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Publication numberUS3642977 A
Publication typeGrant
Publication dateFeb 15, 1972
Filing dateMay 22, 1969
Priority dateApr 8, 1966
Publication numberUS 3642977 A, US 3642977A, US-A-3642977, US3642977 A, US3642977A
InventorsGordon Trent Hewitt
Original AssigneeColgate Palmolive Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Hair shampoo compositions containing certain imidazolines and certain amide-substituted carboxylic acids
US 3642977 A
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Description  (OCR text may contain errors)

United States Patent 3,642,977 HAIR SHAMPOO COMPOSITIONS CONTAINING CERTAIN IMIDAZOLINES AND CERTAIN AMIDE-SUBSTITUTED CARBOXYLIC ACIDS Gordon Trent Hewitt, Upper Montclair, N.J., assignor to Colgate-Palmolive Company, New York, N.Y.

No Drawing. Continuation-impart of application Ser. No. 541,137, Apr. 8, 1966. This application May 22, 1969, Ser. No. 827,042

Int. Cl. A61k 7/06 US. Cl. 424-70 9 Claims ABSTRACT OF THE DISCLOSURE A shampoo composition is described which comprises 25% of a 2-acyclic-1(ethyl-beta-oxipropanoic)-imidazoline, 3 to 20% of an amide-substituted carboxylic acid which is a higher fatty acyl sarcosine or a higher fatty acid amide of polypeptide amino acids, the maximum amount of carboxylic acid being one mole per mole of imidazoline, 0-35% of a lower aliphatic alcohol and water.

This application is a continuation-in-part of copending application Ser. No. 541,137 filed Apr. 8, 1966, now abandoned.

The present invention relates to a cleansing composition, and particularly to a shampoo composition suitable for cleaning and conditioning human hair, comprising in combination the amphoteric surfactant, Z-acyclic-l-(ethylbeta-oxipropanoic acid)-imidazoline and an amide-substituted carboxylic acid selected from the group consisting of N-acyl sarcosines and the fatty acid amides of polypeptide amino acids, as hereinafter described and claimed.

Various types of shampoo compositions have been proposed in the past. In general, they have one or more suitablewater-soluble organic detergents as a primary cleansing component. Thus, some shampoos contain higher fatty acid soaps as a detergent alone or in combination'with compatible synthetic detergents. The products containing synthetic detergents such as the water-soluble sulfates sulfonates are of particular importance since they have received substantial consumer acceptance because of improved cleaning power and freedom from lime soaps. In general, many synthetic detergents tend to remove the natural oils from the hair, leaving it dry and difiicult to manage.

A variety of materials have been added in order to achieve a particular desired effect, such. as viscosity modifiers, foam-improving agents, conditioning agents, opacifiers, emollients, and so forth. There has been a considerable amount of research to discover substances or additives which add to the efficiency or properties of detergent compositions. The formulation of shampoos for human hair is a specialized field and possess certain specific problems involving the use of the shampoo, such as consideration of keratin substantivity and ability of a particular agent to condition the hair during rinsing oif of the deter-gent from the hair and scalp. The number of suitable hair conditioning agents is particularly limited and the discovery of superior hair conditioning agents which have other added desirable properties suitable for use in said shampoos or the like, such as improved foam consistency, compatibility with therapeutic scalp agents, remains a continuing field of research.

It has now been discovered that compositions having particular utility in the cleansing and conditioning of human hair as well as providing a stable acidic base for therapeutic scalp agents comprise essentially amounts of 3,642,977 Patented Feb. 15, 1972 the amphorteris surfactant, 2-acyclic-l-(ethyl-beta-oxipropanoic acid)-imidazoline and an amid-substituted carboxylic acid selected from the group consisting of N- acyl sarcosines and the fatty acid amides of polypeptide amino acids dissolved in an aqueous medium. These compositions have the dual function of washing and conditioning the hair, thereby eliminating the need for use of a conditioning rinse after shampooing. The particular advantage inherent in these novel compositions isktheir strong affinity to the keratin of skin and hair whereby the conditioning action is long-lasting. It leaves the hair soft and more manageable. The necessity for frequent combing is minimized and the act of combing the hair is accomplished with greater facility due to the elimination of tangled hair. The hair is rendered antistatic and exhibits a good sheen after shampooing with the aforesaid compositions. Another very important feature of these compositions is the reduced interference with the natural acid mantle of the skin and the natural oil in the hair. In addition, the volume and stability of the foam produces a copious lather for effective cleansing.

