WO2019077332A1

WO2019077332A1 - Therapeutic compounds

Info

Publication number: WO2019077332A1
Application number: PCT/GB2018/052972
Authority: WO
Inventors: Richard MYERSON; Jonathan Hull; Paul Blaney; Peter RANDS
Original assignee: Small Pharma Ltd
Priority date: 2017-10-16
Filing date: 2018-10-16
Publication date: 2019-04-25
Also published as: GB201716942D0

Abstract

The present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein ≃ is selected from a single bond and a double bond, wherein ≃ is 1, 2 or 3, wherein R1, R2, R3, R4, R5, and R6 are each selected from H and C1-C4 alkyl, and wherein when ≃ is a single bond R7 is selected from OH, O-(C1-C4 alkyl), -OPO3H2 and -OSO3H, and when ≃ is a double bond R7 is selected from H and C1-C4 alkyl.

Description

THERAPEUTIC COMPOUNDS

FIELD OF THE INVENTION

The present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof,

wherein == is selected from a single bond and a double bond,

wherein n is 1, 2 or 3,

wherein R¹, R², R³ R⁴, R⁵, and R⁶ are each selected from H and C1-C4 alkyl, and

wherein when == is a single bond R⁷ is selected from OH, 0-(Ci-C4 alkyl), -OPO3H2 and -OSO3H, and when == is a double bond R⁷ is selected from H and C1-C4 alkyl.

Compounds of the present invention have applications in the treatment of psychiatric disorders, neurological disorders and/or pain disorders.

BACKGROUND OF THE INVENTION

The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, commonly referred to as AMPA receptor, is an ionotropic transmembrane glutamate receptor that mediates fast synaptic transmission in the central nervous system. AMPA receptor activation plays a critical role in glutamatergic transmission and in long-term potentiation, which in turn is involved in the biological processes underlying memory and executive function.

A major concern for increasing glutamatergic transmission is the risk of inducing

excitotoxicity, a pathological process during which high cytosolic calcium (Ca²⁺)

concentrations trigger a cascade of events that results in apoptosis or necrosis of the neurone. This increase in Ca²⁺ load comes about through the entry of extracellular Ca²⁺ through ion channels in the membrane, as well as the release of Ca²⁺ from intracellular stores.

Glutamate receptors play an essential role in facilitating Ca²⁺ entry from the extracellular space. N-methyl-D-aspartate (NMD A) receptors are highly permeable to Ca²⁺, however, during basal transmission these receptors are not activated due to their blockade by Mg²⁺ ions. This block is voltage-dependent, with the Mg²⁺ ion expelled from the channel upon the depolarisation caused by the activation of other glutamate receptors (predominantly AMPA receptors). With the Mg²⁺ ion block removed, NMDA receptors can facilitate large increases in intracellular Ca²⁺ load. Membrane depolarisation resulting from the activation of fast inotropic glutamate receptors may also trigger the activation of voltage-gated calcium channels (VGCCs), leading to the influx of extracellular Ca²⁺. AMPA receptors have also been directly implicated in excitotoxicity, as certain subtypes, which do not contain the GluA2 subunit, are themselves permeable to Ca²⁺.

The benefits of compounds which modulate the glutamatergic system and their use in treatment of various disorders must be balanced with the risk of neurotoxicity. The present invention provides novel compounds which enable glutamate modulation without neurotoxicity.

DESCRIPTION OF THE INVENTION

A first aspect of the present invention provides a compound of Formula I, or a

pharmaceutically acceptable salt thereof,

wherein— — is selected from a single bond and a double bond,

wherein n is 1, 2 or 3,

In preferred embodiments of the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, == is a single bond.

When == is a single bond, R⁷ is preferably selected from OH and 0-(Ci-C4 alkyl). In preferred embodiments of the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, R⁷ is OH. In preferred embodiments of the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, R⁷ is OMe.

In preferred embodiments of the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, == is a double bond and R⁷ is H.

In preferred embodiments of the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, R¹ and R² are H.

In embodiments of the compound of the first aspect of the present invention, or a

pharmaceutically acceptable salt thereof, one or both of R¹ is selected from Me, Et, 'Pr and *Bu. Preferably, one of R¹ and R² is Me.

pharmaceutically acceptable salt thereof, R¹ is selected from Me, Et, 'Pr and *Bu, and R² is H.

