GB2182040A - Benzopyranopyrrole derivatives - Google Patents
Benzopyranopyrrole derivatives Download PDFInfo
- Publication number
- GB2182040A GB2182040A GB08625264A GB8625264A GB2182040A GB 2182040 A GB2182040 A GB 2182040A GB 08625264 A GB08625264 A GB 08625264A GB 8625264 A GB8625264 A GB 8625264A GB 2182040 A GB2182040 A GB 2182040A
- Authority
- GB
- United Kingdom
- Prior art keywords
- general formula
- compound
- physiologically acceptable
- compounds
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P25/24—Antidepressants
-
- 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
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
Abstract
Compounds are disclosed of formula (I): <CHEM> wherein R is hydrogen, or C1-6 alkyl, C1-6 alkyl substituted by C3-7 cycloalkyl, C3-6 alkenyl, C3-6 alkynyl, C3-7 cycloalkyl, or aralkyl (in which the alkyl moiety contains 1 to 5 carbon atoms); and R<1> and R<2>, each independently represents fluorine or chlorine or one of R<1> and R<2> represents hydrogen; and the physiologically acceptable salts thereof. The compounds have a selective alpha 2-adrenorceptor antagonist action and are potentially useful for the treatment of disorders such as depression. The compounds may be prepared, for example by amination of a compound of formula (II): <CHEM> where X is a leaving group, with ammonia or an appropriate amine.
Description
1 4.
GB2182040A 1 SPECIFICATION
Heterocyclic amino compounds This invention relates to heterocyclic amino compounds. More specifically this invention relates to novel benzopyranopyrrole derivatives, to processes for the preparation thereof, to pharmaceutical preparations containing them, and to their use in medicine.
The alpha (a)-adrenoreceptors of the sympathetic nervous system are classified pharmacologically into two sub-groups, namely a, and a, The cz, -type are situated predominantly on the presynaptic terminals of noradrenergic neurones and are activated by the released neurotransmitter. Such activation results in a diminished release of noradrenaline on subsequent stimulation of the neurones, the a2-adrenoreceptors thus forming part of an autoinhibitory feedback mechanism for regulating the synaptic concentration of the neurotransmitter. A selective a2adrenoreceptor antagonist would be expected to produce an increase in the synaptic concentrations of noradre- naline by blocking the autoinhibitory feedback mechanism and would thus be of potential value in 15 human medicine for the treatment of disorders such as depression which are associated with a deficiency of noradrenaline at postsynaptic adrenoreceptors.
a2-Adrenoreceptors also occur at non-neuronal sites such as on bloodplatelets, in pancreatic islet cells, on adipocytes and in the proximal tubules of the kidney. Activation of et,-adrenorecep- tors at these sites leads to platelet aggregation, inhibition of insulin release, inhibition of lipolysis 20 and retention of sodium respectively.
A selective a2-adrenoreceptor antagonist thus has a potential therapeutic use as an antidepressant either alone or in a complimentary combination with an established antidepressant, and in either treating or preventing conditions such as migraine, thrombosis, diabetes, obesity, hypertension, constipation, paralytic ileus and senile dementia.
We have now found that the compounds of formula (1) below and their physiologically acceptable salts have a selective a,-adrenoreceptor antagonist action.
The invention thus provides compounds of general formula (1) R1 H (D R 0 R2 R wherein R is a hydrogen atom or a group selected from C,-6 alkyl (optionally substituted by C3-7 cycloalkyl), C,-, alkenyi, C3-, alkynyl, C3-7 cycloalkyl, and aralkyl (in which the alkyl moiety contains 1-5 carbon atoms); and R' and R2, which may be the same or different, represent a hydroen atom or a fluorine or chlorine atom provided that R' and R2 do not both represent a hydrogdn atom; and the physiologically acceptable salts thereof.
In general formula (1), the alkyl, alkenyl and alkynyl groups represented by R may be straight or branched chain groups.
When R contains a -C=C- or -C=-C- linkage this is not directly attached to the nitrogen atom. When R is alkyl it may be, for example, methyl, ethyl or propyl, methyl being preferred.
When R is an alkyl group substituted by a C3-7 cycloalkyl group it may be, for example, cyclopropyl C1-3 alkyl such such as cyclopropyl methyl. When R is alkenyl it may be, for example, allyl and when R is alkynyl it may be, for example, propynyl. When R is cycloalkyl it may be, for example, cyclopropyl. When R is an aralkyl group it may be, for example, phenCl-,alkyl, such as benzyl.
Suitable physiologically acceptable salts are the acid addition salts formed with inorganic acids, 55 for example hydrochlorides, hydrobromides, phosphates and sulphates, and with organic acids, for example citrates, tartrates, acetates, maleates and succinates. The hydrochlorides are particu larly useful.
It will be appreciated that each compound of general formula (1) is a trans isomer and exists as two enantiomers. The structural formulae herein are to be understood to depict either enantiomer of each compound concerned as well as mixtures of the enantiomers, including racemates, even though the precise structure as set out only relates to one enantiomer.
A preferred group of compounds of general formula (1) is that wherein R is a hydrogen atom.
