WO2001079188A1

WO2001079188A1 - Antihistaminic compounds

Info

Publication number: WO2001079188A1
Application number: PCT/GB2001/001748
Authority: WO
Inventors: Yusuf Khwaja Hamied; Vithal Madhvarao Kulkarni
Original assignee: Cipla Limited; Wain, Christopher, Paul
Priority date: 2000-04-17
Filing date: 2001-04-17
Publication date: 2001-10-25
Also published as: AU4859301A; GB0009479D0

Abstract

Antihistaminic compounds of formula (I) wherein: X is an aliphati c hydrocabonylene linker of preferably C2-C10, such as ethylene or caboxyethylene, wherein the only bond rotation in the linker is provided by an ethylene radical and X is preferably ethylene or carboxyethylene; and Y is a carbocyclic group, a heterocyclic group, a carbocyclic arenyl, a heterocyclic arenyl group, a polycyclic hydrocarbonyl, a heteropolycyclic group or theophylline; and wherein Y can be optionally substituted as defined.

Description

ANTIHISTAMINIC COMPOUNDS The present invention relates to antihistaminic compounds, and more particularly to derivatives of the antihistaminic compound cetirizine (II) ([2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]acetic acid)

(II)

Cetirizine is an antihistamine and is typically delivered in an orally acceptable dosage form. Its principal effects are mediated via selective inhibition of peripheral H, receptors. Cetirizine is indicated for relief of symptoms associated with seasonal allergic rhinitis, perennial allergic rhinitis and for the treatment of the uncomplicated skin manifestations of chronic idiopathic urticaria.

Whilst cetirizine is a useful agent for treating these indications, it suffers from a number of side-effects, the most common of which is drowsiness. Less common, but significant, side-effects include fatigue, dry mouth, dizziness, headache and nausea. The most likely reason why cetirizine induces drowsiness is that it can cross the blood-brain barrier. However, derivatives of cetirizine which incorporate more hydrophobic groups to block blood-brain barrier transport can lead to an unacceptable loss in antihistaminic potency.

For example, the antihistamine clocinizine (III) (l-[(4- chlorophenyl)phenylmethyl]-4-(3-phenyl-2-propenyl)piperazine), shares the

(HI)

(4-chlorophenyl)phenylmethyl piperazinyl part with cetirizine, but instead of the more hydrophilic carboxyl group it has a more hydrophobic phenyl group. However, clocinizine is markedly less active than cetirizine.

We have now found that it is possible to provide compounds which are more active antihistamines than cetirizine, but which are also more hydrophobic.

According to one aspect, the present invention provides an antihistaminic compound of formula (I)

wherein:

X is an aliphatic hydrocarbonylene linker; Y is a carbocyclic group, a heterocyclic group, a polycyclic hydrocarbonyl group, a heteropolycyclic group, a carbocyclic arenyl group, a heteropolycyclic arenyl group, or theophylline; and

Y is optionally substituted with at least one substituent, the or each substituent being chosen from linear or branched C,-C₂₀ alkyl optionally substituted with one or more carbocyclic or heterocyclic groups, or a substituent defined herein up to C₂₀ cycloalkyl optionally including one or more heteroatoms from O, N and S, up to C₂₀ bicycloalkyl optionally including one or more heteroatoms from O, N and S, up to C₂₀ polycycloalkyl optionally including one or more heteroatoms from O, N and S, linear or branched C,-C₁₀ haloalkyl, linear or branched C,-C₁₀ perhaloalkyl, linear or branched C₂-C₁₀ perhaloalkenyl, linear or branched C₂-C₁₀ alkenyl, linear or branched C₂-C₁₀ alkynyl, linear or branched C,-C₁₀ alkoxy, linear or branched C,-C_I0 alkylthio, linear or branched C[-C_I0 alkoxy (linear or branched C,-C,₀ alkyl), linear or branched C_rC₂₀ alkoxycarbonyl, linear or branched C,-C₁₀ hydroxyalkyl, linear or branched aminoalkyl, aryl, substituted aryl, naphthyl, substituted naphthyl phenyl, heteroaryl, halogen, nitrile, nitro, amino, linear or branched C_rC₁₀ alkyl amino, linear or branched C,-C₁₀ dialkyl amino linear or branched C,-C₂₀ alkoxycarbonyl, hydroxyl, formyl acetyl, carboxyl, carbonyl, amido, C,-C₅ alkyl amido C_rC₅ dialkylamido, aroyl, benzoyl, arylamino, diarylamino, aryl C,-C₁₀ alkyl amino, aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino, indolino, piperazino, C,-C₅ N-alkyl piperazino or N-aryl piperazino; and each cyclic substituent can in turn be substituted by one or more substituents as defined herein characterised in that the only bond rotation in the X linker is provided by an ethylene radical.

