AU7753991A - Isoquinoline amides and esters as 5 ht3 receptor antagonists - Google Patents
Isoquinoline amides and esters as 5 ht3 receptor antagonistsInfo
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- AU7753991A AU7753991A AU77539/91A AU7753991A AU7753991A AU 7753991 A AU7753991 A AU 7753991A AU 77539/91 A AU77539/91 A AU 77539/91A AU 7753991 A AU7753991 A AU 7753991A AU 7753991 A AU7753991 A AU 7753991A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
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Description
ISOQUINOLINE AMIDES AND ESTERS AS 5-HT3
RECEPTOR ANTAGONISTS.
This invention relates to novel compounds having useful pharmacological properties, to pharmaceutical compositions containing them, to a process and intermediates for their preparation, and to their use as pharmaceuticals.
GB 2145416A (Sandoz Ltd) describes a group of naphthylene, chromene and quinoline derivatives with saturated
azabicyclic side chains, and having 5-HT3 receptor
antagonist activity.
A class of structurally distinct compounds having an
isoquinoline moiety, has now been discovered. These
compounds have 5-HT3 receptor antagonist activity.
Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein
E is NH or O,
R1 is hydrogen, halogen, C 1 -4 alkyl, C1-4 alkoxy, hydroxy or nitro;
Z is an azacyclic or azabicyclic side chain, such as a group of formula (a), (b) or (c):
wherein
p is 1 or 2; q is 1 to 3; r is 1 to 3;
R3 or R4 is hydrogen or C1-4 alkyl, and Y is a group
-CH2-X-CH2- wherein X is -CH2-, oxygen, sulphur or X is a bond; and
i) the group CO-E-Z is in the 1-position and either R2 is in the 3-position and is hydrogen, C1 -6 alkyl or C1 -6 alkoxy, or R2 is in the 4-position and is hydrogen, halogen, CF3, C1 -6 alkyl, C1 -7 acyl, C1 -7 acylamino, phenyl optionally substituted by one or two C1 -6 alkyl, C1 -6 alkoxy or halogen groups, or amino, aminocarbonyl or aminosulphonyl, optionally
substituted by one or two C1 -6 alkyl or C3 -8
cycloalkyl groups or by C4 -5 polymethylene or by phenyl, C1 -6 alkylsulphonyl, C1 -6 alkylsulphinyl, C1 -6 alkoxy, C1 -6 alkylthio, hydroxy or nitro; or ii) the group CO-E-Z is in the 3-position and either R2 is in the 1-position and is hydrogen, C1 -6 alkyl or C1 -6 alkoxy, or R2 is in the 4-pσsition and is hydrogen or C1 -6 alkoxy; having 5-HT3 receptor antagonist activity.
Suitable examples of the group R1 include hydrogen7 bromo, chloro, methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl, methoxy, ethoxy, n- and iso-propoxy, and n-, iso-, sec- and tert-butoxy.
Suitable examples of Z are described in the art relating to 5-HT3 receptor antagonists, ie. as follows: i) GB 2125398A (Sandoz Limited)
ii) GB 2152049A (Sandoz Limited)
iii) EP-A-215545 (Beecham Group p. I.e.)
iv) EP-A-214772 (Beecham Group p. I.e.)
v) EP-A-377967 (Beecham Group p. I.e.)
vi) EP-A-358903 (Dianippon Pharmaceutical Co. Ltd.)
Particular side chains of interest are depicted thus:
Tropane
Granatane
Oxa/thia-qranatane
Quinuclidine
Isoquinuclidine
Isogranatane
Oxa/thia-isoqranatane
Isotropane
wherein
R is hydrogen or methyl; and X is oxygen or sulphur. Side chains Z of particular interest include tropane and oxagranatane, where R is methyl.