Another preferred group of compounds of general formula (1) is that wherein R is a C,-, alkyl group, particularly a methyl or ethyl group. A further preferred group of compounds of general 65 2 GB2182040A 2 formula (1) is that wherein R' and/or R2 represent a fluorine atom.
A particularly preferred group of compounds of formula (1) are those in which R is a hydrogen atom, and one of R' and R2 is a hydrogen atom and the other represents a fluorine atom.
Important compounds are ( )-trans-5-fluoro-1,2,3,3a,g,gahexahydro[llbenzopyrano[2,3-clpyrrole, and its 3aS- and 3aR-isomers; ( )trans-8-fluoro- 1,2,3,3a,9,9a-hexa hydro[ 1 Ibenzopyrano[2,3-cl-pyrrole, and its 3aS- and 3aR- isomers; and their physiologically acceptable salts, particularly the hydrochlorides.
The compounds of the invention have selective a2-adrenoreceptor antagonist action. The test for determining the a2-adrenoreceptor antagonist action is based on the ability to prevent the action of a selective a27adrenoreceptor agonist such as clonidine or 5- bromo-N-(4,5-dihydro-1H10 imidazol-2-yi)-6-quinoxalinamine-[R-(RR)]-2,3-dihydroxy-butanedioate (UK 14304-18) on the rat field stimulated vas deferens preparation.
The compounds of the invention are thus of interest in the treatment or prevention of migraine, thrombosis, diabetes, obesity, hypertension, constipation, paralytic ileus and senile dementia, and in particular for the treatment of depression.
The invention accordingly further provides compounds of general formula (1) and their physiologically acceptable salts for use in the therapy or prophylaxis of migraine, thrombosis, diabetes, obesity, hypertension, constipation, paralytic ileus and senile dementia and in particular depression. The compounds of the invention may be used either alone or with an additional active ingredient. Thus, for example, in the treatment of depression, the compound of the invention may be used alone, or may be co-administered with an established antidepressant (e.g. desmethylimipramine imipramine or amitriptyline) either in a single formulation or in separate formulations. The established antidepressant can be used in accordance with conventional practice.
The compounds according to the invention may be formulated in a conventional manner, optionally together with one or more other active ingredient, for administration by any convenient route for example for oral, rectal, intravenous or intramuscular administration. Oral administration is preferred.
Thus according to another aspect, the invention provides a pharmaceutical composition comprising a compound of general formula (1) and/or a physiologically acceptable salt thereof to- gether with a physiologically acceptable carrier or excipient. The composition may optionally contain an additional active ingredient, for example an antidepressant such as desmethylimipramine, imipramine or amitriptyline.
For oral administration, the pharmaceutical composition may take the form of, for example, tablets, capsules, powders, solutions, syrups or suspensions prepared by conventional means with physiologically acceptable excipients, including controlled release formulations.
Compositions for rectal administration may be in the form of suppositories using a conven tional suppository excipient.
The compounds may be formulated for intravenous or intramuscular administration in dry form for reconstitution before use, or as a sterile solution or suspension.
A proposed daily dose for administration to man is 0.002 to 10m9/kg, for example 0.01 to 40 1Orng/kg, preferably 0.01 to 3mg/kg, which may be conveniently administered in 1 to 3 doses per day. The precise dose administered will of course depend on the age and condition of the patient. The daily dosage may conveniently be administered in the form of dosage units, each unit containing for example'0.01 to 3mg/kg, preferably 0.002 to 3mg/kg, of active ingredient.
The compounds according to the invention may be prepared by a number of processes. In the 45 following description the groups R, R' and R2 are as previously defined for general formula (1) except where otherwise indicated.
According to a first example (A), compounds of general formula (1) may be prepared by amination of a compound of general formula (11) R' H CH2X CH2 X GO R 2 [where X is a leaving group such as a halogen atom, (e.g. chlorine, bromine or iodine), or a hydrocarbyisulphonyloxy group (e.g. methyisulphonyloxy or p- toluenesulphonyloxy)] with ammo nia, aqueous ammonia or an amine of formula RNH2 where R is as previously defined.
In a particular embodiment of this process, following the amination reaction, the resulting compound of general formula (1) or a salt thereof, may be converted into another compound of general formula (1). Thus, for example, when R is aryimethyi, the amination reaction may option- 65 R qi 3 GB2182040A 3 ally be followed by removal of the aryimethyl group to yield a compound of formula (1) where R is a hydrogen atom.
The amination reaction is conveniently effected at an elevated temperature e.g. at 12WC, optionally in the presence of a suitable base e. g. sodium hydride or an alkali or an alkali metal hydroxide such as sodium hydroxide or preferably in the presence of an excess of the amine RNH2. The reaction may be carried out in the absence or presence of a solvent such as an ether e.g. dioxan, chlorinated hydrocarbon e.g. chloroform or an alcohol e.g. ethanol. Optional removal of an aryimethyl group may be carried out for example by hydrogenolysis or, where appropriate, under acidic conditions, as described below.