In preferred embodiments of the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, R¹ is Me and R¹ is H. In embodiments of the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, one, two or three -OR³ groups may be bonded to the phenyl ring. In preferred embodiments of the invention n is i wherein the -OR³ group is ortho, meta, or para to the C-C bond attaching the phenyl ring to the cyclohexanone ring. In preferred embodiments n is i and the OR³ group is ortho to the C-C bond attaching the phenyl ring to the cyclohexanone ring. In embodiments of the invention n is 2 and one -OR³ group is ortho and the other -OR³ group is ortho or para to the C-C bond attaching the phenyl ring to the cyclohexanone ring. In embodiments of the invention, n is 3 and one -OR³ group is ortho, one-OR³ group is meta, and one -OR³ group is para to the C-C bond attaching the phenyl ring to the cyclohexanone ring. In embodiments of the invention, n is 3 and two -OR³ group are ortho and one -OR³ group is para to the C-C bond attaching the phenyl ring to the cyclohexanone ring.

pharmaceutically acceptable salt thereof, R³ is selected from Me and Et.

pharmaceutically acceptable salt thereof R³ is Me. In preferred embodiments, n is 1, R³ is Me and -OR³ is ortho or meta to the C-C bond attaching the phenyl ring to the cyclohexanone ring, and is most preferably meta.

pharmaceutically acceptable salt thereof, R⁵ is selected from C1-C4 alkyl. In embodiments R⁵ is Me or *Bu, most preferably Me.

pharmaceutically acceptable salt thereof, R⁴ and R⁶ are independently selected from C1-C4 alkyl.

pharmaceutically acceptable salt thereof, R⁴ and R⁶ are Me. In embodiments of the compound of the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, one of R⁴ and R⁶ is Me and the other is H.

pharmaceutically acceptable salt thereof, == is a single bond and R⁷ is selected from -OH, - OMe, -OPO3H2 or -OSO3H. In preferred embodiments R⁷ is H or -OMe.

pharmaceutically acceptable salt thereof, the compound has R,R or S,S stereochemistry. Preferably, the compound has R,R stereochemistry.

A second aspect of the present invention provides a compound of Formula II

wherein n is 1 to 3, R¹, R², and R³ are each selected from H and C1-C4 alkyl, and R⁷ is selected from OH, -O-C1-C4 alkyl, -OPO3H2 and -OSO3H.

In preferred embodiments of the compound of the second aspect of the present invention, or a pharmaceutically acceptable salt thereof, R¹ and R² are H.

In embodiments of the compound of the second aspect of the present invention, or a pharmaceutically acceptable salt thereof, one or both of R¹ and R² is selected from Me, Et, 'Pr and *Bu. Preferably, R¹ is Me or Et.

In embodiments of the compound of the second aspect of the present invention, or a pharmaceutically acceptable salt thereof, R¹ is selected from Me, Et, 'Pr and *Bu, and R² is H. In preferred embodiments of the compound of the second aspect of the present invention, or a pharmaceutically acceptable salt thereof, R¹ is Me and R² is H, or R¹ is Et and R² is H.

In embodiments of the compound of the second aspect of the present invention, or a pharmaceutically acceptable salt thereof, one, two or three -OR³ groups may be bonded to the phenyl ring. In preferred embodiments of the invention n is i wherein the -OR³ group is ortho, meta, or para to the C-C bond attaching the phenyl ring to the cyclohexanone ring. In preferred embodiments n is i and the OR³ group is ortho to the C-C bond attaching the phenyl ring to the cyclohexanone ring. In embodiments of the invention n is 2 and one -OR³ group is ortho and the other -OR³ group is ortho or para to the C-C bond attaching the phenyl ring to the cyclohexanone ring. In embodiments of the invention, n is 2 and both -OR³ group meta to the C-C bond attaching the phenyl ring to the cyclohexanone ring. In embodiments of the invention, n is 3 and one -OR³ group is ortho, one-OR³ group is meta, and one -OR³ group is para to the C-C bond attaching the phenyl ring to the cyclohexanone ring. In embodiments of the invention, n is 3 and two -OR³ group are ortho and one -OR³ group is para to the C-C bond attaching the phenyl ring to the cyclohexanone ring. In embodiments of the invention, n is 3 and two -OR³ groups are meta, and one -OR³ group is para to the C-C bond attaching the phenyl ring to the cyclohexanone ring. In preferred aspects of the present invention, at least one -OR³ group is meta to the C-C bond attaching the phenyl ring to the cyclohexanone ring.

