WO1995001793A2

WO1995001793A2 - 5-ht-3-antagonists as topical medicaments for treatment of peripheral disorders associated with pain

Info

Publication number: WO1995001793A2
Application number: PCT/US1994/007488
Authority: WO
Inventors: Philippe Danjou
Original assignee: American Home Products Corp
Current assignee: Wyeth LLC
Priority date: 1993-07-08
Filing date: 1994-07-06
Publication date: 1995-01-19
Anticipated expiration: 1996-01-08
Also published as: GB9314174D0; WO1995001793A3; AU7254494A

Abstract

Known 5-HT3 antagonists of specified formulae, e.g. (endo)-N-[[8-methyl-8-azabicyclo[3.2.1]octan-3-yl)amino]carbonyl]-2-(cyclopropylmethoxy)benzamide or (endo)-1-cyclohexyl-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-4(1H)oxo-quinoline-3-carboxamide or a pharmaceutically acceptable salt thereof, are administered topically for the treatment of peripheral disorders associated with pain.

Description

5 - HT 3 ANTAGONISTS AS TOPICAL MEDICAMENTS FOR TREATMENT OF PERIPHERAL DISORDERS ASSOCIATED WTTH PAIN.

This invention relates to 5-HT3-antagonists.

EP 0323077 B 1 discloses compounds of the general formula

A-CO-NHCW-Y-B (I)

and the pharmaceutically acceptable acid addition salts thereof. In this formula A represents an aromatic radical of the formula

(a) (b),

(c) or (d)

where the free valence is attached to either fused ring of formula (a) or (b),

Rl represents hydrogen or one or more (eg 1 to 3) same or different substituents selected from lower alkyl, a lower alkoxy group [said lower alkoxy group being selected from loweralkyloxy (eg methoxy, ethoxy, propoxy or butoxy), cyclo(lower)alkyloxy, cyclo(lower)alkyl-loweralkyloxy (eg cyclopropylmethoxy), (lower)alkenyl- (lower)alkyloxy (eg allyloxy) and halo(lower)alkyloxy], hydroxy, halogen (eg chlorine), halo(lower)alkyl (eg trifluoromethyl), amino, nitro, carboxamido, phenyl(lower)alkyloxy (in which the phenyl group may be optionally substituted by one or more lower alkyl, loweralkyloxy or halo substituents), (lower)alkylamino, di(lower)alkylamino or acylamino [eg (lower) alkanoylamino or halo(lower) alkanoylamino] Z!-Z² represents CH2-CH, NR2-CH, O-CH, S-CH, CH₂-N,O-N, S-N, NR2-N, CH-NR2 or N-NR2, [where R2 is hydrogen, (lower)alkyl, or phenyl or phenyl(lower)alkyl in which the phenyl groups may optionally be substituted by one or more lower alkyl, lower alkyloxy or halo substituents]

Z3-Z4 represents CH=CH, O-CH₂ or N=CH

Z5 represents N or CH

Z6 represents O, S or NH

W represents oxygen or sulphur

Y represents NH or O

B represents a saturated azacyclic ring of the formula

(ID

where n is 2, 3 or 4 and R^ is hydrogen, or (lower)alkyl,

or

(IH) or the N-oxide thereof

or

(IV)

where m is 1 , 2 or 3 and R^ has the meaning given above or

(V)

where p is 0, 1 or 2

or

(VI)

where R and R^ are each hydrogen or lower alkyl.

A particularly preferred compound of formula I is disclosed in EP 0422846 A2. This compound is (endo)-N-[[8-methyl-8-azabicyclo[3.2. l]octan-3-yl)amino]carbonyl]-2- (cyclopropylmethoxy)benzamide or a pharmaceutically acceptable acid addition salt thereof. The free base has the formula

(VII)

GB 2236751 A discloses compounds of the general formula

(VIII) and the pharmaceutically acceptable acid addition salts thereof. In this formula

R6 represents hydrogen or one or more substituents selected from lower alkyl, hydroxy, lower alkoxy, halogen, methylenedioxy, halo(lower)alkyl, nitro, amino, (lower)alkylamino and di(lower)alkylamino