According to another example (B), a compound of general formula (1) where R represents a hydrogen atom may be prepared by deprotection of a corresponding compound where R repre sents a protecting group. Suitable protecting groups include, for example, aryimethyl and acyl groups. Conventional deprotection procedures may be used. For example, where appropriate an aryimethyl group (e.g. benzyi) may be removed by hydrogenolysis using, for example, hydrogen in the presence of a catalyst, such as platinum or palladium on a support (e.g. charcoal), in a solvent such as an alcohol e.g. methanol. Alternatively, where appropriate, an aryimethyl group (e.g. trityl) may be removed under acidic conditions, using for example an acid such as trifluoroa cetic acid, formic acid or hydrobromic acid. Acyl groups may be removed by hydrolysis using an acid such as mineral acid or a base such as an alkali metal hydroxide as appropriate. The protected starting materials for this process may be prepared using standard methods for the 20 protection of amines, for example as described by J.F.M McOmie in 'Protective Groups in Organic Chemistry' (Plenum Press, 1973).
The product of either of the processes (A) or (B) described above may be subjected to one or two further reactions comprising: (C)(i) converting the resulting compound of general formula (1) or a salt thereof into another compound of general formula (1); and/or (C)(ii) converting a compound of general formula (1) or a salt thereof into a physiologically acceptable salt thereof.
It is also possible to prepare a compound of general formula (1) by a process comprising interconversion of another compound of general formula (1).
For example, a compound of general formula (1) in which R is a hydrogen atom may be converted by alkylation to a compound of general formula (1) in which R is an alkyl, substituted 30 alkyl, alkenyi, alkynyl or aralkyl group. Conventional alkylation procedures may be used, for example reductive alkylation using an appropriate aldehyde with a complex metal hydride such as sodium or potassium borohydride or sodium cyanoborohydride in a suitable solvent such as an alcohol e.g. methanol.
Alternatively, the alkylation may be performed with an alkylating agent RX (where R is an alkyl, 35 substituted alkyl, alkenyl, alkynyl or aralkyl group and X is a leaving group such as a halogen atom e.g. chlorine or bromine, or a hydrocarbyisulphonyloxy group e.g. p- toluenesulphonyloxy) preferably in the presence of a base, such as potassium carbonate, optionally in a solvent such as an alcohol, e.g. ethanol.
Physiologically acceptable salts of the compounds of general formula (1) may be prepared by reacting the free base of formula (1) or a salt thereof with an appropriate acid, such as hydrogen chloride in the presence of a suitable solvent e.g. an ester such as ethyl acetate, an alcohol such as ethanol, ether or dichloromethane to obtain the desired physiologically acceptable salt.
In the following description relating to the preparation of intermediates, where enantiomers exist, the structural formulae herein are to be understood to depict either enantiomer as well as 45 mixtures, including racemates, although the precise structure as set out only relates to one enantiomer.
The intermediate compounds of general formula (11) may be prepared by reaction of a corre sponding diol of formula (111) 41 cl R1 H CH20H CH20H 0.
R2 H with a halide of formula X1A (where X, is a hydrocarbyisulphonyl group e. g. methyisulphonyl and 60 A is a halogen atom e.g. a chlorine atom) in the presence of a base e.g. triethylamine in a solvent such as dichloromethane; or with a halogenating agent such as thionyl chloride, phosphorous tribromide or hydrogen iodide.
The diols of formula (111) may be prepared by the following sequence of reactions:
4 GB2182040A 4 R1 0 1 0 1 0 rm R (m) R1 0 0 0 R 2 (V) R1 1 10 CH CH20H 15 0 COOCH3 R 2 Reduction of the pyrone (V1) using hydrogen and palladium on charcoal in acetic acid or in a 20 solvent such as ethyl acetate or dioxan containing acetic acid yields the lactone (V), which is converted to the ester (IV) by reaction with potassium carbonate and methanol. Reduction of the ester ([V) using lithium aluminium hydride in tetrahydrofuran then gives the required diol (111).
The intermediate pyrone of formula (V1) may be prepared from a compound of formula (VII) R1 0 OH 0 1 0 H R2 The reaction may be carried out under acidic conditions preferably with heating in a solvent 35 such as glacial acetic acid. Suitable acids for the reaction include mineral acids eg hydrochloric acid or p-toluenesulphonic acid.
The compound (VII) may be prepared from a compound of formula (VIII) R11 CH3 R2 OH M) by reaction with diethyl oxalate in the presence of a strong base such as an alkali metal alkoxide 50 eg sodium ethoxide in a solvent eg an alcohol such as ethanol preferably with heating eg at reflux, followed by subsequent reaction of the product formed with aqueous formaldehyde.
Intermediates of formula (VIII) in which R2 represents a fluorine or chlorine atom and R' is as defined in formula (1) are either known compounds or can be prepared according to the methods described by J A Donnelly and J J Murphy, J. Chem. Soc. (C), 1970, 2596-2598.
Intermediates of formula (Vill) in which R2 represents hydrogen and R' is a fluorine atom may 55 be prepared by the following reaction sequence:
C 1 W GB2182040A 5 M1 1 ---- OCH3 (M) (M11) -me- R' OH L&PC1-13 OCH3 1 (X) R' 0 ACH3 &CCH3 UK) Reaction of the known haloanisole (Xl) with a strong base such as n-butyl lithium at low temperatures eg -75'C, and subsequent addition of acetaldehyde, yields the compound (X), which is oxidised to the ketone (IX) using a suitable oxidising agent such as pyridinium chloro chomate. Demethylation of the ketone (IX) under standard conditions, eg using boron tribromide 25 in a halohydrocarbon solvent such as dichloromethane provides the required intermediates (VIII).