In preferred embodiments of the compound of the second aspect of the present invention, or a pharmaceutically acceptable salt thereof, R³ is selected from Me and Et. In particularly preferred embodiments of the compound of the second aspect of the present invention, or a pharmaceutically acceptable salt thereof, R³ is Me.

In embodiments of the compound of the second aspect of the present invention, or a pharmaceutically acceptable salt thereof, == is a single bond and R⁷ is selected from OH, - OMe, -OPO3H2 or -OSO3H. in preferred embodiments R⁷ is H or -OMe.

In embodiments of the compound of the second aspect of the present invention, or a pharmaceutically acceptable salt thereof, the compound has R,R or S,S stereochemistry. Preferably the compound has R,R stereochemistry.

A third aspect of the present invention provides a compound of Formula I, or a

pharmaceutically acceptable salt thereof,

wherein R¹ and R³ are each selected from H and C 1-C4 alkyl, wherein -OR³ may be ortho, meta or para to the C-C bond attaching the phenyl ring to the cyclohexanone ring.

In preferred embodiments of the compound of the third aspect of the present invention, or a pharmaceutically acceptable salt thereof, R¹ is selected from H, Me, Et, 'Pr and *Bu. In preferred embodiments R¹ is selected from H and Me.

In preferred embodiments of the compound of the third aspect of the present invention, or a pharmaceutically acceptable salt thereof, R¹ is H.

In embodiments of the compound of the third aspect of the present invention, or a

pharmaceutically acceptable salt thereof, R³ is selected from Me, Et, 'Pr and *Bu. In preferred embodiments R³ is Me. In particularly preferred embodiments R³ is Me and -OR³ is ortho or meta to the C-C bond attaching the phenyl ring to the cyclohexanone ring, preferably meta.

A fourth aspect of the present invention provides a compound of the first or second aspect of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurological disorder, a psychiatric disorder, or a pain disorder in a patient.

Preferred compounds of the present invention are selected from Compounds 1 to 72 in Table 1 :







Table 1

DEFINITIONS

Throughout this specification, one or more aspect of the invention may be combined with one or more features described in the specification to define distinct embodiments of the invention.

References herein to a singular of a noun encompass the plural of the noun, and vice-versa, unless the context implies otherwise.

As used herein, the term pharmaceutically acceptable salt is defined as the product of an acid addition reaction in which an amine group of a compound of the invention is protonated by an organic or inorganic acid to form a non-toxic salt, or as the product of a base addition reaction in which an acidic group in a compound of the invention is deprotonated by an organic or inorganic base to form a non-toxic salt. The term pharmaceutically acceptable salt includes solvates thereof. Wherever a compound is referred to by its generic or systematic name, the term is taken to include all pharmaceutically acceptable salts.

As used herein H means a hydrogen atom. Also encompassed in the definition of hydrogen atom are isotopes of hydrogen, for example deuterium or tritium.

As used herein C1-C4 alkyl means a saturated carbon chain having one to four carbon atoms and which may be linear or branched. Examples of alkyl groups include methyl (also referred to herein as Me), ethyl, n-propyl, isopropyl, n-butyl, sec- and tert-butyl (also referred to herein as t-Butyl, t-Bu, or *Bu). Such alkyl groups may in some embodiments be substituted with one or more haloatom independently selected from F, CI, Br, I, wherein F means fluoride, CI means chloride, Br means bromide, I means iodide.

As used herein, -PO3H2 can also mean -PO3H^", and collectively with the oxygen atom to which it is attached represents a phosphate group. As used herein the term -SO3H can also mean -SO3^" and collectively with the oxygen atom to which it is attached represents a sulphate group. In certain embodiments of the invention, the presence of a phosphate group or a sulphate group in compounds of the present invention facilitates formation of a zwitterion wherein the phosphate deprotonated and thus negatively charged and the amino group is protonated and thus positively charged. As used herein the term 'psychiatric disorder' is a clinically significant behavioural or psychological syndrome or pattern that occurs in an individual and that is associated with present distress (e.g., a painful symptom) or disability (i.e., impairment in one or more important areas of functioning) or with a significantly increased risk of suffering death, pain, disability, or an important loss of freedom.

