SI9300609A - New heterocyclic compounds with antiastmatic/antialergic, antiinflammatory, positively ionotropic and anti-hypertensive activity - Google Patents

Abstract

Compounds of the triazinone type having the general formula 1, which have antiasthmatic, antiallergic and cardiovascular activities, and process variants for their preparation were described.

Description

New heterocyclic compounds with anti-asthmatic / anti-allergic, anti-inflammatory, positively inotropic and antihypertensive effect

Description

The invention describes novel arylthriazinones and arylthriazinophthalazines, a process for their manufacture and use of the compounds of the present invention for the treatment of bronchial asthma, allergies of various genesis, inflammatory processes, heart failure and hypertension.

The compounds of the present invention are distinguished, for example, as effective and selective inhibitors of 5-lipoxygenase and can therefore be used in diseases in which the involvement of 5-lipoxygenase or leukotrienes in pathophysiological events is important. Sayed et al (Chinese Journal of Chemistry, No.1, (1991) p. 45) described the synthesis of substituted phthalazinone derivatives by the conversion of phthalides or substituted benzoylbenzoic acid esters with hydrazine. Further conversion leads to 7- (p-ethylphenyl) -2H1,2,4-triazino / 3,4-a / phthalazin-3 (4H) -ones as a by-product. Comparini et al (J. Heterocyclic Chem. 15, 1271 (1978) describe the conversion of iminoesters and substituted hydrazines into 2,5-dihydro-1,2,4-triazine 6 (1 H) -one.

EP-052 422 describes triazinones which are substituted in the 6 position by a substituted aromatic ring. The compounds have cardiotonic properties and are also suitable for the treatment of Morbus Parkinson.

European Patent Application 80 296 describes, with aromatic residues in position 4, substituted oxadiazinones, triazinones and thiadiazinones with cardiotonic and antihypertensive properties.

The compounds of the present invention can be described by the formula:

where:

R 1 and R ₂ may be the same or different, and represent hydrogen or alkyl groups with CrC * chain lengths which may also be branched, benzyl groups substituted by halides such as fluorine, chlorine or bromine, further benzyl substituents the groups may be -CH ₃ , NO ₂ , amino and substituted amino groups, further -CF ₃ ; if R ₂ = benzyl or substituted benzyl, R _{2 may} also be annelated, i.e. in conjunction of aromatic rings.

The compounds of the present invention may also be present in tautomeric forms.

Due to the asymmetric carbon atom in the molecule, the compounds of the present invention may be present in mirror isomeric forms. The compounds of the present invention can be present as enantiomerically pure in the (R) - or (S) -form or in the form of a racemic mixture or in mixtures of any composition.

Synthesis of compounds

All three described variations of the process lead to compounds of general formula 1.

Procedure 1

7-phenyl-2H-triazino (3,4, a) phthalazine-3- (4H) ones

The phenyltriazinophthalazinones of the present invention of formula IV can be prepared according to Scheme I.

The meanings of X and Y correspond to the definitions above.

On the basis of principled methods known in the literature, we make as assumptions

4-arylphthalazinones of formula I (prepared according to J. Pharmaceutical Soc. Jpn 86, 576 (1966) and USP 3.694,442) and by alkylation (according to J. Organic Chem, 50, 1677 (1985)) 4-arylphthalazinone-acetates of formula II. The solvents in the steps of compounds II to III in Scheme 1 include aromatic hydrocarbons which are liquid and may be substituted by one or more alkyl groups such as benzene, toluene and isomeric xylenes.

After conversion to the thioamides of formula III (with P ₂ S ₅ or with Lavvesson's reagent), they are cyclized with hydrazine or substituted hydrazine derivatives at 50 ° C - 80 ° C. Lavvesson's reagent refers to 2,4- (4-methoxyphenyl) 1,3-dithia-2,4-diphosphethane 2,4-disulfide, which can be prepared by Synthesis, page 941 (1979) or by TP Anderson et al, Tetrahedron , 39 (20), 2419 (1983).

Aliphatic alcohols, having one or more hydroxyl groups, with a chain length of 1-4 carbon atoms, may be used as alcohols. For example, methanol, ethanol, propanoes, isopropanol and isomeric butanols are suitable.

