- 19 EXAMPLES
Intermediate Preparations (i) 3-(Hydroxymethyl)-1-pentylpiperidine
A mixture of 3-(hydroxymethyl)piperidine (20g) , 1bromopentane (26.28g), potassium carbonate (24g) and ethanol (400ml) was heated at reflux for 4 days. The solution was filtered, and the solvent removed under reduced pressure. The residue was treated with acetone, filtered, the solvent removed and tlge resulting oil was distilled under reduced pressure to give the title compound as an oil. (24.63g, b.p. 103-104°C @ 0.3mmHg.) (ii) 3-(Hydroxymethyl)-l-propylpiperidine
A mixture of 3-(hydroxymethyl)piperidine (20g), 1bromopropane (21.4g), potassium carbonate (24g) and ethanol (400ml) was heated at reflux for 1 days. The solution was filtered, and the solvent removed under reduced pressure. The residue was treated with acetone, filtered, the solvent removed and the resulting oil distilled under reduced pressure to give the title compound as an oil. (18.21 g, b.p. 101-103°C @ 0.2mmHg.) (iii) l-Cinnamyl-3- (hydroxymethyl)piperidine
A mixture of 3-(hydroxymethyl)piperidine (28g), cinnamyl
22039
AP 0 0 0 2 3 6
- 20 (300ml) was heated at reflux for 2 days. The solution was filtered, and the solvent removed under reduced pressure. The residue was distilled under reduced pressure to give the title compound as an oil. (24.63g, b.p. 164-168 °C @
0.3mmHg.)
Found: C, 77.59; H, 9.18; N, 5.94% (C15H21NO) requires: C, 77.88; H, 9.15; N, 6.05% (iv) 3-Methanesulphonyloxymethy 1-1-pent ylpiperidir.e hydrochloride
Methanesulphonyl chloride (5.8ml) in dichloromethane (20ml) was added to a solution of 3-hydroxymethyl-l15 pentylpiperidine (lOg) in dichloromethane (20ml). The mixture was stirred for 18 hours, treated with hydrogen chloride in ether and recrystallised from ethylacetate to give the title compound (13.2g) m.p. 99-101°C (v) 3- (3-Hydroxypropyl)-l-pentylpyridinium bromide
A solution of 3-(3-hydroxypropyl)pyridine (20g), 1bromopentane (22.05g) and acetone (250ml) was refluxed for 72 hours, cooled and poured into diethylether (200ml).
The oil which precipitated was collected by decantation then washed by decantation with diethyl ether (5 X 100ml) and dried at 50°C (O.lmmHg) to give the title compound (42g)which was used without further purification.
(vi) 3- (3-Hydroxypropyl)-1-pentylpiperidine
BAD ORIGINAL ft
3 3 9
- 21 -
A mixture cf 3-(3-hyz roxyprcpyl)-1-pentylpyridinium
bromide (42.g), plati rum oxide (1.5g) and ethanol <35Cml)
was shaken under an a zmosphere of hydrogen at 50 p.s.i.
for 1 hour. The mixz ure was filtered and the solvent
removed. The residue was dissolved in dilute sodium hydroxide (7Cml) and extracted with dichloromethane (3 x 72ml). The organic extracts were combined, dried over
magnesium sulphate an z the solvent was removed to give the
tide compound as an til (13.Og).
Example 1
3-(4-Fiucroohenoxvmet hvl'-l-oertylDioeridir.e oxalate
A solution cf 3-(hydr oxymethyi;-1-pentylpiperidine (2.Cg),
4-fluorophencl (1.21c; and triphenylphosphine (2.32g) in tetrahydrofuran (40ml) was treated with diethyl azodicarboxylate (l.~4g) in tetrahydrofuran (ICml). The resulting solution was stirred at room temperature for 13 hours, the solvent: was removed and the residue was
chromatographed on si iica gel eluted with
7 o * f 3 Λ Λ 1 '' Q i Λ h 1C Σ C .7.Δ a.ne. The result_ng oil was dissolved
:n e t n y- acetate (; v n. 1) and treated with oxalic acid
(3.62g). The precipi tate was collected by filtration and
recrystallised (methanol/ethyi acetate) to give the title
compound (1.21g), m.p . 126 - 123°C.
