ZA200509277B

ZA200509277B - Cyclic hydroxylamine as psychoactive compounds

Info

Publication number: ZA200509277B
Application number: ZA200509277A
Authority: ZA
Inventors: Parsons Philip; Trasciatti Silvia; Rosini Sergio; Annis Michael
Original assignee: Btg Int Ltd
Priority date: 2003-06-12
Filing date: 2004-06-01
Publication date: 2007-03-28
Also published as: CN1805944B; CN1805944A; GB0313628D0

Description

CYCLIC HYDROXYLAMINE AS PSYCHOACTIVE COMPOUNDS

This invention relates to psychoactive compounds suitable for the treatment of anxiety and depression. In particular, this invention relates to novel hydroxylamine compounds such as ring-opened derivatives of isoxazole compounds and their analogues, their preparation, pharmaceutical formulations thereof and their use in medicine.

A number of psychoactive compounds are known for use in the treatment of anxiety and depression. Diazepam (a benzodiazepine) is well-known, and widely used as an anxiolytic and anti-depressant. Other known psychoactive compounds include . 10 certain tricyclic fused benzo[d]isoxazole compounds having the structure shown . below in formula (A), as disclosed in US patent specification No. 5 707 988 (Boyd et al. / British Technology Group Ltd.):

R; RS X ne

R, ET L ©

Re A) in which X' is O, S, C=0 or NR' wherein R' is hydrogen, Ci alkyl, phenyl or Cri; phenalkyl, R;' and R,' each represent hydrogen or together represent an oxo group and Rj, Ry and Rs' each represent hydrogen or R;' represents hydrogen and two of

Ry, Ry, Ry and Rs' together represent the second bond of a double bond joining positions 7 and 8, 8 and 9 or 9 and 10 with the remaining two of Ry, Ry, Ry and R¢' representing hydrogen, or a salt thereof.

It has been found that, although the compounds of formula (A) demonstrate good efficacy as anxiolytic agents, their efficacy in the treatment of depression is less than ideal. There is therefore a need for new compounds that are effective in the treatment of both anxiety and depression, in particular for the treatment of pathologies in which both conditions occur. The present invention addresses that need.

The following compounds are known as synthetic intermediates:

OH OH

2-phenylpiperidin-1-ol [P5] 2-benzylpiperidin-1-ol [P6] 2-Phenylpiperidin-1-ol is mentioned in the following papers: “Regiochemistry of mercury(l) oxide oxidation of unsymmetrical N,N-disub- stituted hydroxylamines.” Tetrahedron (1996), 52(47), 14917-28 (Ali et al); o “Reaction of pyridine and quinoline N-oxides with phenylmagnesium bromide.” ¥. Org. Chem. (1965), 30(3), 910-13 (Kato et al.); . “Cyclic nitrones (I): dimeric 2,3,4,5-tetrahydropyridine N-oxides.” Chem.

Ber, vol. 89, 2159-67 (1956) (Thesing ef al.). 2-Benzylpiperidin-1-ol is mentioned in the following papers: ° “Synthesis and cycloaddition of 6-substituted 3,4,5,6-tetrahydropyridine 1- oxides.” J. Chem. Res., Synop. (1994), (2), 54-5 (Ali et al.); . “Mercury(I) oxide oxidation of 2-substituted N-hydroxypiperidine: a solution to the regiochemical problem.” Tet. Lett. (1993), 34(33), 5325-6 (Ali etal).

However, there is no disclosure of the compounds for use as pharmaceuticals.

Accordingly, the present invention provides in a first aspect a compound of formula (I):

RA__X.__R" oo KJ (CHy),

OH 0) in which—

X represents O or CHy; rR? and R* each independently represent hydrogen or Cy alkyl; p represent O or 1; and

R represents a five- or six-membered saturated or unsaturated ring selected from:

SAC AETeal

R represents a five- or six-membered oxo-substituted unsaturated ring selected from: 1 2

Ry R 2

RU A bel wherein R! and R? together represent an oxo group, or R! and R? each represent hydrogen, methoxy or ethoxy, or R! and R? together with the interjacent carbon atom represent a 1,3-dioxolane or 1,3-dioxane ring, attached via the 2 position and optionally bearing one or more methyl or ethyl groups; or a tautomer thereof; : or a salt thereof; for use as a pharmaceutical.