Preferably the X linker is a C₂ - C,₀ aliphatic hydrocarbonyl linker such as C₃, C₅ or C₈, but it is preferably an ethylene or carboxyethylene radical.

Without wishing to be bound by theory, we believe that the X linker between the piperazinyl part and the Y part requires a flexible carbon- carbon bond wherein the bond between each carbon atom and from each carbon atom is freely rotatable. We further believe that this flexibility feature aids the interaction of the compounds according to the invention with the H,-receptor.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. According to a further aspect, the present invention provides a compound of the invention for use as a medicament.

The present invention also provides the use of a compound of the present invention in the manufacture of a medicament for the treatment of antihistaminic conditions.

According to a further aspect of the present invention, there is provided the use of 4-chlorobenzhydrylpiperazine ethylchloride to make a compound according to the present invention..

According to a further aspect of the present invention, there is provided the use of 4-chlorobenzhydrylpiperazine to make a compound according to the present invention.

The compounds of the present invention can be formulated for administration to a patient in any convenient manner, for example for oral or parenteral routes of administration. We presently prefer an oral dosage tablet wherein a core containing the active ingredient is coated with an enteric coating. However, the composition may also be provided as a flavoured syrup to mask any unpleasant taste. An injectable formulation is one embodiment of a composition suitable for parenteral administration.

In order that the invention may be more fully understood, reference will be made to the following Examples, by way of illustration only. Example 1

Synthesis of 4-chlorobenzhydrylpiperazine ethylchloride.

4-chlorobenzlhydrylpiperazine ethylchloride is an intermediate for making many of the compounds of the present invention.

20g (0.04944 moles) of 4-chlorobenzhydrylpiperazine ethanol dihydrochloride was dissolved in a 100ml methanol in a 250ml three necked round bottom flask under stirring. To the clear solution 4g (0.1 moles) of sodium hydroxide was added and mixture was stirred for 30 minutes. Sodium chloride obtained was filtered and distilled off methanol completely. Chloroform (100ml) was added to the same flask stirred for 15 minutes. To the clear solution 40ml thionyl chloride was added and reaction mixture was refluxed for 5-6 hrs. Solid precipitated out was filtered.

The filtered solid was transferred to a 500ml round bottom flask containing 200ml acetonitrile and 5.2g (0.5 moles) of sodium carbonate, the mixture was stirred. The reaction mixture was refluxed for 2 hrs and filtered. Acetonitrile was distilled out under reduced pressure to obtain free base. Yield : 15.53g (90%) M.P. : 196-198°C

TLC : Mobile phase : Benzene : MeOH (10:l) Rf: 0.8 Spectral Characteristics: 'H NMR CCDCy

IR(KBr) cm ¹ presence of -OH peak. Example 2

Synthesis of l(4-chlorobenzhydryl)-4-ethyl-[2'[4"-(2-hydroxy- benzhydryl]piperidine]piperazine

2g (0.005730 moles) of 4-chlorobenzhydrylpiperazine ethyl chloride was introduced into a 100ml three necked bottom flask containing 30ml dry DMF, 0.8292g (0.006 moles) of anhydrous potassium carbonate and 0.002g of potassium iodide. The reaction mixture was stirred for 30 minutes. To the same flask 1.52g (0.005730 moles) of azacyclonol was added. The reaction mixture was heated to 100°C for 16 hrs and then allowed to cool to 30°C. A solid separated out by quenching reaction mixture in a ice under stirring. The solid product so obtained was filtered and dried in oven at 60°C for 4 hrs. Yield : 2.8g (84.31%) M.P. : 130-134°C