77 -S · i 7 · - - — · · '-w · t t ‘ ‘ f .79; b, F 4.71%.
(Τ1? η265'ΝΟ.C2H2O4 · lH-:) requires: C, 60.80; H, 7.60; N, 3.70; :, 5.06%.
BAD ORIGINAL
AP 0 0 0 2 3 6
22039
- 22 Example 2
3- (3,4-Methylenedioxyphenoxyrnethyl) -1-pentylpiperidine hydrochloride
A solution of 3-(hydroxymethyl)-1-pentylpiperidine (2.0g), sesamol (1.49g) and triphenylphosphine (2.62g) in tetrahydrofuran (50ml) was treated with diethyl azodicarboxylate (1.74g) in tetrahydrofuran (10ml). The resulting solution was stirred at room temperature for 18 hours, the solvent removed and the residue chromatographed on silica gel eluted with methanol/dichloromethane. The resulting oil was dissolved in ethyl acetate (50ml) and treated with ethereal hydrogen chloride. The precipitate was collected by filtration and recrystallised (methanol/ethyi acetate) to give the title compound (1.01g), m.p. 183 - 184°C.
Found: C, 63.27; H, 8.22; N, 4.17; Cl, 10.37%.
(C18H27NO3-hcD requires: C, 63.25; H, 8.20; N, 4.10;
Cl, 10.40%.
Example 3
3- (3-Phenylpher.oxymethyl) -1-pentylpiperidine oxalate
A solution of 3-(hydroxymethyl)-1-pentylpiperidine (2.0g), 3-phenylphenol (1.70g) and triphenylphosphine (2.62g) in tetrahydrofuran (40ml) was treated with diethyl azodicarboxylate (1.66g) in tetrahydrofuran (50ml). The resulting solution was stirred at room temperature for 18 hours, the solvent was removed and the residue was _
22039
- 23 chromatographed on silica gel eluted with methanol/dichloromethane. The resulting oil (l.lg) was dissolved in ethyl acetate (50ml) and treated with oxalic acid (1.lequivalents). The precipitate was collected by filtration and recrystallised (methanol/ethyl acetate) to give the title compound (0.8g), m.p. 148 - 149°C.
Found: C, 70.46; H, 7.80; N, 3.24%.
(C23H31NO-C2H2°4) requires: C, 70.23; H, 7.78; N, 3.28%
Example 4
3-(2-Phenylphenoxymethyl)-1-pentylpiperidine oxalate
A solution of 3-(hydroxymethyl)-1-pentylpiperidine (2.0g),
2-phenylphenol (1.70g) and triphenylphosphine (2.62g) in tetrahydrofuran (50ml) was treated with diethyl azodicarboxylate (1.74g) in tetrahydrofuran (10ml). The resulting solution was stirred at room temperature for 18 hours, the solvent removed and the residue chromatographed on silica gel eluted with methanol/dichloromethane. The resulting oil was dissolved in ethyl acetate (50ml) and treated with oxalic acid (0.9g). The precipitate was collected by filtration and recrystallised (methanol/ethyl acetate) to give the title compound (1.10g), m.p. 99 - 101°C.
Found: C, 70.00; H, 7.97; N, 3.28% (C23H31NO-C2H2°4) requires: C, 70.23; H, 7.78; N, 3.28%
AP 0 0 0 2 3 6
22039
- 24 Example 5
3- (4-Benzyloxyphenoxymethyl)-1-pentylpiperidine hydrochloride
A solution of 3-(hydroxymethyl)-1-pentylpiperidine (2.0g),
4- benzyloxyphenol (2.Og) and triphenylphosphine (2.62g) in tetrahydrofuran (50ml) was treated with diethyl azodicarboxylate (1.74g) in tetrahydrofuran (10ml). The resulting solution was stirred at room temperature for 18 hours, the solvent removed and the residue chromatographed on silica gel eluted with methanol/dichloromethane. The resulting oil was dissolved in ethyl acetate and treated with hydrogen chloride in diethyl ether. The precipitate was collected by filtration and recrystallised (methanol/ethyl acetate) to give the title compound (0.5g), m.p. 149 - 150°C.