As used herein the term 'neurological disorder' means any disorder of the nervous system, including diseases, conditions, or symptoms resulting from structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves.

As used herein, the term 'pain disorder' refers to an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.

As used herein, the term 'patient' preferably refers to a human patient, but may also refer to a domestic mammal. The term does not encompass laboratory mammals.

The present invention provides non-neurotoxic modulators of glutamatergic pathways, such as those mediated by AMPA and/or MDA receptors, with applications in treating neurological disorders, psychiatric disorders, and/or pain disorders.

SYNTHESIS

The general synthesis of compounds of Formula I from readily available starting materials is provided in Schemes 1, 2 and 3 below, wherein -L is any suitable leaving group and -Pg¹ is one or more optional protecting group:

XXIV

Scheme 3

Stereochemistry

The oxidation of the cyclohexenol ether of Formula XVII with mCPBA is diastereoselective; the hydroxyl at the 6- position preferentially adds to the same face of the cyclohexenol ether as the amine group at the 2-position.

The stereochemistry of the compounds of the present invention can be further driven by the presence of one or more alkyl groups R⁴, R⁵ or R⁶. For example, when R⁵ is alkyl, the amine at the 2-position will preferentially reside on the same face as R⁵. Alternatively, when R⁴ or R⁶ are alkyl, or both are alkyl on the same face, the amine at the 2-position will preferentially reside on the alternative face.

EXAMPLES

Synthesis of 6-hydroxylated compounds: (2R,6R)-2-amino-6-hydroxy-2-(3- methoxyphenyl)cyclohexan-l-one (Compound 10)

Compound 10 is s nthesised according to the synthesis described in Scheme 4:

Scheme 4

Compound 102

3-Methoxyphenyl cyclopentyl ketone (195.6 g, 0.958 mol) as a solution in ethyl acetate (2 L) is treated with copper (II) bromide (470 g, 2.104 mol, 2.2 Eq.) and the suspension heated to reflux over 4 hours. Gases are scrubbed with a water scrubber. The reaction mixture is allowed to cool overnight. The reaction mixture is filtered through a pad of silica (1.2 Kg) and washed with ethyl acetate (2 x 1.3 L). The solvent is removed to leave the product 102 as a dark oil (274.6 g). Compound 103 Compound 102 (274.6 g contains approx. 2% w/w ethyl acetate, 0.958 mol) is stirred whilst liquid ammonia (800 mL, large excess) is added over 5 minutes. The mixture is stirred over 4 h and the ammonia is allowed to evaporate slowly. A cardice/acetone bath is used

periodically to slow the rate of evaporation. The residue (a solid mass) is dissolved in THF (1.2 L) and stirred at 40°C for 30 min. The suspension is allowed to cool to room temperature and filtered to remove the inorganics. The solid is washed with THF (200 mL) and the filtrates are evaporated to leave the product 103 as a pale solid (231.3 g).

Compound 104

Compound 103 (231.3 g, contains approx. 8% w/w THF, 0.958 mol) is dissolved in isobutanol (1.5 L) and heated to reflux for 18 hours. The solvent is removed to leave

Compound 104 as a dark oil (218.6g).

Compound 105

A solution of Compound 104 (9.8 g, 40.2 mmol, approx. 90% purity) in methanol (30 mL) is treated with a solution of L-(+)-pyroglutamic acid (5.2 g, 40.2 mmol, 1 Eq.) in methanol (70 mL) and the solution stirred at room temperature overnight. The solid is filtered and then recrystallised from denatured alcohol.

Compound 106

Compound 105 as the L-pyroglutamate salt (11.2 g, 32 mmol) is suspended in dry THF (320 mL) with stirring under an argon atmosphere; to the stirring solution Et3 (17.9 mL, 128 mmol, 4 Eq.) is added as a single portion over 30 seconds. Di-tert-butyl-dicarbonate (9.1 g, 41.7 mmol, 1.3 Eq.) is added to the reaction vessel as a single portion under an argon stream and following the complete addition the reaction is heated to 70 °C for 18 h. The reaction is then cooled to room temperature and diluted with EtOAc (1 L) then washed with H4C1 (Sat. Aq. 2 x 1 L) then the separated organic phase washed with brine (1 L), dried over Na2S04, filtered and then concentrated in vacuo to afford crude compound. Crude material is purified via flash column chromatography (15-30% EtOAc in heptane) to afford Compound 106 (10.2 g).

