CA1254582A - PHENYL .alpha.-ACYLOXYACETAMIDE DERIVATIVES AND THEIR THERAPEUTIC USE - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Therapeutic as well as preventive measures to alleviate the symptoms of dermatologic and other condi-tions and disorders with phenyl alpha-acyloxyacetamide derivatives is disclosed. Dermatologic and other con-ditions and disorders in humans in which the compounds may be useful include pruritus, atopic dermatitis, eczema, psoriasis, acne, dry skin, dandruff, malodors of integu-mental areas; and various aches, pains and discomforts of skin, joints and other body parts. The phenyl alpha-acyloxyacetamide derivatives include, for example, N-ethyl phenyl alpha-acetoxyacetamide, N-benzyl phenyl-alpha-acetoxyacetamide, N-phenethyl phenyl-alpha-acetoxy-acetamide, N-benzyl diphenyl-alpha-acetoxyacetamide and N-phenethyl diphenyl-alpha-acetoxyacetamide. The compositions containing the active ingredients are also useful for treatment of skin conditions or disorders, and musculoskeletal disorders, of domestic animals, for example dogs, such as dry skin, scurf, eczema, mange, prurigo, malodors, arthritis or myositis. Some phenyl-alpha-acyloxyacetamide derivatives may have a tran-quilizing effect.

Description

` ~.J5~.5~2 I'his invention relates genera1ly to therapeut-ic treatment as well as preventive measures of dermatologic and other conditions and disorders by either topical or systemic administration of phenyl alpha-acylo~yacetamide derivatiYes.
As will be subsequently described in detail, ~e initially discovered that alpha hydroxy or keto QCidS and their derivatives were effective in the topical treatment of disease conditions such as dry skin, ichthyosis, eczema, palmar and plantar hyperkeratoses, dandruff, acne and warts.
We have now discovered that phenyl alpha-acyloxy-acetamide derivatives on topical or systemic administration are effective in therapeutic treatmen~ as well as preventive measures of various dermatologic and other conditions and disorders in humans and animals.
In our U.S. Patent No. 3,879,537, we described and claimed the use of certain alpha hydroxy acids, alpha keto acids and related compounds for topical treatment of fish-scale like Ichthyotic conditions in humans. In our U.S.
Patent No. 3,920,835, we described and claimed the use of these certain alpha hydroxy acids, alpha keto acids and their derivatives for topical treatment of dandruff, acne, and palmar and plantar hyperkeratosis.
In our U.S. Patent No. 4,105,783, we described and claimed the use of alpha hydroxy acids, alpha keto acids and their derivatives for topical treatment of dry slcin.
In our U.S. Patent No. 4,2~6,261, we described and claimed that alpha hydroxy acids, alpha keto acids and their derivatives, in small amounts could greatly enhance the - ~.,5~

therapeutic efficacy of corticosteroids in topical treat~ent of psoriasis, eczema, seborrheic dermatitis and other inflammatory skin conditions.
In our U.S. Patent No. 4,3~3,815, we described and claimed that alpha hydroxy acids and alpha keto acids related to or originating from amino acids, whether or not found in proteins, were effective in topical treatment of skin disorders associated with disturbed keratinization or inflammation. These skin disorders include dry skin, ichthyosis, palmar and plantar hyperkeratosis, dandruff, Darier's disease, lichen simplex chronicus, keratoses, acne, psoriasis, eczema, pruritus and possibly warts and herpes.