Found: C, 71.56; H, 8.71; N, 3.43; Cl, 8.57% (C24H33N°2-HC1) requires: C, 71.35; H, 8.48; N, 3.47;
Cl, 8.78%
Example 6
3-(4-Benzylphenoxymethyl)-1-pentylpiperidine hydrochloride
The title compound was prepared in a similar manner to example 5 starting from 3-(hydroxymethyl)-1pentylpiperidine (2.0g), 4-hydroxydiphenylmethane (1.84g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave
BAD ORIGINAL
22039
- 25 a white solid which was recrystallised from methanol/ethyl acetate (0.51g), m.p. 169 - 171°C.
Found: C, 74.38; H, 8.96; N, 3.68; Cl, 8.22% (C24H33NO-HC1) requires: C, 74.30; H, 8.83; N, 3.61;
Cl, 9.16%
Example 7
3-(3-Triflucromethylphenoxymethyl)-l-pentylpiperidine hydrochloride
The title compound was prepared in a similar manner to example 5 starting from 3-(hydroxymethyl)-1pentylpiperidine (1.85g), 3-trifluoromethylphenol (1.62g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from methanol/ethyl acetate (0.41g), m.p. 165°C.
Found: C, 59.04; H, 7.40; N, 3.91; Cl, 9.67% (C18 H26F3NO-HC1) requires: C, 59.0; H, 7.4; N, 3.8;
Cl, 9.7%
Example 8
3- (4-Nitrophenoxymethyl)-l-pentylpiperidine hydrochloride
The title compound was prepared in a similar manner to example 5 starting from 3-(hydroxymethyl)-1pentylpiperidine (1.85g), 4-nitrophenol (1.39g), triphenylphosphine (2.62g) and diethyl azodicarboxylate
BAD ORIGINAL
AP 0 0 0 2 3 6
22039
- 26 (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from methanol/ethyl acetate (0.13g), m.p. 220°C.
Found: C, 59.22; H, 7.96; N, 8.08; Cl, 10.31% (C17h26n2°3<hc1) requires: C, 59.55; H, 7.94; N, 8.17;
Cl, 10.35%
Example 9
3- (4-Phenylphenoxymethyl) -1-pentylpiperidine oxalate
The title compound was prepared in a similar manner to example 5 starting from 3-(hydroxymethyl)-1-pentylpiperidine (2.0g), 4-phenylphenol (1.7Qg), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (0.60g), m.p. 173.5 - 174°C,
Found: C, 70.17; H, 7.74; N, 3.50% (C23H31NO-C2H2°4) retires: C, 70.23; H, 7.78; N, 3.28%
Example 10
3-(2-Benzylphenoxymethyl)-1-pentylpiperidine oxalate
The title compound was prepared in a similar manner to example 5 starting from 3-hydroxymethyl-l-pentylpiperidine <2.0g), 2-hydroxydiphenylmethane (1.84g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a
bad original $
22039
- 27 white solid which was recrystallised from methanol/ethyl acetate (0.260g), m.p. 120°C.
Found: C, 70.21; H, 7.99; N, 3.20% (C24H33NO-C2H2°4-°-25H2O) requires: C, 69.94; H, 7.96;
N, 3.14%
Example 11
3- (4-Chlorophenoxymethyl)-1-pentylpiperidine oxalate
The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-l-pentylpiperidine (2.0g),
4- chlorophenol (1.28g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (0.82g), m.p. 140°C.
