WO2017049498A1 - Imidazopyridine compound and uses in preparation of pi3k inhibitor - Google Patents

Abstract

Provided are an imidazopyridine compound represented by formula (I) or a pharmaceutically acceptable salt, a solvent compound, an enantiomer, diastereoisomer, tautomer, or a mixture thereof in any proportion. The compound can inhibit the activity of PI3K, and accordingly can be prepared to treat diseases related to the activity of the PI3K, such as inflammatory diseases, immune diseases and cancers.

Description

Imidazopyridine compound and its application in preparing PI3K inhibitor Technical field

The invention belongs to the field of medicines, and in particular relates to an imidazopyridine compound and application thereof in preparing a PI3K inhibitor.

Background technique

PI3K is a family of lipid kinases. According to their function and sequence homology, PI3K is divided into three types (I, II and III), of which the most comprehensive one is type I PI3K. Based on the difference between signaling pathway and regulatory proteins, type I PI3K can be further divided into IA type and IB type. IA type PI3K includes PI3Kα, PI3Kβ, and PI3Kδ, which exist as heterodimers, each heterodimer consisting of a catalytic subunit (p110α, p110β, or p110δ) and a regulatory subunit, and its signal transduction is usually It is mediated by the receptor tyrosine kinase (RTK). The IB type PI3K gamma signal is mediated by a G protein-coupled receptor and consists of a p110 gamma catalytic domain that is linked to a regulatory subunit different from the IA subtype. P13K plays an important role in the regulation of multiple cellular processes including cell cycle regulation, proliferation, survival, apoptosis and migration, and is an important component of the molecular mechanisms of diseases such as cancer, diabetes and immune inflammation.

The frequent occurrence of PI3K gene mutation and amplification in cancer and the loss of PTEN in cancer suggest a close relationship between PI3K and tumorigenesis. Because PI3K is located at the critical signal position of several important signal transduction pathways, it has become a new target for the development of anticancer drugs. The main P13K isoform in cancer is type I P13K. IA type P13K is activated by RTK or Ras to generate phosphatidylinosnol-3,4,5-triphosphate (PIP3), which acts as a second messenger in the cell to activate the downstream target Akt. It plays an important regulatory role in tumor cell development, proliferation, survival and growth.

The two subtypes PI3Kγ and PI3Kδ are mainly expressed in immune-related cells and participate in the process of inflammatory response, and play a key regulatory role in acquired immunity and innate immune system. P13Kδ plays an important role in B cell maturation, T cell activation, and neutrophil migration, and is involved in the activation of leukocytes associated with autoimmune diseases such as macrophages, dendritic cells, and NK T-cells. B cell signaling in P13Kδ mutant mice has specific defects that result in B cell developmental disorders and reduced antibody responses following antigen stimulation. P13Kγ is involved in the regulation of chemokine signal transduction, and its activity is crucial for T cell activation and differentiation. In addition, P13Kγ regulates ROS production in neutrophils and regulates the migration of macrophages and neutrophils, which leads to macrophages and neutrophils towards the inflammatory site. Recruitment disorders and T cell activation disorders. Based on the close relationship between PI3K and inflammation and autoimmune diseases, PI3K has become a new target for the development of eye-catching anti-inflammatory drugs.

Summary of the invention

In order to overcome the deficiencies and shortcomings of the prior art, it is a primary object of the present invention to provide an imidazopyridine compound.

Another object of the present invention is to provide a process for producing the above imidazopyridine compounds.

A further object of the present invention is to provide the use of the above imidazopyridine compounds for the preparation of PI3K inhibitors.