TLC : Mobile Phase : Et.Ac : Benzene : Ammonia (5 : 2 : 0.2) Rf : 0.6 Spectral characteristics: Η NMR (CDC1₃)

IR (KBr) cm^"1

3435.5 (-O-H)

2900-3000 (-C-H str.) Example 3

Synthesis of l-4-chlorobenzhydryl)-4-ethyl-2"[2-methyl-4H- pyrido[ 1 ,2-a]pyrimidin-4-one] piperazine

4G (0.01396) of 4-chlorobenzhydryl piperazine was dissolved in 3 OmI DMF in a three necked 100ml round bottom flask equipped with condensor and thermometer pocket. To the clear solution 1.939g (0.014) of potassium carbonate, 3.134g (0.01396) of pyridopyrimidinone and catalytic amount of potassium iodide was added under stirring. The reaction mixture was refluxed for 10 hrs and then cooled to 25-30°C under stirring. A solid was precipitated out by pouring the reaction mixture in ice-cold water. The solid material obtained was filtered and washed with water thoroughly. The product was dried in oven at 50°C for 4 hrs. Yield : 4.63g (70%) M.P. : 85-90°c

TLC : Mobile Phase : Benzene : Methanol (5 : 0.2) Rf : 0.5 Spectral characteristics Η NMR (CDC1₃)

IR (KBr) cm^"1 1692 (CO) 1098 (C-Cl str.) Example 4

Synthesis of (4-chlorobenzhydryl)-4-ethyl-[2'[4"-(p-chlorophenyl)- 4"-hydroxy]piperidine]piperazine

Compound - 3

2g (0.005730 moles) of 4-chlorobenzhydryl piperazine ethylchloride was introduced in to 100ml three necked round bottom flask containing 1.5g (0.0178 moles) of sodium bicarbonate, 15ml toluene and 0.002g of potassium iodide under stirring. Stirring was continued for 30 minutes. 1.3g (0.005730) of 4-hydroxy-4-(p-chlorophenyl)-piperidine was added and the mixture was refluxed for 16 hrs. The reaction mixture was cooled to 30°C and filtered. Toluene was distilled out completely under vacuum. Water was added to the residue under stirring. Solid precipitated out was filtered and washed with water. The product was dried in oven at 50°C for 4 hrs. Yield : 2.40g (80%) M.P. : 96-100°C

TLC : Mobile Phase : Chloroform : Methanol (9 : 1) Rf : 0.5 Spectral characteristics: 'H NMR CDC

IR (KBr) cm ¹ 3407 (O-H) 2948 (C-H str.) 1089 (C-Cl str.) Example 5

Synthesis of l-(4-chlorobenzhydryl)-4-(3-phenyl-3-propanone)- piperazine

Compound - 4 2g (0.0068) of 4-chlorobenzhydryl piperazine was dissolved in 15ml toluene in a 50ml three necked round bottom flask equipped with thermometer pocket and condensor. To the clear solution 1.126g (0.0068) of 3- chloropropiophenone, 1.2g (0.0086) of potassium carbonate and catalytic amount of potassium iodide was added under stirring. The reaction mixture was refluxed for 4 hrs. and filtered to remove inorganic material. The toluene was distilled out under vacuum to obtain oily residue. The solid was separated out by addition of hexane to the oily material under stirring. The solid product was filtered and dried in oven at 50°C for 2 hrs. Yield : 2.45g (84%) M.P. : 105-108°C

TLC : Mobile Phase : Benzene : MeOH (10 : 0.8) Rf : 0.42 Spectral characteristics: Η NMR (CDC1₃)