Accordingly, a primary object of the present invention is to provide an acidic liquid shampoo having superior hair conditioning properties.

Another essential object of this invention is to provide a stable acidic shampoo base for therapeutic scalp agents.

Still another object of this invention is to provide a composition capable of reducing the electrostatic charge on human hair.

A further object of this invention is to provide an acidic shampoo having desirable foaming properties.

More specifically, the present invention relates to a clear homogeneous aqueous shampoo particularly suitable for simultaneously cleaning and conditioning human hair, consisting essentially of about 5.0% to 25.0% and preferably 12.0% to 18.0% by weight of at least one amphoteric imidazoline having the following structure:

wherein R is a higher acyclic group of 7 to 17 carbon atoms, and about 3.0% to 20%, and preferably about 5.0% to 15.0%, by weight of an amide-substituted carboxylic acid selected from the group consisting of higher fatty acyl sarcosines and fatty acid amides of polypeptide amino acids, said shampoo having an acid pH. The sarcosines and the polypeptide amino acids are in the form of free acid. The amphoteric imidazolines have an iso-electric point of pH 7.3 which enable them to behave as a cation in strongly acidic solutions and as an anion in strongly alkaline solutions. Consequently, the addition of the acid-form of the sarcosine reduces the pH of the neutral Zwitterion to about 4.7 whereby the amphoteric is more nearly in its cationic state, said combination being stable and Water-soluble. This is in direct contrast to the prior art amphoterics which do not form soluble complexes with anionic surfactants in the free acid state, but rather form precipitates therewith. In addition, the water insoluble nature of the N-acyl sarcosines and the un-neutralized or acid form of the condensation products of fatty acids and polypeptides contra-indicates their use in an aqueous shampoo. However, when said polypeptides are combined with the amphoteric imidazoline, a clear, stable aqueous composition having substantially cationic properties is produced.

The cationic nature of the composition allows for the addition of therapeutics which are normally incompatible with conventional anionic surfactants and are unstable in neutral or alkaline compositions. Consequently, cationic polythion'ates, such as his (lauryl trimethyl ammonium) pentathionate described in US. Pat. No. 2,815,- 344, are compatible with the instant composition to give a shampoo having the additional function of medicating the scalp. Other acid-stable therapeutic agents may be added such as salicylic acid, sulfur, selenium disulfide, polythionic acid, etc. These therapeutic agents are added in minor amounts of about 0.55% by weight of the total composition.

The amphoteric imidazolines can be described as 2- acyclic 1 (ethyl-beta-oxipropanoic acid) imidazoline, wherein the acyclic group is derived from higher fatty acids such as stearic, oleic, lauric, coconut oil fatty acids (a mixture of fatty acids containing 8 to 18 carbon atoms), and the like. Alkyl and alkenyl groups of 7 to 17 carbon atoms are preferred acyclic groups. Such detergents and their preparation are described in US. 2,267,- 965. These compounds are Water-soluble, have an isoelectric point at pH 7.3 wherein they are a true zvvitterion, and can be combined directly either with alkali or with acids to form water-soluble salts. It is to be understood, of course, that one or a plurality of the instant imidazolines can be used in the compositions of the invention.

The other essential ingredient of the instant shampoo is an amide-substituted carboxylic acid. Such materials are the reaction product of a higher alkanoic acid containing about 8 to 18 carbons in the acyl group and an aliphatic amino acid.

Included in the foregoing are the higher acyl sarco'sines such as N-lauroyl, N-cocoyl, N-stearoyl, etc. sarcosine.

The other group of amide-substituted carboxylic acids utilized in this invention is the complex amide resulting from the condensation of a higher carboxylic acid and a polypeptide joined together at the amino group of the polypeptide. The detergents contain an amide group and a carboxyl group and can be represented by the general formula:

RCONH (polypeptide)COOI-I wherein the RC0 group contains about 8 to 18 carbon atoms. The RCO group may be derived from coconut oil fatty acids, oleic acid, ste'aric acid, lauric acid, and undecylenic acid.