E is preferably NH. When the group CO-E-Z is in the 1-position suitable examples of the group R2 when in the 4-position, include the
following groups; hydrogen, chloro, bromo, methyl, ethyl, amino, methylamino, dimethylamino, phenyl, C1 -4
alkanoylamino such as formylamino, acetylamino,
propionylamino, n- and iso-butyrylamino, aminosulphonyl, and amino and aminosulphonyl optionally substituted by one or
two methyl, ethyl, n- or iso-propyl, n-, sec-, iso- or
tert-butyl or phenyl groups; nitro, methoxy, ethoxy, n- and iso-propoxy, methylthio, ethylthio, n- and iso-propylthio, hydroxy, methylsulphonyl and ethylsulphonyl or when R2 is in the 3-position suitable examples, include the following groups, hydrogen, methyl, ethyl, n- or iso-propyl, methoxy, and ethoxy.
When the group CO-E-Z is in the 3-position, suitable
examples of the group R2 when in the 1-position, include the groups hydrogen, methyl, ethyl, n- or iso- propyl, methoxy and ethoxy, or when R2 is in the 4-position, suitable examples include the following groups; hydrogen, methoxy and ethoxy.
Preferred R2 groups, in any of the positions specified above, include hydrogen, methyl and methoxy. R2 is
preferably in the 1-position. For the avoidance of doubt, all alkyl and alkyl containing moieties are straight chained or branched.
Examples of R3/R4 when alkyl are methyl, ethyl, n- and
iso-propyl, n-, iso-, sec- and tert-butyl, preferably methyl.
Preferably p, q and r are 1 or 2.
The pharmaceutically acceptable salts of the compounds of the formula (I) include acid addition salts with
conventional acids such as hydrochloric, hydrobromic, boric, phosphoric, sulphuric acids and pharmaceutically acceptable organic acids such as acetic, tartaric, lactic, maleic, citric, succinic, benzoic, ascorbic, methanesulphonic, α-keto glutaric, α-glycerophosphoric, and
glucose-1-phosphoric acids.
The pharmaceutically acceptable salts of the compounds of the formula (I) are usually acid addition salts with acids such as hydrochloric, hydrobromic, phosphoric, sulphuric, citric, tartaric, lactic and acetic acid.
Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula (I) such as the compounds quaternised by compounds Ra-T wherein Ra is C1 -6 alkyl, phenyl-C1 -6 alkyl or C5 -7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of Ra include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl, preferably methyl. Suitable examples of T include halide such as chloride, bromide and iodide.
Examples of pharmaceutically acceptable salts of compounds of formula (I) also include internal salts such as
pharmaceutically acceptable N-oxides. The compounds of the formula (I), their pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) may also form pharmaceutically acceptable
solvates, such as hydrates, which are included wherever a compound of formula (I) or a salt thereof is herein referred to.
It will of course be realised that some of the compounds of the formula (I) have chiral or prochiral centres and thus are capable of existing in a number of stereoisomeric forms including enantiomers. The invention extends to each of these stereoisomeric forms (including enantiomers), and to mixtures thereof (including racemates). The different stereoisomeric forms may be separated one from the other by the usual methods.
It will also be realised that the isoquinoline nucleus in compounds of formula (I) may adopt an endo or exo
configuration with respect to Z. The endo configuration is preferred.
A group of compounds within formula (I) is of formula (II):
wherein the variables are as defined in formula (I).
Examples of the variables and preferred variables are as so described for corresponding variables in relation to formula (I).
A further group of compounds within formula (I) is of formula (III):
wherein q1 is 1 or 2 and the remaining variables are as defined in formulae (I) and (II).
Examples of the variables and preferred variables are as so described for the corresponding variables in formula (I).
There is a further group of compounds within formula (I) of formula (IV):
wherein r1 is 1 or 2 and the remaining variables are as defined in formulae (I) and (II).
Examples of the variables and preferred variables are so described as the corresponding variables in formula (I).
The invention also provides a process for the preparation of a compound of formula (I) which process comprises reacting a compound of formula (V):
with a compound of formula A2-Z ' wherein Z' is Z as defined in formula (I) wherein R3 and R4 are replaced by R3' and
R4', A1 and A2 are moieties which react together to form an amide or ester linkage and R3' and R4' are R3 and R4
respectively, as defined in formula (I) or a
hydrogenolysable protecting group; and thereafter as desired or necessary, converting R3', or R4' when other than R3 or R4 respectively, to R3 and R4 respectively, and optionally forming a pharmaceutically acceptable salt of the compound of formula (I). Suitable values of A1 and A2 are, for example, as described in the aforementioned patent publications. For example, A1 may be an actived carbonyl function such as an acid chloride or N-hydroxysuccinmide ester and A2 may be an amino group, when E in formula (I) is NH.