In the case where R represents a five- or six-membered oxo-substituted unsaturated ring selected from: 1 2

R\ R Rr! R? and bee ; wherein R! and R? together represent an oxo group, or an acetal thereof, wherein R' and R? each represent methoxy or ethoxy, or R' and R* together with the interjacent carbon atom represent a 1,3-dioxolane or 1,3-dioxane ring, attached via the 2 position and optionally bearing one or more methyl or ethyl groups, then preferably p represents 0. The invention thus preferably embraces compounds of formula (IA), (IB), (IC) (ID), (IE) and (IF):

3 4

RNR RA XR

J OT

I N

OH OH

1A) IB) 3 4

R be Rr X rR?

N SP! J

N"-

OH OH

(IC) (ID)

R? be ay" oF ) )

OH OH

(IE) (IF) as well as ketones of formula (IG) and (IH): 3 4 2 oR X R R X R* 0 T

N * )

OH OH

(IE) (IF) and acetals of the ketones of formula (IG) or (TH) with methanol or ethanol; or with ethane-1,2-diol or propane-1,2-diol, optionally bearing one or more methyl or ethyl groups.

When R' and R® together with the interjacent carbon atom represent a 1,3-dioxolane or 1,3-dioxane ring bearing one or more methyl or ethyl groups, preferably one methyl or ethyl group is positioned adjacent to each of the oxygen atoms in the 1,3-dioxolane or 1,3-dioxane ring. Preferably these are in the trans orientation, giving a compound such as:

RN fe) - \

OH

Such compounds might be hydrolysed in vivo to produce the corresponding compound of formula (I) in which R! and R? together represent an oxo group. The compounds having the 3-dioxolane or 1,3-dioxane ring therefore represent potential prodrugs.

However, preferably R' and R* together represent an oxo group.

Ry R o R and hea 5 then preferably X is O.

Synthesis is facilitated if the heterocyclic ring demonstrates some symmetry

Thus preferably R® and R* are identical. Preferably R® and R* each represents hydrogen.

In a second aspect, the present invention provides a compound of formula (II):

RA__O._R ow XJ ens. ON ( 2)p

OH (1 in which—

R? and R* each independently represent hydrogen or Cy alkyl; p represent 0 or 1; and

R represents a five- or six-membered oxo-substituted unsaturated ring selected from: :

R\ RF 2

RL 1 wherein R' and R? together represent an oxo group, or R' and R? each represent hydrogen, methoxy or ethoxy, or R' and R? together with the interjacent carbon atom represent a 1,3-dioxolane or 1,3-dioxane ring, attached via the 2 position and optionally bearing one or more methyl or ethyl groups; or a tautomer thereof; or a salt thereof.

A further preferred embodiment of the present invention is a compound of formula (II):

RL FR? )

N

OH

(1m) in which—

R! and R? each represent hydrogen or together represent an oxo group; or a salt thereof.

In this specification the term “alkyl” includes both straight and branched chain groups, as well as saturated and unsaturated groups.

When R! and R? together represent an oxo group, certain compounds of the invention might exist as tautomers where the N-hydroxyl group has reacted with the carbonyl group to form a hemiacetal of formula (IV) or (V):

R?. oo. _R* HO R* 0 Y O—N"Y

MY — GN

OH R® av) rRA__Oo.__R Mo. R*

Jo. 7

JL, CU 0) OH R® ™)

Thus the hemiacetals of formula (IV) and (V) are within the scope of the invention.