The foregoing amide-substituted carboxylic acid is formed by reacting the appropirate acyl halide, e.g., undecylenyl chloride, with the polypeptide obtained by hydrolysis of protein materials such as hides, hoofs, gelatin, collagen, and the like, with collagen protein being preferred. During hydrolysis the protein materials are gradually broken down into their constituent polypeptides and amino acids by prolonged heating with acids, e.g., sulfuric acid, or alkalis, e.g., sodium hydroxide, or treatment with enzymes, e.g., peptidases, with the alkaline or basic hydrolysis being the usual method. First, high molecular weight polypeptides are formed; and as hydrolysis proceeds these are converted progressively to simpler and simpler polypeptides, to tripeptides, dipeptides, and finally to amino acids. It is obvious that the polypeptides derived from proteins are complex mixtures and in practice the average molecular weight of the hydrolysate will vary from about 120 (amino acids) to about 20,000. The preferred hydrolysates have an average molecular weight between 300 and 10,000 and are characterized by identifying the amino acids in a completely hydrolyzed polypeptide solution. Methods of forming these acylated polypeptides are well known as shown in US. Pat. Nos. 2,015,912; 2,113,819; 2,151,241; and 2,728,759.

A preferred acylated polypeptide for use in the compositions of this invention is the undecylenic acid polypeptidate sold by the Stepan Chemical Company under the trade name Maypon UD Acid. This material is prepared by hydrolyzing a solution containing leather scraps in the presence of an effective amount of alkali to obtain a product having an average molecular weight of about 350550 and a molecular Weight range from to about 10,000 as determined by the viscosity of a 20% aqueous solution. The conditions of hydrolysis are well known and are not critical so long as the reaction is terminated when the appropriate molecular weight is achieved. When the resultant polypeptide is completely hydrolyzed, the following amino acid distribution is obtained.

Percent Glutamic acid 10.3 Lysine 4.2 Leucines 4.9 Aspartic acid 6.3 Proline 14.3

Serine 3.1 Phenylalanine 2.7 Threonine 2.2 Valine 2.6 Alanine 9.6 Glycine 25.6

74 parts of the foregoing solution (ca., 35% solids) of polypeptide is then reacted with 26 parts of undecylenic acid chloride to yield a condensate linking the fatty acid with the amino groups of the polypeptide, i.e., undecylenic acid polypeptidate. The acylated polypeptide is neutralized with aqueous potassium hydroxide to form a solution containing the water-soluble potassium salt of the acylated polypeptide. The resultant solution is concentrated by evaporation and then acidified to form the undecylenic acid polypeptide.

When reference is made to a coco compound, the term coco refers to the mixture of fatty acid groups derived from coconut oil. Such acids contain from 8 to 18 carbon atoms per molecule, predominating in C -C acids.

The combination of higher acyclicimidazoline and amide-substituted carboxylic acid should be suitably proportioned to achieve the desired results such as hair conditioning, hair cleansing, improved foaming, etc. In general, stoichiometric quantities of each ingredient are preferable, although an excess of the imidazoline may also be dissolved in the aqueous medium.

Although the amide-substituted carboxylic acids are insoluble in an aqueous medium, the combination thereof with the imidazoline yields a water-soluble product. This is believed to be due to a reaction between the imidazoline and said carboxylic acid whereby a condensation product is formed, represented by the following structure, when reacting equimolecular amounts of the imidazoline and N-acyl sarcosine:

It is now electronically neutral although at two places in the neutral salt, there is probably only limited dissociation of the and ions, wherein R and R are higher alkyl or higher alkenyl groups derived from the same or different fatty acids. This reaction product probably represents the major constituent of the active ingredients when using equimolecular amounts of the imidazoline and the amide-substituted carboxylic acid, which is preferred. The presence of an excessof the imidazoline, whereby the composition contains the imidazoline as such, is also contemplated by this invention. However, an excess of the N-acyl sarcosine or its polypeptide analogue produces a cloudy composition due to its poor solubility in water and/ or lower aliphatic alcohols. Consequently, it is desirable to limit the amido-fatty acid content to a maximum of one mole per moleof imidazoline. The final composition generally contains about 8.0% to 35.0% by weight of active ingredients, and preferably about 15.0%. to 27.0% by weight thereof.

