CA1140854A - Anti-ulcer compositons containing oxime ethers - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Pharmaceutical compositions having anti-ulcer activity, containing as an active ingredient a compound of the formula (I):

Description

~ U854 Anti-ulcer compositions containing oxime ethers.

This invention relates to pharmaceutical compositions having anti-gastric ulcer activity, to certain oxi~e ether derivatives for use in these compositions, and to methods for the preparation of these com-pounds.
In Farmaco. Ed. Sci. i9, 668-702 (1964), Chem. Abstr. 61, 10545e (1964), phenyl 2-pyridinyl ketone, O-dimethylaminoethyl oxime methiodide has been described, which compound showed acetylcholine antagonistic activity. The salts of the tertiary amine should possess papaverine-like activity in vitro.
In U.S. Patent No. 3,205,234 a number of N-oxides of pyridinyl ketone O-hydrocarbon oximes have been mentioned, wherein the hydrocar-bon group may be saturated or unsaturatedacyclic aliphatic, cyclo-aliphatic, cycloaliphaticalkyl or araliphatic, containing up to twelve carbon atoms. The N-oxides are said to be active and useful as anti-15 inflammatory agents and drug-potentiators (e.g. potentiation of bar-biturate-induced sleep in mammals), although this statement has not been supported by any pharmacological data.
According to this reference, these N-oxides are prepared by reacting a corresponding pyridinyl ketone 0-hydrocarbon oxime with a 20 peroxide. The starting oxime ethers are only described as intermediates.
Thus, no pharmacological activity of these compounds has been mentioned.
In U.S. Patent No. 3,290,320, which corresponds to British Patent No. 1,070,964, phenyl 2-pyridinyl ketone, 0-di(m)ethylamino-ethyl/propyl oximes have been describedS which compounds showed anti-25 androgenic activity.

., .

: . .

In J. Pharm. Sci. 58, 138-141 (1969) phenyl 2-pyridinyl ketone, O-di(m)ethylaminoethyl oxime; 4-methoxyphenyl 2-thienyl ketone, O-dimethylaminoethyl oxime; and phenyl 2-picolinyl ketone, 0-dimethylamino-ethyl oxime have been described, which compounds showed anti-androgenic 5 activity, but the effective dose was véry close to the toxic dose.
It has now been found that certain oxime ethers derived from heterocyclic ketones possess anti-ulcer activity in the gastro-intestinal tract, e.g. by inhibition of gastric acid secretion and/or stimulation of mucus formation, and that pharmaceutical compositions containing them 10 may be used in the treatment and/or prophylaxis of disorders of the gastro-intestinal tract.
The present invention provides a pharmaceutical composition having anti-ulcer activity, which composition comprises an anti-ulcer effective amount of a compound of the formula (I) :
Het-(CH2) -C-(CH2) -Ar (I) N
OR
20 or an N-oxide thereof, or a pharmaceutically acceptable salt of said compound or said N-oxide, wherein Het is a 2-, 3- or 4-pyridinyl group, or such group substituted by one or more halogen atoms or C1 6 alkyl or C1 6 alkoxy groups, Ar is a phenyl or a 5- or 6-membered monocyclic heteroaromatic group, or such a group substituted by one or more halogen atoms or C1 6 alkyl, C1 6 alkoxy, trifluoromethyl or hydroxymethyl groups, R is a C1 3 alkyI, C3 4 alkenyl, C3 4 alkynyl, cyano C1 3 alkyl, a carbamidoalkyl g~up with the formula -(CH2)pC(O)NR R , wherein 2 p is 1 or 2, R1 and R2 are each hydrogen or C1 3 alkyl, or R1 and R
together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring in which another hetero atom may be present, or an aminoalkyl group with the formula ~(CH2)qNR3R4, wherein q is 2 or 3, R3 and R4 are each hydrogen or C1 3 alkyl, or R and R together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring in which another hetero atom may be present, and m and n are each O or 1, with the proviso that m + n is not 2, . ~ .. .

in association with a pharmaceutically acceptable carrier or di-luent.
Most of the above compounds of formula (I) (and their N-oxides and addition salts) are believed to be novel and consti-tute a further aspect of the present invention. These compounds include those of formula (I) wherein Ar is a 5- or 6-membered monocyclic heteroaromatic group, or such a group substituted by one or more halogen atoms or Cl 6 alkyl, Cl 6alkoxy, trifluoro-methyl or hydroxymethyl groups. Suitable or preferred compounds of this group are hereinafter described in relation to the phar-maceutical compositions containing such compounds.
The compounds of formula (I) may be substituted or un-substituted in Het, as described. However, it is believed that a preferred class of such compounds for their utility is that in which Het is unsubstituted.
Ar as a phenyl group is preferably unsubstituted phenyl.
Ar as a heteroaromatic group is preferably 2- or 3-thienyl, 2- or 3-furyl, 2- or 4-pyridinyl, of which 2-thienyl and