The object of the invention is achieved by the following technical solution:

An imidazopyridine compound which is a compound of formula I or a pharmaceutically acceptable salt thereof, and a solvent compound, enantiomer, diastereomer of said compound of formula I or a pharmaceutically acceptable salt thereof a construct, a tautomer or a mixture thereof in any ratio, including a racemic mixture;

Wherein Ar is a substituted or unsubstituted aryl or arylhetero group, and the substituted aryl or arylhetero group may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy and cyanogen. base;

R ₁ is -H, halogen, hydroxy, cyano or C ₂ -C ₆ alkynyl;

R ₂ is -H or C ₁ -C ₆ alkyl;

The aryl group means a carbocyclic hydrocarbon group having 6 to 14 ring carbon atoms and having at least one ring, wherein at least one ring is an aromatic ring, such as a phenyl group;

The heteroaryl group means a monocyclic aromatic hydrocarbon group having 6 ring atoms, such as a pyridyl group;

The halogen or halogen means fluorine, chlorine, bromine or iodine;

The hydroxyl group refers to an -OH group;

The cyano group refers to a -CN group;

The C ₂ -C ₆ alkynyl group means an alkynyl group having 2 to 6 carbon atoms, and examples of the alkynyl group include, but are not limited to, an ethynyl group, a 2-propynyl group and a 2-butynyl group;

The C ₁ -C ₆ alkyl group means an alkyl group having 1 to 6 carbon atoms, and examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, and iso Butyl, sec-butyl and tert-butyl;

The imidazopyridine compound is preferably a compound having a structure represented by A, B or C:

Or a pharmaceutically acceptable salt thereof, and a solvent compound, enantiomer, diastereomer, or mutual compound of the compound having the structure represented by A, B or C or a pharmaceutically acceptable salt thereof Isomers or mixtures thereof in any ratio, including racemic mixtures;

The preparation method of the imidazopyridine compound comprises the following steps:

(1) reacting methyl 2-amino-5-bromo-isonicotinate with 2,5-hexanedione under the action of the catalyst p-toluenesulfonic acid to obtain 5-bromo-2-(2,5-dimethyl Methyl pyrrol-1-yl)-isonicotinate;

(2) Methyl 5-bromo-2-(2,5-dimethylpyrrol-1-yl)-isonicotinate obtained by the step (1) under the action of the catalyst tetrakis(triphenylphosphine)palladium Suzuki reaction with Ar-B(OH) ₂ to obtain product 1;

(3) under alkaline conditions, the product 1 obtained in step (2) is subjected to a hydrolysis reaction to obtain a product 2;

(4) under the action of the condensing agent EDCI, the product 2 obtained in the step (3) and N, O-dimethylhydroxylamine hydrochloride condensation reaction to obtain the product 3;

(5) The product 3 obtained in the step (4) is reacted with the format reagent R ₂ MgBr to obtain the product 4;

(6) under the action of the catalyst tetraethyl titanate, the product 4 obtained in step (5) and (R)-tert-butyl sulfenamide catalyzed condensation reaction to obtain the product 5;

(7) under the action of the reducing agent L-tri-sec-butyl borohydride, the product 5 obtained in step (6) is subjected to a reduction reaction to obtain a product 6;

(8) The product 6 obtained in the step (7) is reacted with hydroxylamine hydrochloride and triethylamine to obtain the product 7;

(9) under basic conditions, the product 7 obtained in step (8) and chloroacetaldehyde cyclization reaction to obtain the product 8;

(10) Under acidic conditions, the product 8 obtained in the step (9) is taken off the tert-butylsulfinyl group to obtain the product 9;

(11) The product 9 obtained in the step (10) is reacted with 4-amino-6-chloro-pyridine-5-cyano group under the action of DIPEA to obtain the product 10, that is, the imidazole wherein R ₁ is -H Pyridine compound;

(12) Step (11) the product obtained is reacted with compound 10 containing a halogen, hydroxyl, cyano or C ₂ ~ C ₆ alkynyl group, to give compound 11, i.e. R ₁ is halo, hydroxy, cyano or C ₂ to C ₆ alkynyl imidazopyridine compounds;

The synthetic route of the imidazopyridine compound is as follows:

The use of the imidazopyridine compound in the preparation of a PI3K inhibitor;

The use of the imidazopyridine compound for the preparation of a medicament for treating a PI3K mediated disease;

Preferably, the imidazopyridine compound is used in the preparation of a medicament for treating cancer, diabetes and/or immunoinflammatory;

The medicament may contain one or more pharmaceutically acceptable carriers, excipients or diluents;

The medicament includes various clinical pharmaceutical dosage forms, such as tablets, injections, liposome nanoparticles, controlled release agents, and the like;