It is preferred to prepare the combination of higher acyclic imidazoline and amide-substituted carboxylic acid inwateror mixtures of water with a lower aliphatic alcohol of 2-3 carbons, such as ethanol or isopropyl alcohol, to form a clear, homogeneous liquid containing preferably 12.0% to 18.0% by weight of-imidazoline, 5.0% to.15.0%. by weight of amide-substituted carboxylic acid and the balance being water or water and ethanol. Minor amounts, e.g., less than 50% by weight, such as up to about 35% and preferably from to 20% by weight of alcohol may be present as desired. The alcohol assists in solubilization of the active ingredients, thereby retaining the clarity and homogeneity of the clear shampoo product. 1

In general, the shampoo products are manufactured; by dissolving the acyclic imidazoline in water and simply admixing the,amide-substituted carboxylic acid therewith. In some instances, it may be necessary to slightly heat the mixture to facilitate dissolution, or to dissolve the mixture in the alcohol with or without heat prior to the addition of the water, v

Another, method ofv formulating the instant shampoo consists in first reacting the anhydrous amphoteric imidazoline with N-acyl sarcosine or the polypeptide analogue thereof in equimolecular proportions by heating the two in the presence or absence of ethanol, whereby the anhydrous water-soluble reaction product is formed, prior to dissolution in an aqueous medium.

It is common to add various adjuvant materials to shampoo compositions and the'like. Thus, the shampoo ordinarily will contain a perfume which should be selected so as to be compatible with the character of the shampoo. Other ingredients may include a small amount of a buffer material to aid in the adjustment and maintenance of the desired acid pH of the finished product, preferably pH 3 to pH 5 in Water. Suitable buffering materials include borax, the various inorganic water-soluble I phosphates such as disodium phosphate, or sodium pyrophosphate, citric acid, etc. Other ingredients which may be used in shampoos for imparting desired qualities and may be incorporated in the present compositions include minor amounts of fatty acid cationic surfactants such as lauroyl pyridinium salts (i.e., chloride, bromide, acetate, sulfate, and the like); other fatty acid pyridinium salts as well as substituted fatty acid pyridinium salts such as N (lauroyl colamino formylmethyl) pyridinium chloride; stearyl or oleyl dimethyl benzylammonium chloride; stearyl amino acetate, stearyl dimethyl amino hydrochloride; lauryl dimethyl amino oxide; etc. Other additives include minor amounts of compatible synthetic gum thickeners, where a relatively viscous liquid is desired, such as hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethylcellulose, etc. Acid-stable nonionic stabilizers or preservatives may also be added such as sodium benzoate, phenyl mercuric acetate, Formalin, etc. A minor amount of dyes or pigments may be added to impart a color to the liquid, as desired.

The following specific examples are further illustrative of the nature of the present invention, and it is to be understood that the invention is not limited thereto. All parts are by weight unless otherwise indicated.

6 EXAMPLE 1 Ingredients: I i Percent Z-C- -C alkyl -l- (ethyl-beta oxipropanoic acid)-imidazoline 1O Undecylenyl acid amide of polypeptide amino acid (purchased from Stepan Chemical under the trade name Maypon UD Acid) 20 Ethyl alcohol 15 Deionized water 55 a The alkyl group is derived from coconut oil fatty acids.

The above ingredients were admixed to give a clear, fluid mixture, having apH of 4.7. To 50 ml. of this clear liquid was added 50 ml. of a 15% of 2-undecyl-1 (ethylbeta-oxipropaoic acid)-imidazoline dissolved in water and buffered with citric aicd to a pH of 4.3. The resultant product foamed well when applied to the hair, cleansed and conditioned the hair, leaving the hair lustrous, antistatic, soft and easy to comb.

EXAMPLE II The ingredients are thoroughly mixed by simple stirring.

A water soluble coloring material may be added in amounts up to 0.5% if desired. The resultant product is a clear, homogeneous liquid which exhibits adequate foaming during shampooing, leaving the-hair easy to comb when wet and free of static when combed dry.

, v EXAMPLES HI AND IV v I Salicylicacid was added to the product of Example II a in'amounts of 0.5% and 1.0% and the water content reduced accordingly. This yielded a stable and improved shampoo having additional therapeutic properties.

