WO2007138343A1

WO2007138343A1 - N-phenylamidines as 5-ht2a receptor antagonists

Info

Publication number: WO2007138343A1
Application number: PCT/GB2007/050274
Authority: WO
Inventors: Christopher Swain
Original assignee: Merck Sharp & Dohme Limited
Priority date: 2006-05-25
Filing date: 2007-05-17
Publication date: 2007-12-06
Also published as: GB0610376D0

Abstract

Compounds of formula (I), are 5-HT2A receptor antagonists, and hence find use in treatment of a variety of adverse conditions of the 10 central nervous system.

Description

N-PHENYLAMIDINES AS 5-HT₇A RECEPTOR ANTAGONISTS

The present invention relates to a class of compounds which act on serotonin receptors (also known as 5-hydroxytryptamine or 5-HT receptors). More particularly, the invention concerns a class of N- phenylamidines, also known as carboximidamides. These compounds are potent and selective antagonists of the human 5-HT_2A receptor and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of adverse conditions of the central nervous system, including sleep disorders such as insomnia, psychotic disorders such as schizophrenia and psychiatric disorders such as anxiety.

Compounds of the invention typically display more effective binding to the human 5-HT_2A receptor than to other human receptors such as D₂ and IKr receptors. They can therefore be expected to manifest fewer side-effects than compounds which do not discriminate in their binding affinity between such receptors. In particular these compounds have lower effects on the IKr receptors and there is a separation of the desired effect from side effects such as cardiac effects.

By virtue of their potent human 5-HT_2A receptor antagonist activity, the compounds of the present invention are effective in the treatment of neurological conditions including sleep disorders such as insomnia, psychotic disorders such as schizophrenia, and also depression, anxiety, panic disorder, obsessive-compulsive disorder, pain, eating disorders such as anorexia nervosa, and dependency or acute toxicity associated with narcotic agents such as LSD or MDMA; and moreover are beneficial in controlling the extrapyramidal symptoms associated with the administration of neuroleptic agents. They are also effective in the lowering of intraocular pressure and hence in treating glaucoma, and may also be effective in treating menopausal symptoms, in particular hot flushes (see Waldinger et al, Maturitas, 2000, 36, 165- 8).

Various classes of compounds have been disclosed as 5-HT_2A receptor antagonists, many containing inter alia a sulphonyl moiety as described in WO 2005/047246, WO 2005/047247, WO 03/099786, WO 2004/101518, WO 01/74797, WO 00/43362, WO 96/35666, EP-A-0261688, EP-

0304888, and US Patents 4,218,455 and 4,128,552, DE-A-3901735 and Fletcher et al, J. Med. Chem., 2002, 45, 492-503. None of these publications, however, discloses or suggests the class of compounds provided by the present invention.

GB 1,105,426 and US Patents Nos. 3,325,506, 3,336,192 and 3,478,046 disclose the use of certain N-aryl-(4-thiazolyl)amidines as intermediates in the synthesis of benzimidazoles having antihelmintic properties. However, there is no disclosure of any therapeutic utility for these amidines.

The compounds according to the present invention are potent and selective 5-HT_2A receptor antagonists, suitably having a human 5-HT_2A receptor binding affinity (K₁) of 1000 nM or less, typically of 500 nM or less and preferably of 100 nM or less. The compounds of the invention may possess at least a 10-fold selective affinity, suitably at least a 20-fold selective affinity and preferably at least a 50-fold selective affinity, for the human 5-HT_2A receptor relative to the human dopamine D₂ receptor and/or the human IKr receptors. Many compounds also show selectivity relative to the human 5-HT_2c receptor. According to the invention there is provided a pharmaceutical composition comprising a compound of formula I:

(I)

or a pharmaceutically acceptable salt or hydrate thereof, wherein: n is O, 1, 2 or 3;

X is S or N-C_Malkyl; each R'is independently selected from halogen,

CF₃ and OCF₃; and R² represents H, Ci_₆alkyl, C₃.₆cycloalkyl-(CH₂)_m-. phenyl-(CH₂)_m-, or heteroaryl-(CH₂)_m-, where m is 0 or 1 and the phenyl and heteroaryl groups bear 0-3 substituents selected from halogen,

Ci- ₄alkoxy, CF₃ and OCF₃, and where the heteroaryl group contains 5 or 6 ring atoms; and a pharmaceutically acceptable carrier.