Intermediates of the formula (V) are generally known or are prepared by analogous methods to those used for structurally related known compounds. Intermediates of formula A2-Z' may be prepared from the corresponding exocyclic keto derivative of the azabicyclic side chain, prepared by condensation methods, often using a substituted piperidine, as described in the aforementioned patent references.
In a particular aspect, the invention also provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula (VI):
with a compound of formula HJ-Z', or when J is oxygen, an active derivative thereof, wherein J is oxygen or NH, Q is a leaving group; R3' and R4' respectively is R3 and R4
respectively, as defined, or a hydrogenolysable protecting group; and the remaining variables are as hereinbefore defined; and thereafter optionally converting R3' or R4', when other than R3 or R4, to R3, or R4 respectively, and optionally forming a pharmaceutically acceptable salt of the resultant compound of formula (I).
Examples of leaving groups Q, displaceable by a nucleophile, include halogen such as chloro and bromo, C1-4 alkoxy, such as CH3O and C2H5O-, PhO-, or activated hydrocarbyloxy, such as Cl5C6O- or COQ forms a mixed anhydride, so that Q is carboxylic acyloxy.
If a group Q is a halide or COQ forms a mixed anhydride, then the reaction is preferably carried out at non-extreme temperatures in an inert non-hydroxylic solvent, such as benzene, dichloromethane, toluene, diethyl ether,
tetrahydrofuran (THF) or dimethylformamide (DMF). It is also preferably carried out in the presence of an acid acceptor, such as an organic base, in particular a tertiary amine, such as triethylamine, trimethylamine, pyridine or picoline, some of which can also function as the solvent. Alternatively, the acid acceptor can be inorganic, such as calcium carbonate, sodium carbonate or potassium carbonate. Temperatures of 0°-100°C, in particular 10-80°C are
suitable.
If a group Q is C1-4 alkoxy, phenoxy or activated
hydrocarbyloxy, or activated ester, such as N- hydroxysuccinimide, then the reaction is preferably carried out in an inert polar solvent, such as toluene or
dimethylformamide. It is also preferred that the group Q is CI3CO- and that the reaction is carried out in toluene at
reflux temperature.
If a group Q is hydroxy, then the reaction is generally carried out in an inert non-hydroxylic solvent, such as dichloromethane, THF or DMF optionally in the presence of a dehydrating agent such as a carbodiimide, for example dicyclohexylcarbodiimide, optionally in the presence of N- hydroxysuccinimide. The reaction may be carried out at any non-extreme temperature, such as -10 to 100°C, for example, 0 to 80°C. Generally, higher reaction temperatures are employed with less active compounds whereas lower
temperatures are employed with the more active compounds.
If a group Q is carboxylic acyloxy, then the reaction is preferably carried in substantially the same manner as the reaction when Q1 is halide. Suitable examples of acyloxy leaving groups include C1-4 alkanoyloxy and C1 -4
alkoxycarbonyloxy, in which case the reaction is preferably carried out in an inert solvent, such as dichloromethane, at a non-extreme temperature for example ambient temperatures in the presence of an acid acceptor, such as triethylamine. C1 -4 alkoxycarbonyloxy leaving groups may be generated in situ by treatment of the corresponding compound wherein Q is hydroxy with a C1-4 alkyl chloroformate.
If a group Q is activated hydrocarbyloxy then the reaction is preferably carried out in an inert polar solvent, such as dimethylformamide. It is also preferred that the activated hydrocarbyloxy group is a pentachlorophenyl ester and that the reaction is carried out at ambient temperature.
When J is O the compound of formula HJ-Z', may be in the form of a reactive derivative thereof, which is often a salt, such as the lithium, sodium or potassium salt.