~ f DESCRIPTION OF THE INVENTION
It has now been discovered that a class of new compounds named phenyl alpha-acyloxyacetaMide derivakives can be therapeutically useful on topical or systernic administration against varieties of dermatologic and other conditions and disorders including pruritus, atopic dermatitis, eczema, psoriasis, acne, dry skin, dandruff, malodors of integumental areas and various discomforts and pains of diverse body parts in humans and animals.
In accordance with the present invention, phenyl alpha-acyloxyacetamide derivatives which are incorporated in therapeutic compositions for topical or systemic administration to prevent or alleviate the symptoms of dermatologic or other conditions and disorders are grouped in the following two categories.
The first category of phenyl alpha-acyloxyacetamide derivatives is N-alkyl or aralkyl phenyl alpha-acyloxyacetamides as shown by the following chemical structure:

~ _ c - CON \

wherein Rl, R2 = H, alkyl or aralkyl group of saturated or unsaturated, straight or branched chain or cyclic form, having l to 25 carbon atoms, ,~ f~
~ - 4 !`i ~ R3 = alkyl, aralkyl or aryl group of saturated or unsaturated, straight or branched chain or cyclic form, having 1 to 25 carbon atoms~
The hydrogen atom of the phenyl, ~1~ R2 or P.3 rnay b~
substituted by a nonfunctional element such as F, Cl, Br, I or a radical such as a lower alkyl or alkoxy of saturated or unsaturated, having 1 to 9 carbon atoms.
? The carbon atom of Rl or R2 may be substituted by a nonfunctional N, S or 0.
Phenyl alpha-acyloxyacetamide derivatives of this category may also exist as stereoisomers such as D, L and '` DL forms.
.- The typical alkyl or aralkyl group for Rl or Rz ~ includes ethyl, isopropyl, t-butyl, allyl, cyclohexyl, i. ~ 15 benzyl, phenethyl, p-chlorobenzyl, p-methoxybenzyl, _-methoxyphenethyl, 3,4~dimethoxyphenethyl, diethyla-. minoethyl, hydroxyethylthloethyl, piperazinoethyl, p-fluorobenzyl , dimethylaminopropyl, diethylaminopropyl and ~ picolyl. When one or more amino groups are present in R
.~ 20 or R2, the compound may form a salt with inorganic or organic acid such as HCl or tartaric acid.
The typical alkyl, aralkyl or aryl group for R3 includes methyl, ethyl, benzyl and phenyl.
The representative N-alkyl or aralkyl phenyl alpha-acyloxyacetamideS which are useful for topical or systemic administration to alleviate dermatologic or other conditions or disorders are listed below:

.

.. . .. ..... ..... . ....... .. . ... .... . . .....

1. N-ethyl phenyl-alpha-acetoxyacetamide 1 C2H5~ R2 = H, R3 = CH3

2. N-phenethyl phenyl-alpha-acetoxyacetamide 1 CH2cH2c6H5~ R2 = H~ R3 = CH3

3. N-ethyl phenyl-alpha-phenylacetoxyacetamide Rl = C2H5~ R2 = H, R3 CH2 6 5

4. N-phenethyl phenyl-alpha-phenylacetoxyacetamide 1 CH2CH2C6H5' R2 = H~ R3 = CH2C6H5

5. N-ethyl phenyl-alpha-benzoyloxyacetamide 1 C2H5, R2 = H~ R3 = C6H5

6. N-benzyl phenyl-alpha-acetoxyacetamide Rl CH2C6H5, R2 = H~ R3 = CH3

7. N-ethyl phenyl-alpha-propionyloxyacetamide 1 C2H5, R2 = H~ R3 = C2H5 3. N-phenethyl phenyl-alpha-propionyloxyacetamide - R - H, R - C H
Rl - CH2CH2C6H5' 2 3 ~ 5 9. N-allyl phenyl-alpha-acetoxyacetamide 1 ~3Hs~ R2 = H~ R3 = CH3 10. N-ethyl phenyl-alpha-lauroyloxyacetamide Rl = C2H5, R2 = H~ R3 Cll 23 11. N-phenethyl phenyl-alpha-linoleoyloxyacetamide Rl CH2CH2C6H5~ R2 = H~ R3 = C17H31 .. . .. ...... . . .. . . . . . .. .