As indicated above, the compounds of the invention may exist in the form of a salt, preferably an amine salt. Such salts may be formed with a physiologically acceptable inorganic or organic acid. Physiologically acceptable acids include hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, isethionic, acetic, fumaric, maleic, salicylic, p-toluenesulfonic, tartaric, citric, lactobionic, formic, malonic, pantothenic, succinic, naphthalene-2-sulfonic, benzenesulfonic, methanesulfonic and ethanesulfonic acid. Hydrochloric acid is preferred. However, in general it is preferred to use the free base rather than the salt. : .

The compounds of the invention possess a chiral centre (denoted *) at the carbon atom adjacent the nitrogen of the N-OH group. It will be appreciated that the compounds of the invention can be resolved into their enantiomeric forms, or exist as a racemate. Depending on the nature of the substituents, a number of diastereoisomers is also possible.

In the case where p represents 0 and R represents a five- or six-membered oxo-substituted unsaturated ring selected from:

R\ R? » R?

Salley the compounds of the invention may be prepared by the reaction of a compound of formula (VI) or (VIA) with a compound of formula (VID):

R\ R . RA__X.__R'

RL R X T

Sow

I

VD (VIA) wm in which R!, R? and X are as defined with respect to formula ([). It will be appreciated that this will be most straightforward when R! and R? together represent an oxo group, as the double bond compound of formula (VI) or (VIA) will then be activated by the presence of the carbonyl group. Other electron-withdrawing groups would also facilitate reaction.

The reaction is preferably carried out by combining the compounds of formulae (VI) or (VIA) and (VII) at a temperature in the range of from room temperature to 100 °C, and then heating the reaction mixture to a temperature in the range of from 50 to 150 °C, more preferably 55 to 65 °C for several hours in a suitable solvent. Ambient pressure may be used, but preferably the reaction is carried out at ultrahigh pressure in a sealed tube. The compound of formula (VI) or (VIA) may itself be a suitable solvent for the reaction; for example, in the case where R' and

R? together represent an oxo group, the resultant 2-cyclohexenone and 2-cyclopenten- one are both readily available.

The compound of formula (I) is thereby produced via the formation of a tricyclic intermediate of formula (VIII) or (VIIA): o! rR: R? yr RA R: y~

H |, H |. oO Oo

H (VII) H (VIIA) which may be isolated or left to remain in sifu. Protonation of the intermediate (V IIT) or (VIIA), or a corresponding base-catalysed reaction, leads to the formation of compound (I). Ring opening presumably appears by an Elcb elimination (“cb” denoting “conjugate base”), or the corresponding acid-catalysed reaction, preferably at elevated temperature.

The compound of formula (VII) is preferably formed in situ from a compound of formula (IX):

“CY”

N

Ho via oxidation, preferably a pertungstate-catalysed oxidation. The nitrone (VII) has a tendency to polymerise and, if it needs to be isolated, care should be taken to avoid polymerise happening by storing in a freezer.

Any of the compounds of the invention may also be prepared by the reaction of a Grignard reagent of formula R(CH,),MgHal with a compound of formula (VII): “T°

Swe (vm in which Hal represents halide and R, R!, R? and X are as defined with respect to formula (I). We have fund that the Grignard reagents prepared using a chloride anion to be perfectly satisfactory.

The reaction is preferably carried out by combining the Grignard reagent of formula R(CH,),MgHal with the compound of formula (VII) at a temperature of ~10 °C, and then holding the reaction mixture at a temperature of 0 °C in a suitable solvent. Tetrahydrofuran is a suitable solvent for the reaction.

Tt will be appreciated that the compounds of formula (I) may also be prepared by modifications of these processes and by other alternative processes, which will be apparent to a person skilled in the chemical art.

The compounds of the invention have been found to effective in the treatment of both anxiety and depression. They are particularly useful for the treatment of anxiogenesis caused by withdrawal from benzodiazepines (as they exhibit cross tolerance with these benzodiazepines in comparison with buspirone, for example, which does not). The compounds are also of use in the treatment of anxiogenesis caused by abruptly ceasing the administration of drugs of abuse such as nicotine, alcohol and cocaine.