IR (KBr) cm^'1 2913-3000 (C-H str.) 1681 (C=0) 1089 (C-Cl str.) Example 6

Synthesis of l-(4-chlorobenzhydryl)-piperazine-4-ethyl-2'[4"(2,3. 4-trimethoxy benzyl)]piperazine

Compound 5 2g (0.005770 moles) of 4-chlorobenzhydryl piperazine ethyl chloride and 1.9426g (0.005730 moles) of trimetazidine were added in a 100ml three necked round bottom flask containing 20ml dry DMF, 1.575g (0.01 14 moles) of potassium carbonate and 0.00 lg of potassium iodide. The reaction mixture was heated to 100-1 10°C for 8 hrs and then allowed to cool to 30°C. It was P T/GB01/01748

14 then added to a beaker containing ice water under stirring. The product was extracted with chloroform (2 1.5ml) and chloroform layer was washed with water. The washed chloroform layer was dried over an sodium sulfate and the chloroform was evaporated completely. Etheral hydrochloride was added to the residue and the pH was adjusted to 2 under stirring precipitating a solid.

The solid was filtered and dried in a vacuum at 60°C.

Yield : 2.8g (75%)

M.P. : 234-236°C

TLC : Mobile Phase : Ethyl acetate Rf : 0.42

Spectral characteristics:

Η NMR (DMSOd₆)

IR ( Br) cm^'1 2960-3000 (C-H str.) 1099 (C-O-C str.) Example 7

Synthesis of l -(p-chlorobenzhydryl)4-ethyl-2'-[l ,3-dimethyl xanthinej-piperazine

Compound - 6

2g (0.0047 moles) of 4-chlorobenzhydryl piperazine ethylchloride dihydrochloride was added to a 100ml three necked bottom flask containing 30ml DMF, 2.7g (0.01950) moles of potassium carbonate and 0.00 lg of potassium iodide. The reaction mixture was stirred for 30 minutes. To the same flask 0.853g (0.0047 moles) of theophylline was added. The reaction mixture was heated to 100-1 10°C for 16 hrs and then allowed to cool to 30°C. A solid was precipitated by quenching the reaction mixture in icy water under stirring. The solid product obtained was filtered and dried in oven at 50°C for 4 hrs.

Yield 2.03g (87%)

M.P. 98-100°C

TLC Mobile Phase : Ethyl acetate Rf : 0.5 Spectral characteristics: ■H NMR (CC1⁴)

Η NMR CC1.

IR (KBr) cm^"' 2960 (C-H str.) 1653 (C=O str.)

Example 8 Biological Activity Testing

Antihistaminics are evaluated in vitro by Magnus procedure (see Ghosh, M N and Schild, H O, Fundamentals of Experimental Pharmacology, 63, 1971 ; Schmidt, L and Seeger E, Arzneim. Forsch (Drug Research), 6, 22, 1956) in which the minimum amount of drug is measured which relaxes histamine-induced spasm in an isolated strip of guinea pig's small intestine immersed in Tyrode solution. The isolated ileum of guinea pig is the most sensitive and accurate test object for the assay of histamine. A piece of terminal ileum was suspended in an isolated bath in Tyrode solution containing 0.6mg/ml atropine sulphate. This eliminates or reduces contractile responses due to cholinergic agents, causes relaxation of the guinea pig ileum producing a fixed base line and reduces or eliminates spontaneous contractile activity in the guinea pig ileum. The bath was kept at 35°C, and kept oxygenated with a continuous supply of oxygen or air. A frontal writing lever magnified 10 times and with tension of lg was used for recording the contractions.

