CA1241331A - Isothiazolo(5,4b)pyridin-3-one derivatives and process for preparing the same - Google Patents

Abstract

The present invention relates to compounds of general formula: <IMG> (I) in which R1 is a mono or polyhydroxyalkyl radical having from 2 to 5 carbon atoms, an alkenyl radical having from 3 to 6 carbon atoms or a cycloalkyl radical having from 3 to 6 carbon atoms, and their salts with a pharmaceutically acceptable mineral or organic acid, such as hydrochloric acid or hydrobromic acid. The invention also relates to a process for the preparation of the compounds of formula (I). These compounds are useful as an anti-acne agent.

Description

33 ~.

This is a division of the patent application No 441 958 filed November 25, 1983.

The present invention relates to derivatives iso-thiazolo- (5,4b) pyridine one-3, which are in particular useful as an anti-acne agent, as well as a method for the preparation of these derivatives.
Acne usually manifests on the face but also the neck and possibly the back and the chest by the appearance of pimples, blackheads or pustules.
This handling of acne mainly results from hyperkeratinization of the sebaceous gland ducts.
As a result, the sebum cannot freely flow, therefore forms an environment conducive to proliferation bacterial ration leading to certain phenomena of flammation, bacteria are indeed likely to rupture the ducts of the sebaceous glands which releases irritating fatty acids.
In order to avoid these irritation phenomena, it it is therefore important to use certain substances likely to act effectively with regard to the main germs of the spectrum of acne namely corinebacterium acnes and propionibacterium granulosum.
In fact by inhibiting the activity of these germs prevents hydrolytic cleavage of normal triglycerides of the sebum, which helps prevent fatty acids from forming long chains which we have noticed that the provocation what are the phenomena of inflammation typical of lesions of acne.
The active compounds according to the invention are in this regard of excellent anti-acne agents as far as they have proven to be particularly selective with regard to of the two main germs in the acne spectrum corinebacterium acnes and propionibacterium granu osum.

r ~

~ 2 ~ L ~ 33 ~.

The tests carried out using these compounds active by the diffusion method in pellets allowed to check and confirm this specificity on these two germs.
The subject of the present invention is therefore a active compound corresponding to the following general formula:

~ N - R (I ') in which R1 represents a mono or polyhydroxy- radical alkyl having 2 to 5 carbon atoms, an alkenyl radical having 3 to 6 carbon atoms or a cycloalkyl radical having 3 to 6 carbon atoms, (preferably a radical mono or polyhydroxy alkyl having 2 to 5 carbon atoms) as well as its salts with mineral or organic acids pharmaceutically acceptable.
The invention further relates to a method for the preparation of these compounds of formula (I), characterized in that:
- either react an amine of formula:

Rl NH2 in which R1 has the previous meaning, on the : 2-chloro nicotinic acid acid chloride, obtains the 2-chloro nicotinamide of formula (3 ~:
CONHRl (3) N ~ Cl . ~ s .

~.
.

l33 ~.

in which Rl has the previous meaning, submit this compound of formula (3) with the action of sulfhydr ~ te potassium, obtains the mercapto-2 nicotinamide of formula (4):

CONHR

~ N ~ Sll in which R1 has the previous meaning, which we isolates then subjected to an oxidation reaction to obtain the sought compound which is isolated and, if desired, transformed into one of its salts with mineral or organic acids pharmaceutically acceptable, - either for the preparation of a compound of formula general (I ') in which Rl represents a mono radical or polyhydroxyalkyl having 2 to 5 carbon atoms, one subjects isothiazolo- (5,4b) pyridine one-3 or hydroxy-3 isothiazolo- (5,4b) pyridine with the action of an epoxide of formula:

R - CH - CH
\ O /

in which R represents a hydrogen atom, a radical alkyl having 1 to 3 carbon atoms or a mono radical or polyhydroxyalkyl having from 1 to 3 carbon atoms, and obtains the desired compound which is isolated and, if desired, transforms into one of its salts with mineral acids or organic pharmaceutically acceptable.

~ 2 ~ 33 ~.