EXAMPLES V AND VI The therapeutic scalp agent, bis-(lauryl trimethyl ammonium) pentathionate was added to the formulation of Example 11, in amounts of 2% and 3%, and the water content reduced accordingly. This shampoo is capable of medicinally' treating the scalp in addition to cleaning and conditioning the hair.

EXAMPLE VII A shampoo similar to that of Example II is produced by substituting 2-heptadecyl-1 (ethyl-beta-oxipropanoic acid)-imidazoline for the Z-heptadecenyl homologue.

EXAMPLE VIII Ingredients: Percent 2 undecyl 1 1(ethyl beta oxipropanoic acid)-imidazoline 2 C7C17 alkyl 1(ethyl beta oxipropanoic acid)-imidazoline 2 heptadecenyl 1(ethyl beta oxipropanoic acid)-imidazoline 5 Lauroyl sarcosine 10 Ethanol 15 Deionized water 59 Perfume 0.5 Salicylic acid 0.5

The three imidazolines, the sarcosine and the alcohol were stirred at 105 F. until all the ingredients dissolved in the alcohol to form a clear, thin solution, which was subsequently diluted with 20% water. To this clear solution was added the remainder of the water, i.e., 39%, in which was dissolved the perfume and the salicylic acid. The resultant product was clear and of low viscosity and exhibited superior foaming and conditioning in addition to therapeutically treating the scalp.

EXAMPLE IX Ingredients: Percent A mixture of equal amounts of 2 undecyl,

2-C C alkyl and 2-heptadecenyl-1(ethylbeta oxipropanoic acid) imidazoline 15 Lauroyl sarcosine Ethanol 31.5 Deionized water 40 Perfume 0.5

Bis (lauryl trimethyl ammonium) pentathionate 3.0

The imidazolines, sarcosine and parts ethanol were stirred at 105 F. until all the ingredients dissolved in the alcohol to form a clear, thin solution, which was subsequently diluted with parts of water. The perfume and cationic pentathionate were dissolved in 16.5 parts ethanol and added to the aforesaid solution, which remained clear. The remainder of the water, i.e. 20%, was subsequently added to yield a superior shampoo formulation, similar to the products of the previous examples.

The Z-undecyl, Z-heptadecyl, and Z-heptadecenyl groups of the imidazoline compound in the foregoing examples are derived from lauric acid, stearic acid and oleic acid respectively.

Although the present invention has been described with reference to particular embodiments and examples, it will be apparent to those skilled in the art that variations and modifications of this invention can be made and that equivalents can be substituted therefor without departing from the principles and true spirit of the invention.

What is claimed is:

1. A clear, homogeneous, acidic shampoo composition particularly suitable for simultaneously cleansing and conditioning human hair consisting essentially of an aqueous solution having a pH of about 3 to 5 of about 5-25% by weight of at least one amphoteric imidazoline having the following structure:

wherein R is a higher alkyl or alkenyl group containing about 7 to 17 carbon atoms and about 3-20% by weight of an amide-substituted carboxylic acid selected from the group consisting of higher fatty acyl sarcosines containing about 8 to 18 carbon atoms in the fatty acyl group and fatty acid amides of polypeptide amino acids wherein said fatty acid contains about 11 to 18 carbon atoms and said polypeptide amino acids are derived from hydrolysis of collagen protein material and have a molecular weight in the range of 120 to 20,000, the content of said amide-substituted carboxylic acid being a maximum of one mole per mole of imidazoline.

2. A composition in accordance with claim 1, which contains equimolecular amounts of the imidazoline and the acid.

3. A composition in accordance with claim 1, wherein said amide-substituted carboxylic acid is the undecylenyl acid amide of polypeptide amino acid, said polypeptide amino acid being derived from hydrolysis of collagen and having a molecular weight in the range of about 300 to 4. A composition in accordance with claim 1, wherein said amide-substituted carboxylic acid is N-lauroyl sarcosine.

5. A composition in accordance with claim 1, wherein the R group of said imidazoline is the mixture of alkyl groups containing 7 to 17 carbon atoms derived from coconut oil fatty acids.

6. A composition in accordance with claim 1 which contains in addition from 5% to 20% by weight of a lower aliphatic alcohol containing 2 to 3 carbon atoms.