R3' and R4' when other than R3 and R4 respectively, may be a hydrogenolysable protecting group which is benzyl optionally substituted by one or two groups selected from halo, C1-4 alkoxy and C1 -4 alkyl. Such benzyl groups may, for example, be removed, by conventional transition metal catalysed hydrogenolysis to give compounds of the formula (VII) or (VIII) respectively:
R
wherein the variables are as hereinbefore defined. This invention also provides a further process for the preparation of a compound of the formula (I) wherein Z is a) or c) or a pharmaceutically acceptable salt thereof, which comprises N-alkylating a compound of formula (VII) or (VIII)
respectively, and optionally forming a pharmaceutically acceptable salt of the resulting compound of the formula (I). In this further process of the invention 'N-alkylation' comprises the substitution of the N-atom depicted in formula (VII) or (VIII) respectively, by a group R3 or R4
respectively as hereinbefore defined. This may be achieved by reaction with a compound R3Q3 or R4Q3 as necessary wherein R3 and R4 are as hereinbefore defined and Q3 is a leaving group.
Suitable values for Q3 include groups displaced by
nucleophiles such as Cl, Br, I, OSO2CH3 or OSO2C6H4pCH3.
Favoured values for Q3 include Cl, Br and I.
The reaction may be carried out under conventional
alkylation conditions, for example in an inert solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate. Generally the reaction is carried out at non-extreme temperature such as at ambient or slightly above. Alternatively, 'N-alkylation' may be effected under
conventional reductive alkylation conditions.
Interconverting R3 and R4 respectively in the compound of the formula (VII), or (VIII) respectively, before coupling with the compound of the formula (VI) is also possible.
Such interconversions are effected conveniently under the above conditions. It is desirable to protect any amine function with a group readily removable by acidolysis such as a C2-7 alkanoyl group, before R3 or R4 interconversions.
It is often convenient in the preparation of such a compound of formula (VII) or (VIII) to prepare the corresponding
compound wherein the methylene group is replaced by -CO-, or for R3 or R4 is methyl, where the methyl group is replaced by alkoxycarbonyl. Such compounds may then be reduced using a strong reductant such as lithium aluminium hydride to the corresponding compound of formula (VII) or (VIII)
respectively.
The compounds of formula (VI) are known or are preparable analogously to, or routinely from, known isoquinoline compounds.
It will be realised that in the compounds of the formula (I) having a tropane, granatane or oxa/thia-granatane side chain, the -COE- linkage has an endo orientation with respect to the ring of the bicyclic moiety to which it is attached. A mixture of endo and exo isomers of the compound of the formula (I) may be synthesised non-stereospecifically and the desired isomer separated conventionally therefrom e.g. by chromatography; or alternatively the endo isomer may if desired by synthesised from the corresponding endo form of the compound of the formula (II). Corresponding
geometric isomeric pairs are possible for the
isoquinuclidine, isogranatane, oxa/thia-isogranatane and isotropane side chains.
Pharmaceutically acceptable salts of the compounds of this invention may be formed conventionally. The acid addition salts may be formed for example by reaction of the base compound of formula (I) with a pharmaceutically acceptable organic or inorganic acid.
The compounds of the present invention are 5-HT3 receptor antagonists and it is thus believed may generally be used in the treatment or prophylaxis of pain, emesis, CNS disorders and gastrointestinal disorders. Pain includes migraine, cluster headache, trigeminal neuralgia and visceral pain;
emesis, includes in particular that of preventing vomiting and nausea associated with cancer therapy, and motion sickness. Examples of such cancer therapy include that using cytotoxic agents, such as cisplatin, doxorubicin and cyclophosphamide, particularly cisplatin; and also radiation treatment. CNS disorders include anxiety, psychosis, senile dementia and drug dependence. Gastrointestinal disorders include irritable bowel syndrome and diarrohea. 5-HT3 receptor antagonists may also be of potential use in the treatment of obesity and/or arrhythmia.
The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid
preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, since they are more convenient for general use.
Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional
excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art, for example with an enteric coating.
Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants
include starch, polyvinylpolypyrrolidone and starch
derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be
presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,
emulsifying agents, for example lecithin, sorbitan
monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents.
The oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large
quantities of fillers. Such operations are, of course, conventional in the art.
For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.
Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by
exposure of ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform
distribution of the compound of the invention. The invention further provides a method of treatment or prophylaxis of pain, emesis, CNS disorders and/or
gastrointestinal disorders in mammals, such as humans, which comprises the administration of an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
An amount effective to treat the disorders hereinbefore described depends on the relative efficacies of the
compounds of the invention, the nature and severity of the disorder being treated and the weight of the mammal.
However, a unit dose for a 70kg adult will normally contain
0.05 to 1000mg for example 0.1 to 500mg, of the compound of the invention. Unit doses may be administered once or more than once a day, for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day, that is in the range of
approximately 0.0001 to 50mg/kg/day, more usually 0.0002 to 25 mg/kg/day.
No adverse toxicological effects are indicated at any of the aforementioned dosage ranges.
The invention also provides a pharmaceutical composition for use in the treatment and/or prophylaxis of pain, emesis, CNS disorders and/or gastrointestinal disorders which
composition comprises an effect non-toxic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.
The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for use in the treatment of pain, emesis, CNS disorders and/or
gastrointestinal disorders.
The invention further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment and/or prophylaxis of pain, emesis, CNS disorders and/or
gastrointestinal disorders. The followinG Examples illustrate the preparation of
compounds of formula (I), the following descriptions
illustrate the preparation of intermediates.
Description 1
4-Methyl-1-isoquinoline carboxaldehyde (D1) To a solution of 1,4-dimethyl isoquinoline (9.46g) (K.C. Agrawal, P.D. Mooney and A. C. Sartorelli, J. Med. Chem., 1976, 1 9, 970) in 1,4-dioxane (250 ml) was added selenium dioxide (6.65g) and the mixture heated under reflux, under an atmosphere of nitrogen, for 4h. After allowing the reaction mixture to cool to room temperature, the
precipitated selenium was removed by filtration and the filtrate concentrated to dryness. The residue was purified by flash chromatography on silica gel, using light petroleum ether (bp 60-80°C) and diethyl ether (up to 20% v/v) as eluent, to afford the aldehyde (D1) (3.78g) as a tan solid. Mp. 61-63°.
M.S. M+ 171
n.m.r. (CDCI3, 250 MHz)
δ 2.74 (s. 3H)
7.71-7. .87 (m. 2H)
8.05 (d, 1H)
8.63 (s, 1H)
9.38 (d, 1H)
10.35 (s, 1H)
Description 2
4-Methyl-1-isoquinoline carboxylic acid (D2)
To an aqueous solution of silver oxide (prepared by the addition of silver nitrate (5g) in water (10 ml) to a stirred solution of sodium hydroxide (2.40g) in water (10 ml)) was added, at 0°C, 4-methyl-1-isoquinoline
carboxaldehyde (D.1) (2.50g), in portions. The reaction mixture was stirred at ambient temperatures overnight. The silver suspension was removed by filtration and washed with hot water (3x5 ml). The combined filtrate and washings were acidified with cone. HCl and extracted with chloroform (3x50 ml). The organic phase was dried (MgSO4) and concentrated in vacuo to afford the title compound (D2) (980 mg) as a beige solid mp. 155-57°. M.S. mr 188
n.m.r. (CDCI3, 250 MHz)
δ 2.75 (s. 3H)
7.79-7 .92 (m, 2H)
8.07 (d, 1H)
8.43 (s, 1H)
9.67 (d, 1H)
10.58 (bs, 1H)
Example 1 endo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)isoquinolin- 1-carboxamide (E1)
A solution of isoquinolin-1-carboxylic acid (2g),
N-hydroxysuccinimide (1.5g) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.6g). was stirred in dry DMF (50ml) at room temperature for 4 hours. The reaction mixture was cooled at 0°C,
endo-N-(9-methyl-9-azabicyclo[3.3.1]nonan-3-amine (2g) in CH2CI2 (30ml) was added and the mixture stirred at room temperature overnight. The solvent was removed and the residue dissolved in CH2CI2, washed with saturated aqueous NaHCO3 solution, dried and concentrated. The residue was recrystallised from Ethyl acetate and petrol (Bpt. range 60-80°C), to give the title compound (2.4g). m.p. 155-157°C.