Compound 107

Diisopropylamine (10.7 mL, 76 mmol) is dissolved in dry THF (150 mL) with stirring under an argon atmosphere then the mixture was cooled to -78 °C. n-BuLi (1.03 M in hexanes, freshly titrated; 70.8 mL; 2 Eq.) is added dropwise over 2 minutes and the reaction mixture is stirred for 15 minutes; after which a solution of 106 (11.5 mg, 36 mmol) in dry THF (2 mL) is added dropwise over 2 minutes and the reaction stirred for 25 minutes.

Chlorotrimethylsilane (6.2 mL, 0.79 mmol, freshly distilled from CaH2) is added to the reaction dropwise and the reaction stirred for 15 minutes at -78 °C then warmed to 0 °C and stirred for 1 h. After this time the reaction is diluted with heptane (3 L), washed with

NaHC03 (Sat. Aq. 3 L) and the organic phase is separated and dried over Na2S04, filtered and then concentrated in vacuo to afford crude 107. The crude 107 is purified via column chromatography (2-20% EtOAc in heptane) to afford Compound 107 as a clear colourless oil (14.1 g).

Compound 108 Compound 107 (19.8g, 50 mmol) is dissolved in dichloromethane (25 mL) and cooled to -15 °C (ice-lithium chloride), under a nitrogen atmosphere. 3-Chloroperbenzoic acid (9.5g, 1.1 eq.) is then added as a solid. The reaction is stirred for one hour at -15 °C, then the temperature is raised to room temperature and an additional 25 mL of dichloromethane is added. The reaction is stirred a further 0.5 hours. The reaction is then quenched by being poured into a 50/50 mixture of saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate. The reaction is extracted into dichloromethane and the solvent removed by rotary evaporation. Then THF (25 mL) is added to the crude material. The reaction is cooled to -5 °C, and tetrabutylbutyl ammonium fluoride (1.0 M in THF, 60 mL, 1.2 eq.) is added. The reaction is stirred for 2 minutes, before being quenched by addition to saturated aqueous sodium bicarbonate. Extraction into ethyl acetate, and removal of the solvent by rotary evaporation gives the crude final product 108. Purification by silica gel

chromatography (0% to 70% ethyl acetate in hexanes), gives the purified final product as solid Compound 108 (12.2 g).

Compound 10

Compound 108 (12 g, 36 mmol) was transferred into a round bottom flask under an argon atmosphere with a stirrer bar and HC1 (3M in CPME, 2 L (large excess)) was added with stirring; and the reaction was stirred under an argon atmosphere for 18 hours. After this time the reaction was filtered to collect the formed precipitate, which was then washed with pentane (3 x 3 mL) and dried under an argon stream to afford Compound 10 as the hydrochloride salt, as a white crystalline solid (8.4 g).

An alternative synthesis for Compound 10 from Compound 101 which reduces the number of synthetic steps from eight to seven is disclosed in Scheme 5.

r.t.

1 h

Scheme 5 Compound 102

3-Methoxyphenyl cyclopentyl ketone as a solution in ethyl acetate is treated with copper (II) bromide and the suspension heated to reflux over 4 hours. Gases are scrubbed with a water scrubber. The reaction mixture is allowed to cool overnight. The reaction mixture is filtered through a pad of silica and washed with ethyl acetate. The solvent is removed to leave the product 102 as a dark oil.

Compound 109

Compound 102 is stirred in toluene whilst benzylamine is added over 5 minutes. The mixture is stirred over 5 days and then purified by column chromatography to yield crude product 109. Crude 109 is then treated with HC1 in PCME to produce the crystalline iminium salt of 109 in high purity.

Compound 110

Compound 109 is dissolved in isobutanol and heated to 150°C in a microwave for 2 hours. The solvent is removed to leave Compound 110 as a dark oil.