Contraction of the guinea pig ileum to histamine was observed for 30 seconds; relaxation during rinsing or washing of the bath with 2 or 3 changes of Tyrode solution was also almost complete in 1.5 minutes. Hence contractions for exactly 30 seconds were regularly obtained at intervals of 1.5 minutes. The tissue preparation gave good response to histamine in various concentration range (lμg-lOOμg). The results were analysed using the 'Latin Square' technique to provide a standard curve of histamine response, and the mean contraction of the responses for each dose of histamine was calculated. For quantitative estimation of IC₅₀ value of the synthesized compounds, the one single standard dose of histamine was repeated until the fixed standard length of contraction of histamine response was obtained. The mean length of contraction of standard histamine was evaluated as the 100%) std. response, and this was used to determine the IC₅₀ and IC₁₀₀ for the antihistamine (antagonist) to be tested. Antagonists were added to the Tyrode solution simultaneously with the standard dose of histamine and the contraction response was determined. The tissue was washed with fresh Tyrode solution before addition of a different antagonist concentration. Comparative compounds

Cetirizine

Clocinizine

Comparative

l-(4-chlorobenzhydryl)-4-(3-phenyl-3-propanol)-piperazine

Comparative

l-(4-chlorobenzhydryl)-4-methyl(2-cyanobiphenyl)-piperazine Comparative

l-(4-chlorobenzhydryl)-4-(2(2',4'-dichlorobenzene)ethan-z-one

Comparative

l-(4-chIorobenzhydryl)-4-(2(2',4'-difluorobenzene)ethan-2-one)piperazine

The results of the Magnus procedure experiment for each of compounds 1 to 6 and the comparative compounds 1 to 6 and the comparative compounds cetirizine, clocinizine and comparative compounds 1 to 4 are shown in Table 1 below.

Table 1: Results of Magnus procedure experiments

In the above table, the % inhibition values were determined from kaymograph. The log[C] vs % inhibition was plotted to get ED₅₀ values for the compounds 1-11. Further, -IogED_J0 was calculated to obtain PA₂ values.

As will be seen by comparing the ED50 and PA₂ (log ED50) values, compounds 1 to 4 are potent H,-receptor antagonist by reference to the known antihistamine cetirizine and clocinizine, whilst compounds 5 and 6 show a moderate, but significant, increase in potency. Comparative compound 1 has a similar activity to cetirizine, but it is more lipophilic.

The calculated LogP of the synthesized and tested compounds between 5-7.7 was found optimum for good H_rreceptor antagonist activity. Hence logP, a parameter for lipophilicity, shows that lipophilicity has an important role for eliciting the biological response of these compounds. LogP by its nature governs the pharmacokinetic profile of the compounds. The more lipophilic a compound the less likely it is to cross the blood-brain barrier. Compounds 1 to 6 and comparative compound 1 are therefore less likely to cause drowsiness.

Furthermore, a comparison of the activity of clocinizine and comparative compound 1 with compounds 1 to 6 shows that an important feature of the present invention is that the linker X in formula (I) should be ethylene or a radical including a carbon-carbon bond which is free to rotate. A substituted propylene radical X linker (compare compound 4 and comparative compound 1) including two freely rotatable carbon-carbon bonds results in a less antihistaminically active molecule,

Example 9

Oral dosage tablet containing lOmg of l-(4-chlorobenzhydryl)-4- ethyl-[2'[4"-(2-hydroxybenzhydryl]piperidine] piperazine (compound 1)- hydrochloride.

INGREDIENTS QTY/TAB

(mg)

Compound 1 hydrochloride 10.0

Lactose IP 80.0

Starch IP 25.20

Magnesium stearate IP 2.0

Colloidal Silicon dioxide IP 1.0

Talc IP 1.8 .

120.0

The above formulation includes standard fillers and glidants well known to those of skill in the art. The skilled person will be able to scale-up production to batch size using the above amounts as a guide or with routine experimentation. The processes for dry mixing of the ingredients for tablet compression or for encapsulation into capsules are also well known and will not be discussed further herein.

Tablets so formed may be coated with suitable water soluble or water insoluble polymers or polymers which have pH dependent solubility, as desired.