A PI3K inhibitor comprising the above imidazopyridine compound;

A medicament for treating a PI3K mediated disease comprising the above imidazopyridine compound;

The compound of the present invention is selective for PI3Kδ, which is a selective inhibitor of PI3Kδ; said "selective inhibitor of PI3Kδ" means that the compound binds or inhibits the affinity or potency of the PI3Kδ subtype compared to PI3K other The subtype (ie PI3Kα, PI3Kβ or PI3Kγ) is larger. The compounds of the invention may have a selectivity to PI3Kδ of at least about 400 fold, at least about 800 fold, or at least about 1000 fold.

The present invention has the following advantages and effects over the prior art:

The compounds of the invention may inhibit the activity of PI3K and may be useful in the preparation of diseases suitable for the treatment of PI3K activity, including, for example, inflammatory conditions, immunological disorders, cancer, and other diseases.

detailed description

The present invention will be further described in detail below with reference to the embodiments, but the embodiments of the present invention are not limited thereto.

Example 1

Compound A: (S)-4-amino-6-[1-(3-chloro-6-native-imidazo[1,2-a]pyridin-7-yl)-ethylamino]-pyrimidine-5 -Cyano, the synthetic route is as follows:

(1) Methyl 5-bromo-2-(2,5-dimethylpyrrol-1-yl)-isonicotinate

Methyl 2-amino-5-bromo-isonicotinate (10 g, 43.2 mmol) and 2,5-hexanedione (5.4 g, 47.5 mmol) were dissolved in 100 ml of toluene (toluene) and p-toluene was added. The sulfonic acid (TsOH, 93 mg, 0.43 mmol) was refluxed overnight using a water separator. After cooling to rt, EtOAc (EtOAc m.) Yield: 90.22%, MS (m/z) = 311.0 [M+H] ⁺ 312.1 [M+2H] ⁺ .

(2) Methyl 2-(2,5-dimethyl-pyrrol-1-yl)-5-phenyl-isonicotinate

The product obtained in the step (1) (12.05 g, 38.98 mmol), phenylboric acid (7.13 g, 58.46 mmol) was dissolved in 100 ml of a mixed solvent of dioxane and 5 ml of water, and added under nitrogen atmosphere. Tetrakis(triphenylphosphine)palladium (0.45 g, 0.39 mmol) and potassium carbonate (10.77 g, 77.96 mmol), mp. Yield: 70.35%, MS (m/z) = 307.1 [M+H] ⁺ .

(3) 2-(2,5-Dimethyl-pyrrol-1-yl)-5-phenyl-isonicotinic acid

The product obtained in the step (2) (8.4 g, 27.42 mmol) was dissolved in 40 ml of methanol (MeOH) and 10 ml of water, and sodium hydroxide (3.29 g, 82.25 mmol) was added and allowed to react at room temperature for 4 hours. The reaction solution was diluted with water, and the pH was adjusted to acid with 3 mol/L hydrochloric acid, and the obtained solid was the title product (6.2 g). Yield: 77.35%, MS (m/z) = 293.1 [M+H] ⁺ .

(4) 2-(2,5-Dimethyl-pyrrol-1-yl)-N-methoxy-N-methyl-5-phenyl-pyridinecarboxamide

The product obtained in the step (3) (6.2 g, 21.21 mmol), N,O-dimethylhydroxylamine hydrochloride (3.1 g, 31.81 mmol) and EDCI (4.88 g, 25.45 mmol) were dissolved in dichloromethane (DCM), triethylamine (Et ₃ N, 8.58 g, 84.84 mmol) was added at room temperature, and the mixture was reacted overnight at room temperature, and then concentrated to give a brown oil (5.8 g). MS (m/z) = 336.1 [M+H] ⁺ .

(5) 1-[2-(2,5-Dimethyl-pyrrol-1-yl)-5-phenyl-pyridin-4-yl]ethanone

The product obtained in the step (4) (5.8 g, 17.29 mmol) was dissolved in 40 ml of dry tetrahydrofuran (THF), and methylmagnesium bromide (MeMgBr, 12.68 ml, 38.04 mmol) was added at 0 °C. After the reaction was carried out for 3 hours at room temperature, the mixture was stirred with EtOAc EtOAc EtOAc. Rate: 59.76%, MS (m/z) = 291.1 [M+H] ⁺ .