12. N-phenethyl phenyl-alpha-linolenoyloxyacetamide 1 H2CH2C6H5~ R2 = ~ R3 = C17H29 13. N,N-diethyl phenyl-alpha-acetoxyacetamide 1 C2H5~ ~2 = C2H5~ R3 = CH3 514. N-isop~opyl phenyl-alpha-acetoxyacetamide 1 ~3H7, R2 = H, R3 = CH3 15. N-t-butyl phenyl-alpha-acetoxyacetamide 1 C4Hg~ R2 = H, R3 = CH3 16. N-p-chlorobenzyl phenyl-alpha-acetoxyacetamide 10Rl = CH2C6H4Cl~ R2 H, R3 3 17. N-p-methoxybenzyl phenyl-alpha-ace~oxyacetamide ~
Rl = CH2C6H4OCH3~ R2 H, R3 3 18.. N-~-methoxyphenethyl phenyl-alpha-acetoxyacetamide 151 CH2cH2c6H4ocH3~ R2 = H~ R3 = CH3 19. N-(3,4-dimethoxyphenethyl)phenyl-alpha-acetoxyacetamide 1 2cH2c6H3(ocH3)2~ R2 = H, R3 = CH3 20. N-(N',NI-diethylaminoethyl)phenyl-alpha-20acetoxyacetamide 1 CH2cH2N(c2~5)2~ R2 = H~ R3 = CH3 21. N-hydroxyethylthioethylphenyl-alpha acetoxyacetamide Rl = CH2CH2SCH2CH2H~ R2 = H~ R3 = CH3 ~ 7 --22. M-piperazinoethyl phenyl-alpha-acetoxyacetamide Rl = CH2cH2N~cH2cH2)2NHl R2 3 3 23. N-(N',N'-diethylarninopropyl) phenyl-alpha-acetoxyacetamide S Rl ~ CH2cH2cH~N(c2H5)2l R2 3 3 24. N-(N',N'-dimethylaminopropyl) phenyl-alpha-acetoxyacetamide Rl = CH2cH2cH2N(cH3)2~ R2 3 3 25. N~(2,3-dihydroxypropyl~phenyl-alpha-acetoxyacetamide Rl = CH2CHOHCH2OH, R2 H, R3 3 26. N,N-diethanol phenyl-alpha-acetoxyacetamide R = CH CH OH, R2 = CH2CH2OH, R3 = CH3 27. N-(2-phenylethanol)phenyl-alpha-acetoxyacetamide Rl = CH2CH(C6H5) O~, R2 = H, R3 = ~H3 28. N-(N',N'-diethanolaminopropyl)phenyl-alpha-acetoxyacetamide Rl = CH2CH2CH2N(CH2C~2OH)2~ R2 ' 3 3 29. N-(l-ethyl 2,2'-dihydroxyisopropyl)phenyl-alpha-acetoxyacetamide Rl = C(C2H5) (CH2OH)2~ R2 3 3 30. N,N-dibenzyl phenyl-alpha-acetoxyacetamide Rl ~ CH2C6H5, R2 ~ CH2 C6 5, 3 3 31. N-hydroxyethoxyethyl phenyl alpha-2S -acetoxyacetamide Rl = CH2CH2OCH2CH2OH~ R2 = H, R3 = CH3 , , . . . ... ... .. ... , .. ,, . , . .. ., ~ .. . . ,, , ., ", ,, . ~ . ~ ,. . . .. . . . . .. .. . .
.. . . . . . . . . .