The cycloalkyl radical is preferably the cyclopentyl or cyclohexyl radical.
Among the active compounds of formula (I ') below above mentioned, we can in particular mention the following:

l) (2-hydroxypropyl) -2 isothiazolo- (5,4b) pyri-dine one-3

2) (1,2-dihydroxy propyl) -2 isothiazolo- (5,4b) py-ri.dine one-3

3) 2-cyclohexyl isothiazolo- ~ 5.4b) pyridine one-3.
The compounds of formula (I ') can in particular be obtained according to the following reaction scheme:
DIAGRAM I

~ 2> ~ COCl ~ ClNHR

(l) (2) ~ ~ 3) L33 ~

2) CH3CO2H ~ ONH ~ R

~

The preferred method of preparing the compounds active ingredients of formula (I ') initially consists of pre-adorn a 2-nicotinamide chloro (3) by reacting a excess of an amine (R1NH2) on the acid chloride of the acid 2-nicotinic chloro (2) in solution in 1,2-dichloro ethane, possibly in the presence of water.
The mercapto-2 nicotinamides (4) are prepared by reaction of potassium sulfhydrate on 2-chloro nico-tinamides (3) dissolved in methyl or ethyl cellosolve. After concentration of the reaction medium the residue is taken up in water and mercapto-2 nicotinamide (4) is precipitated by adding acetic acid to obtaining a pH of around 4, then purified by crystal-lization in a suitable solvent.
Isothiazolo- (5,4b) pyridine ones-3 are then obtained by oxidation of 2-mercapto nicotinamides (4) to using sodium metaperiodate fixed on acid alumina, this oxidizing reagent being described by Kwang Ting Liu & Yung Chien Tong, J. Org. Chem 1978, 43 p. 2717.
Using this reagent it is possible to obtain selectively isothiazolo- ~ 5,4b) pyridine ones-3.
The metaperiodate oxidation reaction is performed at room temperature by adding in one times an equivalent of oxidizing reagent attached to alumina at a 2-mercapto-nicotinamide alcoholic solution (4).
The reaction is very fast (a few minutes) then the reaction mixture is filtered, the alumina is washed ~ 2 ~ 33 ~.

with ethanol and the filtrate is concentrated under pressure reduced to lead to the expected product which is purified on a silica gel chromatography column in view to eliminate the iodine which is released at the necks of the reaction.
The active compounds of formula (I ') in which the radical R1 represents a mono or polyhydroxy- radical alkyl (5) can be prepared from isothiazolo- (5,4b) pyridine one-3 (or hydroxy-3 isothiazolo- (5,4b) pyridine) in causing it to react with an epoxide as shown in the diagram (II):

_SCHEMA II

~ + R - C ~ - C ~ 2 ~ / NC ~ 2C ~ O ~

NOT

The active compounds of formula (I ') are generally-used when mixed with an excipient, to define a composition, at a concentration of between 0.05 and 10% and preferably between 0.3 and 3 ~ by weight per relative to the total weight of the composition.
These compositions can be presented under different shapes suitable for topical application on the skin area ~ traitx in particular in the form of a lotion, ointment, powder, milk, cream, as a gel or as an aerosol.
Lotions are liquid preparations, aqueous or hydroalcoholic which may also contain certain some suspending or dispersing agents such as derived from cellulose, gelatin and gums as well than glycerin or propylene glycol.
Gels are semi-solid preparations pre-prepared by gelation of a solution or suspension of an active compound of formula (I ′) using gel agents fiants such as "bentone gel" (sold by NL Company Industries) for an oily phase or polyacrylic acid crosslinked for an aqueous phase such as that sold by the ~ GOODRICH company under the trademark "Carbopol", and used in neutralized form.
According to a preferred embodiment, the compositions are in the form of a cream, that is to say say in the form of a water-in-oil type emulsion or oil-in-water.
Among the different oils likely to constitute the oil phase, various products can be used such as:
- animal oils such as horse oil, pork oil, lanolin, - vegetable oils like almond oil sweet, avocado oil, castor oil, olive oil, grape seed oil, flaxseed oil, rapeseed, peanut oil, mals oil, hazelnuts, jojoba oil, cartame oil and oil wheat germ, - hydrocarbon oils such as paraffin, Purcellin oil, perhydrosqualene and microcrystalline wax solutions in oils, - mineral oils and in particular oils of which the initial point of distillation at atmospheric pressure risk is around 250C and end point of the order of ~ 2 ~

- silicone oils soluble in the others oils.
You can also use certain products synthetics such as for example saturated esters and in particular isopropyl palmitate, isopropyl myristate pyle, butyl and cetyl, hexadecyl stearate, ethyl palmitate and acid triglycerides octanoic, decanoic and cetyl ricinoleate.
The oil phase of the emulsions can also hold certain waxes and in particular carnauba wax, beeswax, ozokerite or cane wax dellila.
As an emulsifying agent, the agents or mixtures of known emulsifying agents such as those with a total mean HLB between l and 14 (and in particular between 3 and 13) for example the mixture of triethanolamine stearate and oxyethyl stearic acid ene, oxyethylenated oleic alcohol with 10 moles of oxide ethylene and glycerol monostearate.
In these emulsions, the emulsifier is generally present in a proportion between 1 and 12 ~ relative to the total weight of the composition.
These cream compositions can also contain other ingredients such as agents preservatives, perfumes, dyes, filters sun, pigments, humectants, fillers such only talc, nylon powder, starch and polyethylene.
In order to strengthen the anti-acne activity of active compounds of formula (I ') it is possible to use according to the invention certain antibiotics such as tetracyclines such as for example chlortetracycline or oxytetracycline or macrolides such as for example erythromycin, aminoglycosides such as ~ 2 ~ 3 ~.