The invention further provides a compound of formula I as defined above, or a pharmaceutically acceptable salt or hydrate thereof, for use in medicine.

The invention further provides the use of a compound of formula I as defined above, or a pharmaceutically acceptable salt or hydrate thereof, for the manufacture of a medicament for treatment or prevention of a condition mediated by 5-HT_2A receptor activity.

The invention further provides a compound of formula I as defined above, or a pharmaceutically acceptable salt or hydrate thereof with the proviso that when X is S, R² is not H.

The invention further provides a method of treatment of a subject suffering from or prone to a condition mediated by 5-HT_2A receptor activity which comprises administering to that subject an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof.

In one aspect of the invention, the condition mediated by 5-HT_2A receptor activity is sleep disorder, in particular insomnia. In a further aspect of the invention, the condition mediated by 5-HT_2A receptor activity is selected from psychotic disorders (such as schizophrenia), depression, anxiety, panic disorder, obsessive-compulsive disorder, pain, glaucoma, eating disorders (such as anorexia nervosa), dependency or acute toxicity associated with narcotic agents such as LSD or MDMA, and hot flushes associated with the menopause. Where a variable occurs more than once in formula I or in a substituent group thereof, the individual occurrences of that variable are independent of each other, unless otherwise specified.

As used herein, the expression "Ci_-Xalkyl" where x is an integer greater than 1 refers to straight- chained and branched alkyl groups wherein the number of constituent carbon atoms is in the range 1 to x. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl. Derived expressions such as "Ci.

₄alkoxy" are to be construed in an analogous manner.

The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred and fluorine particularly preferred. The expression "C₃-6cycloalkyl" as used herein refers to nonaromatic monocyclic hydrocarbon ring systems comprising from 3 to 6 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexenyl.

For use in medicine, the compounds of formula I may be in the form of pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of formula I or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, benzenesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.

When the compounds according to the invention have one or more asymmetric centres, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention. When the compounds of formula I have two or more tautomeric forms, it is to be understood that all such tautomeric forms and mixtures thereof in any proportion are encompassed within the scope of the present invention.

In formula I, X represents S or N-Ci_₄alkyl (such as N-CH₃). In a particular embodiment, X represents S. Each R¹ is independently selected from halogen (such as F, Cl or Br),

(such as methyl, ethyl, n-propyl, isopropyl or t-butyl), Ci.₄alkoxy, (such as methoxy), CF₃ and OCF₃. Typically, n is 0, 1 or

2, and in a particular embodiment n is 1.

Examples of substitution represented by (R')_n include: 2,4-difluoro, 2,4-dimethyl, 4-fluoro, A- chloro, 4-bromo, 2-chloro, 4-methyl, 4-ethyl, 4-isopropyl, and 4-methoxy. R² represents H,

C₃.6cycloalkyl-(CH₂)_m-, phenyl-(CH₂)_m- or heteroaryl-(CH₂)_m- where m is 0 or 1 and the phenyl and heteroaryl groups bear 0-3 substituents as defined previously. In a particular embodiment, m is 0. Phenyl or heteroaryl groups comprised by R² are preferably unsubstituted or monosubstituted. Typical substituents include halogen (especially F),

(especially methyl) and

CF₃. Heteroaryl groups comprised by R² may be 5- or 6-membered, but are preferably 6-membered (such as pyridyl, pyrimidinyl or pyrazinyl). Specific examples of groups represented by R include H, methyl, phenyl, 4-trifluoromethylphenyl and 3 -pyridyl.