~S~5 32. N-diphenylmethyl phenyl-alpha-acetoxyacetamide Rl CH(C6H5)2, R2 = H, R3 = CH3 33. N-(2-phenyl-27-hydroxyisopropyl)phenyl-alpha acetoxyacetamide Rl = CH(CH2OH) CH2C6H5, R2 3 3 34. N-(2-hydroxy-2-phenyl-2'-hydroxyisopropyl) phenyl-alpha-acetoxyacetamide Rl = CH(CH2OH)CH(OH)(C6H5)r R2 3 3 35. N (2-hydroxyisopropyl)phenyl-alpha-acetoxyacetamide Rl = CH(CH2OH)CH3, R2 H, R3 3 36. N-(2-hydroxy-t-butyl)phenyl-alpha-acetoxyacetamide Rl = C(CH2OH)(CH3)2, R2 H, R3 3 37. N-(l-methyl-2-ethylpyrrole)phenyl-alpha-acetoxyacetamide Rl = CH2CH2C4H3NCH3, R2 = H, R3 = CH3 38. N-(l-methyl-2-ethylpyrrolidine~phenyl-alpha-acetoxyacetamide 1 CH2cH2c4H7~cH3~ R2 = H~ R3 = CH3 39. N-p-fluorobenzyl phenyl-alpha-acetoxyacetamide Rl = cH2C6H4F~ R2 H, R3 3 40. N-p-methylbenzyl phenyl-alpha-acetoxyacetamide Rl CH2C6H4CH3, R2 = H, R3 = CH3 41. N-p-chlorophenethyl phenyl-alpha-acetoxyacetamide Rl = CH2CH~CfiH4Cl, R2 = H, R3 = CH3 ,, . , . ., .. . .. , . ... , . . . ~, .. . . .. . . .

5~

_ g _ 42. N-phenylpropyl phenyl-alpha-acetoxyacetamide 1 CH2CH2CH2C6H5~ R2 = H~ R3 = C~3 43. N-phenylbutyl phenyl-alpha-acetoxyacetamide Rl = CH2CH2CH2cH2c6H5' ~2 3 3 During the syntheses of phenyl alpha-acyloxyacetamide derivatives of the instant invention certain intermediate products and related compounds which are not represented by ~he foregoing generic ctructures have also been tested for their therapeutic efficacy against dermatologic and other disorders and diseases. We have found that these intermediate products and related compounds are therapeutically effective but in general less so than phenyl alpha-acyloxyacetamide derivatives represented by the above generic structures. These intermediate products and related compounds are listed below:

1. N-ethyl phenyl-alpha-hydroxyacetamide 2. N-phenethyl phenyl~alpha-hydroxyacetamide 3. N-benzyl phenyl-alpha-hydroxyacetamide 4. N-isopropyl phenyl-alpha-hydroxyacetamide 5. N-t-butyl phenyl-alpha-hydroxyacetamide 6. N,N-diethyl phenyl-alpha-hydroxyacetamide 7. N (N',N'-diethylaminoethyl)phenyl-alpha-hydroxyacetamide

8. N-piperazionethyl phenyl-alpha-hydroxyacetamide

9. N-allyl phenyl-alpha-hydroxyacetamide

10. N-P-chlorobenzyl phenyl-alyha-hydroxyacetarnide

11. N-P-methoxybenzyl phenyl-alpha-hydroxyacetamide

12. N-P-methoxyphenethyl phenyl-alpha-hydroxyacetamide

13. N~(3,4-dimeth oxyphenethyl)phenyl-alpha-hydroxyacetamide

14. N-hydroxyethylthioethyl phenyl-alpha-hydroxyacetamide

15. N-(N'N'-diethylaminopropyl)phenyl-alpha-hydroxyacetamide

16. N-P-fluorobenzyl phenyl-alpha-hydroxyacetamide

17. N-(N',N'-dimethylaminopropyl)phenyl-alpha-hydroxyacetamide The second category of phenyl alpha-acyloxyacetamide derivatives is N-alkyl or aralkyl phenyl alpha-alkyl aralkyl or aryl, alpha-acyloxyacetamides as shown by the following chemical structure:

~ O ~ _ C - CON <

wherein Rl, R2 = H, alkyl or aralkyl group of saturated or unsaturated, straight or branched chain or cyclic form, having 1 to 25 carbon atoms, R3 and R4 = alkyl, aralkyl or aryl group of saturated or unsaturated, strai~ht or branched chain or cyclic form, having 1 to 25 carbon atoms.

.. . ,. . , .. . ~ .. . ,. , . . ., . , . ... ,. ,, " .. ~ ... .... ..... .. . . .