Intermediate diols of formula (111) are novel compounds and constitute a further aspect of the present invention.
A specific enantiomer of general formula (1) may be prepared by resolution of a mixture of enantiomers of formula (1) by conventional methods, e.g. by salt formation with an optically active acid followed by separation of the resulting diastereoisomeric salts, e.g. by fractional crystallisation. Alternatively, resolution may be effected at any suitable intermediate stage.
The following examples illustrate the invention. All temperatures are in 'C. 'Dried' refers to drying using magnesium sulphate unless otherwise stated. Chromatography was carried out using silica gel. THF denotes tetrahydrofuran.
Intermediate 1 2-Fluoro-6-methoxy-a-methyl benzenemethanol. n-Butyl lithium (3.9mis of 1.14M in hexane) was added dropwise to a solution of 3fluoroanisole (0.45mls) in dry THF (10mis) at -75' under nitrogen. The solution was kept at -75' for 1 hour, and then acetaldehyde (0.68mis) was added dropwise and the mixture allowed to warm up. 2M Hydrochloric acid (20mis) was added, the mixture was extracted with ether, the organic solution was dried and the solvent was evaporated. The product was distilled to give the title compound as an oil (0.4g). NMR (CDC13) 6 7.17 (1 H, d of t, 4- H), 6.75-6.6(2H, m, 3-H, 5-H), 5.24(1 H, m, CHO-), 3.89(3H, s, OCH,), 3.27 (1 H, d OH), 1.56(3H, cl, CH3).
Intermediate 2 1-(2-Fluoro-6-methoxyphenyl)ethanone. Pyridinium chlorochromate (479) was added in portions to a stirred solution of Intermediate 1 (259) in dichloromethane (20Omls). After 3 hours, a further 10g of reagent was added and stirring was continued overnight. The solution was decanted, the residue was washed thoroughly with ether (200mis), and the combined solutions were washed through a short column of silica gel, using ether as solvent. Evaporation of the solvent gave a liquid (24g). A portion was distilled to yield the title ketone (10.4g). NIVIR (CDOJ 6 7. 30(1H, d of t, 4-H), 6.77-6.65(2H, m, 3-H, 5-H), 3.85(3H, s, OCH3), 2.53(3H, s, CH,).
Intermediate 3 1-(2-Fluoro-6-hydroxyphenyl)ethanone.
Boron tribromide (7.3mis) was added to a stirred solution of Intermediate 2 (12.69) in dichloro methane (80mis) at -65', and the mixture was allowed to warm to 20' over 2 hours. Water 60 (50mis) was added dropwise to the stirred mixture, while cooling in a water bath. The layers were separated, the aqueous layer was extracted with dichloromethane and the combined or ganic solutions were dried (phase separating paper) and the solvent was evaporated. The resulting oil was distilled under vacuum to give the title compound as an oil (6.59) NMR (CDCI,) 3 12.71 (1 H, s, OH), 7.36 (1 H, d of t, 4-H), 6.85-6.4 (2H, m, 3-H, 5-H), 2.69(3H, cl, CH,). 65 6 GB2182040A 6 Intermediate 4 4-[(3-Fluoro-2-hydroxyphenyl)carbonyll-3-hydroxy-2(5H)furanone. A solution of 1-(3-fluoro-2-hydroxyphenyi)ethanone (30g) and diethyl oxalate (31g) in ethanol (60Omls) was added dropwise to sodium ethoxide (from 9.859 of sodium) in ethanol (600mis) and the mixture was stirred and heated at reflux for 2 days. The mixture was cooled, diluted with 60-80 petrol and the solid was collected and dried. A suspension of the product in water (1.2 Q) was stirred with formaldehyde (24mis of 37%) for 1.5 hours. The solid was filtered out, the filtrate was washed with ether, and traces of ether were removed by evaporation under vacuum. The aqueous solution was acidified to pH3, the precipitate was collected, washed with 10 water and recrystallised from acetone/water to give the title compound as yellow needles (18.7g). M.p. 194-208' (decomp), i.r. pmax (nujol) 1768, 1642 cm-1 (C=O).
Intermediate 5 5-Fluoro- 1H-furo[3,4-bl[ llbenzopyran-3,9-dione. A solution of Intermediate 4 (249) in acetic acid (200 mls) and concentrated hydrochloric acid (40mis) was heated at reflux for 1 hour. The mixture was allowed to cool, and was concentrated to a volume of 10Omls. Water was added, the precipitate solid was collected, washed with water and dried to yield the title compound. M.p. 164.
Intermediate 6 Cis-(:t-5-Fluoro-9,9a-Dihydro- 1H-furo[3,4-bl[ llbenzopyran-3(3aH)-one. Intermediate 5 (239) in 1,4-dioxan (500mis) was hydrogenated for 5 days over 10% palladium on carbon (39). Acetic acid (10mis) and a further 0.8g of catalyst were added, and hydrogena- tion was continued for a further 23 hours. The catalyst was filtered off, washed with ethyl acetate and the filtrate was concentrated to a volume of 150mls. The suspension was filtered, the filtrate was evaporated to dryness, and the resulting gum was purified by chromatography eluting with dichloromethane to give the title compound as a white solid. M.p. 75. 5-77.5'.