(6) (R)-2-methyl-propane-2-sulfinic acid {1-[2-(2,5-dimethyl-pyrrol-1-yl)-5-phenyl-pyridine-4- Sub-ethylidene}-amide

The product obtained in the step (5) (3.0 g, 10.33 mmol) and (R)-tert-butylsulfinamide (1.5 g, 12.39 mmol) were dissolved in 20 ml of dry tetrahydrofuran (THF), and tetraethyl titanate was added. Ester (Ti(OEt) ₄ ). After refluxing, the reaction mixture was cooled to room temperature. EtOAc was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ) = 394.2 [M + H] ⁺ .

(7) (R)-{(S)-1-[2-(2,5-Dimethyl-pyrrol-1-yl)-5-phenyl-pyridin-4-yl]-ethyl}-2 -methylpropane-2-sulfinamide

The product obtained in the step (6) (3.5 g, 8.89 mmol) was dissolved in 30 ml of dry tetrahydrofuran (THF), and L-tri-sec-butyl borohydride (L-selectride, 17.78 mmol) was added at -78 ° C, - The reaction was carried out at 78 ° C for 2 hours, and the title compound was obtained (3 g) Yield: 85.22%, MS (m/z) = 396.2 [M+H] ⁺ .

(8) (R)-[(S)-1-(2-Amino-5-phenyl-pyridin-4-yl)-ethyl]-2-methylpropane-2-sulfinamide

The product obtained in the step (7) (3.0 g, 7.58 mmol) and hydroxylamine hydrochloride (7.91 g, 75.8 mmol) were dissolved in 20 ml of ethanol (EtOH) and 20 ml of water, and triethylamine (Et ₃ N, 7.67 g) was added. , 75.8 mmol, refluxing, rt, EtOAc, EtOAc, EtOAc. Ee%=99.5%, MS (m/z) = 318.1 [M+H] ⁺ .

(9) (R)-[(S)-1-(6-phenyl-imidazo[1,2-a]pyridin-7-yl)-ethyl]-2-methylpropane-2-sulfin Amide

The product obtained in the step (8) (1.1 g, 3.46 mmol) and chloroacetaldehyde (3.4 g, 17.33 mmol) were dissolved in 20 ml of ethanol (EtOH), and sodium hydrogencarbonate (2.32 g, 27.68 mmol) was added. The reaction was refluxed overnight, concentrated and separated by column chromatography to give the title product (0.85 g), yield: 72.03%, MS (m / z) = 342.2 [m + H] +.

(10) (S)-1-(6-Phenyl-imidazo[1,2-a]pyridin-7-yl)-ethylamine

The product obtained in the step (9) (0.85 g, 2.49 mmol) was dissolved in 10 ml of ethyl acetate (EA) and 5 ml of methanol (MeOH), and 5 ml of 4 M HCl ethyl acetate solution was added and reacted at room temperature for 1 hour. Concentration gave the title title product (0.8 g), ield: 100%, MS (m/z) = 238.1 [M+H] ⁺ .

(11) (S)-4-Amino-6-[1-(6-phenyl-imidazo[1,2-a]pyridin-7-yl)-ethylamino]-pyrimidine-5-cyano

The product obtained in the step (10) (80 mg, 0.29 mmol) and 4-amino-6-chloro-pyridin-5-cyano (67 mg, 0.43 mmol) were dissolved in n-butanol (n-BuOH). Diisopropylethylamine (DIPEA, 112 mg, 0.87 mmol) was added, and the reaction mixture was stirred at 120 ° C overnight. (m/z) = 356.1 [M+H] ⁺ .