The hydrogen atom of the phenyl, Rl, R2, R3 or R4 may be substituted by a nonfunctional element such as F, Cl, Br, I or a radical such as a lower alkyl or alkoxy of saturated or unsaturated, having 1 to 9 carbon atoms.
The carbon a~om of Rl or R2 may be substituted by a nonfunctional N, S or O.
Phenyl alpha-acyloxyacetamide derivatives of the second category may also exist as stereoisomers such as D, L and DL forms.
~he typical alkyl or aralkyl group in Rl or R2 is ethyl, isopropyl, t-blltyl, allyl, cyclohexyl, benzyl, phenethyl, p-chlorobenzyl, ~-methoxybenzyl, p-methoxyphenethyl, 3,4-dimethoxyphenethyl, p-fluorobenzyl, diethylaminoethyl, hydroxyethylthioethyl, dimethylaminopropyl, piperazinoethyl, diethylamino propyl and picolyl. When one or more amino groups are present in Rl or R2 the compound may form a salt with inorganic or organic acid such as H2S O4 or citric acid~
The typical alkyl, arakyl or aryl group in R3 or R4 is methyl, ethyl, benzyl and phenyl.
The representative compounds of this second category of phenyl alpha-acyloxyacetamide derivatives are listed below:

1. N-ethyl diphenyl-alpha-acetoxyacetamide 25 1 2H5~ R2 H~ R3 = CH3, R4 = C6H

5~2 2. N-phenethyl diphenyl-alpha-acetoxyacetamide 1 2cH2c6Hs~ ~2 = H, R3 = CH3, R4 = C6H5 3. N-ethyl diphenyl-alpha-phenylacetoxyacetamide 1 2 5~ R2 H, R3 = cH2C6H5, R4 = C6H5 4. N-phenethyl diphenyl~alpha-phenylacetoxyacetamide 1 2 H2C6H5' R2 = H~ R3 = CH2C6H5, R4 = C6H
S. N-ethyl phenyl alpha-methyl-alpha-acetoxyacetamide Rl = C2H5~ R2 = H~ R3 = CH3, R4 3 6. N-phenethyl phenyl alpha-methyl-alpha-acetoxy-acetamide Rl = CH2CH2C6~5' R2 = H~ R3 CH3, 4 3 7. N-isopropyl diphenyl alpha-acetoxyacetamide Rl = C3H7, R2 = H~ R3 = CH3, R4 6 5 8. N-t-butyl diphenyl alpha-acetoxyacetamide Rl = C4Hg, R2 = H~ R3 = CH3, R4 6 5 9. N-benzyl diphenyl-alpha-acetoxyacetamide 1 2C6H5~ R2 = H, R3 = CH3, R4 = C6H5 10. N-allyl diphenyl-alpha-acetoxyacetamide Rl = C3H5, R2 = H~ R3 = CH3, R4 6 5 11. N-phenethyl diphenyl-alpha-propionyloxyacetamide Rl = CH2CH2C6H5' R2 = H~ R3 C2 5' 4 6 5 , ., ~ . . ., .. , .. . . . . , . , . " . . . .. . ~, , . " ., " . . . . .. .. . . .. . . .. .
.. . .

~,5~

12. N-ethyl diphenyl-alpha-linolenoyloxyacetamide 1 2H5~ R2 = R~ R3 = C17H29~ R4 ~ C6H5 13. N-ethyl-N-methyl diphenyl-alpha-acetoxyacetamide 1 2~5' R2 CH3, R3 = CH3~ R4 = C6H5 14. N,N-diethyl diphenyl-alpha-acetoxyacetamide 1 2H5, R2 = C2H5 ~3 = CR3, R4 = C H
15. N-P-chlorobenzyl diphenyl-alpha-acetoxyacetamide Rl = CH2C6H4Cl, R2 = H~ R3 = CH3, R4 = C6H5 16. N-P-methoxybenzyl diphenyl-alpha-acetoxyacetamide Rl = CH2C6H4OCH3, R2 = H, R3 CH3~ 4 6 5 17. N-P-methoxyphenethyl diphenyl-alpha acetoxyacetamide Rl = CH2CH2C6H4OCH3, R2 = H, R3 - CH3, R4 = C6H5