Intermediate 7 trans-(:t)-B-Fluoro-3,4-dihydro-3-(hydroxymethyl)-2H-1benzopyran-2-carboxyl ic acid methyl ester. A mixture of Intermediate 6 (2g) and dried potassium carbonate (3.99) in dry methanol (20mis) was stirred under nitrogen for 23 hours. Wet ethyl acetate was added, and the mixture was stirred for 20 minutes. Further quantities of ethyl acetate and water were added, the ethyl acetate layer was separated, washed with water, dried and the solvent was evaporated. The resulting oil (0.58g) was purified by chromatography eluting with dichloromethane-methanol (15: 1) to yield the title compound as an oil. NMR (CDC13) 6 7.0-6.72 (3H, m, aromatic), 4.96 (1H, d, 2-H), 3. 87 (3H, s, methyl ester), 3.67 (2H, d, CH20_), 2.9-2.5(3H, m, 3-H, 4-H,), 2.15 (1 H, Br, OH).
Intermediate 8 trans-(:t)-B-Fluoro-3,4-dihydro-2H1-benzopyran-2,3-dimethanol.
A solution of Intermediate 7 (2.29) in dry THF (30mis) was added dropwise to a stirred suspension of lithium aluminium hydride (0.469) in THF (30mis) at 0-5'. After 1 hour, saturated ammonium chloride solution (10mis) was added, the solid was filtered off and washed with THF. 45 Evaporation of the combined solutions yielded a gum which was partitioned between ethyl acetate and water. The aqueous layer was evaporated to dryness, the residue was extracted with ethyl acetate and the combined ethyl acetate layers were dried and the solvent was evaporated. A solution of the product in a small volume of ethyl acetate was diluted with petrol until no more solid precipitated. The solid was collected and dried to yield the title compound 50 (1.5g), M.P. 111, Intermediate 9 trans-(:t)-5-Fluoro-3,4-dihydro-2H- 1-benzopyran-2, 3dimethanol.
The title compound, m.p. 99-101', was prepared from 1 -(2-fluoro-6-hyd roxyphenyl) etha none 55 (the product of Intermediate 3) by a sequence of reactions analogous to those described in Intermediates 4, 5, 6, 7 and 8.
Intermediate 10 trans-(:t)-B-Fluoro-3,4-dihydro-2H-1-benzopyran-2,3-dimethanol, bis(methanesulphonate).
Methanesulphonyl chloride (1.4g) was added dropwise to a stirred suspension of Intermediate 8 (1.49) in dichloromethane containing triethylamine (1.69) at 0-5'. After 1.5 hours the mixture was washed with 2M hydrochloric acid, the acid layer was extracted with dichloromethane, and the combined organic solutions were dried (phase separating paper) and evaporated to dryness.
The residue was purified by column chromatography eluting with dichloromethane-methanol c 0 7 19 GB2182040A 7 (20: 1) to yield the title compound as a gum (2.49). NIVIR (CID03) (5 7.0- 6.75 (3H, m, aromatics), 4.54 (2H, cl, 2-CH20), 4.42-4.22 (3H, m, 3-CH20, 2-H), 3.10, 3.05 (6H, s, s, CH3), 3.02-2.76 (2H, rn, 4-1-12), 2.53 (1 H, m, 3-H).
Intermediate 11 trans-(:L)-5-Fluoro-3,4-dihydro-2H-1-benzopyran-2,3dimethanoI bis (methanesulphonate). A solution of methanesulphonyl chloride (0.77mis) in dichloromethane (10mis) was added dropwise to a stirred solution of Intermediate 9 (0.969) and triethylamine (1.9mis) in dichloromethane (10mis) at 0. After 1 hour the solution was washed successively with 2M hydrochloric acid and sodium bicarbonate solution. The organic phase was dried (phase separating paper) and 10 the solvent was evaporated. The resulting solid was triturated with ether, and recrystallised from toluene/cyclohexane to give the title compound as white crystals (0.7g).M.p. 116-118'.
Example 1 trans-(:t)-8-Fluoro- 1,2,3,3a,9,9a-hexahydro-2-(phenyimethyl)-[ llbenzopyrano[2,3-clpyrrole A mixture of Intermediate 11 (0.63g) and benzylamine (0.93mls) was heated at 120' under nitrogen for 45 minutes. Water (10mis) was added to the cold mixture to give a solid which was collected, washed with water and dried to give the title compound (0. 43g), t.l.c. (petroleum ether b.p. 60-80'-ethyl acetate 1:11) Rf 0.65, NIVIR (CIDG3W 7.4-7.2 (5H, m, Ph), 7.06 (1H, q, 6-H), 6.7-6.58(2H, m, 5-H, 7-H), 4.05 (1H, d of t, 3a-H), 3.88, 3.79(2H, ABq, CH2Ph), 3.18, 20 3.0 (each 2H, t, 1-1-12, 3-1-12), 2.67-2.42(2H, m, 9-1-12), 2.29(1H, m, 9a-H).