2-furyl are most preferred.
R is preferably R' where R' is methyl, ethyl, _-propyl, allyl, propargyl, cyanomethyl, dimethylaminoethyl or -propyl, of which Cl 3 alkyl, particularly methyl, and dimethylaminopropyl are most preferred.
Preferably, m and n are zero. If, however, n is one, the preferred of Ar is phenyl.
The pharmaceutically acceptable salts include the acid addition salt and quaternary addition salts. Among the thera-peutically appropriate acids for the formation of additions salts are inorganic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid and phosphoric acid, and organic acids such as citric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, lactic acid, succinic acid, tartaric acid ~)i ,~

and methanesulphonic acid, of which hydrochloric acid, sulphuric acid, maleic acid, fumaric acid and methanesulphonic acid are preferred.
It will be realized that each compound of formula (I) may exist in two different forms (E and Z-isomer). Both such forms are included within this invention. The compounds of the invention, as represented by formula (I), include free base and additions salt forms, separated isomeric forms and mixtures there-of.
Particularly preferred compounds within formula (I) in which Ar is phenyl include the 2-, 3- and 4-piperidinyl phenyl k~etone, 0-methyl, 0-2-N,N-dimethylaminoethyl and 0-3-N,N-dimethylaminopropyl oximes.

- 3a -,i:

Particularly preferred compounds within formula (I) in which Ar is a heteroaromatic group include compounds of formula (I)' :
Het - C - Ar~
N (I)' bR' wherein Het is as previously defined, Ar' is 2-thienyl or 2-furyl and R' is methyl or dimethylaminopropyl.
Especially preferred compounds within the formula (I)' are :
2-pyridinyl 2-thienyl ketone, 0-3-N,N-dimethylaminopropyl oxime, and 2-furyl 2-pyridinyl ketone, 0-3-N,N-dimethylaminopropyl oxime.
The compounds (I) of the invention can be prepared according to methods which are known ~ se for the preparation of this type of compound or methods analogous thereto.
A suitable method for the preparation of a compound of 15 formula (I) comprises the reaction of a compound of formula (II) :

Het-(CH2)m-C-(CH2)n-Ar (II) 20 wherein Het, Ar, m and n are as defined in relation to formula (I) and C = Q is a carbonyl group or a protected carbonyl group, with a 0-substituted hydroxylamine derivative of formula (III) :

H2N-R (III) or a salt thereof, wherein R is as defined in relation to formula ~I).
Suitable protected carbonyl groups are, for example, ketals and oximes. The preferred meaning of Q is oxygen. If Q i8 an alkylene-dioxy group, it is preferably ethylenedioxy.
The reaction may be carried out under reaction condition9 ; which are commonly used for this type of reaction. Preferably the reaction is carried out in a solvent, such as an alcohol, dioxane, dimethyl formamide, tetrahydrofuran or pyridine. Usually, the reaction temperature will be between room temperature ant the boiling tempera-35 ture of the reaction mixture.
The compound (III) is preferably added in the form of its acid salt, preferably its hydrochloride, to compound (II), which i~

''' '' ,' ' ' , ' : :

preferably dissolved in pyridine.
A further suitable method for the preparation of a compound of formula (I) comprises the reaction of a compound of formula (IV) :

Het-(CH2) -C-(CH2) -Ar (IV) N
OM

10 wherein Het, Ar m and n are as defined in relation to formula (I) and N is a hydrogen or an alkali metal atom, with a compound of formula (V):
RY (V) 15 wherein R is as defined in relation to formula (I) and Y is a suitable leaving group, such as a chloride, bromide, iodide or tosyloxy group.
The reaction may be carried out in a conventional solvent, such as methanol, ethanol, acetone, methyl ethyl ketone, dioxane, dimethylglycol ether or dimethyl formamide.
20 If in formula (IY) M represents a hydrogen atom, it may be useful to add an acid binding agent to the reaction mixture. Suitable acid binding agents are, for example, alkali metal hydrides, hydroxides, carbonates and alkoxides, tertiary amines, pyridine and the like.
The reaction conditions are as commonly used for this type of reaction.
25 Usually, the reaction temperature will be between room temperature and the boiling temperature of the reaction mixture.
The conversion of the oxime compound (IV) into compound (I) is usually effected by alkylation with an alkyl, alkenyl, alkynyl, carbamidoalkyl, cyanoalkyl or (tert-amino)alkyl halide, such as 30 the chloride, bromide or iodide, in the presence of, for instance, sodium hydride, an alkali metal hydroxide or alkoxide, preferably sodium methoxide, dissolved in a suitable solvent, preferably dimethyl formamide or methyl alcohol.
Generally, the preferred method of preparing any particular 35 compound of formula (I) will depend to some extent on the compound itself.
It will be clear to those skilled in the art that, in a 1~44~85~