Scheme I

Synthesis of aryl-triazino-phthalazines

Z-CH ₂ CO ₂ Et U

N-CH ₂ CO ₂ Et

I

N

Lavvesson / toluene reagent or. P ₂ S _s

R ¹ -N ₂ H ₃ / Alcohol

N-CH ₂ CO ₂ Et

N at £ emer Z = S / O / NH

Example 1

7-Phenyl-2H-triazino (3,4a) phthalazin-3 (4H) -one (D-19509) g (0.032 mol) of 4-phenylphthalazinone (melting point: 232-234 ° C) was prepared in 100 ml of toluene and 0.8 portions were added portionwise. g (0.036 mol) of sodium hydride at room temperature. It is then refluxed for one hour and after cooling to 50 ° C it is mixed with 5.4 g (0.032 mol) of ethyl bromoacetic acid. It was refluxed for five hours, the precipitate was separated and the solution concentrated. The precipitated crystals were dissolved in 200 ml of toluene and the solution was mixed with 9 g (0.022 mol) of Lawesson's reagent (2,4-bis (4-methoxyphenyl) -2,4-dithioxo-1,3,2,4-dithiophosphane). After 24 hours at 80 ° C, it was concentrated in vacuo and the precipitated thioamide was isolated. Dissolve 8 g (0.025 mol) of thioamide in 100 ml of ethanol, add 1.5 g (0.03 mol) of hydrazine hydrate and reflux for 18 hours. The precipitate was filtered off with suction, suspended in water and dried. Melting point: 251-252 ° C.

DC (chloroform / methanol / 25% ammonia solution 95/5/1) Rf = 0.69

The following compounds of Table 1 of Formula IV were prepared according to Example 1.

Ex. Compound of Formula IV Christ, from Melting Point

no. X Y R1 Y, 2 3-methoxy 4-methoxy H H methanol 249-252 ° C 3 3-methoxy 4-methoxy H 7-methyl methanol 237-239oC 4 3-Oxyethylene 4-Oxyethylene H H ledocet 266 ° C 5 3-fluorine 4-fluorine H H ethanol 269 ° C 6 4-fluorine H H H butanol 257-259 ° C 7 4-methoxy H H H dioxane 266oC 8 4-OBzl H H H dioxane 272 ° C 9 N (CH ₃ ) ₂ H H H dioxane 268 ° C 10 4-S-CH ₅ H H H ledocet 282 ° C 11 3-CI 4-OH H H methanol 275-277oC 12 4-OH H H H butanol 308oC 13 4- (2-pyridyl- methyl) oxy Cl H H ledocet 263-264 ° C 14 4- (2-pyridyl- methyl) oxy 3-CI H H ledocet > 300 ° C 15 4- (2-quinolyl- methyloxy 3-CI H H ledocet > 300 ° C

Procedure 2

3-Phenyl-4,5-dihydro-1,2,4-triazin-6-ones

The compounds of the present invention can be prepared according to Scheme II.

Substituted 4-hydroxy- or 4-amino-benzoylamino acid esters of formula V (prepared according to the literature, for example EP 422191 or Buli. Chem. Soc. Chim. Belg., 92 (11), 1029 (1983)) serve as forerunners.

The benzoylamino acid V esters are converted in a known manner with aryl or heteroarylalkyl halides in organic solvents such as toluene or DMA or mixtures thereof using an auxiliary base into the corresponding arylalkyl or heteroalkylether, thioether or -amine type VI.

Alkali metal carbonates, alkaline earth metal carbonates and aliphatic amines, for example, sodium carbonate, potassium carbonate or triethylamine, may be used as auxiliary bases.

Activation of the formation of the amide in VI by the formation of imidchlorides (using POCI ₃ / PCI ₅ or SOCI ₂ as a reagent) or the production of thioamides (using P ₂ S ₅ or Lavvesson's reagent) yields intermediate stages VII.

Hydrazine or substituted hydrazine derivatives in C-alcohols, in particular ethanol or butanol, give the compounds of the present invention type VII at temperatures of 40 ° C-80 ° C.

Substituted hydrazine derivatives include alkylhydrazines, such as methyl-, ethylhydrazine, and benzylhydrazine.