Specific compounds useful in this invention include those compounds exemplified hereinafter and their pharmaceutically acceptable salts. - A -

The compounds of formula I have an activity as antagonists of the human 5-HT_2A receptor and hence find use in the treatment or prevention of disorders mediated by 5-HT_2A receptor activity. The compounds useful in the invention are typically used in the form of pharmaceutical compositions comprising one or more compounds of formula I and a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, transdermal patches, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. The principal active ingredient typically is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate and dicalcium phosphate, or gums, dispersing agents, suspending agents or surfactants such as sorbitan monooleate and polyethylene glycol, and other pharmaceutical diluents, e.g. water, to form a homogeneous preformulation composition containing a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. Tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, liquid- or gel-filled capsules, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil or coconut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, poly(ethylene glycol), poly(vinylpyrrolidone) or gelatin.

In the treatment envisaged herein, for example of insomnia or schizophrenia, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day but preferably once per day, for example before going to bed. If desired, the compounds according to this invention may be co-administered with another sleep inducing or anti-schizophrenic or anxiolytic medicament. Such co-administration may be desirable where a patient is already established on sleep inducing or anti-schizophrenic or anxiolytic treatment regime involving other conventional medicaments. In particular, for the treatment of sleep disorders, the compounds of the invention may be co-administered with a GABA_A receptor agonist such as gaboxadol, or with a short term and/or rapid-onset hypnotic such as Zolpidem, or a benzodiazepine, a barbiturate, a prokineticin modulator, an antihistamine, trazodone, or derivative of trazodone as disclosed in WO 03/068148.

According to a further aspect of the invention, there is provided the combination of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof and gaboxadol for use in treatment or prevention of sleep disorders, schizophrenia or depression.

Also according to the invention, there is provided a method of treatment or prevention of sleep disorders, schizophrenia or depression comprising administering to a subject in need thereof a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof in combination with gaboxadol. As used herein, the expression "in combination with" requires that therapeutically effective amounts of both a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof and gaboxadol are administered to the subject, but places no restriction on the manner in which this is achieved. Thus, the two species may be combined in a single dosage form for simultaneous administration to the subject, or may be provided in separate dosage forms for simultaneous or sequential administration to the subject. Sequential administration may be close in time or remote in time, e.g. one species administered in the morning and the other in the evening. The separate species may be administered at the same frequency or at different frequencies, e.g. one species once a day and the other two or more times a day. The separate species may be administered by the same route or by different routes, e.g. one species orally and the other parenterally, although oral administration of both species is preferred, where possible. According to a further aspect of the invention there is provided a pharmaceutical composition comprising, in a pharmaceutically acceptable carrier, a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof and gaboxadol.

The invention further provides the use, for the manufacture of a medicament for treatment or prevention of sleep disorders, schizophrenia or depression, of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof and gaboxadol.

The invention further provides a kit comprising a first medicament comprising a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof and a second medicament comprising gaboxadol together with instructions for administering said medicaments sequentially or simultaneously to a patient suffering from a sleep disorder, schizophrenia or depression. As used herein, the term "gaboxadol" is inclusive of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol in free base or zwitterionic form and also of pharmaceutically acceptable acid addition salts thereof such as the hydrochloride salt. Most suitably, gaboxadol is in the form of a crystalline monohydrate of the zwitterionic form. Compounds of formula I may be prepared by methods disclosed in GB 1,105,426 and US 3,478,046. A preferred route involves reaction of an aniline (1) with a nitrile (2) in the presence of AICI3:

(1 ) (2)

where n, X, R¹ and R² have the same meanings as before.

The reaction may be carried out by heating a neat mixture of the reagents at above 200⁰C under an inert atmosphere.

Where they are not themselves commercially available, the starting materials and reagents described above may be obtained from commercially available precursors by means of well known synthetic procedures and/or the methods disclosed in the Examples section herein.

It will be appreciated that any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further desired compound of formula I using techniques known from the art. Where the above-described processes for the preparation of the compounds of use in the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as di-p-toluoyl-D- tartaric acid and/or di-p-toluoyl-L-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T. W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

Compounds were tested for their binding to the 5-HT_2A receptor and to other receptors such as 5-HT₂c and IKr using the methodology described in Fletcher et al, J. Med. Chem., 2002, 45, 492-503. EXAMPLES

Preparation of nitrile intermediates (Method A)

The desired carboxylic acid (1 g) was refluxed in 10 ml of SOCI₂ for 2h. SOCI₂ was removed under reduced pressure. Dry toluene was added. The solution was cooled to O⁰C with ice bath. Ammonia was bubbled in toluene for 30 min. Solid was filtered and the filtrate was concentrated to obtain the crude amide which was used to next step without further purification.