Found: C, 59.27; H, 7.26; N, 3.80; Cl, 8.93% (C17H26C1NO-C2H2°4) requires: C, 59.14; H, 7.31; N, 3.63; Cl, 9.19%
Example 12
3- (4-Cyanophenoxymethyl)-1-pentylpiperidine oxalate
The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-l-pentylpiperidine (2.0g),
4- cyanophenol (1.19g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a white solid which was
BAD ORIGINAL &
AP 0 0 0 2 3 6
22039
- 28 recrystallised from methanol/ethyl acetate (0.79g), m.p. 104°C.
Found: C, 63.83; H, 7.59; N, 7.47% ^18^26^0^2^204^ requires: C, 63.81; H, 7.50; N, 7.44%
Example 13
3-Phenoxymethyl-l-pentvIpiperidine cxalate
The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-l-pentylpiperidine (2.0g), phenol (0.94g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (1.02g), m.p. 144.5°C.
Found: C, 65.15; H, 8.43; N, 4.02% (C17h27NO’C2h2°4) requires: C, 64.93; H, 8.32; N, 3.99%
Example 14
3- (4-Fluorobenzvloxvmethyl)-1-pentyIpiperidine oxalate
A solution of 3-hydroxymethyl-l-pentylpiperidine (3.0g) in dimethylformamide (30 ml) was treated with sodium hydride (0.0162 mole) and then stirred for 0.5 hour when 4fluorobenzyl chloride (2.35g) was added. The mixture was stirred for 2 days and the solvent removed. Water (100 ml) and dichloromethane (100 ml) were added and the organic layer was separated, washed with saturated sodium chloride (150 ml) and dried over magnesium sulphate. The
22039
- 29 solvent was removed and the residue chromatographed on silica gel using methanol/dichloromethane as eluent. The resulting oil was dissolved in ethyl acetate and treated with oxalic acid (1.1 mole equivalent). The precipitate was collected by filtration and recrystallised (methanol/ethyl acetate) to give the title compound (1.2g), m.p. 126 - 127°C.
Found: C, 62.64; H, 7.97; N, 3.66%.
(C18H28FNO-C2H2°4) requires: C, 62.64; H, 7.89; N, 3.65%
Example 15
3-(3,4-Methylenedioxyphenoxymethyl)-1-propylpiperidine hvdrochloride
The title compound was prepared in a similar manner to example 5 starting from 3-(hydroxymethyl)-1-propylpiperidine (1.57g), sesamol (1.38g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride gave a white solid which was recrystallised from methanol/ethyl acetate (0.30g), m.p. 154°C.
Found: C, 59.14; H, 7.63; N, 4.62; Cl, 10.77% (C16H23NO3-HC1'°-5H2O) retires: C, 59.47; H, 7.74;
N, 4.34; Cl, 10.84%
AP 0 0 0 2 3 6
22039
- 30 Example 16 l-Cinnamyl-3-(3,4-dichlorophenoxymethyl)piperidine oxalate
The title compound was prepared in a similar manner to example 1 from l-cinnamyl-3-hydroxymethylpiperidine (2.00g), 3,4-dichlorophenol (1.41g), triphenylphosphine (2.27g) and diethyl azodicarboxylate (1.51g). Treating the product with oxalic acid in ethyl acetate gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (1.27g), m.p.206°C.
Found: C, 59.37; H, 5.46; N, 3.16; Cl, 15.16% (C21H23C12NO*C2H2°4) requires: C, 59.24; H, 5.40; N, 3.00; Cl, 15.16%
Example 17 l-Cinnamyl-3-(4-fluorophenoxymethyl)piperidine oxalate
The title compound was prepared in a similar manner to example 1 from l-cinnamyl-3-hydroxymethylpiperidine (2.00g), 4-fluorophenol (0.971g), triphenylphosphine (2.27g) and diethyl azodicarboxylate (1.51g). Treating the product with oxalic acid in ethyl acetate gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.7g), m.p.!23°C.