Example 16

- 3-Chloro-4 - [(2-quinolyl) methoxy / phenyl -4-methyl-4,5-dihydro-1,2,4-triazin-6-one (D-20783)

a) N- (3-chloro-4-hydroxy) -benzoyl-sarcosinethyl ester

An example of a compound of formula V

172.6 g (1 mol) of 3-chloro-4-hydroxybenzoic acid, 153.6 g (1 mol) of sarcosine-ethyl ester hydrochloride and 3 moles of triethylamine were prepared in 1.5 I of dichloromethane and cooled to -10 ° C. 60 g (0.4 mol) of 1-hydroxybenzotriazole hydrate and 211 g (1.1 mol) of N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride were added and stirred for 1 h at -10 ° C. The mixture was then stirred at room temperature for so long that the starting products were no longer visible on the thin layer chromatography. The organic solution was then poured into 4 l of water and the aqueous phase was extracted twice more with 300 ml of dichloromethane. The organic phases are combined and dried over sodium sulfate and concentrated.

The resulting product (yellow oil) is dried with an oil pump and then further processed as a crude product.

b) N- [3-chloro-4- (2-quinolyl) methoxy / benzoyl-sarcosinethyl ester (2)

An example of a compound of formula VI

271.7 g (1 mol) (1) and 195.4 g (1.1 mol) of chloromethylquinoline are prepared in 600 ml of toluene and 200 ml of dimethylacetamide. 1.2 moles of potassium carbonate powder are added and the suspension is refluxed for 6 hours. After completion of the reaction, the residue was sucked off and washed with toluene. The filtrate was concentrated to give a dark oil.

c) N- [3-chloro-4- (2-quinolyl) -methoxy / phenyl-thioxo-sarcosinethyl ester (3)

Example of a compound of general formula VII

412.8 g (1 mol) (2) was prepared in 1 I of toluene abs. and mixed with 202.2 g (0.5 mol)

Lawesson's reagent (= 2,4-bis- (4-methoxyphenyl) -2,4-dithioxo-1,3,2,4 dithiadiphosphethane). Heat for 4 hours at 80 ° C. The solution was concentrated on a rotary evaporator. A brown viscous oil is obtained which is converted as a crude product.

d) 3- (3-chloro-4 - [(2-quinolyl) methoxy) phenyl] -4-methyl-4,5-dihydro-1,2,4-triazin-6-one (D-20783)

428.9 g (1 mol) (3) was prepared in 1 I of ethanol and mixed with 65 g (1.3 mol) of hydrazine hydrate. It is then heated for 6 to 10 hours at reflux. The reaction solution was concentrated on a rotary evaporator. A brown crystalline slurry was obtained which was mixed with 1.5 I acetone and stirred at room temperature for 1 hour. The aspirated, acetone-washed crude product is dried.

Yield: 39.89 g (12%), melting point: 205-209oC.

NMR data (500 MHz, D ₆ -DMSO): (ppm)

10.45 (s, 1H, NH), 7.6-8.5 (m, GH, quinolyl residue)

7.55 (s, 1H, 2H aroma), 7.4 (d, 1H, GH aroma)

7.35 (a, 1H, 5H-aromatic), 5.55 (s, 2H, OCH ₂ )

3.8 (s, 2H, N-CH ₂ ), 2.75 (s, 3H, N-CH ₃ ).

Compounds VII of the following Table 2 can be made according to Example 16.

The compounds of the present invention of type VII 3-aryl-4,5-dihydro-1,2,4-triazin-6-ones can also be prepared by alternative synthesis routes. These can be seen from the llb and Ilc schemes and viewed as exemplary.