Examples 2 to 6
The following compounds are prepared analogously to example 1 or as hereinbefore described.
Example 2 endo-N-(8-Methyl-8-azabicvclo[3.2.1]octan-3-yl)isoquinolin- 1-carboxamide (E2) mp 87- 88°
1H-NMR . (CDCI3)
δ 9.67 (d, 1H)
8.75 (d, 1H)
8.48 (d, 1H)
7.9-7.6 (m, 4H)
4.42-4.28 (m, 1H)
3.25 (brs, 2H)
2.42-1.70 (m, IIH including 2.35, s, 3H)
Example 3 endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)
isoguinolin-3-carboxamide (E3) mp 133-136°
1H-NMR (CDCI3)
δ 9.19 (s, 1H)
8.85 (brd, 1H)
8.60 (s, 1H)
8.10-7.95 (m, 2H)
7.80-7.65 (m, 2H)
4.36 (dt, 1H)
3.25 (brs, 2H)
2.44-1.95 (m, 9H including 2.36, s, 3H)
1.85 (brd, 2H)
Example 4
N-(Quinuclidin-3-yl)isoquinolin-1-carboxamide(E4) mp 115-117°
1H-NMR (CDCI3)
δ 9.62 (d, 1h)
8.51-8.40 (m, 2h)
7.9-7.62 (m, 4h)
4.35-4.15 (m, 1h)
3.58-3.41 (m, 1h)
3.10-2.82 (m, 4h)
2.75 (dd, 1h)
2.41-1.5 (m, 5h)
Example 5 endo-N-(9-Methyl-9-aza-3-oxabicyclo[3.3.1]nonan-7-yl)- isoquinolin-1-carboxamide (E5) mp 148-150°
1H-NMR (CDCI3)
δ 10.03 (brd, 1H)
9.42 (d, 1H)
8.50 (d, 1H)
7.9-7.62 (m, 4H)
4.88-4.72 (m, 1H)
4.10 (d, 2H)
3.68 (d, 2H)
2.75 (brs, 2H)
2.67-2.50 (m, 5H including 2.60, s, 3H) 1.60 (d, 2H)
Example 6 endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)-4-methyl- 1-isoquinolin-1-carboxamide hydrochloride (E6) A solution of 4-methyl-1-isoquinoline carboxylic acid (500 mg) (D2) and N-hydroxy succinimide (368 mg) in dry DMF (15 ml) was stirred under an atmosphere of nitrogen at ambient temperatures for 30 min. 1-Ethyl-3-(3-dimethylaminopropyl)- carbodiimide (768 mg) was added in one portion and stirring continued for 1h. The reaction mixture was cooled to 0°C and a solution of endo-8-methyl-8-azabicyclo[3.2.1}octan-3- amine (374 mg) in DMF (5 ml) was added dropwise and stirring continued for 20h at ambient temperatures. The solvent was removed in vacuo and the residue partitioned between
chloroform (50 ml) and 10% aq. NaOH (5 ml). The organic phase was dried (MgSO4) and evaporated under reduced
pressure. The residue was purified by flash chromatography on silica gel, using chloroform and ethanol (up to 10% v/v) as the eluent to afford an oil. Treatment with ethanolic HCl gave the title compound (200 mg) as a pale yellow solid, m.p. 140-43°.
M.S. M+ 309 (Free base)
1H-NMR (d4-MeOH, 250 MHz)
δ 2.33-2.52 (m, 5H)
2.59-2.65 (m, 2H)
2.84 (s, 3H)
2.92 (s, 3H)
3.02 (d, 1H)
3.89-4.06 (m, 2H)
4.40-4.53 (m, 1H)
8.10 (t, 1H)
8.30 (t, 1H)
8.44-8.60 (m, 3H)
5-HT3 Receptor Antagonist Activity
Compounds are evaluated for antagonism of the von
Bezold-Jarisch reflex evoked by 5-HT in the anaesthetised rat according to the following method:
Male rats 250-350g, are anaesthetised with urethane
(1.25g/kg intraperitoneally) and blood pressure and heart rate are recorded as described by Fozard J.R. et al., J. Cardiovasc. Pharmacol. 2, 229-245 (1980). A submaximal dose of 5-HT (usually 6μg/kg) is given repeatedly by the
intravenous route and changes in heart rate quantified.