(12) (S)-4-Amino-6-[1-(3-chloro-6-phenyl-imidazo[1,2-a]pyridin-7-yl)-ethylamino]-pyrimidine-5 -cyano

The product obtained in the step (11) (64 mg, 0.18 mmol) was dissolved in 5 ml of chloroform, and N-chlorosuccinimide (NCS, 24 mg, 0.18 mmol) was added, and the reaction was refluxed overnight and concentrated. chromatography to give the title product as a white solid (47 mg), yield: 66.98%, MS (m / z) = 390.1 [m + H] +; 1 H NMR (400MHz, cdcl 3) δ8.03 (s, 1H ), 7.91 (s, 1H), 7.63 (s, 1H), 7.55 (s, 1H), 7.51-7.49 (m, 2H), 7.47-7.45 (m, 1H), 7.43-7.41 (m, 1H), 5.43–5.36 (m, 2H), 5.29 (s, 2H), 1.36 (d, J = 6.5, 3H).

Example 2

Compound B: (S)-4-amino-6-[1-(3-chloro-6-pyridine-2-imidazo[1,2-a]pyridine-7-)-ethylamine]pyrimidine -5-Cyano, the synthetic route is as follows:

(1) (S)-4-Amino-6-[1-(-6-pyridine-2-imidazo[1,2-a]pyridine-7-)-ethylamine]pyrimidin-5-cyano

(S)-1-(6-pyridine-2-imidazo[1,2-a]pyridine-7-)ethylamine hydrochloride (purchased from Suzhou Jinyun Pharmaceutical Technology Co., Ltd.) (100 mg, 0.36 m Methyl) and 4-amino-6-chloro-5-cyanopyrimidine (85 mg, 0.55 mmol) were added to n-butanol (n-BuOH, 5 mL) and diisopropylethylamine (DIPEA, 93) Mg, 0.72 mmol), heated to reflux overnight. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated evaporated evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ⁺ .

(2) (S)-4-Amino-6-[1-(3-chloro-6-pyridine-2-imidazo[1,2-a]pyridine-7-)-ethylamine]pyrimidine-5-cyanide base

(S)-4-Amino-6-[1-(-6-pyridine-2-imidazo[1,2-a]pyridine-7-)-ethylamine]pyrimidin-5-cyano (100 mg, 0.28 mmol) and N-chlorosuccinimide (NCS, 38 mg, 0.28 mmol) were added to chloroform (5 ml) and refluxed for 2 hr. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated evaporated evaporated. mjjjjjjjjjjjjjjjjjjjj H]+. ¹ H NMR (400 MHz, cdcl3) δ 8.90-8.88 (m, 1H), 8.52 (d, J = 8.0, 1H), 8.14 (s, 1H), 8.07 (d, J = 0.5, 1H), 7.92 7.88 (m, 1H), 7.73 (s, 1H), 7.63-7.61 (m, 1H), 7.59 (s, 1H), 7.43-7.40 (m, 1H), 5.82-5.75 (m, 1H), 5.27 ( s, 2H), 1.19 (d, J = 7.1, 3H).

Example 3

Compound C: (S)-4-amino-5-[1-(3-fluoro-6-pyridin-2-yl-imidazo[1,2-a]pyridin-7-yl)-ethylamine]- Pyrimidine-5-cyano, the synthetic route is as follows:

(S)-4-Amino-6-[1-(6-pyridin-2-yl-imidazo[1,2-a]pyridine-7-)-ethylamino]-pyrimidine-5-cyano (30 </ RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; Solid product (10 mg), yield: 31.73%, MS (m/z) = 375.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, cdCl ₃ ) δ 8.87 (dd, J = 4.9, 0.9, 1H ), 8.50 (d, J = 7.3, 1H), 8.13 (s, 1H), 7.92 (s, 1H), 7.89-7.85 (m, 1H), 7.63 (d, J = 1.5, 1H), 7.58 (d) , J = 7.8, 1H), 7.44 - 7.38 (m, 1H), 7.21 (d, J = 7.1, 1H), 5.77 - 5.71 (m, 1H), 5.36 (s, 2H), 1.17 (d, J = 7.1, 3H).