neomycin, sulfonamides (sulfanylamides), syner-gistines, AB polypeptidi ~ ues or chloramphenicol.
Acne treatment using compounds according to the invention consists in applying two or three times per daily a sufficient amount on the skin areas to treat and this for a period of time which may be between 1 and 6 weeks.
In order to illustrate the present invention, we will now give without any limitation several examples of preparation of active compounds for anti-acne according to the invention.
EXAMPLE I Preparation of isothiazolo- (5,4b) pyridine ones-3 according to reaction scheme I.
-1) Preparation of the acid chloride of the acid chloro-2 nicotinic-1 (2) A 17.2 g of 2-chloro nicotinic acid (1) (0.11 mole), stirred at room temperature and away from humidity, add 70 cm3 of chloride pure thionyl. The reaction mixture is then brought to the boiling point of thionyl chloride which is maintains until a homogeneous medium is obtained (1 hour About 30 is required). Thionyl chloride is then moved by distillation under reduced pressure. The acid chloride hydrochloride then crystallizes at the ordinary temperature in quantitative yield.

2) Preparation of chloro-2 nicotinamides d_ formula:

~ \ ~ coN ~ Rl ~ 1..
N ~ \ Cl (3) 33 ~.

To a solution of acid chloride hydrochloride obtained according to Example I) in 1,2-dichloroethane, cooled to 0C, a dropwise addition is added with stirring excess amine ~ R1NH2), either in aqueous solution or in solution in 1,2-dichloroethane. After the end of the addition, the reaction medium is left for 2 hours at the ordinary temperature then the organic phase is decanted, washed with a minimum of ice water and dried over sulphate sodium. After concentration under reduced pressure the residue is recrystallized from a suitable solvent. When the amine is added in aqueous solution, the aqueous phase of decantation is concentrated to dryness and the precipitate obtained is taken up in toluene, which makes it possible to isolate part amide slightly soluble in water.
A 2-nicotinamide chloro of formula (3) obtains naked according to this pxocédé appears in the following table u 1:

'~

33 ~.

~ i o ~

where oo C ~
~ r V ~
~ 9 where co ~ r where u ~
U
oo o *

m '' o N ~
, ~
h , ~
o ~ $
~ ~
oo ~

.

-. . . .:,,. ~

3 ~.

3) Preparation of the mercapto-2 nicotinamides of formula:
~ CoNHR

~ N ~ SH

(4) To a solution of 2-chloro nicotinamide (0.05 mole) as obtained under 2) above in methyl or ethyl cellosolve, add at room temperature and with stirring, a previously prepared solution of potassium sulfhydrate. This solution is obtained by passing under stirring and cooling to 0C a stream of hydrogen sulfide in 0.11 mole solution of potash in 50 cm3 of methyl cellosolve until that it no longer gives coloring to phenolphthalein.
The mixture thus obtained is brought to 125 ° C. for 4 hours.
then concentrated under reduced pressure. The residue is agitated in 400 cm3 of water then acidified with acetic acid up to pH around 4. Mercapto-2 nicotinamide expected precipitates, then is wrung and dried.
A mercapto-2 nicotinamide of formula (_) obtained according to this process appears in the following table 2:

, 3 ~

0 \

U ~
In o o \, o N ~ D
where X

VS:
~ O ~
o \ O ~ ~
t ~ OO

O ~ ~ r ~ C5 NOT

~; ~

h a ~

~ n ~ o O
~ 0 0 a ~

4) Preparation of isothiazolo- (5,4b) pyridine formula ones-3:

r, (I) To a stirred solution of 2-mercapto nicotinamide, obtained according to Example I 3) in ethanol or methanol ~ the ordinary temperature, an equivalent is added all at once sodium metaperiodate attached to alumina. (This reagent is prepared by the method of Kwang Ting Liu & Yung Chien Tong, J. Org. Chem, 1978 43 p. 2717). The disappearance of mercapto-2 nicotinamide, usually very fast, is followed by thin layer chromatography. The reaction mixture-nel is filtered, the alumina is washed with methanol and then the filtrate is concentrated under reduced pressure. The residue obtained is dissolved in the minimum amount of chloroform and the chloroformic solution deposited on a column of silica gel chromatography to remove released iodine during the reaction. Isothiazolo- (5,4b) pyridine ones-3 are then recrystallized from a suitable solvent then wrung and dried. An active compound of formula (I ') obtained according to this process appears in table 3 following:

.:.
. . ,,. - ~.
- '. ~ ~ "'~'' :

3 ~
oo u ~
o \ O ~ D ~ r U ~
U ~ o \ Ci ~
P ~ Z ~ ~
U ~ ~ ~
z o \ O ~ ~
~ o ~

o \ OR ~ ~
~ D tD

o * i--.

m ~ 0 \ oo ~ '~

at) X
o ~ C o C ~ ~ *

, EXAMPLE II _reparation of isothiazolo- (5,4b) pyridine ones-3 according to reaction scheme II.
1) Preparation of 3-hydroxy isothlazolo- (5,4b) pyrldlne.
To a stirred solution at ordinary temperature, of 3 g of mercapto-2 nicotinamide in 75 cm3 of acetic acid which is added drop by drop 7.3 cm3 of hydrogen peroxide at 30 volumes. The reaction medium gradually becomes homogeneous. After one hour of reaction, we do not detect more in the reaction medium of mercapto-2 nicotinamide.
The mixture is then concentrated under reduced pressure and the solid obtained is recrystallized from methanol. The hy-droxy-3 isothiazolo- (5.4b) pyridine (2.7 g) comes in form of yellow needles with a melting point of 220C.
Analysis: C6H4N2OS
Calc: C 47.36 H 2.65 N 18.41 S 21.07 Tr: 47.42 2.83 18.66 21.25 2) Preparation of (2-hydroxypropyl) -2 isothia-zolo- (5,4b) pyridine one-3 (compound n 1) We give up at room temperature, under agitation and protected from air humidity, a mixture consisting of 1 g of 3-hydroxy isothiazolo- (5,4b) pyridine in 10 cm3 of propylene oxide in the presence of two drops diaza-1,5 bicyclo L ~ -4-0- ~ undecene-5 (DBU). After 10 days the excess propylene oxide is moved under pressure scaled down. The residue obtained is dissolved in chloroform and deposited on a column of silica gel. The compound expected is then eluted with ethyl acetate and then crystallized in this solvent with a yield of 30%. I1 introduces himself in the form of white crystals with a melting point of 112C.

,.

.

13 ~.

C9H10N22S analysis Calc: C 51.41 H 4.79 N 13 ~ 32 S 15.25 Tr: 51.46 4.92 13.51 15.31 3 ~ Preparation of (1,2-dihydroxy propyl) -2 iso-thiazolo- (5,4b) pyridine one-3 (compound n 2).
The tetra- is brought to the boiling point hydrofuran a mixture of 1 g of hydroxy-3 isothiazolo-(5.4b) pyridine (6.6.10 3 mole), 1 cm3 of glycidol and 2 drops of DBU for 42 hours. The reaction mixture-nel is then concentrated, taken up by the minimum of chloro-form and the solution obtained deposited on a gel column silica. The expected compound is eluted with acetone and then recrystallized from this solvent. It comes in the form a white powder, obtained with a yield of 67% and has a melting point of 125C.

C9H10N23S analysis Calc: C 47.78H 4.46N 12.28 S 14.17 Tr: 47,494.76 12.36 14.14 , .
.

Claims (14)

The embodiments of the invention, concerning the-what an exclusive property right or lien is claimed, are defined as follows: 1. Process for the preparation of a compound of general formula (I '):

(I ') in which R1 represents a mono or polyhydroxy- radical alkyl having 2 to 5 carbon atoms, an alkenyl radical having 3 to 6 carbon atoms or a cycloalkyl radical having 3 to 6 carbon atoms as well as its salts with pharmaceutically acceptable mineral or organic acids bles, characterized in that:
- either react an amine of formula:

in which R1 has the previous meaning, on the 2-chloro nicotinic acid acid chloride, obtains the 2-chloro nicotinamide of formula (3):

(3) in which R1 has the previous meaning, submit this compound of formula (3) with the action of potassium, obtains the mercapto-2 nicotinamide of formula (4):