Example 2 trans-(k)-B-Fluoro-1,2,3,3a,9,9a-hexahydro[llbenzopyrano[2,3-clpyrrole hydrochloride A solution of Example 1 (0.42g) in methanol (10mis) was treated with excess hydrogen chloride 25 in methanol and the solution was evaporated to dryness. The residue was redissolved in methanol and was hydrogenated over 10% palladium on charcoal (50mg) at 40- 50' until reac tion was complete. The solvent was evaporated, the product was treated with hydrogen chloride in ethanol, evaporated to dryness and the solid was triturated with isopropyl alcohol to give the title compound (0.259).M.p. 220-2'. NMR (DMS0dr,)6 9.72 (2H, Br-s, NH,'), 7.22 (1H, q, 6-H), 30 6.9-6.7 (2H, m, 5-H, 7-H), 4.21 (1H, d of t, 3a-H), 3.78-2.6(6H, m, 3-H, 1-1-1, 9-H,), 2.22 (1 H, m, ga-H).
Example 3 trans-(:t)-5Fluoro-1,2,3,3a,9,9a-hexahydro-2-(phenylmethyl)[llbenzopyrano[ 2,3-clpyrrole, hydro- 35 chloride.
A mixture of benzylamine (6.79) and Intermediate 10 (2.3g) was stirred and heated to 120' under nitrogen for 50 minutes. After cooling, the mixture was partitioned between ethyl acetate and 2M sodium hydroxide solution, the layers were separated and the aqueous layer was further extracted with ethyl acetate. The combined organic solutions were washed with brine and then 40 shaken with 2M hydrochloric acid. The precipitated solid was collected, washed with water and ethyl acetate, and dried to give the title compound as a white powder (1. 39). M.p. 210-212'.
NMR (DIVISOdj(5 12.28, 12.00 (1H, 2xBr S, NHI), 7.8-7.6, 7.6-7.4 (5H, m, Ph), 7.2-6.85(3H, m, 7-H, 6-H, 8-H), 4.65-4.1(3H, m, CHPh, 3a-H), 3.9-2.25 (7H, m, 1-1-1, 3- 1-121 9-1-12 9a-H).
Example 4 trans-( )-5-Fluoro-1,2,3,3a,9,9a-hexahydro[llbenzopyrano[2,3-clpyrrole hydrochloride.
A solution of Example 3 (1.29) in methanol (50mis) was hydrogenated over 10% palladium on charcoal (0.29) for 17 hours. The catalyst was filtered off, and the filtrate was evaporated to dryness. Crystallisation of the resulting solid from isopropyl alcohol/ methanol gave the title compound (0.639). M.p. 259'. NMR (DIVISOdj 39.9 (2H, Br S, NI-12% 7.2-6. 85 (3H, m, aromatic), 4.24 (1H, d of t, 3a-H), 3.8-2.78 (6H, m 1-1-12, 3-1-12, 9-1- 12), 2.27 (1H, m, 9a-H).
Pharmaceutical Examples In the following examples, 'Active Ingredient' refers to ( ) trans-5- fluoro-1,2,3,3a,9,9a-hexahydro[llbenzopyrano[2,3-clpyrrole hydrochloride. Other compounds of the invention may be formu laed in similar fashion.
1. Oral Capsule per capsule 60 Active Ingredient 10 mg Magnesium stearate 0.5 mg Anhydrous lactose 90 mg Blend the active ingredient with the lactose and magnesium stearate. Fill the blend into 65 8 GB2182040A 8 appropriate size hard gelatin capsules (lock fitting type) on an automatic capsule filling machine.
2. Oral Syrup per 5 m] dose Active Ingredient 10 mg 5 Sodium citrate 25 mg Citric acid to pH 4.5 Sunset yellow FCF (Dye) 0.25 mg Methyl hydroxybenzoate sodium 5.0 mg Propyl hydroxybenzoate sodium 2.0 mg 10 Liquid orange flavour qS Sucrose 3.50 g Purified water to 5.0 mi Dissolve the sucrose in a minimum quantity of water. Add a concentrated solution of sodium 15 citrate with stirring and adjust the pH to 4.5 with citric acid. With continued stirring, add a 10% aqueous solution of the active ingredient, followed by a solution of the dye, a solution of the hydroxybenzoates and lastly the flavour. Adjust almost to volume with water and stir. Check the pH and adjust to 4.5 with citric acid if necessary. Make up to volume with water.
20 3. Oral Tablet (A) per tablet Active Ingredient 10 mg Polyvinylpyrrolidone 4.0 mg Sodium starch glycollate 10.0 mg 25 Magnesium stearate 2.0 mg Lactose to tablet core weight to 200 mg Blend the active ingredient with the lactose. Add a sufficient quantity ofpolyvinylpyrrolidone solution to produce a damp mass suitable for granulation. Prepare the granules and dry using a 30 tray or fluid bed dryer. Pass through a sieve, blend with the remaining ingredients and compress into 8mm diameter tablets on a tablet machine.
Film coat the tablet cores with hydroxypropyl methyl cellulose or similar film forming material, using either an aqueous or non-aqueous solvent system. A plasticizer and suitable colour may be included in the film coating solution.