7. A composition in accordance with claim 1, which contains in addition about 0.5-5% of bis (lauryl trimethyl ammonium) pentathionate.

8. A composition in accordance with claim 1, which contains in addition about 0.5-5% of salicylic acid.

9. A composition in accordance with claim 1 wherein said imidazoline is present in an amount of 12% to 18% by weight and said amide-substituted carboxylic acid is present in an amount of 5% to 15% by weight.

References Cited UNITED STATES PATENTS 2,041,265 5/1936 Orthner et al. 2601125 2,815,344 12/1957 Neesby 260247.1

3,085,067 4/1963 Anderson 252-153 3,285,818 11/1966 Ohta et al 424 FOREIGN PATENTS 6413627 1/1965 Netherlands 260309.6

0 STANLEY J. FRIEDMAN, Primary Examiner V. D. TURNER, Assistant Examiner US. Cl. X.R.

252DIG 7, DIG 13, 142, 152; 424359 UNITED STATES PATENT OFFICE CERTIFICATE OF C'O'RECHON Patent No. 36u2977 Dated February 52 97 I Imentofls) Gordon Trent Hewitt It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 57, change "possess" to --possesses--; and in line 71, after "essentially" insert --equimolecular--. Column 2, line 1, change "amphorteric" to --amphoteric--; in line 2, change "amid-substituted" to --a.mide-substituted--; and in lines LZ-ML, the formula should read:

H -N+H H C C- R Column 6, line 27, change heptadenceneyl to --heptadecenyl and in line 29, change "undecyleneyl" to undecylenyl--.

Signed and sealed this 9th day of January 1973..

(SEAL) Attest:

EDWARD M.FLETCHEH,JR. ROBERT GOTISCHALK Attesting Officer Commissionerof Patents F ORM po-loso (ad-s9) USCOMM-DC 60376-P69 e us. sovlmmnn PRINTING OFFICE nun o-sse-au

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4001394 *Jan 30, 1974Jan 4, 1977American Cyanamid CompanyShampoo creme rinse containing a quaternary ammonium saccharinate, cyclamate or phthalimidate
US4009256 *Nov 13, 1975Feb 22, 1977National Starch And Chemical CorporationNovel shampoo composition containing a water-soluble cationic polymer
US4011097 *Dec 22, 1975Mar 8, 1977Sharp Thomas LMethod of removing iron sulfide and sludge from metal surfaces
US4076800 *Jan 7, 1976Feb 28, 1978The Procter & Gamble CompanyProtein-containing detergent compositions for protecting keratinous materials
US4087518 *Mar 11, 1976May 2, 1978The Procter & Gamble CompanyAlkylbenzene sulfonate and auxiliary surfactants, hydroxyalkylated gelatin
US4115548 *Dec 20, 1974Sep 19, 1978The Procter & Gamble CompanyProtection of keratinous material from effects of detergents and weather
US4195077 *Jun 26, 1978Mar 25, 1980The Procter & Gamble CompanyFor protecting keratinous material from detergents and weather
US4511497 *Sep 28, 1983Apr 16, 1985Strombecker CorporationBubble composition using multipurpose surfactant base
US4822604 *May 20, 1985Apr 18, 1989S. C. Johnson & Son, Inc.Local treatment of dandruff, seborrheic dermatitis, and psoriasis
USB438048 *Jan 30, 1974Mar 23, 1976 Title not available
EP0202621A2 *May 15, 1986Nov 26, 1986S.C. JOHNSON & SON, INC.Local treatment of dandruff, seborrheic dermatitis and psoriasis
EP1221313A2 *Dec 20, 2001Jul 10, 2002Zschimmer & Schwarz Italiana S.p.A.Salts of undecylenoyl glutamate or of undecylenoyl hydrolyzate of wheat or rice proteins in detergent or cosmetic compositions
U.S. Classification424/70.19, 510/119, 424/70.14, 424/70.22, 510/500, 510/126, 510/123, 514/773, 510/501, 424/70.21, 510/490
International ClassificationC07D233/14
Cooperative ClassificationA61K2800/596, A61Q5/12, A61Q5/02, C07D233/14, A61K8/4946, A61K8/44
European ClassificationC07D233/14, A61K8/44, A61K8/49F1, A61Q5/12, A61Q5/02