number of cases, certain reaction steps described may be carried out in a different sequence or simultaneously or without isolating intermediates, and these possibilities are all included in the inven-tion. For example, the introduction of the group R in compound (I) 5 according to the reaction of compound (II) with compound (III) may also be carried out by reacting compound (II) with a compound of formula (VI) :
H2N-OZ (VI) lO wherein Z is a group replaceable by or convertable into R, R being as hereinbefore defined. The compound of formula (VII) thus obtained :

Het-(CH2) -C-(CH2)n-Ar (VII) N

OZ

wherein Het, Ar, Z, m and n are as hereinbefore defined, can then be converted to the compound of formula (I).
The N-oxides of the compounds of formula (I) are preferably prepared by reacting a compound of formula (I) with a peroxide agent, for example, hydrogen peroxide, benzoyl peroxide, or a similar compound, of which hydrogen peroxide is preferred. The reaction is preferably carried out in an inert solvent, such as, for example, acetic acid, 25 propionic acid, and the like, at temperature generally ranging between 50 C and 90 C.
The N-oxides can also be prepared by reacting a compound of formula (II), wherein Het is the N-oxide of the previously defined hetero group (instead of the hetero group itself), with a hydroxylamine 30 derivative of formula (III), in the manner hereinbefore de8cribed.
Pharmaceutically acceptable salts can be prepared from the compounds of the formula (I) in a conventional manner.
The intermediate compounds with formulae (II) and (IV) have been described in the literature or can be prepared by methods 35 known per se.
Clearly the formulation of the pharmaceutical compositions of the invention will depend on the nature of the activity shown by .' ; ' .

the chosen compound of the formula (I), and on other factors such as a preference ill a particular area of therapy for a particular mode of administration.
The compositions may be, for example, in the form of tablets, 5 capsules, powders,granules, lo~enges or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, fillers, tabletting lubricants, disintegrants, and 10 acceptable wetting agents and the like. The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other l5 suitable vehicles before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils) preservatives, and if desired conventional flavouring or colouring agents, and the like.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound of the formula (I) and a sterile vehicle. The compound9 depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter 25 sterilized before filling into a suitable vial or ampoule and sealing.
Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents can be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved 30 and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitateuniform distribution of the compound.
The compositions of this invention may be in the form of a microfine powder for insufflation.
As is common practice, the compositions will ufiually be , accompanied by written or printed directions for use in the medical treatment concerned.
It will of course be realized that the precise dosage used in the treatment of any of the hereinbefore described disorders will 5 depend on the actual compound of the formula (I) used and also on other factors such as the seriousness of the disorder being treated.
Broadly, the dose may vary from about 100 mg up to about 25 g per day per patient.
The invention also provides a method of treatment and/or 10 prophylaxls of gastric disorders in human beings which comprises the administration to the sufferer of an anti-ulcer effective amount of a compound of the formula (I), or an N-oxide thereof, or a pharmaceuti-cally acceptable salt of said compound or said N-oxide.
Normally, the compounds of formula (I) will be administered 15 as pharmaceutical compositions.
The "effective amount" will of course vary with factors such as the severity of the ulceration, the weight of the sufferer and the specific compound of the formula (I) used.
The following Examples illustrate the preparation of compounds 20 of the formula (I) and their pharmacological properties.

EXAMPLE I

Phenyl 4- pyridinyl ketone, 0-methyl oxime (1) 25 Phenyl 4_pyridinyl ketone (18.3 g) and 0-methylhydroxylamine hydro-chloride (12 g) dissolved in 200 ml of pyridine were refluxed for 8 hours. Pyridine was evaporated at reduced pressure and the residue was treated with chloroform and water. The chloroform layer was separated and dried over magnesium sulphate. Evaporation of the solvent afforded 30 phenyl 4-pyridinyl ketone, 0-methyl oxime as a 1:1 mixture of the E
and Z-isomers (21.0 g), which was converted into the hydrochloride addition salts (m.p. 146-149 C).
If desired, the E and Z-isomers may be separated from the mixture by column chromatography (e.g. silica gel with cyclohexane -35 ethyl acetate 3:1 a8 ~he eluant). Identification of the isomers occurredby NNR.
In a similar manner the following compounds were prepared :