The dosage level of the compounds of formula (I) required to achieve effective anxiolysis or anti-depressant activity will vary with the mammal treated and will depend on factors such as the mammal’s body weight, its surface area, age and general state of health. It will also depend upon the mode of administration. Dosage levels of 0.01 mg/kg to 100 mg/kg, particularly 1 mg/kg to 10 mg/kg, are suitable.

Depending upon the nature and severity of the condition being treated, the doses may be repeated up to 2 or 3 times per day during the period of treatment. Doses outside these ranges may be administered if appropriate.

The compounds of formula (I) may be administered using oral, rectal, parenteral, subcutaneous or topical routes.

The compounds of formula (I) may be administered alone or together with a pharmaceutically acceptable carrier, such as an excipient or diluent. The invention therefore further provides a pharmaceutical composition comprising a compound of formula (I) in association with a pharmaceutically acceptable carrier therefor. The composition may further comprise additional therapeutic agent(s) or ingredient(s).

The compounds and compositions of the invention may conveniently be presented as unit dosage forms prepared using techniques that are well known to a person skilled in the art. In general, preparation of the unit dosage form includes the step of bringing one or more therapeutically active compounds into association with the carrier. The active compound(s) or and/or carrier ingredient(s) are preferably in the form of a finely divided solid or a liquid.

Compositions suitable for oral administration include discreet units such as tablets, capsules, caplets, cachets or lozenges, each containing a predetermined amount of the therapeutic compound. Solutions and suspensions of the therapeutic compound in an aqueous or a non-aqueous liquid are also suitable for oral administration and include syrups, elixirs and emulsions. The compound may also be presented as a bolus, electuary or paste.

Administration of the compound by a parenteral routes includes intravenous, intraperitoneal, intra-muscular and intra-articular administration. Compositions suitable for parenteral administration conveniently include a sterile aqueous preparation of the active compound, suitable for injection or infusion

Compositions suitable for topical administration include lotions, creams and pastes. The compositions of the invention may also be presented in the form of an aerosol or a suppository.

Accordingly the present invention also provides a method for preventing or alleyiating the symptoms of anxiety and/or depression, which method comprises administering to a patient in need of such treatment, particularly a warm-blooded animal such as a human, a non-toxic, therapeutically effective amount of a compound of a compound of formula (I), or a salt thereof, or a composition containing such a compound.

The invention also includes a compound of formula (0) for use as a medicament, and the use of a compound of formula (I), or a salt thereof, in the manufacture of a medicament for treatment of both anxiety and depression, particularly for the treatment of anxiogenesis caused by withdrawal from benzodiazepines, or caused by abruptly ceasing the administration of drugs of abuse such as nicotine, alcohol and cocaine.

The invention will now be described by reference to the following Examples.

Variations on these Examples falling within the scope of the invention will be apparent to a person skilled in the art.

EXAMPLES

Example 1 — Preparation of 2-( 4-hydroxy-3-morpholinyl)-2-cyclohexenone 0 B

Ah

OH

Morpholine (10.97 g; 0.126 M) and sodium tungstate hydrate (1.54 g; 4.67 mM) were cooled to 0 °C in a 250 mL flask. Hydrogen peroxide (32.5 mL (30% aq.); 0.286 mM) was slowly added, keeping the reaction temperature at 0 °C. The reaction mixture was stirred for a further 1.5 h and excess hydrogen peroxide was destroyed using sodium bisulfate. 2-Cyclohexenone (12.1 mL; 0.12 5M) was added slowly to the flask, and the reaction mixture was stirred for a further 48 h. The reaction mixture was heated to 55 °C for 2h and then 65 °C for a further 2 h. The reaction mixture was then poured into aqueous sodium chloride and was extracted with dichloromethane (3 x 100 mL). The organic layer was washed with saturated sodium bicarbonate solution, separated and dried over magnesium sulfate. Removal of the solvent gave a light brown oil, which was subjected to Kugelrohr distillation at 50-60 °C under vacuum, producing a dark oil (3.5 g; 14%). The compound was further purified by chromatography on a silica column using a dichloromethane (CH,Cl,) : acetonitrile (CH;CN) eluent (5:1; 0.27).

