Improved lactam solubility.

Abstract

------15 / 05 / 2561------(OCR) ------------

Description

IMPROVED LACTAM SOLUBILITYThis application claims priority from EP 15181847.3 filed 20 August 2015 which is herein incorporated by reference for all purposes.The present invention relates to compositions comprising lactams and an alcohol. The compositions are suitable for use as anti-microbial, anti-biofilm and bacteriostatic compositions. WO 2007 / 085042 and WO 2004 / 016588 disclose lactams for antimicrobial benefit and steps towards their synthesis. WO2014 / 1 18240 discloses antimicrobial compositions comprising a lactam and a hydrotope.However, use of these lactams is limited by relatively low solubility, especially in aqueous compositions.The present invention relates to combinations of lactams and an alcohol. The combination has been shown to improve lactam solubility. More specifically, the present invention relates to lactams as described inWO 2007 / 085042 and WO 2004 / 016588 in combination with an alcohol. The contents of WO 2007 / 085042 and WO 2004 / 016588, and in particular the lactam structures explicitly drawn out therein, are incorporated by reference. For example, in a first aspect, the present invention relates to a composition comprising a lactam and an alcohol, wherein the lactam is a lactam of formula (I) or (II):wherein:Ri and R2 are each independently selected from hydrogen, halogen, alkyl, cycloalkyl, alkoxy, oxoalkyl, alkenyl, heterocyclyl, heteroaryl, aryl and aralalkyl; andR3 is selected from hydrogen, hydroxyl, alkyl, cycloalkyl, alkoxy, oxoalkyl, alkenyl, heterocyclyl, heteroaryl, cycloalkyl, aryl, aralalkyl and -C(0)CR6=CH2;R4and R5 are independently selected from hydrogen, aryl, heterocyclyl, heteroaryl, and arylalkyl; andR6 is selected from hydrogen and methyl; andR7is selected from hydrogen and -C(0)CR6=CH2; and Preferably, at least one of R4and R5 is hydrogen.It will be appreciated that, where appropriate groups may be optionally substituted.Optional substituents may include halogens, Ci-4alkyl, Ci-4haloalkyl (for example, CF3) and Ci-4alkoxy.Alkyls may, for example, be Ci-i2alkyls, such as Ci-6alkyls. Aryls may, for example, be C6-ioaryls, for example, phenyls.Preferably, at least one of Ri and R2 is selected from heterocyclyl, heteroaryl, aryl and arylalkyl.Preferably, Ri is hydrogen. Preferably, R3 is hydrogen. Preferably, R4is hydrogen. Preferably, R5 is hydrogen. Preferably, R6 is hydrogen. Preferably, R7is hydrogen. Preferably, R2 is aryl or aralalkyl. More preferably, R2 is a phenyl group or a substituted phenyl group, for example, a mono-substituted phenyl group. Substitution may be ortho, meta, or para. Preferably, it is para. Preferred substituents include halogen and methyl. For example, and without limitation, R2 may be selected from phenyl, 4-fluorophenyl, 4- chlorophenyl, 4-bromophenyl and 4-methylphenyl.Accordingly, in a first aspect, the present invention may provide to a composition comprising a lactam and an alcohol, wherein the lactam is a lactam of Formula la or Formula lla:wherein R is H, halogen (preferably, F, CI, or Br), or Ci-4alkyl (preferably methyl).In some embodiments, the lactam is a lactam of formula la. In some embodiments, the lactam is a lactam of formula lla.Preferred lactams may include:; 4-(4-chlorophenyl)-5-methylene-pyrrol-2-one (Ref. 488);; 5-methylene-4-(p-tolyl)pyrrol-2-one (Ref. 491 ); 4-phenyl-5-hydroxy-5-methyl-1 H-pyrrol-2-one (Ref. 131 ); 4-(4-fluorophenyl)-5-hydroxy-5-methyl-1 H-pyrrol-2-one (Ref. 258); 4-(4-bromophenyl)-5-hydroxy-5-methyl-1 H-pyrrol-2-one (Ref. 316).The composition may be aqueous or non-aqueous. Preferably, the composition miscible with water. For example, the composition may be alcohol-based or alcohol-water-based.The composition may be, without limitation, any of a personal care composition, a homecare composition, a pharmaceutical composition, or an industrial composition such as an anti-biofilm coating or paint, for example, for use in maritime environments. The composition may also be an agricultural chemical. The compositions may be suitable for use as antimicrobial, anti-biofilm and bacteriostatic compositions. Non-limiting examples of such compositions are provided herein. The compositions may also be used as additive compositions; in other words, the composition may be combined with further ingredients such as excipients to form a composition as described above.Preferably, the composition has a high alcohol content (for example at least 50% wt. of the composition). Such compositions may be useful as, for example, deodorant compositions. Suitably, the alcohol is a Ci-6alkyl alcohol. It may be a mono-alcohol or a polyol. For example, in some cases, the alcohol is a Ci-6alkyl alcohol having 1 , 2, or 3 OH groups. For example, the alcohol may comprise one, two, or three carbon atoms.The alkyl may, where appropriate, be straight chain or branched. The or each OH group may be primary, secondary or tertiary.In some cases, the alcohol is a mono-alcohol having one to three carbon atoms.Certain preferred alcohols include methanol, ethanol, propanol, and glycerol. Methanol and ethanol are preferred, with ethanol being most preferred.The composition may comprise at least 10% wt. alcohol, for example, at least 15% wt. alcohol, or higher amounts such as 20% wt., 25% wt., 30% wt, 40% wt, or even as high as 50% wt. In some cases, the composition comprises even high amounts of alcohol, for example at least 60% wt., at least 70% wt., alcohol.For example, the may comprise 10 - 50% wt. of alcohol, such as 10 - 25% wt. or higher amounts such as 25 - 50% wt. It will be apparent that the amount of alcohol may be selected to suit the intended use of the composition. For example, higher amounts of alcohol may permit larger lactam loadings, but may be less preferred for personal care compositions. It will be appreciated that higher amounts may be especially useful for industrial and agricultural compositions such as paints.Preferably the composition contains 0.000001 to 