Compounds are given intravenously and the concentration required to reduce the 5-HT-evoked response to 50% of the control response (ED50) is then determined.
Claims (19)
1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:
wherein
E is NH or 0,
R1 is hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, hydroxy or nitro;
Z is an azacyclic or azabicyclic side chain; and i) the group CO-E-Z is in the 1-position and either R2 is in the 3-position and is hydrogen, C1 -6 alkyl or C1 -6 alkoxy, or R2 is in the 4-position and is hydrogen, halogen, CF3, C1 -6 alkyl, C1 -7 acyl, C1 -7 acylamino, phenyl optionally substituted by one or two C1 -6 alkyl, C1 -6 alkoxy or halogen groups, or amino, aminocarbonyl or aminosulphonyl, optionally
substituted by one or two C1 -6 alkyl or C3-8
cycloalkyl groups or by C4 -5 polymethylene or by phenyl, C1 -6 alkylsulphonyl, C1 -6 alkylsulphinyl, C1 -6 alkoxy, C1 -6 alkylthio, hydroxy or nitro; or ii) the group CO-E-Z is in the 3-position and either R2 is in the 1-position and is hydrogen, C1 -6 alkyl or C1 -6 alkoxy, or R2 is in the 4-position and is hydrogen or C1 -6 alkoxy; having 5-HT3 receptor antagonist activity.
2. A compound according to claim 1 wherein E is NH.
3. A compound according to claim 1 or 2 wherein CO-E-Z is in the 1-position.
4. A compound according to any one of claims 1 to 3 wherein R1 is hydrogen.
5. A compound according to any one of claims 1 to 4 wherein Z is tropane, granatane, oxa/thia-granatane,
quinuclidine, isoquinuclidine, isogranatane, oxa/thia- isogranatane or isotropane.
6. endo-N-(9-Methyl-9-azabicyclo[3.3.1]nonan-3-yl)iso- quinolin-1-carboxamide.
7. endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)- isoquinolin-1-carboxamide.
8. endo-N-(8-Methyl-8-azabicvclo[3.2.1]octan-3-yl)- isoquinolin-3-carboxamide.
9. N-(Quinuclidin-3-yl)isoquinolin-1-carboxamide.
10. endo-N-(9-Methyl-9-aza-3-oxabicyclo[3.3.1]nonan-7-yl)- isoquinolin-1-carboxamide.
11. endo-N-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)-4- methyl-1-isoquinolin-l-carboxamide.
12. A pharmaceutically acceptable salt of a compound according to any one of claims 6 to 11.
13. A compound according to claim 1 substantially as defined herein with reference to the Examples.
14. A process for the preparation of a compound according to claim 1, which process comprises reacting a compound of formula (V):
with a compound of formula A2-Z' wherein Z' is Z as defined in claim 1 wherein R3 and R4 are replaced by R3' and R4', A1 and A2 are moieties which react together to form an amide or ester linkage and R3' and R4' are R3 and R4 respectively, as defined in claim 1, or a hydrogenolysable protecting group; and thereafter as desired or necessary, converting R3', or R4' when other than R3 or R4 respectively, to R3 and R4 respectively, and optionally forming a pharmaceutically acceptable salt of the compound of formula (I).
15. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
16. A method of treatment or prophylaxis of pain, emesis, CNS disorders and/or gastrointestinal disorders in mammals, such as humans, which comprises the administration of an effective amount of a compound according to claim 1.
17. A compound according to any one of claims 1 to 13 for use as an active therapeutic substance.
18. A compound according to any one of claims 1 to 13 for use in the treatment of pain, emesis, CNS disorders and/or gastrointestinal disorders.
