GB2167064A

GB2167064A - Pyridine derivatives

Info

Publication number: GB2167064A
Application number: GB08525767A
Authority: GB
Inventors: Roger Crossley
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1984-11-06
Filing date: 1985-10-18
Publication date: 1986-05-21
Also published as: GB2167064B; US4678794A; GB8525767D0; GB8428007D0

Description

1 GB 2 167 064 A 1

SPECIFICATION

Pyridine derivatives The invention relates to pyridine derivatives useful as pharmaceuticals, processes for their preparation 5 and pharmaceutical compositions containing them.

The invention provides compounds having the formula 1 R R 2 -A-NH-CO 1 ' 10 N 0 'I- (1) and their pharmaceutically acceptable acid addition salts for use as pharmaceuticals. In formula 1 R, is hydrogen or lower alkyl, A is a direct bond or lower alkylene and R, is pyridinyl, optionally monosubsti tuted by lower alkyl. The compounds are novel except where R, is methyl at the 6-position of the ring.

The term "lower" as used herein in respect of such groups as aikyl and alkylene indicates that the group contains 1-6, preferably 1-4 carbon atoms.

R, is hydrogen or lower alkyl, e.g. methyl or ethyl. R, is preferably hydrogen. A represents a direct bond or lower alkylene. The lower alkylene may be branched or a straight chain. Examples include meth ylene, dimethylene and trimethylene. A preferably represents a direct bond or methylene. R2 'S pyridyl, i.e. 2-, 3- or 4-pyridyl, preferably 2-pyridyl which may be unsubstituted or monosubstituted by lower al- 25 kyl, for example, methyl or ethyl.

Examples of acid addition salts are those formed from inorganic and organic acids, for instance, hydro chlorides, hydrobromides, hydroiodides, sulphates, nitrates, phophates, sulphonates (e.g. the methane sulphonate or p-toluene sulphonate), acetate, maleate, citrate, fumarate, tartrate, malonate and formate.

The compounds of the invention may be prepared by a process in which an amine having the formula 30 R,-A-NI-12 (11) (where R, and A are as defined above) or a reactive derivative thereof is coupled with an acid having the formula Ill R 1 35 0 <- N (III) 0 HO 2 c (where R, is as defined above) or a reactive derivative thereof. If desired the process may also include conversion of an acid addition salt of the compound having formula I into the compound of formula I by neutralisation with a base or conversion of a compound having formula I into a pharmaceutically accept able salt thereof by addition of an acid.

The coupling reaction may be carried out by reacting the amine 11 with the acid III in the presence of a 45 condensing agent, for instance, a carbodiimicle. The use of 1,1'- carbonyidiimidazole as condensing agent is recommended. Alternatively, the acid III may be reacted with a compound in which the amino function of the amine III has been activated, for instance, by forming the phosphazo derivative. The coupling may be carried out by reacting the amine 11 with a reactive derivative of the acid 111, for example, active esters, acyl halides, simple or mixed anhydrides and the acid azide. The acid halides, particularly the acid chlo- 50 ride, are especially suitable. The reaction product can be recovered from the reaction mixture by stand ard isolation procedures.

The amines 11 and acids III are generally known or, if new, can be prepared in known manner.

The compounds having formula I are indicated for use as pharmaceuticals. They are useful as anti ulcer agents and are indicated for treatment of peptic ulcer diseases. Where A is a direct bond, the com- 55 pounds are also anti-secretory agents and may be used to treat gastric hypersecretion. The compounds may be tested as anti-ulcer agents by assessing their effect upon gastric ulcers caused in rats by cold restraint stress, in particular by a modification of the procedure of H.M. Manson and D.A. Brodie, J. Appl.

Physiol., 15, 291-294 (1960). The end compounds of Examples 1 and 2 herein, when so tested, exhibit activity at 100mg/kg p.o. Compounds may be tested for anti-secretory activity in known manner, in par- 60 ticular by the procedure of H. Shay, D. Sun and M. Gruenstein, Gastroenterology 26:906-913 (1954). The end compound of Example 1, when so tested, exhibits activity at 30mg/kg id.

The invention also includes pharmaceutical compositions containing a compound having formula I or a pharmaceutically acceptable salt thereof in association or combination with a pharmaceutically accepta ble carrier.

2 GB 2 167 064 A For the pharmaceutical compositions any suitable carrier known in the art can be used. In such a composition, the carrier may be a solid, liquid or mixture of a solid and a liquid. Solid form compositions include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, binders, or tablet disintegrating agents; it can also be encapsulating material. In powders the carrier is a finely divided solid which is in admix ture with the finely divided active ingredient. In tablets the active ingredient is mixed wit " h a carrier hav ing the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from 5 to 99, preferably 10-80% of the active ingredi ent. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, 1() dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax 10 and cocoa butter. 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 carriers, which is thus in association with it. Similarly cachets are included.

Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. 15 The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both. The active ingredient can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol containing from 10 to 75% of the glycol by weight is generally suitable. Other compositions can be made by dispersing the finely-divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution, or in a suitable oil, for instance 20 arachis oil.