50% wt. lactam, more preferably 0.001 to 50% wt. even more preferably 0.01 to 5% wt., most preferably 0.01 to 2%.DESCRIPTIONLactams may be obtained using methods as described in WO 2007 / 085042 and WO 2004 / 016588, which are herein incorporated by reference in their entirety. CompositionsThe compositions described herein may be compositions having anti-microbial activity. In some cases, the compositions are anti-bacterial. They may have bactericidal and / or bacteriostatic activity. The inventor(s) have observed desirable bacteriostatic activity. Accordingly, in some cases, the composition is a bacteriostatic composition.The compositions may also prevent and / or inhibit biofilm formation. Biofilms are formed when microorganisms stick to a surface. Biofilm extracellular polymeric substances may be formed. Biofilms (also referred to as slime) present problems in industrialenvironments; for example, they may form in pipes in apparatus, or industrial and agricultural structures, on solar panels, and on boat hulls and other marine structures. Biofilms may also pose a problem in domestic environments. For example, biofilms may form in domestic appliances such as washing machines. Biofilms are also present in personal care, for example, they may form on tooth surfaces. Compositions suitable for any and all of these applications are within the scope of the invention. In some cases, the composition is a paint or other coating. In such cases, the composition may further comprise a binder, optionally a pigment and optionally one or more conventional additives (for example, to modify surface tension, improve flow properties, improve the finished appearance, increase wet edge, improve pigment stability, etc - such additives are known in the art). The composition may comprise an aqueous solvent or an organic solvent to suit purpose.The composition may also be used in medical applications, for example to coat equipment including medical devices.In some cases, the composition is a pharmaceutical composition. In other words, the composition may comprise a lactam as described herein and a pharmaceutically acceptable excipient. The composition may be suitable for topical use (for example, itmay be a cream or lotion), it may be suitable for ocular use (for example, it may be an used as a pharmaceutical eye drop), it may be suitable for otic use (for example, it may be used as an ear drop), it may be suitable as a mouth wash, or it may be suitable for oral administration.In some cases, the composition is a composition suitable for use in the home (often referred to as a homecare composition) or institutions. Homecare compositions include, without limitation, cleaning products, laundry detergents, and fabric conditioners. In some cases, the composition is a homecare composition, for example a laundry liquid. The composition may therefore comprise a detergent surfactant and a builder. Thecomposition may be a fabric conditioner (also called a fabric softener) and may comprise an antistatic agent. The composition may also be a domestic cleaning product.In some cases, the composition is a personal care composition. For example, the composition may be intended for use on the skin (for example, a cream, cleanser or serum). For example, the composition may be useful in the prevention or treatment of acne. For example, the composition may comprise one or more of dimethicone, petrolatum, a humectant such as hyaluronic acid or glycerin; and ceramide(s). In some cases, the composition is a personal care composition comprising a detergent, for example, the composition may be a face wash or shower gel or hair shampoo. The composition may be a hair treatment composition other than a shampoo. Thecomposition may be a deodorant composition (for example, a deodorant powder, paste or liquid). The composition may be an oral care composition (such as a toothpaste or mouthwash and may include, for example, fluoride and / or flavourings.In some cases, the composition is a contact lens cleaning fluid.The composition may be a composition suitable for use in agriculture, for example, as a soil additive (solid or liquid).The composition may be a composition suitable for use in the treatment of ormanufacture of glass or lens for example as an additive / treatment for solar panels.EXAMPLESThe following example uses, without limitation, 4-(4-chlorophenyl)-5-methylene-pyrrol-2- one. Excess solid lactam (~3mg) was placed in a Whatman® Mini Uniprep sample vial, fitted with a 0.45 μηη nylon filter. Water or water + alcohol (500 μΙ_) was added the mixture shaken and tapped briefly to initially disperse the solid and the mixture then agitated for 48 hours using a plate shaker fitted with a vial holder (see image below). After 48 hours, the solid was removed from the system by pressing down the plunger with integral filter on the vial (see image below). This removes the solid and provides filtered solution within the inner chamber which is then ready for analysis.The level of lactam dissolved in solution was quantified using HPLC analysis. Samples were analysed on an Agilent 1200® series HPLC fitted with a Thermo Hypersil® Gold C18 column (15 x 2.1 x 3 μηη), isocratic elution with 60 / 40 methanol / water (+0.1 % Formic Acid), 0.4 mL / min flow rate, using a DAD detector at 285 nm. 4-(4-chlorophenyl)-5- methylene-pyrrol-2-one has a retention time of -2.8 minutes.The absolute level of lactam in solution is measured and reported as an increase in solubility of lactam relative to water alone. The results are shown below.Mean LactamLevel in Solubility% Additive in Solution Increase vsAdditive Water (ppm) water alone0 6.2 1.000.5 7.5 1.201 9.0 1.452 8.2 1.32MeOH5 10.4 1.6710 15.7 2.5225 48.8 7.8750 315.6 50.900 6.2 1.000.5 7.9 1.271 8.9 1.442 10.7 1.73EtOH5 13.4 2.1610 18.3 2.9525 82.1 13.2450 1800.2 290.350 5.7 1.000.5 1.7 0.291 2.3 0.412 3.1 0.54Glycerol5 5.2 0.9110 9.0 1.5925 15.8 2.7750 95.3 16.72— oOo—It will be appreciated that, except where expressly provided otherwise, all preferences are combinable.