V max (cmt) = 3435 (OH); 2958, 2941, 2916, 2901, 2874 (CH); 2777w; 1699s (C=0); 1476; 1101.

Acc. Mass spectrometry: calculated = 198.1130 (MH); found = 198.1130. o oy

OH

(P1]

Activated MnO, (0.65 g, 7.41 mmol) was added to a solution of N- hydroxymorpholine (0.25 g, 2.47 mmol) in dichloromethane (15 mL) at 0 °C and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of

Celite™ and Na,SOs. The filtrate was added dropwise to a solution of phenylmagnesium chloride (2.0 M in tetrahydrofuran, 2.47 mL, 4.94 mmol) at — 10°C. The reaction mixture was stirred at 0 °C for 0.5 h and then saturated aqueous ammonium chloride solution (15 mL) and dichloromethane (15 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2 x 20 mL). The combined organic layers were dried (N2;SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO; eluting with 25% diethyl ether in hexanes to give the title compound (0.045 g, 11%) as a white crystalline solid.

Vmax(NujoI™ mull)/cm™ 3201 (br., 0-H), 1104 (s, C-0) 8y (300 MHz): 7.22 (m, 5H), 3.85 (d, 1H, J = 10.5 Hz), 3.72-3.50 (m, 3H), 3.31 (, 1H, J=10.5 Hz), 3.12 (d, 14, J=10.5Hz), 2.81 (td, 1H, J; = 11.2 Hz, J; = 3.4 Hz). 8c (75.5 MHz): 138.1 (0), 128.6 (1), 127.9 (1), 72.45 (2), 72.16 (1), 66.78 (2), 57.67 2).

HRMS (electrospray mode): m/z = 180.1026710 (MH) (calc. 180.1019051).

Example 3 — Preparation of 3-henzylmorpholin-4-ol [2] 0)

LL

OH

[P2]

Activated MnO, (1.29 g, 14.8 mmol) was added to a solution of N- hydroxymorpholine (0.50 g, 4.95 mmol) in dichloromethane (25 mL) at 0 °C and the mixture was stirred for 1 h. The reaction mixture was filtered through a pad of

Celite™ and Na,SOs. The filtrate was added dropwise to a solution of benzylmagnesium chloride (2.0 M in tetrahydrofuran, 4.95 mL, 9.90 mmol) at —10 : °C. The reaction mixture was stirred at 0 °C for 0.5 h and then saturated aqueous ammonium chloride solution (25 mL) and dichloromethane (25 mL) were added. The aqueous phase was separated and extracted with dichloromethane (2 x 30 mL). The combined organic layers were dried (Na;SO4) and concentrated under reduced pressure. The crude product was subjected to flash chromatography on SiO: eluting with 25% diethyl ether in hexanes to give the title compound (0.326 g, 34%) as a white crystalline solid.

Vinax(MNujol™ mull)/om™ 3203 (br., 0-H), 1107 (s, C-0). © 8 (300 MHz): 7.23 (m, 5H), 3.89 (d, 1H, J=11.7 Hz), 3.74-3.56 (m, 2H), 3.44 (d, 1H, J = 13.0 Hz), 3.23 (m, 2H), 2.87 (m, 2H), 2.39 (t, 1H, J= 10.5 Hz).

Sc (75.5 MHz): 137.7 (0), 129.2 (1), 128.5 (1), 126.4 (1), 70.22 (2), 67.76 (1), 66.60 (2),58.60(2),35.85 (1).

HRMS (electrospray mode) = 194.1186060 (MH) (calc. 194.1175552).

