GB2301774A

GB2301774A - Piperidine derivatives as 5-HT-2C receptor antagonists

Info

Publication number: GB2301774A
Application number: GB9608631A
Authority: GB
Inventors: Elaine Anne Forster; Allan Fletcher
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1995-04-26
Filing date: 1996-04-25
Publication date: 1996-12-18
Anticipated expiration: 2016-04-25
Also published as: GB9508438D0; GB9608631D0; GB2301774B

Abstract

Piperidine derivatives of general formula I wherein R 1 is 3- or 4-pyridyl and R is hydrogen or fluorine, and R is bonded to any of the vacant naphthalene ring positions, e.g. 5- or 7-, or pharmaceutically acceptable acid addition salts thereof, are useful in the treatment of anxiety, OCD or panic attacks and as 5-HT 2C receptor antagonists.

Description

MEDICAL TREATMENT This invention relates to the use of certain piperidine derivatives in the treatment of anxiety, OCD and panic attacks.

The piperidine derivatives are those of general formula

or salts thereof, wherein R1 is 3- or 4-pyridyl, R is hydrogen or fluorine, and is bonded to any of the vacant naphthalene ring positions, e.g. 5- or 7-.

The piperidine derivatives of formula (I) and their method of preparation are disclosed in European Patent Publication No 228795 (John Wyeth & Brother Limited). The compounds have now surprisingly been found to inhibit the function of the 5-HT2C receptor.

The preferred compounds of formula (I) are: N-[[[1-[(6-fluoro-2-naphthalenyl)methyl]-4 piperidinyl]amino]carbonyl]-3-pyridinecarboxamide or N [[[1-[(6-fluoro-2-naphthalenyl)methyl]-4-piperidinyl]- amino]carbonyl]-4-pyridine carboxamide and their pharmaceutically acceptable acid addition salts.

The present provides in one aspect, a method of treating anxiety, obsessive compulsive disorder (OCD) or panic attacks which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable acid addition salt thereof. In a second aspect the invention provides the use of a compound of formula (I) as defined above or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment of anxiety, obsessive compulsive disorder (OCD) or panic attacks. Suitably, the mammal is a human.

Suitably, the compound is administered repeatedly.

In this specification the terms "treatment" and "treating" relate to the administration of the compounds to prevent the disorder as well as to treat the disorder or to alleviate the symptoms of the disorder.

The compounds may be used in their free base form or as acid addition salts.

Examples of acid addition salts are those formed from inorganic and organic acids, such as sulphuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic, ptoluenesulphonic, oxalic and succinic acids.

The compounds may be used for treating anxiety, OCD or panic attacks in the form of pharmaceutical compositions which comprise a compound of formula I or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier.

Any suitable carrier known in the art can be used to prepare the pharmaceutical composition. In such a composition, the carrier is generally a solid or liquid or a mixture of a solid or liquid.

Solid form compositions include powders, granules, tablets, capsules (e.g. hard and soft gelatine capsules), suppositories and pessaries. A solid carrier can be, for example, one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aides, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99%, eg from 0.03 to 99%, preferably 1 to 80% of the active ingredient.Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier, which is thus in association with it.

Similarly cachets are included.

Liquid form compositions include, for example, solutions, suspensions, emulsions, syrups, elixirs and pressurised compositions. The active ingredient, for example, can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilisers or osmo-regulators.Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, eg cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols, eg glycerol and glycols) and their derivatives, and oils (eg fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection.

Sterile solutions can also be administered intravenously.

When the compound is orally active it can be administered orally either in liquid or solid composition form.

Preferably the pharmaceutical composition is in unit dosage form, eg as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged composition, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquid. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

The quantity of the active ingredient in unit dose of composition may be varied or adjusted from 0.5 mg or less to 750 mg or more, according to the particular need and the activity of the active ingredient.

The following Examples illustrate the invention: Example l Presaratlon of Tablets Amount per tablet ma N-[[[l-[(6-fluoro-2-naphthalenyl) methyl] -4-piperidinyl] amino] carbonyl]-3-pyridinecarboxamide 1 5 10 Microcrystalline cellulose 49.25 47.25 44.75 Modified food corn starch 49.25 47.25 44.75 Magnesium stearate 0.5 0.5 0.5 Tablets are prepared from bulk amounts of ingredients in the proportions given above.