Found: C, 66.51; H, 6.31; N, 3.44% (C21h24FNO*C2h2°4) requires: C, 66.49; H, 6.31; N, 3.37%
bad original $
22039
- 31 Example 18
3- (3,4-Dichlorophenoxymethyl)-1-pentylpiperidine hydrochloride
The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-l-pentylpiperidine (2.00g),
3,4-dichlorophenol (1.63g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride in ether gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (1.10g), m. p . 188-190°C.
Found: C, 55.92; H, 7.18; N, 3.86; Cl, 9.64% (C17H25CI2NO.HCI) requires: C, 55.67; H, 7.15; N, 3.82; Cl, 9.68%
Example 19
3- (4-iso-Propylphenoxvmethyl)-1-pentylpiperidine hydrochloride
The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-l-pentylpiperidine (2.00g),
4- iso-propylphenol (1.36g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with hydrogen chloride in ether gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.18g),
m.p.172-174°C.
AP 0 0 0 2 3 6
22039
- 32 (C20H33NO-HC1) re<Tuires: C, 70.66; H, 10.08; N, 4.12%
Example 20
3-(3-iso-Propylphenoxymethyl)-1-pentylpiperidine hydrochloride
The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-1-pentylpiperidine (1.5g), 3-iso-propylphenol (l.lg), triphenylphosphine (2.12g) and diethyl azodicarboxylate (1.41g). Treating the product with hydrogen chloride in ether gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.8g), m.p.138-140°C.
Found: C, 69.89; H, 9.91; N, 4.10; Cl*, 10.33% (C20H33N°-HC1·0·25 H20) requires: C, 69.74; H, 9.95; N, 4.07; Cl, 10.29%
Example 21
3-(3-tert-Butylphenoxymethyl)-1-pentylpiperidine hydrochloride
The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-l-pentylpiperidine (1.50g), 3-tert-butylphenol (1.22g), triphenylphosphine (2.12g) and diethyl azodicarboxylate (1.41g). Treating the product with hydrogen chloride in ether gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (1.035g), m.p. 185-187°C.
BAD ORIGINAL ft
22039
- 33 Found: C, 71.39; H, 10.33; N, 4.09; Cl, 9.92% (C21H35NO-HC1) r®TJires: C, 71.26; H, 10.25; N, 3.96;
Cl,10.02%
Example 22
3- (4-Fluorobenzylaminomethyl) -1-pentylpiperidine dihydrochloride
A mixture of 4-fluorobenzylamine (2.49g) and 3methanesulphonyloxymethyl-1-pentylpiperidine hydrochloride (2g) was heated at 150°C for 2.5 hours. The mixture was dissolved in dichloromethane and the dichloromethane solution washed with dilute sodium hydroxide solution, dried over sodium sulphate and the solvent removed. The residue was chromatographed on silica gel with dichloromethane - methanol as eluent and treated with hydrogen chloride in ether to give a solid. Recrystallisation from ethyl acetate gave the title compound (0.92g), m.p. 207-209°C.
Found: C, 58.12; H, 8.55; N, 7.67; Cl, 19.41% (C18H29FN2-2HC1,0-3H2O) requires: C, 58.26; H, 8.57; N, 7.54; Cl, 19.09%
Example 23
3- (4-Fluorophenylaminomethyl)-1-pentylpiperidine dihydrochloride
Substituting 4-fluoroaniline for 4-fluorobenzylamine (9.12g) in example 22 gave the title compound (0.593g) as a white microcrystaline solid, m.p. 196-198’C
BAD ORIGINAL fl
AP 0 0 0 2 3 6
22039
Found: C, 56.77; H, 8.12; N, 7.83; Cl, 19.63% (C17H27FN2-2HC1,0-5H2O) requires: C, 56.66; H, 8.39; N
7.77; Cl, 19.68%
Example 24
3- (3, 4-DichIorophenylaminoTnethyl) -1-pentylpiperidine dihydrochlcride
Substituting 3, 4-dichloroaniline for 4-fluorobenzyla.m.ine (4.04g) in example 22 gave the title compound (0.38g) as a white microcrystaline solid, m.p. 185-187°C
Found: C, 50.99; H, 7.02; N, 6.99% (C17H26C12N2,2HC1) requires: C, 50.76; H, 7.02; N, 6.96%
Example 25
3- (4-tert-Butylphenoxymethyl)-1-pentylpiperidine hydrochloride
The title compound was prepared in a similar manner to example 1 from 3-hydroxymethyl-l-pentylpiperidine (1.50g),
4- tert-butylphenol (1.22g), triphenylphosphine (2.12g) and diethyl azodicarboxylate (1.41g). Treating the product with hydrogen chloride in ether gave a white solid which was recrystallised from ethyl acetate/methanol to give the title compound as a white crystalline solid (0.205g),
m.p. 197-199°C.