X represents -O- or -NR^- where R^ represents lower alkyl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, cyclo(lower)alkyl-loweralkyl, aryl, aryl(lower)alkyl, a group of formula -(CH2)r-Y-R^ (where r is an integer of 1 to 4, Y is O, S or NR^, where RIO is hydrogen or lower alkyl and R^ is hydrogen, lower alkyl or cycloloweralkyl) or a group of formula -Z- which is connected to the 8-position of the aromatic ring so as to form a heterocyclic ring of 5 to 7 ring members wherein the ring members represented by Z are one or more methylene groups (optionally substituted by one or more lower alkyl groups) and optionally a hetero group selected from O, S, SO2 or NRlO where RlO is hydrogen or lower alkyl

Y'represents O or NR8 where R8 is hydrogen or lower alkyl and B' represents a saturated azabicyclic ring or an N-oxide thereof wherein the saturated azabicyclic ring has the formula

(IX)

where m' is 2, 3 or 4 and R9 is hydrogen, or (lower)alkyl,

or

(X)

or

(XI) where p' is 1 , 2 or 3 and R9 has the meaning given above

or

(Xii)

where q is 0, 1 or 2.

The above mentioned EP 0323077 B 1 discloses that compounds of formula (I) and the pharmaceutically acceptable acid addition salts thereof possess 5-HT3 antagonistic activity and are useful in the treatment of migraine, emesis, anxiety, gastrointestinal disorders and as anti-psychotics. The above mentioned GB 2236751 A discloses that the compounds of formula (VIII) and their pharmaceutically acceptable salts also have 5- HT3 antagonistic activity and as such may be useful in the treatment of neuro-psychiatric disorders such as anxiety, psychotic disorders (eg schizophrenia), dependency on drugs or other substances of abuse, cognitive disorders, in the treatment of gastro-intestinal disorders such as emesis and nausea and in the treatment of migraine.

The present invention relates to the topical use of a compound of formula (I) or (VIII) or a pharmaceutically acceptable salt thereof for the treatment of peripheral disorders associated with pain.

According to a first aspect, the present invention provides a method of treating peripheral disorders associated with pain in mammals, particularly humans, which comprises topically administering to a mammal an effective amount of a compound of formula (I) or (Vπi) (as defined above) or a pharmaceutically acceptable acid addition salt thereof.

According to a second aspect, the present invention provides the use of a compound of formula (I) or (VIII) (as defined above) or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for topical administration to a mammal, particularly a human, for the treatment of peripheral disorders associated with pain.

According to a third aspect, the present invention provides a semi-solid pharmaceutical composition useful for the topical treatment of peripheral disorders associated with pain in mammals, particularly humans, comprising a compound of formula (I) or (VIII) (as defined above) or a pharmaceutically acceptable acid addition salt thereof and a topical pharmaceutically acceptable carrier.

The compounds of formulae (I) and (VIQ) and their pharmaceutically acceptable salts (hereinafter sometimes referred to as "the compounds of the invention") can be topically administered to treat a variety of peripheral disorders associated with pain, for example peripheral neuropathic pain, inflammatory pain, neuralgia (eg post-herpetic neuralgia, trigeminal neuralgia), sunburn, first degree burns, erythema and burns following radiotherapy, bites and bums caused by insects, spiders, jellyfish and the like.

Preferred compounds of the invention are disclosed in the above mentioned prior specification. Particularly preferred compounds are the compound of formula (VII) and its salts (eg the maleate) and (endo)-l-cyclohexyl-N-(8-methyl-8-azabicyclo[3.2.1]octan- 3-yl)-4(lH)oxo-quinoline-3-carboxamide and its salts (eg the maleate).

The compounds of the invention can be administered topically in a composition containing the compound and a topical pharmaceutically acceptable carrier.

By 'a semi-solid pharmaceutical composition' is meant an ointment, cream, salve, paste, jelly or other pharmaceutical or cosmetic composition of substantially similar consistency suitable for application to the skin. Examples of semi-solid compositions are given in Chapter 17 of The Theory and Practice of Industrial Pharmacy, Lachman, Lieberman and Kanig, published by Lea and Febiger (1970) and in Chapter 67 of Remington's Pharmaceutical Sciences, 15th Edition (1975) published by Mack Publishing Company.

Preferably, the novel compositions of the present invention contain from about 0.1 % to about 20% (eg to about 15%) by weight of the active ingredient. The compositions may, for example, contain from about 0.5% (preferably from about 1%) to about 10% by weight of the active ingredient.

The carrier used in the compositions of the present invention may be any carrier suitable for preparing topical semi-solid compositions. Examples of suitable carriers for semi- solid compositions are given in Lachman, Lieberman and Kanig (loc-cit and in Chapter 67 of Remington's Pharmaceutical Sciences, (loc-cit). The carrier may be, for example an emulsion base of the oil in water class (eg an emulsion of soft and liquid paraffins in water). Alternatively, the carrier may be an absorption base (eg a mixture of wool fat and soft paraffin). A third class of suitable carriers are water miscible bases (eg mixtures of high and low molecular weight polyethylene glycols).