Example 4 Determination of PI3K enzyme activity

Biochemical analysis of PI3K kinase activity was performed using Promega's ADP-Glo technology. The ADP-Glo kinase assay kit and PI3Kβ kinase were purchased from Promega, and PI3Kα, PI3Kδ, and PI3Kγ kinase were purchased from Millipore Corporation. All experiments were performed in 384 well plates at room temperature. The kinase mixture was diluted with kinase buffer including 50 mM HEPES (pH 7.5), 3 mM MgCl ₂ , 100 mM NaCl, 1 mM EGTA, 0.03% CHAPS and 2 mM DTT. The ATP/substrate mixture contained 5 μM PIP2/PS and 25 μM ATP. Compounds to be tested (A, B and C) were dissolved in 100% DMSO and diluted to a final concentration with ddH ₂ O. 2 μL of the diluted test compound and 4 μL of ATP/substrate mixture were added to each well of a 384-well assay plate. At the beginning of the reaction, 4 μL of the kinase mixture was added to each well. The final reaction volume was 10 μL, the final concentration of PIP2/PS was 2 μM, and the final concentrations of PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ kinase were 0.2, 0.6, 0.25 and 0.4 nM, respectively, and the corresponding ATP final concentrations were 40, 40, 40 and 25 μM, respectively. Add 10 μL of kinase ADP-Glo reagent to each well and incubate for 1 h. Then add 20 μL of kinase assay to each well. After incubation for 30 min, the luminescence readings were measured with Envision plate reader. The inhibition rate of the compound was calculated and the IC _{50 was} calculated by XLFIT5 software. (50% inhibitory concentration) value. The inhibition data of the measured compounds against PI3K kinase activity are shown in Table 1. The results show that the compounds listed as selective inhibitors of PI3Kδ that PI3Kδ IC of at least ₅₀ and lower than other subtypes of PI3K (i.e. PI3Kα, PI3Kβ or PI3Kγ) 400 times, such as a PI3K inhibitor compound, with For the treatment of diseases associated with PI3K activity, including, for example, inflammatory conditions, immune-based disorders, cancer, and other diseases.

Table 1 Analysis of inhibition results of PI3K kinase activity by test compounds

The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and combinations thereof may be made without departing from the spirit and scope of the invention. Simplifications should all be equivalent replacements and are included in the scope of the present invention.

Claims (10)

An imidazopyridine compound characterized by being a compound of formula I or a pharmaceutically acceptable salt thereof, and a solvent compound, enantiomer, non-isomer of said compound of formula I or a pharmaceutically acceptable salt thereof Enantiomers, tautomers or mixtures thereof in any ratio, including racemic mixtures;

Wherein Ar is a substituted or unsubstituted aryl or a aryl group; R ₁ is -H, halogen, hydroxy, cyano or C ₂ -C ₆ alkynyl; R ₂ is -H or a C ₁ -C ₆ alkyl group. The imidazopyridine compound according to claim 1, wherein: The substituted aryl or arylhetero group may be optionally substituted by one or more substituents independently selected from the group consisting of halogen, hydroxy and cyano. The imidazopyridine compound according to claim 1 or 2, which is characterized in that: The aryl group is a phenyl group. The imidazopyridine compound according to claim 1 or 2, which is characterized in that: The heteroaryl group is a pyridyl group. The imidazopyridine compound according to claim 1, wherein: The C ₂ -C ₆ alkynyl group is an ethynyl group, a 2-propynyl group or a 2-butynyl group. The imidazopyridine compound according to claim 1, wherein: The C ₁ -C ₆ alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. The imidazopyridine compound according to claim 1, wherein: The imidazopyridine compound is a compound having a structure represented by A, B or C:

Or a pharmaceutically acceptable salt thereof, and a solvent compound, enantiomer, diastereomer, or mutual compound of the compound having the structure represented by A, B or C or a pharmaceutically acceptable salt thereof Isomers or mixtures thereof in any ratio, including racemic mixtures. Use of the imidazopyridine compound according to any one of claims 1 to 7 for the preparation of a PI3K inhibitor. Use of the imidazopyridine compound according to any one of claims 1 to 7 for the preparation of a medicament for treating a PI3K-mediated disease. The use of an imidazopyridine compound according to claim 9 for the preparation of a medicament for the treatment of a PI3K mediated disease, characterized in that: The medicament may contain one or more pharmaceutically acceptable carriers, excipients or diluents.