Found: C, 70.98; H, 10.21; N, 4.00; Cl, 9.82%
22039
- 35 (C21h35N0*HC1) requires: C, 71.26; H, 10.25; N, 3.96;
Cl,10.02%
Example 26
3-[3-(4-Fluorophenoxy)propyl1-1-pentylpiperidine oxalate
The title compound was prepared in a similar manner to example 1 from l-pentyl-3-(3-hydroxypropyl)piperidine (2.13g), 4-fluorophenol (1.12g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (1.10g), m.p. 115 - 118°C.
Found: C, 63.53; H, 8.11; N, 3.80% <C19H30FNO-C2H2°4) requires: C, 63.48; H, 8.06; N, 3.53%
Example 27
3-(3-(3,4-Dichlorophenoxy)propyl1-1-pentylpiperidine oxalate
The title compound was prepared in a similar manner to example 1 from l-pentyl-3-(3-hydroxypropyl)piperidine (2.13g), 3,4-dichlorophenol (1.63g), triphenylphosphine (2.62g) and diethyl azodicarboxylate (1.74g). Treating the product with oxalic acid gave a white solid which was recrystallised from methanol/ethyl acetate (0.5g), m.p. 127-130°C.
Found: C, 56.35; H, 6.90; N, 3.25% ^C19H29C12NO,C2H2°4^ requires: C, 56.25; H, 6.97; N, 3.12%
BAD ORIGINAL £>
AP Ο Ο Ο 2 3 6
.e 28 a ’ ' - 3 - (4-Sency loxychencxymethy1) -1-penty loiper Irilr.e b ; (-) -3- (4-Benzy1oxyphenoxymethy1) -1-pentyIpiperidine
The product from example 5 (55mg) was partitioned between diethyl ether and dilute sodium bicarbonate solution. The ether phase was separated, cried and the solvent removed. Tne residue was chromatographed cn a Chiralcel CJ h.p.i.o.
chro~atography column using ethanoi/hexane as eluent. The two enantiomers were collected. The (-) enantiomer being eluted first. Yield (8.0mg) rotation (-1.38° @ 22CT in mechanoi). The second peak gave the (+) enantiomer, yield (~.2mg) rotation (-1.24° @ 22°C in methanol).
Example 29 chlorobenzylaminomethyl)-1-pentylpioeridine ci!3’/cir3c!3loricie
Substituting 3,4-dichlorobenzyiamine for 4f lu o r oher.zy lamine ( 3.5 8 7 g) in example 22 gave the title compound (0.46g) as a white microcrystaline solid, m.p.

Claims (14)

  1. Claims:
    W Λ ·
    II»
    1. A compound of structure (I):
    (CH^ACCH^Ar
    M IS (I) in which
    R is Cj.galkyl(phenyl)p, C2_8alkenyl(phenyl)p, C2_8alkynyl(phenyl)p, C3_8cycloalkyl or
    C1_8alkylC3_8cycloalkyl;
    p is 0 to 2;
    n is 0 to 6;
    A is a bond, oxygen, sulphur or NR1;
    R1 is hydrogen, Ci_8alkyl or phenylC1_4alkyl;
    m is 0 to 3; and
    Ar is aryl or heteroaryl, each of which may be optionally substituted, or a salt thereof.