In addition to the active ingredient and the carrier base, the compositions of the invention may contain other ingredients such an antioxidants, buffers, emulsifying agents, perfumes, preservatives and solvents which confer on the product properties desirable in a topical formulation. In particular, buffers may be employed to adjust the pH of the composition to within the range of, for example 4 to 5.5 (eg 4.8) to maintain the active ingredient in its free acid form. The composition can also contain active ingredients in addition to the compounds of formulae I or VIII or their salts.

The following Examples illustrate the invention.

Examples 1-4

Water-in-oil emulsions are prepared from the following ingredients.

Example 1 Example 2 Example 3 Example 4

Cetyl palmitate l lg l lg l lg l lg

White beeswax 12g 12g 12g 12g

Liquid paraffin 61g 61g 61g 61g

EDTA O.lg O.lg O.lg O.lg

Distilled water 10.9g 10.9g 10.9g 10.9g

(endo)-N-[[8-methyl- 95mg 10.5g

8-aza-bicyclo[3.2.1]- octan-3-yl)amino]- carbonyl]-2-cyclo- propyl-methoxy)- benzamide maleate

(endo)-l-cyclo- - 95mg 10.5g hexyl-N-(8-methyl-

8-azabicyclo[3.2.1]- octan-3-yl)-4(lH)- oxoquinoline-3- carboxamide maleate Example 5

The topical activity of (endo)-l-cyclohexyl-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)- 4(lH)-oxoquinoline-3-carboxamide maleate (hereinafter termed "Compound A") was investigated in rats.

Using laser Dδppler flow metering the vasodilator dose response and time-course of 5- hydroxytryptamine (5-HT) injected locally was established in rat skin. Subsequently, the effect of the 5-HT3 receptor antagonist Compound A on the blood flow response induced by 5-HT was investigated. Compound A was administered as a pretreatment by intradermal injection (validation) and as a topical application in a cream base at 3 different concentrations, 0.1%, 1% and 10%.

Male Wistar rats (230-300g) were sedated by i.m. injection of Hypnorm

(fentanyl/fluanisone) at 0.3mg/Kg. The dorsal skin was shaved and depilated. The dorsal skin was then rinsed thoroughly with warm water and the animals left for at least 2 hour before measurements were commenced.

During the experiment the rats were kept moderately sedated with Hypnorm in an air conditioned room at 23-25°C. Before injection of test compounds, baseline blood flow was measured in the dorsal skin with a laser Dδppler flow probe (Perimed II) at 6-8 marked sites. Each reading takes 15 seconds and the mean of three readings is taken. Results were recorded as red cell flux and are expressed as a percentage of a standardised signal. Doppler is set at 4Hz, gain 10. The output was recorded via a MacLab A-D converter to a Macintosh computer. Data are expressed as mean ± SEM.

Results

The pre-injection of Compound A inhibited the local blood flow response induced by 5- HT in a dose-related fashion. The topical pre-treatment with Compound A at 10% w/v in the cream vehicle also inhibited the increased blood flow response to 5-HT by 60% at 30 minutes (5-HT + control: = 26.1 ± 15.1% versus 5-HT + Compound A: + 10.3 ± 16.8%) and by 63% at 60 minutes (5-HT + control: + 31.4 ± 8.2% versus 5-HT + Compound A: +11.5 + 9%). The two lower concentrations tested 0.1% w/v and 1% w/v did not demonstrate activity. (The full efficacy of the cream treatment could not be determined because of an increase in blood flow induced by the particular vehicle used in the study). It is evident that Compound A administered by intradermal or topical routes antagonises the effect of injected 5-HT in the rat skin.