Scheme II a

Synthesis of 3-aryl-4,5-dihydro-1,2,4-triazin-6-ones

or ₂ n \ · ⁰ ^ Rj O vi

X = Het-alkyl / ar-alkyl-S / O / N + H ₂ NNHR ³ x H ₂ O / Alcohol

VIII

Scheme II b

W = OH, S H, NH,

X = Het-alkyl / ar-alkyl-S / O / NH

vni

A = alkyl C, -C _n , benzyl R, = H, alkyl, benzyl R ₂ ~ H, alkyl, benzyl

Scheme II c £ cc

A = alkyl C, - ^, benzyl R, = H, alkyl, benzyl R ₂ = H, alkyl, benzyl

Table 2, compounds of formula VII

Ex. Compound of Formula VIII Solvent Melting point

no. X Y A R · r ₂ 17 OH no ₂ H H H ledocet 242-244 ° C 18 OH nh ₂ H H H acetone 213-215 ° C 19 OH H H H H methanol 249-251 ° C 20 OH Cl ch ₃ H H acetone Mp 228-231 ° C 21 OH Cl H H H isopropanol / methanol 236-239oC 22 OH och ₃ H H H isopropanol / methanol 256-258 ° C 23 OH och ₃ H H H isopropanol / methanol 261-264 ° C 24 OH och ₃ H ch ₃ H isopropanol 244-247oC 25 Bzl-0 · * H H H H methanol 199-202oC 26 3- [1- (2-methoxyphenyl) H -piperazinyl / -propyloxy H H H isopropanol / methanol 133-135oC 27 3- / 1- (2-methoxyphenyl) -piperazinyl / -ethoxy H H H H isopropanol / methanol 139-141 ° C 28 (2-pyridylmethoxy) H H H H isopropanol 178-182oC 29 Bzl-0 H ch ₃ H H isopropanol / methanol 168-171 ° C 31 3- / 1- (2-methoxyphenyl- Cl ch ₃ H H isopropanol 113-115oC

piperazinyl / -ethoxy

Ex. A compound of formula VIII

Solvent Melting point

no. X A R1 R2 32 Bzl-0 och ₃ H H isopropanol / methanol 231-233 ° C 33 Bzl-0 Cl ch ₃ H isopropanol 252-254oC 34 Bzl-0 Cl H H isopropanol 241-243 ° C 35 Bzl-0 och ₃ ch ₃ H isopropanol / methanol Mp 212-214 ° C 36 3-Pyridylmethoxy C H H isopropanol / methanol 246-249 ° C 37 3-Pyridylmethoxy och ₃ H H methanol 243-245oC 38 3-Pyridylmethoxy Cl ch ₃ H isopropanol Mp 158-162 ° C 39 3-Pyridylmethoxy och ₃ H H isopropanol Mp 186-188 ° C 40 (4-Fluoro) -Bzl-O och ₃ H H isopropanol Mp 189-191 ° C 41 Bzl-0 och ₃ H ch ₃ isopropanol / methanol Mp 228-231 ° C 42 Bzl-S F H H isopropanol / methanol 244-247 ° C 43 Bzl-S H H H isopropanol 250-252oC 44 Bzl-NH och ₃ ch ₃ H isopropanol 181-183 ° 45 Bzl-NH H H H methanol > 250oC 46 Bzl-S F CH ₃ H isopropanol. 138oC 47 Bzl-S nh ₂ ch ₃ H isopropanol / methanol 245-247 ° C 48 Bzl-NH och ₃ ch ₃ H isopropanol 252-254cC 49 3-Pyridylmethylamino H ch ₃ H isopropanol 238-241 oC 50 3-Pyridylmethylamino och ₃ ch ₃ H isopropanol / 229-232oC

methanol

Ex. no. Compound of Formula Vlil R1 R2 Solvent Melting point X A 51 (4-methoxy) benzyloxy och ₃ H H isopropanol 198-201 oC 52 (4-methoxy) benzyloxy Cl H H isopropanol 181-183 ° C 53 3-Pyridylmethylamino och ₃ H H methanol 73-75 ° C 54 3-Pyridylmethylamino H H H isopropanol 231-233 ° C 55 (2,3,4-trimethoxy) - -benzyloxy Cl H H isopropanol / methanol 194-197oC 56 2-quinolylmethoxy Cl ch ₃ H isopropanol / methanol 205-209 ° C 57 2-quinolylmethoxy och ₃ ch ₅ H 238-241 ° C 58 2-quinolylmethoxy Cl H H isopropanol / 203-205 ° C

methanol

Procedure 3

Example 59

10-methyl-3-oxo-3,4-dihydro-2H- (1,2,4) triazino / 4,3-c-quinazoline (D-19749)

Based on the known derivatives of quinazolin-4-on-3-yl-acetic acid ethyl esters of formula IX (see M. Suisse, S. Johme, J. Pract. Chem. (2), 326. 342 (1984) or RH Clark, EC Wagner J. J. Chem Chem 9. 55 (1944) afforded the corresponding quinolin-4-thion-3-yl-acetic acid ethyl esters of formula X by sulfuration with P ₂ S ₅ or Lavvesson's reagent.