Claims

CLAIMS:

1. An antihistaminic compound of formula (I)

(I) wherein:

X is an aliphatic hydrocarbonylene linker; Y is a carbocyclic group, a heterocyclic group, a polycyclic hydrocarbonyl group, a heteropolycyclic group, a carbocyclic arenyl group, a heterocyclic arenyl group or theophylline; and

Y is optionally substituted with at least one substituent, the or each substituent being chosen from linear or branched C,-C₂₀ alkyl optionally substituted with one or more carbocyclic or heterocyclic groups, or a substituent defined herein up to C₂₀ cycloalkyl optionally including one or more heteroatoms from O, N and S, up to C₂₀ bicycloalkyl optionally including one or more heteroatoms from O, N and S, up to C₂₀ polycycloalkyl optionally including one or more heteroatoms from O, N and S, linear or branched C,-C_I0 haloalkyl, linear or branched C,-C₁₀ perhaloalkyl, linear or branched C₂-C10 perhaloalkenyl, linear or branched C₂-C₁₀ alkenyl, linear or branched C₂-C₁₀ alkynyl, linear or branched C,-C₁₀ alkoxy, linear or branched C,-C₁₀ alkylthio, linear or branched C,-C₁₀ alkoxy (linear or branched C,-C₁₀ alkyl), linear or branched C , -C₂₀ alkoxycarbonyl, linear or branched C _] -C , ₀ hydroxyalkyl, linear or branched aminoalkyl, aryl, substituted aryl, naphthyl, substituted naphthyl phenyl, heteroaryl, halogen, nitrile, nitro, amino, linear or branched C,-C₁₀ alkyl amino, linear or branched C,-C₁₀ dialkyl amino linear or branched C,-C₂₀ alkoxycarbonyl, hydroxyl, formyl acetyl, carboxyl, carbonyl, amido, C_rC₅ alkyl amido C C₅ dialkylamido, aroyl, benzoyl, arylamino, diarylamino, aryl C C₁₀ alkyl amino, aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino, indolino, piperazino, C,-C₅ N-alkyl piperazino or N-aryl piperazino; and each cyclic substituent can in turn be substituted by one or more substituents as defined herein characterised in that the only bond rotation in the X linker is provided by an ethylene radical.

2. A compound according to claim 1, wherein X is a C₂-C₁₀ aliphatic linker, preferably ethylene or carboxyethylene radical.

3. A compound according to claim 1 or 2, wherein Y is aziridino, pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino, C_rC₅ N-alkyl piperazino or N-aryl piperazino, pyrrolino, pyridino quinolino, pyrimidino, purino, pyrazino, pyrazolino, pteridino, pyridazino or pyridopyrimidinono, or an optionally substituted version thereof.

4. A compound according to claim 1, 2 or 3, wherein the Y group is substituted with a group including an aryl or substituted aryl group.

5. l -(4 -ch l orob enzhydryl)-4 - ethyl [2 ' [ 4 " -(2 -hydroxy- benzhydryl]piper idinejpiperazine.

6. l -4-chlorobenzhydryl)-4-ethyl-"[2-methyl-4H-ρyrido[ l ,2- a]pyrimidin-4-one]piperazine.

7. (4-chlorobenzhydryl-4-ethyl-[2'[4"-p-chlorophenyl)-4"- hydryoxy]piperidine]piperazine.

8. 1 -(4-chlorobenzhydryl)-4-(3-phenyl-3-propanone)piperazine.

9. l -(4-chlorobenzhydryl)-ρiperazine-4-ethyl-2'[4"(2,3 ,4- trimethoxybenzyl)piperazine.

10. A pharmaceutical composition comprising a compound according to any preceding claim and a pharmaceutically acceptable carrier.

11. A compound according to any of claims 1 to 9 for use as a medicament.

12. The use of a compound according to any preceding claim in the manufacture of a medicament for the treatment of an antihistamic condition.

13. The use of 4-chlorobenzhydryl piperazine ethyl chloride to make a compound according to any of claims 1 to 9.

14. The use of a 4-chIorobenzhydryl piperazine to make a compound according to any one of claims 1 to 9.

15. An antihistamine compound substantially as described herein with reference to the accompanying Examples.

16. The use of 4-chlorobenzhydryl piperazine ethyl chloride or 4- chlorobenzhydrylpiperazine substantially as described herein with reference to examples 1 to 7.

17. A pharmaceutical composition for oral administration substantially as described herein with reference to Example 9.