Claims

CLA S

1. The use of a compound of formula (I)

A-CO-NHCW-Y-B (I)

wherein A represents an aromatic radical of the formula

(a) (b),

(c) or (d)

where the free valence is attached to either fused ring of formula (a) or (b),

Rl represents hydrogen or one or more same or different substituents selected from lower alkyl, a lower alkoxy group [said lower alkoxy group being selected from loweralkyloxy, cyclo(lower)alkyloxy, cyclo(lower)alkyl- loweralkyloxy, (lower)alkenyl(lower)alkyloxy and halo(lower)alkyloxy], hydroxy, halogen, halo(lower)- alkyl, amino, nitro, carboxamido, phenyl(lower)alkyloxy (in which the phenyl group may be optionally substituted by one or more lower alkyl, loweralkyloxy or halo substituents), (lower)alkylamino, di(lower)alkylamino or acylamino

Z!-Z² represents CH2-CH, NR2-CH, O-CH, S-CH. CH2-N, O-N, S-N, NR²-N, CH- NR2 or N-NR2, [where R2 is hydrogen, (lower)alkyl, or phenyl or phenyl(lower)alkyl in which the phenyl groups may optionally be substituted by one or more lower alkyl, lower alkyloxy or halo substituents] Z3-Z4 represents CH=CH, O-CH₂ or N=CH

Z5 represents N or CH

Z6 represents O, S or NH

W represents oxygen or sulphur

Y represents NH or O

B represents a saturated azacyclic ring of the formula

(II)

where n is 2, 3 or 4 and R^ is hydrogen, or (lower)alkyl,

or

(in) or the N-oxide thereof

or

(IV)

or

where m is 1, 2 or 3 and R^ has the meaning given above or

(V)

where p is 0, 1 or 2

or

(VI)

where R4 and R^ are each hydrogen or lower alkyl

or a compound of formula (VIE)

<VΠD

where R^ represents hydrogen or one or more substituents selected from lower alkyl, hydroxy, lower alkoxy, halogen, methylenedioxy, halo(lower)alkyl, nitro, amino, (lower)alkylamino and di(lower)alkylamino

X represents -O- or -NR⁷- where R⁷ represents lower alkyl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, cyclo(lower)alkyl-loweralkyl, aryl, aryl(lower)alkyl, a group of formula -(CH2)rY-R^ (where r is an integer of 1 to 4, Y is O, S or NR^O, where RIO is hydrogen or lower alkyl and R 3 is hydrogen, lower alkyl or cycloloweralkyl) or a group of formula -Z- which is connected to the 8-position of the aromatic ring so as to form a heterocyclic ring of 5 to 7 ring members wherein the ring members represented by Z are one or more methylene groups (optionally substituted by one or more lower alkyl groups) and optionally a hetero group selected from O, S, SO2 or NRlO where RlO is hydrogen or lower alkyl

Y' represents O or NR8 where R8 is hydrogen or lower alkyl and B' represents a saturated azabicyclic ring or an N-oxide thereof wherein the saturated azabicyclic ring has the formula

(IX)

where m' is 2, 3 or 4 and R9 is hydrogen, or (lower)alkyl,

or

(X)

or

(XI)

where p' is 1, 2 or 3 and R9 has the meaning given above

or

(XII)

where q is 0, 1 or 2 or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for topical administration to a mammal for the treatment of peripheral disorders associated with pain.

2. The use as claimed in claim 1 wherein the compound is (endo)-N-[[8-methyl-8- azabicyclo[3.2.1 ]octan-3-yl)amino]carbonyl]-2-(cyclopropylmethoxy)benzamide or (endo)-l-cyclohexyl-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-4(lH)oxo-quinoline-3- carboxamide or a pharmaceutically acceptable salt thereof.

3. A semi-solid pharmaceutical composition useful for the topical treatment of peripheral disorders associated with pain in mammals comprising a compound of formula (I) or (VIE) (as defined in claim 1) or a pharmaceutically acceptable acid addition salt thereof and a topical pharmaceutically acceptable carrier.

4. A composition as claimed in claim 3 wherein the compound is (endo)-N-[[8- methyl-8-azabicyclo[3.2.1]octan-3-yl)amino]carbonyl]-2- (cyclopropylmethoxy)benzamide or (endo)- l-cyclohexyl-N-(8-methyl-8- azabicyclo[3.2.1]octan-3-yl)-4(lH)oxo-quinoline-3-carboxamide or a pharmaceutically acceptable salt thereof.

5. A method of treating peripheral disorders associated with pain in mammals which comprises topically administering to a mammal an effective amount of a compound of formula (I) or (VIII) (as defined in claim 1) or a pharmaceutically acceptable acid addition salt thereof.

6. A method as claimed in claim 5 wherein the compound is (endo)-N-[[8-methyl-8- azabicyclo[3.2.1]octan-3-yl)amino]carbonyl]-2-(cyclopropylmethoxy)benzamide or (endo)-l-cyclohexyl-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-4(lH)oxo-quinoline-3- carboxamide or a pharmaceutically acceptable salt thereof.