  2. 2. A compound according to claim 1 wherein R is Ci_8alkyl, phenyl(C-^.g)alkyl or phenyl(C2_8)alkenyl.
  3. 3. A compound according to claim 1 or claim 2 in which A is oxygen.
  4. 4. A compound according to any of claims 1 to 3 wherein n is 0 to 3.
  5. 5. A compound according to any of claims 1 to 4 wherein m is 0 to 3.
    BAD ORIGINAL
    22039
    AP 0 0 0 2 3
  6. 6
    - 38 6. A compound according to any of claims 1 to 5 in which Ar is optionally substituted phenyl.
  7. 7. A compound according to claim 1 which is:
    5 3-(4-fluorophenoxymethyl)-1-pentylpiperidine,
    3-(3,4-methylenedioxyphenoxymethyl)-1-pentylpiperidine,
    3-(3-tr i fluoromethylphenoxymethy1)-1-pentylp iper id ine,
    3-(3-phenylphenoxymethyl)-1-pentylpiperidine,
    3-(2-phenylphenoxymethy1)-1-pentylpiperidine,
    10 3-(4-phenylphenoxymethy1)-1-pentylpiperidine,
    3-(2-benzylphenoxymethyl)-1-pentylpiperidine,
    3-(4-benzylphenoxymethyl)-1-pentylpiperidine,
    3-(4-benzyloxyphenoxymethyl)-1-pentylpiperidine, l-cinnamyl-3-(3,4-dichlorophenoxymethyl)piperidine,
    15 3-(4-iso-propylphenoxymethy1)-1-pentylpiperidine; or
    3-(3,4-dichlorophenylaminomethyl)-1-pentylpiperidine; or a pharmaceutically acceptable salt thereof.
  8. 8. A process for preparing a compound of structure
    20 (I) which comprises:
    (a) for compounds of structure (I) in which A is O, S or NR1, reaction of a compound of structure (II):
    I (II)
    30 N^
    I
    R
    BAD ORIGINAL fi
    22039
    - 39 in which R and n are as described for structure (I) and A1 is 0, S or NR1, with a compound of structure L(CH2)nAr in which m and Ar are as described for structure (I), and L is a leaving group;
    (b) for compounds of structure (I) in which A is 0, S or NR1, reaction of a compound of structure (III):
    R in which n and R are as described for structure (I) and 20 L1 is a group displaceable by a nucleophile, with a compound of structure HA1(CH2)mAr where m and Ar are as described for structure (I) and A1 is as described for structure (II); or
    25 (c) for compounds of structure (I) in which A is NR1, reduction of a compound of structure (IV) :
    BAD ORIGINAL
    22039
    AP 0 0 0 2 3 6
    - 40 ir. which R^ represents the group
    0 0 , H !l .
    -(CH2)nN(R1)C(CH2)m_.Ar or -(CH2)n-jCNCR1)(CH2)mAr,
    5 and n, m, R and Ar are as described for structure (I);
    (d) for compounds of structure (I) in which A is a bond reaction of a compound of structure (V) :
    15 R (wherein R, L~, m and n are as hereinbefore defined).
    20 with a compound of structure X^Ar in which Ar is as described for structure (I), and X1 is an alkali metal;
    (e) introduction of the group R into a compound of formula (VI) :
    CCH2V(CH2>mAr (VI) by reaction with a compound RL2, wherein L2 is a leaving group;
    BAD ORIGINAL
    22039
    - 41 (f) Reduction of a compound of formula (VII) wherein R5 is C1_7alkyl(phenyl)p, C2_7aiker.yl (phenyl) p, C?_7alkynvl(phenyl)p or C1_7alkylC3_8cycloalkyl;
    (g) Reduction of a compound of structure (VIII):
    (VIII) wherein R, A, Ar m and n are as hereinbefore defined and o
    25 is a counter ion;
    and optionally thereafter forming a salt.
  9. 9. A pharmaceutical composition comprising a 30 compound of structure (I) as claimed in any of claims 1 to 7 or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier.