Example 4 — Preparation of 3-cyclohexylmorpholin-4-ol 0 ~~

OH

[P3]

Activated MnO, (1.29 g, 14.8 mmol) was added to a solution of N- hydroxymorpholine (0.50 g, 4.95 mmol) in dichloromethane (25 mL) at 0 °C and the

Claims

1. A compound of formula (I): R? be * ps (CHy), OH @ in which— X represents O or CHy; R?® and R* each independently represent hydrogen or C_g alkyl; p represent O or 1; and R represents a five- or six-membered saturated or unsaturated ring selected from: R represents a five- or six-membered oxo-substituted unsaturated ring selected from: R\ R® 2 R\ and Or 5 wherein R! and R? together represent an oxo group, or R! and R? each represent hydrogen, methoxy or ethoxy, or R! and R? together with the interjacent carbon atom represent a 1,3-dioxolane or 1,3-dioxane ring, attached via the 2 position and optionally bearing one or more methyl or ethyl groups; or a tautomer thereof; . or a salt thereof; for use as a pharmaceutical.

2. A compound as claimed in claim 1 in which R represents a five- or six- -membered oxo-substituted unsaturated ring selected from:

1 52 Ry R ]! R and be ; wherein R! and R® together represent an 0X0 group, or R! and R? each represent methoxy or ethoxy, or R! and R? together with the interjacent carbon atom represent a 1,3-dioxolane or 1,3-dioxane ring, attached via the 2 position and optionally bearing one or more methyl or ethyl groups, and p represents 0.

3. A compound as claimed in claims 1 or 2 in which R® and R? together represent an oxo group.

4. A compound as claimed in any preceding claim in which R represents a five- or six-membered oxo-substituted unsaturated ring selected from: Rl R? R ]! R? and be ; and X is O.

5. A compound as claimed in any preceding claim in which R® and R* are identical.

6. A compound as claimed in any preceding claim in which R® and R* each represents hydrogen.

7. A compound of formula (II): RL__O.__R' * kJ (CH,), ] OH fy) in which— R> and R* each independently represent hydrogen or Cy alkyl; p represent 0 or 1; and R represents a five- or six-membered saturated or unsaturated ring selected from:

SANG ACTS ak R represents a five- or six-membered oxo-substituted unsaturated ring selected from: 1 52 Ry R 2 rR R and be ; wherein R! and R? together represent an oxo group, or R! and R? each represent hydrogen, methoxy or ethoxy, or R! and R? together with the interjacent carbon atom represent a 1,3-dioxolane or 1,3-dioxane ring, attached via the 2 position and optionally bearing one or more methyl or ethyl groups; or a tautomer thereof; or a salt thereof.

8. A compound as claimed in claim 7 which is a compound of formula (IIT): RU R® © ) \ : OH ny in which— R! and R? each represent hydrogen or together represent an oxo group; or a salt thereof.

9. A process for the manufacture of compound of formula (I) as claimed in claim 7 or 8 where p represents 0 and R represents a five- or six-membered oxo-substituted unsaturated ring selected from: 1 2 R R =! R? and be by the reaction of a compound of formula (VI) or (VIA) with a compound of formula (VID:

RL R \ RS X Rr? RY R he T

10. A process as claimed in claim 9 in which R' and R? together represent an oxo group.

11. A process as claimed in claim 9 or 10 in which the compound of formula (VID) ) is formed in situ from a compound of formula (IX): “7° H ax) via oxidation

12. A process for the manufacture of compound of formula (I) as claimed in claim 7 or 8 by the reaction of a Grignard reagent of formula R(CH;),MgHal with a compound of formula (VII): “Y" Sis ° wm in which X is O, Hal represents halide and R, R! and R? are as defined with respect to formula (I).

13. A pharmaceutical composition comprising a compound of formula (I), or a salt thereof, as claimed in any one of claims 1 to 8 in association with a pharmaceutically acceptable carrier therefor.

14. Use of a compound of formula (I), or a salt thereof, as claimed in any one of claims 1 to 8 in the manufacture of a medicament for treatment of anxiety or depression.

15. Use as claimed in claim 14 in the manufacture of a medicament for the treatment of anxiogenesis caused by withdrawal from benzodiazepines, or caused by abruptly ceasing the administration of drugs of abuse.