.

ll~U854 phenyl 2-pyridinyl ketone, 0 methyl oxime.HCl m.p. 149-152 C (E-isomer) (2)phenyl 3-pyridinyl ketone, 0-methyl oxime.HCl m.p. 97-99 C (E-isomer) (3) 5 phenyl 4-pyridinyl ketone, O-methyl oxime.HCl m.p. 188-190 C (E-isomer) (4) 2-methylphenyl 2-pyridinyl ketone, 0-methyl oxime, m.p. 97-99 C (Z-isomer) (5) 4-methylphenyl 4-pyridinyl ketone, 0-methyl oxime.HCl m.p. 155-170 C (E:Z ~ 1:1) (6) 4-methoxyphenyl 4-pyridinyl ketone, O-methyl oxime.HCl m.p. 203-205 C (dec.) (Z-isomer) (7) 4-fluorophenyl 4-pyridinyl ketone, 0-methyl oxime.HCl m.p. 198-202 C (Z-isomer) (8) 15 4-chlorophenyl 4-pyridinyl ketone, 0-methyl oxime.HCl m.p. 195-200 C (dec.) (Z-isomer) (9)

3,4-dichlorophenyl 4-pyridinyl ketone, 0-methyl oxime.HCl m.p. 229-234 C (dec.) (10) 2-wridinyl 2-thienyl ketone, 0-methyl oxime, oil (30 % E, 70 % Z-i~omer) (11) 2-pyridinyl 3-thienyl ketone, 0-methyl oxime, oil (40 % E, 60 % Z-isomer) (12) 3-pyridinyl 2-thienyl ketone, O-methyl oxime, oil (50 Z E, 50 & Z-isomer) (13) 25 4-pyridinyl 2-thienyl ketone, 0-methyl oxime, m.p. 47-50 C (25 % E, 75 2 Z-isomer) (14) 2-furyl 2-pyridinyl ketone, O-methyl oxime, oil phenyl 2-pyridinylmethyl ketone, 0-methyl oxime.HCl m.p. 77-110 C (16) di-2-pyridinyl ketone, 0-methyl oxime, oil (17)

4-pyridinyl 4-trifluoromethylphenyl ketone, 0-methyl oxime.HCl m.p. 183-185 C (18) 35 4-hydroxymethylphenyl 4-pyridinyl ketone, 0-methyl oxime, m.p. 97-100 C (19) ll~V854 Phenyl 4-pyridinyl ketone, 0-cyanomethyl oxime (20) Phenyl 4-pyridinyl ketone oxime (5.4 g) was stirred in 50 ml of di-

5 methyl formamide containing 1.5 g of a 50 ~ dispersion of sodium hydride in oil, for O.S hours at room temperature. After the hydrogen evolution was completed, chloroacetonitrile (2.5 g) was added. The reaction mixture was stirred for 1 hour. The greater part of the di-methyl formamide was evaporated at reduced pressure, and then the 10 residue was treated with ether and water. The ether layer was separated and dried over magnesium sulphate. The product was recrystalli~ed from a mixtu.e of ether and petroleum ether (40-60 C), yielding pure phenyl 4-pyridinyl ketone, 0-cyanomethyl oxime (4.9 g, m.p. 101.5 -103 C) In a similar manner, the following compounds were prepared :

phenyl 4-pyridinyl ketone, O-ethyl oxime.HCl m.p. 174.5-176 C (21) 20 phenyl 4-pyridinyl ketone, 0-allyl oxime.~Cl m.p. 164-165 C (22) phenyl 4-pyridinyl ketone, O-propargyl oxime, m.p. 61-62 C (23) phenyl 2-pyridinyl ketone, 0-2-N,N-dimethylaminoethyl oxime.oxalate m.p. 154-156 C (24) phenyl 2-pyridinyl ketone, 0-3-N,N-dimethylaminopropyl oxime.oxalate~
m.p. 146-148 C (25) phenyl 3-pyridinyl ketone, 0-2-N,N-dimethylaminoethyl oxime, oil, b.p. 143 C/0.01 mm (26) 30 phenyl 3-pyridinyl ketone, 0-3-N,N-dimethylaminopropyl oxime, oil, b.p. 147 C/0.01 mm (27) phenyl 4-pyridinyl ketone, 0-2-N,N-dimethylaminoethyl oxime.2 HCl m.p. 191-193 C (dec.) (28) phenyl 4-pyridinyl ketone, 0-3-N,N-dimethylaminopropyl oxime.2 HCl m.p. 197-200 C (29) 2-pyridinyl 2-thienyl ketone, 0-3-N,N-dimethylaminopropyl oxime, oil 1~408S4 2-furyl 2-pyridinyl ketone, 0-3-N,N-dimethylaminopropyl oxime, oil (31) The preparation of compounds (24) and (25) has been described in 5 U.S. Patent No. 3,290,320. However, no melting points were mentioned in said patent.