    22039
    AP 0 0 0 2 3 6
    - 42
  10. 10. A compound of structure (I) according to any of claims 1 to 7 or a pharmaceutically acceptable salt thereof for use in therapy.
    5
  11. 11. Use of a compound of structure (I) according to any of claims 1 to 7 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of conditions caused or exacerbated by the accumulation of calcium in the brain cells of mammals.
  12. 12. A method of treatment of a condition caused or exacerbated by the accumulation of calcium in the brain cells of mammals which comprises administering to a subject in need thereof an effective amount of a compound
    15 of structure (I) according to any of claims 1 to 7 or a pharmaceutically acceptable salt thereof.
  13. 13.
    condition
    A method according to is stroke.
    claim 12
  14. 14. A method according to claim 12 wherein the mammal is a human.
APAP/P/1991/000314A 1990-08-06 1991-08-06 "3-substituted piperdine derivatives, pharmaceutical compositions containing them and their use in therapy". AP236A (en)

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GB909017225A GB9017225D0 (en) 1990-08-06 1990-08-06 Compounds
GB909021852A GB9021852D0 (en) 1990-10-08 1990-10-08 Compounds
GB919107780A GB9107780D0 (en) 1991-04-12 1991-04-12 Compounds

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MA (1) MA22251A1 (en)
MX (1) MX9100517A (en)
NZ (1) NZ239267A (en)
PT (1) PT98575A (en)
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GB9319534D0 (en) * 1993-09-22 1993-11-10 Boots Co Plc Therapeutic agents
WO1995024390A1 (en) * 1994-03-11 1995-09-14 Smithkline Beecham Plc Novel phenyl(-alkyl/alkoxy)-1-aminoalkyl-substituted piperidines and pyrrolidines as calcium channel antagonists
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GB9411052D0 (en) * 1994-06-02 1994-07-20 Smithkline Beecham Plc Medicaments
GB9411045D0 (en) * 1994-06-02 1994-07-20 Smithkline Beecham Plc Compounds and use
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CA2232147A1 (en) * 1997-04-03 1998-10-03 F. Hoffmann-La Roche Ag Phenoxymethyl piperidine derivatives
AU1600599A (en) 1998-02-27 1999-09-15 Warner-Lambert Company Heterocyclic substituted aniline calcium channel blockers
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WO2000009491A1 (en) * 1998-08-12 2000-02-24 Smithkline Beecham Corporation Calcilytic compounds
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EP3337788A4 (en) 2015-08-21 2019-03-27 Portola Pharmaceuticals, Inc. Phenylpiperazine proprotein convertase subtilisin/kexin type 9 (pcsk9) modulators and their use
HK1260897A1 (en) 2015-08-21 2019-12-27 Portola Pharmaceuticals, Inc. Composition and methods of use of tetrahydroisoquinoline small molecules to bind and modulate pcsk9 protein activity
EP3337497B1 (en) 2015-08-21 2023-07-12 SRX Cardio, LLC Composition and methods of use of novel phenylalanine small organic compounds to directly modulate pcsk9 protein activity
WO2017147328A1 (en) 2016-02-23 2017-08-31 Portola Pharmaceuticals, Inc. Compounds for binding proprotein convertase subtilisin/kexin type 9 (pcsk9)
US12115154B2 (en) 2020-12-16 2024-10-15 Srx Cardio, Llc Compounds for the modulation of proprotein convertase subtilisin/kexin type 9 (PCSK9)

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JPH06500092A (en) 1994-01-06
WO1992002501A1 (en) 1992-02-20
CN1062349A (en) 1992-07-01
TW239860B (en) 1995-02-01
MA22251A1 (en) 1992-04-01
IL99074A0 (en) 1992-07-15
IE912760A1 (en) 1992-02-12
AP9100314A0 (en) 1991-10-31
MX9100517A (en) 1992-04-01
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CA2088490A1 (en) 1992-02-07
PT98575A (en) 1992-06-30

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