Preferably the pharmaceutical composition is in unit dosage form, the composition is sub-divided in unit doses containing appropriate quantities of the active ingredient; the unit dosage form can be a packaged composition, the package containing specific quantities of compositions, for example packeted powders or vials or ampoules. The unit dosage form can be a capsule, cachet or tablet itself, or it can be 25 the appropriate number of any of these in packaged form. The quantity of active ingredient in a unit dose of composition may be varied or adjusted from 10 to 500 mg or more, e.g. 25 mg to 250 mg, according to the particular need and the activity of the active ingredient. The invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form.

The anti-ulcer compositions of the invention will be administered orally in either liquid or solid compo- 30 sition form. These compositions may include one or more antacid ingredients, e.g. aluminium hydroxide, magnesium hydroxide or bismuth carbonate, aluminium glycinate, calcium carbonate, magnesium trisili cate, sodium bicarbonate or the alumina gel described in British Specification No. 1,284,394.

The invention is illustrated by the following Examples:- 2 Example 1

N-(Pyridin-2-yl)pyridine-2-carboxamide-l-oxicte 1,1-Carbonyidiimidazole (4.254g, 26.2 mol) was added to a solution of picolinic acid N-oxide (3.318g, 23.9 mol) in dry dimethylformamide (50mi). After 4 hours, 2-aminopyridine (2.466g, 26.2 mol) was added. 40 After 1 hour, the solution was warmed to 100' for 80 minutes and cooled to room temperature. After 18 hours the solution was subjected to evaporation in vacuo to give an oil which slowly crystallised. The solid was recrystallised from ROH to give the title compound (3.775g) as needles, m.p. 140-5'.

Analysis Found: C, 61.8%; H, 4.05%; N, 20.0%.

C,1-1.N.02 requires C, 61.4%; H, 4.2%; N, 19.5%.

Example 2

N-(Pyridin-2-ylmethyl)pyridine-2-carboxamide- 1-oxide 1 -1'-Carbonyidiimidazole (4.461 g, 27.5 mol) was added to a solution of picolinic acid N-oxide (3.479g, 25.6 mol) in dry DMF (50mi). After 4 hours, 2-amino-methylpyridine (2. 84mi, 27.5 mol) was added. After 2 hours, the solution was evaporated in vacuo to give a yellow oil. The oil was dissolved in water (50mi) and the solution was extracted with methylene chloride (3 x 70mi). The extracts were dried (M9S04) and 55 evaporated in vacuo to give an oil which was purified by chromatography [A1,03; CH,C12-Me01-1 (50:1)l to give an oil which slowly crystallised as the title compound (3.299g), m.p. 85-94% Anaylsis Found: C, 62.8%; H, 4.6%; N, 18.5%; C,2H,,N30, requires C, 62.9%; H, 4.8%; N, 18.3%.

3 GB 2 167 064 A 3

Claims

1. A compound for use as a pharmaceutical, the compound being a compound having the formula 1 R, 0 <-N / \ 10 R2A-NH-CO 10 or a pharmaceutically acceptable salt thereof, wherein R, is hydrogen or lower alkyl, A is a direct bond or lower alkylene and R, is pyridinyl or pyridinyl monosubstituted by lower alkyl. 15

2. A compound having the formula 1 0 4,-- N R 2 -A-NH-C R or a pharmaceutically acceptable salt thereof, wherein R, is hydrogen or lower alkyl subject to the prov iso that R, is other than methyl in the 6- position, A is a direct bond or lower alkylene and R2 is pyridinyl 25 or pyridinyl substituted by lower alkyl.

3. N-(pyridin-2-yl)pyridine-2-carboxamide-1 -oxide or a pharmaceutically acceptable salt thereof.

4. N-(pyridin-2-yl m ethyl) pyrid i ne-2-ca rboxa m ide-1 -oxide or a pharmaceutically acceptable salt thereof.

5. A process for the preparation of a compound as claimed in Claim 2, wherein an amine having the 30 formula R2-A-NH2 (where R2 and A are as defined in Claim 2) is coupled with an acid having the formula III 1 0 <-N HO,C R (III) (where R, is as defined in Claim 2) or a reactive derivative thereof.

6. A process as claimed in Claim 5, carried out substantially as described in Example 1 or 2 herein.

7. A compound as claimed in Claim 2, whenever prepared by a process as claimed in Claim 6.

8. A pharmaceutical composition comprising a compound as claimed in Claim 1 in association or 45 combination with a pharmaceutically acceptable carrier.

9. A pharmaceutical composition comprising a compound as claimed in Claim 2 or 7 in association or combination with a pharmaceutically acceptable carrier.

10. A pharmaceutical composition comprising a compound as claimed in claim 3 or Claim 4 in associ 50ation or combination with a pharmaceutically acceptable carrier.

Printed in the UK for HMSO, D8818935, 3186, 7102.

Published by The Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.