10 Phenyl 4-pyridinyl ketone, O-methyl oxime, N-oxide (Z-isomer) (32) A mixture of 9.1 g of phenyl 4-pyridinyl ketone, O-methyl oxime, 40 ml of glacial acetic acid and 15 ml of 30 ~ hydrogen peroxide in water was heated overnight on a water bath at a temperature of 70 C.
The reaction mixture was concentrated at reduced pressure, treated with 15 chloroform and a saturated aqueous solution of sodium bicarbonate.
The chloroform layer was separated and dried over magnesium sulphate.
Evaporation of the solvent and successive crystallization from a mix-ture of ether and petroleum ether (40-60 C) afforded the title compound (6.2 g, m.p. 98-99 C).
Pharmacological Data 1. Effects on Gastric Secretion in the Pyloric Ligated Rat.
The method as described by Shay et al. (Gastroenterol. 26, 25 906 (1945)) was used. After overnight starvation the pylorus of a rat was ligated under halothane aenesthesia and the compound under test or vehicle only administered intraduodenally and the rats allowed to reco-ver. They were sacrificed three hours later and the gastTic juice removed.
After measurement of the volume of secretion, its hydrogen ion concen-30 tration, [Hl , was determined by titration with 0.05n NaOH to pH 7.Groups of 4-6 animals were used for each treatment and the inhibitory effect of the compound was ascertained by comparison of the mean values obtained with those from a simultaneously set up control group of animals which received vehicle only. Students 'tl test was applied for 35 significance between groups. The mean values for ~ inhibition obtained for a number of experiments are shown in the following Table 1, the dosage being 100 mg/kg i.d.

2. ~nti-ulcer activity This was assessed by the inhibition of indomethacin induced gastric damage in the rat according to the method of Elegbe (Israeli J. Ned. Sci. 10, 1451 (1974)).
Rats were starved overnight, given indomethacin subcutaneously ~15 mg/kg) and sacrificed 5 hours later. Stomachs were inflated with 0.9 ~ saline1 cut along the greater curvature, pinned out and scored for gastric damage by the following system :-Score 1-3 according to the degree of erythema and slight 10 haemorrhage.
Score 4-6 according to the degree of mucosal erosion.
Score 7-9 according to the depth of gastric damage.
Groups of 7 rats were used for each treatment level of the compound under test and a similar group receiving vehicle only was set up on 15 each occasion of testing. Compound or vehicle was administered orally 30 minutes prior to, and at 2 hours after dosing with indomethacin.
Nean values per treatment were obtained using the above scoring system and the Nann Witney test applied for significance between such values.
The mean inhibition of gastric damage from a number of experiments is 20 shown in the following Table 2 ; the dosage being 100 mg/kg orally.

, .

, 114~J854 Compound No.Table 1 Table 2 % In] .ibition ~ Inhibition Volume [H+]

6 81 89 80 ]0 7 88 142 78 20 l7o7o .

; 20 96 : 21 77 24 100 : ~ 25 24 81 36 100 28 83 92 g2 ~ 50 mg/kg

Claims (5)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVIIEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A pharmaceutical composition having anti-ulcer acti-vity, which composition comprises an anti-ulcer effective amount of a compound of the formula (I):

(I) or a pharmaceutically acceptable acid addition salt of said compound wherein Het is the 2-pyridinyl group, Ar is the phenyl group, R is an aminoalkyl group with the formula -(CH2)q-NR3R4, wherein q is 2 or 3 and R3 and R4 are methyl in association with a pharmaceutically acceptable carrier or diluent.

2. A composition according to claim 1, wherein the compound of formula I is phenyl 2-pyridinyl ketone, O-2-N,N-dimethylaminoethyl oxime.oxalate.

3. A composition according to claim 2, in which the compound is in the form of an oxalate.

4. A composition according to claim 1, in which the compound of formula I is phenyl 2-pyridinyl ketone, O-3-N,N-dimethylaminopropyl oxime.oxalate.

5. A composition according to claim 4, in the form of an oxalate.