All of the active compound, cellulose and a portion of the corn starch are mixed and granulated to 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 1, 5 and 10 mg of the active ingredient per tablet.

Example 2 Preparatlon of powder filled capsules Amount ma N-[[[1-[(6-fluoro-2-naphthalenyl) methyl] -4-piperidinyl] amino] carbonyl-4-pyridine carboxamide 10 15 Avicel 45 Lactose 153 Starch (1500 NF) - 117 Sodium starch glycollate Magnesium stearate 2 2 The formulations are prepared by admixing the ingredients in the proportions given above and filling two-part hard gelatin capsules with the required amount of the resulting mixture to give capsules containing 10 or 15 mg of the active compound.

Example 3 E-[[[1-[(6-Fluoro-2-naphthalenyl)methyl]-4- piperidinyl]amino]carbonyl-3-pyridine carboxamide, dihydrochloride, hemihydrate (WY 27587) (10 mg/kg p.o.

b.i.d.) or vehicle was administered to rats for 14 days and behavioural testing performed 24 hours after the last dose.

The hypolocomotor response (cf Knight and Fletcher, 1989, Br J Pharmacol., 97, 461P) to 6-chloro-2-(1- piperazinyl)pyrazine hydrochloride) (MK-212) (0.75 and 2.0 mg/kg i.p. 30 min predose; n=6) was measured for a 2 min period using automated open fields. Results are set out in Table 1.

Table 1: Effects of Wv 27587 on MK-212-induced hypolocomotion MK-212 Locomotor activity (mg/kg i.p.) mean + standard error mean Vehicle WY 27587 0 120.5#5.3 127.8i7.1 0.75 92.3i7.3* 110.7#2.9* 2 28.3+7.1** 66.8i4.1** *P < 0.05; **P < 0.001 versus respective vehicle-controls; P < 0.05 versus respective chronic-vehicle group using twoway ANOVA/Fisher's protected LSD (locomotor activity).

Claims

CLAIMS:

1. A piperidine derivative of general formula I

wherein R1 is 3- or 4-pyridyl and R is hydrogen or fluorine, and R is bonded to any of the vacant naphthalene ring positions, e.g. 5- or 7-, or a pharmaceutically acceptable acid addition salt thereof, for use as a 5-HT2C receptor antagonist.

2. A piperidine derivative of general formula I

wherein R1 is 3- or 4-pyridyl and R is hydrogen or fluorine, and R is bonded to any of the vacant naphthalene ring positions, e.g. 5- or 7-, or a pharmaceutically acceptable acid addition salt thereof, for use in the treatment of anxiety, OCD or panic attacks.

3. The use of a piperidine derivative of general fcrmula

wherein R1 is 3- or 4-pyridyl and R is hydrogen or fluorine, and R is bonded to any of the vacant naphthalene ring positions, e.g. 5- or 7-, or a pharmaceutically acceptable acid addition salt thereof, in the manufacture of a medicament for use as a 5 HT2C receptor antagonist.

4. The use of a piperidine derivative of general formula

wherein R1 is 3- or 4-pyridyl and R is hydrogen or fluorine, and R is bonded to any of the vacant naphthalene ring positions, e.g. 5- or 7-, or a pharmaceutically acceptable acid addition salt thereof, in the manufacture of a medicament for the treatment of anxiety, OCD or panic attacks.

5. A use as claimed in claim 3 or claim 4 wherein the compound of formula I is: -[[[l-[ (6-fluoro-2-naphthalenyl)methyl-4- piperidinyl]amino]carbonyl]-3-pyridinecarboxamide; or N-[[[1-[(6-fluoro-2-naphthalenyl)methyl]-4-piperidinyl]- amino]carbonyl]-4-pyridine carboxamide or a pharmaceutically acceptable acid addition salt of one of these compounds.

6. A pharmaceutical composition comprising a piperidine derivative of general formula I

wherein R1 is 3- or 4-pyridyl and R is hydrogen or fluorine, and R is bonded to any of the vacant naphthalene ring positions, e.g. 5- or 7-, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable diluent or carrier for use in the treatment of anxiety, OCD or panic attacks.