(B) per tablet Active Ingredient 1 Omg Microcrystalline cellulose 132.Omg Sodium starch glycollate 5.Omg 40 Sodium lauryl sulphate 3.mg Sieve the active ingredient and the microcrystalline cellulose through a 40 mesh screen. Sieve the sodium starch glycollate and sodium lauryl sulphate through a 60 mesh screen. Blend the powders together in a suitable blender until homogeneous. Compress on appropriate punches on 45 an automatic tablet machine. The tablets may be covered in a thin polymer coat applied by the usual film coating techniques. A pigment may be included in the film coat.
Claims (11)
1. Compounds of general formula fl):
R1 INR 0 R2 wherein R is a hydrogen atom or a group selected from Cl-, alky], C,-, alkyl substituted by C,-, cycloaikyl, C,-, alkenyl, C,-, alkyny], C,-, cycloalkyl, and aralkyl (in which the alkyl moiety contains 1 to 5 carbon atoms); and R' and R2, each independently represents a fluorine atom or a chlorine atom or one of R' and 65 7 h v 9 GB2182040A 9 9 R2 represents a hydrogen atom; and the physiologically acceptable salts thereof.
2. Compounds according to claim 1, wherein, in the general formula (1), R is a hydrogen atom.
3. Compounds according to claim 1, wherein, in the general formula (1), R' and/or R2 repre5 tsents a fluorine atom.
4. Compounds according to claim 1, wherein, in the general formula (1), R is a hydrogen atom, and one of R' and R2 is a hydrogen atom and the other represents a fluorine atom.
5. ( )-trans-5-Fluoro- 1,2,3,3a, 9,9a-hexa hydro[ 11 benzopyrano[2,3Ipyrrole and its 3aS- and 3aR- isomers and the physiologically acceptable salt thereof.
6. Compounds according to any of claims 1 to 5 wherein the physiologically acceptable salts 10 are selected from hydrochlorides, hydrobromides, phosphates, sulphates, citrates, tartrates, ace tates, maleates and succinates.
7. Compounds according to claim 6, wherein the physiologically acceptable salts are the hydrochlorides.
8. A pharmaceutical composition comprising a compound of general formula (1) as defined in 15 claim 1 and/or a physiologically acceptable salt thereof together with a physiologically acceptable carrier or excipient.
9. A pharmaceutical composition according to claim 8, which contains an additional active ingredient selected from desmethylimipramine, imipramine and amitriptyline.
10. A process for preparing a compound of general formula (1) as defined in claim 1, or a 20 physiologically acceptable salt thereof which comprises (A) aminating a compound of general formula (ii):
H CH2X CH2 X (R) R 2 R wherein X is a leaving group and R' and R2- are as defined in claim 1, ammonia, aqueous ammonia or an amine of formula RNI-12, where R is as defined in claim 1; or (B) in order to prepare a compound of general formula (1) where R represents a hydrogen 35 atom, deprotecting a corresponding compound where R represents a protecting group, and, if necessary or desired, subjecting the resulting compound to one or two further reactions com prising:
(C) (i) converting the resulting compound of general formula (1) or a salt thereof into another compound of general formula fl): and/or (C) (5) converting a compound of general formula (1) or a salt thereof into a physiologically acceptable salt thereof.
11. Compounds of formula (Ill):
v R1 H CH20H (M) CH20H 0 R2 wherein R' and R2 are as defined in claim 1.
Printed for Her Majesty's Stationery Office by Burgess & Son (Abingdon) Ltd, Dd 8991685, 1987. Published at The Patent Office, 25 Southampton Buildings, London, WC2A 1 AY, from which copies may be obtained.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB858526210A GB8526210D0 (en) | 1985-10-23 | 1985-10-23 | Chemical compounds |
Publications (3)
Publication Number | Publication Date |
---|---|
GB8625264D0 GB8625264D0 (en) | 1986-11-26 |
GB2182040A true GB2182040A (en) | 1987-05-07 |
GB2182040B GB2182040B (en) | 1989-10-11 |
Family
ID=10587163
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB858526210A Pending GB8526210D0 (en) | 1984-04-24 | 1985-10-23 | Chemical compounds |
GB8625264A Expired GB2182040B (en) | 1985-10-23 | 1986-10-22 | Benzopyranopyrrole derivatives |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB858526210A Pending GB8526210D0 (en) | 1984-04-24 | 1985-10-23 | Chemical compounds |
Country Status (11)
Country | Link |
---|---|
EP (1) | EP0224332B1 (en) |
JP (1) | JPS62103078A (en) |
AT (1) | ATE55388T1 (en) |
AU (1) | AU584247B2 (en) |
DE (1) | DE3673348D1 (en) |
DK (1) | DK507186A (en) |
ES (1) | ES2029795T3 (en) |
GB (2) | GB8526210D0 (en) |
GR (1) | GR3000988T3 (en) |
NZ (1) | NZ218034A (en) |
ZA (1) | ZA868019B (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5225431A (en) * | 1987-10-23 | 1993-07-06 | Burroughs Wellcome Co. | Therapeutic substituted indole compounds and compositions thereof |