To obtain the triazinoquinazolinones of formula XI, thioamides of formula X were converted to XI with hydrazine hydrate in alcohols.

All C 1 -C 4 aliphatic alcohols such as methanol, ethanol, propanol, isopropanol and isomeric butanols are considered alcohol.

a) 6-Methylquinazolin-4-thion-3-yl-acetic acid ethyl ester

A suspension of 20 g (0.081 mol) of 6-methylquinazolin-4-one-3-yl-acetic acid ethyl ester and

17.1 g (0.042 mol) of Lavvesson's reagent in 300 ml of toluene was stirred for 33 h at 80 105 ° C, slowly forming an orange to dark red solution. After the reaction was complete, the solution was cooled, concentrated and the residue was washed with a little cold toluene, then with petroleum ether and recrystallized from dichloromethane / methanol.

Melting point: 130-132 ° C

b) 10-methyl-3-oxo-3,4-dihydro-2H- (1,2,4) -triazino- (4,3-c) quinazoline

8.7 g (0.033 mol) of thioamide were suspended in 200 ml of ethanol and mixed with 10.1 g (0.2 mol) of hydrazine hydrate and the mixture heated to reflux. After four hours, the precipitate was filtered off with suction, washed with ethanol and the product recrystallized from ethanol / ice.

Melting point: 298-304 ° C - decomposition

According to Example 59, the following compounds were obtained from the table.

Scheme 3

XI

Table 3, formula XII

Solvent Melting point

Ex. A compound of formula XII

no. X Y Ri r ₂ 60 ch ₃ H H H 61 ch ₃ H ch ₃ H 62 och ₃ och ₃ och ₃ H 63 Cl H H H 64 Cl H Cl H 65 Cl H H ch ₃ 66 Cl H Cl ch ₃ 67 H H H H

ethanol / glacial acetic acid 298-304 oC ethanol / glacial acetic acid 265-269 ° C ethanol / glacial acetic acid Mp 273-275 ° C dichloromethane / methanol > 300 ° C ethanol / glacial acetic acid > 300 ° C ethanol / glacial acetic acid > 300 ° C ethanol / glacial acetic acid > 300 ° C ethanol > 300 ° C

The compounds of the present invention have anti-inflammatory (lipoxygenase inhibition) and bronchospasmolytic (carbachol model of pre-contracted guinea pig trachea).

The compounds also act on the bloodstream (increase in left ventricular contractility, decrease in blood pressure).

The compounds also inhibit histamine-induced rhinitis in the rat as well as release of histamine from mast cells.

Pharmacological testing for the efficacy of allergen-induced histamine release in sensitized rats was performed according to the test regulations according to P. A. Shore et al, I. Pharmacol. Exp. Ther .. 127 (1959), page 182.

The effect of substances on muscle relaxation was determined on carbachol (INN) precontracted guinea pig tracheas according to Tallandria et al, Manual of Pharmacoiogical Calculations with Computer Programs, Springer, 1981.

Inhibition of the production of the resulting lipoxygenase products was performed on rat macrophages as prescribed in Murphy et al., Methods in Enzymology 86, pages 409 - 416.

The compound of Example 1 shows the following values:

In allergic-induced histamine release, at a concentration of 10 pmol / l, the inhibition of release is 25%.

The compound of Example 16 shows an attempt to inhibit the delayed phase of guinea pig eosinophils according to the Cartvvright regulation. Diagnostic Laboratory Hematology, 1986, page 48 and Mac Fortare et al, Eosinophil Counting, Brit. .Med. 9, 2, 1187 (1951) at a dose of 30 mg per kilogram body weight. days p.o., inhibition value 80%.

In inhibition of the LTD-4-receptor bond according to Borbe and Zierenberg, Pharmacopsychiatry 18, 314 319 (1985), we found a 50% inhibition of activity at a concentration of 7.4 pmol / l.