(4) in which R1 has the previous meaning, which we isolates then subjected to an oxidation reaction to obtain the sought compound which is isolated and, if desired, transformed into one of its salts with mineral or organic acids pharmaceutically acceptable;
- either for the preparation of a compound of formula general (I ') in which R1 represents a mono radical or polyhydroxyalkyl having 2 to 5 carbon atoms, one subjects isothiazolo- (5,4b) pyridine one-3 or hydroxy-3 isothiazolo- (5,4b) pyridine with the action of an epoxide of formula:

in which R represents a hydrogen atom, a radical alkyl having 1 to 3 carbon atoms or a mono radical or polyhydroxyalkyl having from 1 to 3 carbon atoms, and obtains the desired compound which is isolated and, if desired, transforms into one of its salts with mineral acids or pharmaceutically acceptable organic. 2. Process for the preparation of a compound of formula (I '):

(I ') in which R1 represents a mono or polyhydroxy- radical alkyl having 2 to 5 carbon atoms, an alkenyl radical having 3 to 6 carbon atoms or a cycloalkyl radical having 3 to 6 carbon atoms, and its salts with pharmaceutically acceptable organic mineral acids tables, characterized in that an amine of formula:

Rl NH2 in which R1 has the previous meaning, on the 2-chloro nicotinic acid acid chloride, obtains the 2-chloro nicotinamide of formula (3):

(3) in which R1 has the previous meaning, isolates this compound of formula (3) and subjects it to the action of sulfhy-potassium drate, obtains 2-naptinamide mercapto from formula (4):

(4) in which R1 has the previous meaning, which we isolates then submits to the action of an oxidizing agent to obtain the desired compound which is isolated and, if desired, transforms into one of its salts with mineral acids or pharmaceutically acceptable organic. 3. Method according to claim 2, characterized in that an excess of amine is reacted on the chloride 2-nicotinic acid acid dissolved in either 1,2-dichloro ethane or a mixture of 1,2-dichloro ethane and water. 4. Method according to claim 2, characterized in that the 2-chloro nicotinamide of formula (3):

(3) in which R1 has the meaning indicated in the claim cation 2, is dissolved in methylcellosolve or ethylcellosolve then subjected to the action of potassium. 5. Method according to claim 2, characterized in that the oxidizing agent consists of metaperiodate of sodium fixed on an acid alumina. 6. Method according to claim 1, for the pre-paration of a compound of general formula (I '):

(I ') in which R1 represents a mono or polyhydroxy- radical alkyl having 2 to 5 carbon atoms, and its salts with mineral or organic acids pharmaceutically acceptable, characterized in that isothiazolo-(5,4b) pyridine one-3 or 3-hydroxy isothiazolo- (5,4b) pyridine with the action of an epoxide of formula:

in which R represents a hydrogen atom, a radical alkyl having 1 to 3 carbon atoms or a mono radical or polyhydroxyalkyl having from 1 to 3 carbon atoms, and obtains the desired compound which is isolated and, if desired, transforms into one of its salts with mineral acids or pharmaceutically acceptable organic. 7. Process for the preparation of cyclohexyl-2 isothiazolo- (5,4b) pyridine one-3, characterized in that cyclohexylamine is reacted with the acid chloride 2-chloro nicotinic acid, obtains N-cyclohexyl 2-chloro nicotinamide which is isolated and subjected to the action of potassium sulfhydrate, obtains N-cyclohexyl mercapto-2 nicotinamide that is isolated and subjected to the action of an agent oxidation to obtain the desired compound which is isolated. 8. Process for the preparation of (2-hydroxy propyl) -2 isothiazolo- (5,4b) pyridine one-3, characterized in what we subject the 3-hydroxy isothiazolo- (5,4b) pyridine to propylene oxide action and obtains the desired compound that we isolate. 9. Process for the preparation of (dihydroxy-1,2 propyl) -2 isothiazolo- (5,4b) pyridine one-3, characterized in that one submits the 3-hydroxy isothiazolo- (5,4b) pyridine to the action of glycidol and obtains the compound sought that we isolate. 10. A compound of general formula (I '):

(I ') characterized in that R1 represents a mono radical or polyhydroxyalkyl having 2 to 5 carbon atoms, one alkenyl radical having 3 to 6 carbon atoms or a cycloalkyl radical having 3 to 6 carbon atoms, thus that its salts with mineral or organic pharma-ceutically acceptable. 11. A compound of general formula (I '):

(I ') characterized in that R1 represents a mono or poly- radical hydroxyalkyl having from 2 to 5 carbon atoms, as well as its salts with mineral or organic pharmaceutical acids only acceptable. 12. Cyclohexyl-2 isothiazolo- (5,4b) pyridine one-3. 13. (2-Hydroxy propyl) -2 isothiazolo- (5,4b) pyridine one-3. 14. La (dihydroxy-1,2 propyl) -2 isothiazolo-(5,4b) pyridine one-3.