19. The use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment and/or prophylaxis of pain, emesis, CNS disorders and/or gastrointestinal disorders.
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GB9009542 | 1990-04-27 | ||
GB909009542A GB9009542D0 (en) | 1990-04-27 | 1990-04-27 | Novel compounds |
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EP (1) | EP0526545A1 (en) |
JP (1) | JPH05507071A (en) |
AU (1) | AU7753991A (en) |
CA (1) | CA2081350A1 (en) |
GB (1) | GB9009542D0 (en) |
IE (1) | IE911399A1 (en) |
NZ (1) | NZ237957A (en) |
PT (1) | PT97490A (en) |
TW (1) | TW199157B (en) |
WO (1) | WO1991017161A1 (en) |
ZA (1) | ZA913123B (en) |
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EP1478646A1 (en) | 2002-02-20 | 2004-11-24 | PHARMACIA & UPJOHN COMPANY | Azabicyclic compounds with alfa7 nicotinic acetylcholine receptor activity |
GB0310867D0 (en) | 2003-05-12 | 2003-06-18 | Novartis Ag | Organic compounds |
WO2006068760A2 (en) | 2004-11-19 | 2006-06-29 | The Regents Of The University Of California | Anti-inflammatory pyrazolopyrimidines |
WO2008127226A2 (en) | 2006-04-04 | 2008-10-23 | The Regents Of The University Of California | P13 kinase antagonists |
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JP5547099B2 (en) | 2008-03-14 | 2014-07-09 | インテリカイン, エルエルシー | Kinase inhibitors and methods of use |
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US8697709B2 (en) | 2008-10-16 | 2014-04-15 | The Regents Of The University Of California | Fused ring heteroaryl kinase inhibitors |
US8476282B2 (en) | 2008-11-03 | 2013-07-02 | Intellikine Llc | Benzoxazole kinase inhibitors and methods of use |
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WO2011047384A2 (en) | 2009-10-16 | 2011-04-21 | The Regents Of The University Of California | Methods of inhibiting ire1 |
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CN106619647A (en) | 2011-02-23 | 2017-05-10 | 因特利凯有限责任公司 | Combination of mtor inhibitors and pi3-kinase inhibitors and uses thereof |
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EP2900673A4 (en) | 2012-09-26 | 2016-10-19 | Univ California | Modulation of ire1 |
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WO1984001151A1 (en) * | 1982-09-24 | 1984-03-29 | Beecham Group Plc | Amino-azabicycloalkyl derivatives as dopamine antagonists |
DE3587151T2 (en) * | 1984-12-20 | 1993-07-15 | Sandoz Ag | TREATING GASTROINTESTINAL DISEASES BY USING 5-HT3 ANTAGONISTS. |
EP0200444B1 (en) * | 1985-04-27 | 1992-11-11 | Beecham Group Plc | Azabicyclononyl-indazole-carboxamide having 5-ht antagonist activity |
-
1990
- 1990-04-27 GB GB909009542A patent/GB9009542D0/en active Pending
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1991
- 1991-04-22 AU AU77539/91A patent/AU7753991A/en not_active Abandoned
- 1991-04-22 EP EP91908698A patent/EP0526545A1/en not_active Withdrawn
- 1991-04-22 JP JP91508211A patent/JPH05507071A/en active Pending
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- 1991-04-22 WO PCT/GB1991/000636 patent/WO1991017161A1/en not_active Application Discontinuation
- 1991-04-25 ZA ZA913123A patent/ZA913123B/en unknown
- 1991-04-25 IE IE139991A patent/IE911399A1/en unknown
- 1991-04-26 PT PT97490A patent/PT97490A/en not_active Application Discontinuation
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PT97490A (en) | 1992-01-31 |
CA2081350A1 (en) | 1991-10-28 |
IE911399A1 (en) | 1991-11-06 |
WO1991017161A1 (en) | 1991-11-14 |
GB9009542D0 (en) | 1990-06-20 |
TW199157B (en) | 1993-02-01 |
JPH05507071A (en) | 1993-10-14 |
EP0526545A1 (en) | 1993-02-10 |
ZA913123B (en) | 1992-05-27 |
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