Claims

------01 / 02 / 2562------(OCR) Page 1 of 2 Claims 1. The composition consists of lactam and alcohol, where the lactam is of the formula la or lla (chemical formula) (chemical formula) lalla where R is H, halogen or C1-4 alkyl; where the composition contains at least 30% alcohol by weight.

2. The composition under claim 1 where R is H, F, Cl, Br or Me.

3. The composition under any preceding claim where the lactam is selected from (chemical formula). Page 2 of 2 The composition under any preceding claim where the alcohol is (chemical formula).

16. Alkyl alcohol compositions under any prior claim where such alcohol is selected from methanol, ethanol, propanol and glycerol; alternatives where such alcohol is methanol or ethanol; compositions under any prior claim where the alcohol is mono-alcohol; compositions under any prior claim where the alcohol is ethanol; compositions under any prior claim where the composition contains at least 50% alcohol. By weight of the components according to any one of the preceding claims where the components are deodorizing components for personal care------------------15 / 05 / 2018------(OCR)Page 1 of 2 pages Claims 1. The components consist of lactam and alcohol, where such lactam is of formula a or formula lla (table structure), where R is H, halogen or C1-4 alkyl; where the components contain at least 30% alcohol by weight.

2. Components according to claim 1 where R is H, F, Cl, Br or Me. 3.

1. The composition according to one of the preceding claims where such lactam is selected from (table structure) page 2 of number 2, page 4.

2. The composition according to one of the preceding claims where such alcohol is a C1-6 alkyl alcohol.

5. The composition according to one of the preceding claims where such alcohol is selected from methanol, ethanol, propanol and alternative glycerol where such alcohol is methanol or ethanol.

6. The composition according to one of the preceding claims where the alcohol is a mono-alcohol.

7. A composition under any prior claim where the alcohol is ethanol.

8. A composition under any prior claim where the composition contains at least 50% alcohol by weight.

9. A composition under any prior claim where the composition is a deodorant for personal care. ------------ Page 1 of 2 pages of Claims 1. A composition contains lactam and alcohol where such lactam is of formula la or formula lla, formula la or lla where R is H, halogen or C1-4 alkyl. 2.

1. The composition according to claim 1 where R is H, F, Cl, Br or Me.

3. The composition according to any of the preceding claims where the lactam is selected from (Ref.488);(Ref.491);(Ref.313);(Ref.258);(Ref.316); 4. The composition according to any of the preceding claims where the alcohol is C, .6 alkyl alcohol. Page 2 of 2.

5. The composition according to any of the preceding claims where the alcohol is selected from methanol, ethanol, propanol and glycerol alternatives where the alcohol is methanol or ethanol.

6. The composition according to any of the preceding claims where the amount of alcohol is 10 to 50% by weight of the composition.