Compound 111

Diisopropylamine is dissolved in dry THF with stirring under an argon atmosphere then the mixture was cooled to -78 °C. n-BuLi is added dropwise over 2 minutes and the reaction mixture is stirred for 15 minutes; after which a solution of 110 in dry THF is added dropwise over 2 minutes and the reaction stirred for 25 minutes. Chlorotrimethylsilane is added to the reaction dropwise and the reaction stirred for 15 minutes at -78 °C then warmed to 0 °C and stirred for 1 h. After this time the reaction is diluted with heptane, washed with NaHCC and the organic phase is separated and dried over Na₂S04, filtered and then concentrated in vacuo to afford crude 111. The crude 111 is purified via column chromatography to afford

Compound 105.

Compound 112

Compound 111 is dissolved in dichloromethane and cooled to -15 °C (ice-lithium chloride), under a nitrogen atmosphere. 3-Chloroperbenzoic acid is then added as a solid. The reaction is stirred for one hour at -15 °C, then the temperature is raised to room temperature and an additional 25 mL of dichloromethane is added. The reaction is stirred a further 0.5 hours. The reaction is then quenched by being poured into a 50/50 mixture of saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate. The reaction is extracted into dichloromethane and the solvent removed by rotary evaporation. Then THF is added to the crude material. The reaction is cooled to -5 °C, and tetrabutylbutyl ammonium fluoride is added. The reaction is stirred for 2 minutes, before being quenched by addition to saturated aqueous sodium bicarbonate. Extraction into ethyl acetate, and removal of the solvent by rotary evaporation gives the crude final product 112. Purification by silica gel

chromatography (0% to 70% ethyl acetate in hexanes), gives the purified final product as solid Compound 112.

Compound 113 and Compound 10

Compound 112 is transferred into a round bottom flask under an argon atmosphere with a stirrer bar and HC1 (3M in CPME) was added with stirring; and the reaction was stirred under an argon atmosphere for 18 hours. After this time the reaction was filtered to collect the formed precipitate, which was then washed with pentane (3 x 3 mL) and dried under an argon stream to afford Compound 113 as the hydrochloride salt, which was then purified by chiral chromatography to produce Compound 10.

Synthesis of Compounds 1 to 9, 11 to 18, 55 to 60 and 64 to 69

The following compounds are synthesised by the method set out in scheme 1 following procedures analogous to those described in Scheme 4, and starting from precursors as described in Table 2:

Synthesis of dehydro compounds: (R)-6-amino-6-(3-methoxyphenyr)cyclohexen-2-one (Compound 46)

Compound 46 is synthesised according to the synthesis described in Scheme 6:

Scheme 6 A solution of Compound 105 in aqueous HBr is heated to 70°C and bromine is added dropwise. Reactants are stirred and then allowed to cool to room temperature. The resulting mixture is diluted with water, washed with saturated sodium bicarbonate and extracted with DCM. After concentration the residue is dissolved in acetonitrile and DBN is added. This mixture is then refluxed for 24 hours. The solvent is evaporated and the residue diluted with ether and 5% aqueous NaOH. The layers are separated and the organic layer extracted with 5% aqueous HC1. Resultant aqueous fraction is basified with 50% aqueous NaOH. The crystalline precipitate is then removed by filtration, washed with water, and dried to

Compound 46.

Synthesis of Compounds 37 to 45 and 47 to 54

These compounds are synthesised from the corresponding cyclohexanone of formula XV by the method set out in scheme 3 following procedures analogous to those described in Scheme 6.

Claims

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof,

wherein == is selected from a single bond and a double bond,

wherein n is 1, 2 or 3,

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein == is a single bond.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein == is a double bond and R⁷ is H.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R¹ and R² are H.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R¹ is H and R² is Me.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein n is 1.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R³ is selected from Me and Et.

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof wherein n is 1 and R³ is Me.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R⁵ is Me.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein one or more of R⁴ and R⁶ are independently selected from C1-C4 alkyl.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein both R⁴ and R⁶ are Me, or wherein one of R⁴ and R⁶ is Me and the other is H.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R⁷ is selected from OH, -OPO3H2 or -OSO3H.

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, having R,R or S,S stereochemistry.

14. The compound of any one of claims 1, 2, 4 to 8, 12 or 13, or a pharmaceutically

acceptable salt thereof, having Formula II

15. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurological disorder, a psychiatric disorder, or a pain disorder in a patient.