To a stirred mixture of amide (1.0 eq) and Et₃N (4.5eq) was added dropwise (CF₃CO)₂θ (TFFA, 2 eq) at - 78⁰C under N₂. The mixture was stirred overnight at room temperature. Ice water was added to destroy TFAA. The mixture was extracted with CH₂Cl₂. The organic phases were combined, dried over Na₂Sθ₄ and concentrated to afford the product.

Preparation of nitrile intermediates (Method B)

The desired carboxylic acid (1.0 g, 1 eq), t-butylamine (1 eq), EDCI (1.2 eq), NEt₃ (2 eq) and HOBT (20 mg) were dissolved in 15ml of dichloromethane. The solution was stirred at room temperature over night, a further 15 ml dichloromethane added, and the solution washed with 1 N NaOH and brine, dried and concentrated to afford the amide. This was refluxed in POCl₃ overnight, evaporated under reduced pressure, and the crude product purified by column chromatography. EDCI = l-ethyl-3-(3'-dimethylaminopropyl)carbodiimide HOBT = 1 -hydroxybenzotriazole.

Preparation of Products

To a mixture of nitrile (60 mg) and substituted aniline (leq) was added AlCl₃ (leq). The mixture was heated up to 200⁰C and stirred for 20 min under N₂. The mixture was cooled and the product purified by preparative HPLC. Using these methods, the following were prepared:

Claims

A pharmaceutical composition comprising a compound of formula I:

©

or a pharmaceutically acceptable salt or hydrate thereof, wherein: n is O, 1, 2 or 3; X is S or N-C_Malkyl; each R'is independently selected from halogen,

CF₃ and OCF₃; and

R represents H,

C₃_6cycloalkyl-(CH₂)_m-. phenyl-(CH₂)_m-, or heteroaryl-(CH₂)_m-, where m is O or 1 and the phenyl and heteroaryl groups bear 0-3 substituents selected from halogen,

2. A compound according to formula I as defined in claim 1, or a pharmaceutically acceptable salt or hydrate thereof, for use in medicine.

3. A compound according to formula I as defined in claim 1, or a pharmaceutically acceptable salt or hydrate thereof, for use in treatment or prevention of a condition mediated by 5-HT_2A receptor activity.

4. A compound a defined in claim 3 wherein said condition is selected from psychotic disorders (such as schizophrenia), depression, anxiety, panic disorder, obsessive-compulsive disorder, pain, glaucoma, eating disorders (such as anorexia nervosa), dependency or acute toxicity associated with narcotic agents such as LSD or MDMA, and hot flushes associated with the menopause.

5. The use of a compound according to formula I as defined in claim 1, or a pharmaceutically acceptable salt or hydrate thereof, for the manufacture if a medicament for treatment or prevention of a condition selected from psychotic disorders (such as schizophrenia), depression, anxiety, panic disorder, obsessive-compulsive disorder, pain, glaucoma, eating disorders (such as anorexia nervosa), dependency or acute toxicity associated with narcotic agents such as LSD or MDMA, and hot flushes associated with the menopause.

6. A compound according to formula I as defined in claim 1, or a pharmaceutically acceptable salt or hydrate thereof, with the proviso that when X is S, R is not H.

7. A compound according to claim 6 wherein n is 0, 1 or 2 and each R¹ is independently selected from F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, t-butyl, methoxy, CF₃ and OCF₃.

8. A compound according to claim 7 wherein (R')n is selected from 2,4-difluoro, 2,4- dimethyl, 4-fluoro, 4-chloro, 4-bromo, 2-chloro, 4-methyl, 4-ethyl, 4-isopropyl, and 4-methoxy.

9. A compound according to any of claims 6-8 wherein R is selected from H, methyl, phenyl, 4-trifluoromethylphenyl and 3-pyridyl.

10. A compound according to any of claims 6-9 wherein X represents S.