AU5272296A (en) * | 1995-04-06 | 1996-10-23 | Novo Nordisk A/S | Benzopyranopyrrole compounds, their preparation and use |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0162592A1 (en) * | 1984-04-24 | 1985-11-27 | Glaxo Group Limited | Heterocyclic amino compounds |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL70034A0 (en) * | 1982-10-25 | 1984-01-31 | Glaxo Group Ltd | Heterocyclic amino compounds,their preparation and pharmaceutical compositions containing them |
AU577367B2 (en) * | 1984-04-24 | 1988-09-22 | Glaxo Group Limited | Beuzodioxinopyrrole derivatives |
-
1985
- 1985-10-23 GB GB858526210A patent/GB8526210D0/en active Pending
-
1986
- 1986-10-22 DK DK507186A patent/DK507186A/en not_active Application Discontinuation
- 1986-10-22 NZ NZ218034A patent/NZ218034A/en unknown
- 1986-10-22 EP EP86308208A patent/EP0224332B1/en not_active Expired - Lifetime
- 1986-10-22 DE DE8686308208T patent/DE3673348D1/en not_active Expired - Fee Related
- 1986-10-22 ES ES198686308208T patent/ES2029795T3/en not_active Expired - Lifetime
- 1986-10-22 GB GB8625264A patent/GB2182040B/en not_active Expired
- 1986-10-22 ZA ZA868019A patent/ZA868019B/en unknown
- 1986-10-22 AT AT86308208T patent/ATE55388T1/en active
- 1986-10-22 JP JP61251555A patent/JPS62103078A/en active Pending
- 1986-10-22 AU AU64352/86A patent/AU584247B2/en not_active Ceased
-
1990
- 1990-10-26 GR GR90400663T patent/GR3000988T3/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0162592A1 (en) * | 1984-04-24 | 1985-11-27 | Glaxo Group Limited | Heterocyclic amino compounds |
Also Published As
Publication number | Publication date |
---|---|
GB8526210D0 (en) | 1985-11-27 |
ATE55388T1 (en) | 1990-08-15 |
GB8625264D0 (en) | 1986-11-26 |
NZ218034A (en) | 1989-07-27 |
EP0224332A1 (en) | 1987-06-03 |
DK507186D0 (en) | 1986-10-22 |
AU6435286A (en) | 1987-04-30 |
EP0224332B1 (en) | 1990-08-08 |
GB2182040B (en) | 1989-10-11 |
DK507186A (en) | 1987-04-24 |
JPS62103078A (en) | 1987-05-13 |
ES2029795T3 (en) | 1992-10-01 |
DE3673348D1 (en) | 1990-09-13 |
ZA868019B (en) | 1987-07-29 |
AU584247B2 (en) | 1989-05-18 |
GR3000988T3 (en) | 1991-12-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CH648553A5 (en) | NEW 3,4-DIHYDRO-5H-2,3-BENZODIAZEPINE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF. | |
EP0198456B1 (en) | 1,7-naphthyridine derivatives and medicinal preparations containing same | |
US4420480A (en) | Hexahydronaphth[1,2-b]-1,4-oxazines | |
US4496579A (en) | Benzodioxinopyrrole derivatives and processes for their preparation | |
EP0080115B1 (en) | Hexahydronaphth(1,2-b)-1,4-oxazines, process for their preparation and pharmaceutical formulation containing them | |
JPS5943956B2 (en) | Novel dibenzopyrans | |
HU196073B (en) | Process for production of derivatives of spirodioxolane, spiroditiolane and spirooxa-tiolane and medical compounds containing such compositions | |
KR920003065B1 (en) | Process for preparing benzodioxyno pyrrole derivatives | |
US4769367A (en) | Heterocyclic amino compounds | |
GB2182040A (en) | Benzopyranopyrrole derivatives | |
HU178886B (en) | Process for preparing pyrazol-indazol derivatives | |
PL191091B1 (en) | Novel indanolic compounds, method of obtaining them and pharmaceutic compositions containing such compounds | |
AU2009242219B2 (en) | Benzocycloheptane and benzoxepine derivatives | |
EP0162592B1 (en) | Heterocyclic amino compounds | |
US4404221A (en) | 2'-Substituted-spiro[benzofuran-2(3H),1'-cyclohexanes] and its pharmaceutical use | |
EA004711B1 (en) | New indenoindolone compounds, a process for their preparation and pharmaceutical compositions containing them | |
US3501484A (en) | Certain substituted 3 - (2-indolyl)-1,2,5,6-tetrahydropyridines and derivatives thereof | |
EP0080116B1 (en) | Octahydrobenzo(6,7)cyclohept(1,2-b)-1,4-oxazines, process for their preparation and pharmaceutical formulation containing them | |
GB2174087A (en) | Heterocyclic amino compounds | |
JPS6130588A (en) | Benzo(c)(1,8)naphthylidine, manufacture, use and medicine | |
KR102190332B1 (en) | Fluoropiperidine compounds as pure 5-HT6 receptor antagonists | |
US4594435A (en) | Intermediates for 2'-substituted-spiro[benzofuran-2(3H),1'-cycloalkanes] | |
NZ204187A (en) | Hexahydronaphth(1,2-b)-1,4-oxazine derivatives and pharmaceutical compositions | |
CA1210763A (en) | 1,5-diphenyl-pyrazolin-3-one compounds, process and intermediates for preparation thereof and pharmaceutical compositions containing them | |
JP2018531267A (en) | Oxa-azaspiro compounds having activity against pain |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
7732 | Case decided by the comptroller ** patent revoked (sect. 73(2)/1977) |