Claims (11)

1. Compounds of formula I wherein: R 1 and R ₂ may be the same or different and represent hydrogen or alkyl groups with chain lengths which may also be branched, benzyl groups substituted by halides such as fluorine, chlorine or bromine, further benzyl group substituents may be -CH ₃ , NO _2i amino and substituted amino groups, further -CF ₃ ; if R ₂ = benzyl or substituted benzyl, R _{2 may} also be annelated. A-B can mean _ n - c - or - HC = C - c H = N, where: R ₄ means alkyl, branched chain chain alkyl to C ₄ , phenyl, halogen and / or nitro groups substituted phenyl with one or more times, phenyl substituted alkyl groups with 3-6 carbon atoms, which may be straight or branched chain, with alkoxy groups, cyclic alkoxy, thioalkyl-quinuclidyl, aryl groups or heteroarylmethoxy groups substituted phenyl. A can be straight chain or branched alkyl having a chain length of 1-6 carbon atoms or benzyl or halogen substituted benzyl. B may mean hydrogen if there is no bond between A and B. X may mean aryl or heteroaryl, aryl or heteroarylmethoxy, heteroarylmethylamino or heteroarylmethylthio, Y may mean halogen, hydroxy, O-alkyl, having a chain length of 1-6 carbon atoms, NO ₂ , NR ₅ R ₆ , wherein R ₅ and R _{e may be the} same or different and hydrogen, alkyl, branched alkyl of 1 - 6 carbon atoms. X and Y can also occur several times. 2. A process for the preparation of compounds of formula I, characterized in that the compounds of general formula I are converted with the compounds of formula Z-CH ₂ -COO Et into compounds of formula II, and then further converted with Lavvesson's reagent or P ₂ S ₅ to compounds of formula III and substituted hydrazines to compounds of formula IV, wherein Z = S / O / NH. 3. A process for the preparation of compounds of formula I, characterized in that the compounds of general formula VI, with Lavvesson's reagent or P ₂ S _{5, are} converted into compounds of general formula VII and then substituted hydrazines into compounds of formula Vlil. Process for the manufacture of compounds of formula I, characterized in that the compounds of general formula IX, with Lavvesson's reagent or P ₂ S _{5, are} converted into compounds of formula X and then substituted hydrazines into compounds of formula XI. Use of compounds of formula I for the manufacture of medicaments. 6. A medication characterized by this. that it contains a compound of formula I in an amount of from 1 mg to 1000 mg and the usual additives and excipients. 7. A method for the manufacture of a medicament, wherein the compounds of general formula I are in an amount between 1 mg and 1000 mg. process with conventional carriers, compounds and excipients into a preparation. 8. Substance selected from the group 7-phenyl-2H-triazino / 3.4-a / phthalazin-3 (4H) ones, 7- (3,4-difluorophenyl) -2H-triazino / 3.4-a / phthalazin-3 (4H) ) -one, 7- / 4- (2-pyridylmethoxy) -phenyl-2H-triazino (3.4-a) phthalazin-3 (4H) one, 3- (3-methoxy-4- (3-pyridylmethylamino) -phenyl) -4-Methyl-4,5-dihydro-1,2,4-triazin-6-one. 3- [3-chloro-4- (3-pyridylmethyloxy) -phenyl] -4-methyl-4,5-dihydro-1,2,4-triazin-6-one. 3- (3-chloro-4- (3-pyridylmethyloxy) -phenyl) -4,5-dihydro-1,2,4-triazin-6-one, 3- (3-methoxy-4- (3-pyridylmethoxy) -phenyl) -4,5-dihydro-1,2,4-triazin-6-one, 3- (3-methoxy-4- (3-benzyloxy) -phenyl) -4-methyl-4,5-dihydro-1,2,4-triazin-6-one. 3- [3-methoxy-4- (3-benzylmercapto) phenyl] -4-m, ethyl-4,5-dihydro-1,2,4-triazin-6-one, 10-methyl-3-oxo-3,4-dihydro-2H- (1,2,4) triazino- (4,3-c) quinazoline, 3- (3-chloro-4- (2-quinolylmethoxy) -phenyl) -4-methyl-4,5-dihydro-1,2,4-triazin-6-one, 3- (3-methoxy-4- (2-quinolylmethoxy) -phenyl) -4-methyl-4,5-dihydro-1,2,4-triazin-6-one. Use of compounds according to claim 8 for the manufacture of medicaments. A medicament comprising one or more compounds of claim 8 in an amount of between 1 mg and 1000 mg, and conventional additives and excipients. 11, A process for the manufacture of medicaments, characterized in that one or more compounds according to claim 8, in an amount of between 1 mg and 1000 mg, is processed into a medicament by conventional carriers, preservatives and excipients.