18. N-(3,4-dimethoxy phenethyl)diphenyl-alpha-acetoxyacetamide Rl = CH~cH2c6~3(OcH3)2~ R2 3 3 R4 = C6 5

19. N-(N',N'-diethylaminoethyl) diphenyl-alpha-acetoxyacetamide 1 2 2N(C2H5)2~ R2 = H~ R3 = CR3~ R4 = C H

20. N-hydroxyethylthioethyl diphenyl-alpha-acetoxyacetamide Rl _ CcH~CH2SCH2CH2H~ R2 = H~ R3 = CH 3, - . - . . ., . . . . :. . .. .... . . . . . .. . . .

21. N-(N',N'-diethylaminopropyl) diphenyl-alph~
acetoxyacetamide R~ - C ~ 2CH2N(C2H5)2~ R2 ~ H~ R3 = CH3,

22 . N- (N ', N ' -dimethylaminopropyl) diphenyl-alpha-acetoxyacetamide Rl - CH~CH2CH2N(CH3)2, R2 = H, R3 = CH3,

23. N-piperazinoethyl diphenyl-alpha-acetoxyacetamide . .
Rl - CH~cH2N(cH2cH2)2 NH~ R2 = H~ R3 = CH3,

24. N-(2,3-dihydroxypropyl) diphenyl-alpha-acetoxy-acetamide Rl = CH2CHOHCH2OH, R2 = H, R3 CH3~ 4 6 5

25. N,N-diethanol diphenyl-alpha-acetoxyacetamide Rl - CH~CH2OH, R2 = CH2CH2OH, R3 = CH3,

26. N-(2-phenylethanol) diphenyl-alpha-acetoxy-acetamide Rl = CH2CH(C6H5)OH, R2 = H, R3 = CH3, R4 = C6H5

27. N-(N',N'-diethanoiaminopropyl) diphenyl-alpha-acetoxyacetamide Rl _ CH~cH2cH2N(cH2cH2oH)2~ R2 = H~ R3 = CH3~

28. N-(l-ethyl-2,2'-dihydroxyisopropyl) diphenyl-alpha-acetoxyacetamide Rl - CC(CH2H5)(CH2H)2~ R2 = H, R3 = CH3, - . i ........... ~

3~

29. N-p-fluorobenzyl diphenyl-alpha-acetoxyaceta~id~
Rl = CH2C6H4F~ ~ = H~ ~3 CH3, 4 ~ 5

30. N-p-methylbenzyl diphenyl-alpha-acetoxyacetamide Rl = CH2C6H4CH3, R2 = H, R3 CH3~ 4 6 5

31. N-p-chlorophenethyl diphenyl-alpha-acetoxyacetamide 1 2 H2C6H4Cl, R2 = H, R3 = CH3 t R4 = C6H

32. N-phenylpropyl diphenyl-alpha-acetoxyacetami.de R = CH2CH2CH2C6H5, R2 = H, R3 CH3~ 4 6 5

33. N-phenylbutyl diphenyl-alpha-acetoxyacetamide Rl - CH~CH2CH2cff2c6HS' R2 ' 3 3 As with the first category of derivatives, certain intermediate products and related compounds of N-alkyl or aralkyl phenyl alpha-alkyl, aralkyl or aryl, alpha-acyloxyacetamides which are not represented by the generic structures have also been tested for their therapeutic efficacy against dermatologic and other disorders and diseases. We have found that these intermediate products and related compounds are therapeutically efficacious to a degree but less than the acylated derivatives represented by the foregoing generic structures. These intermediate products and related compounds are listed below:
1. N-ethyl diphenyl-alpha-hydroxyacetamide 2. N-phenethyl diphenyl-alpha-hydroxyacetamide 3. N-benzyl diphenyl-alpha-hydroxyacetamide 4. N,N-diethYl diphenyl-alpha-hydroxyacetamide 5. N-(N~N~-diethylaminoethyl)diphenyl-alpha hydroxyacetamide 6. N-(N~Nl-diethylaminopropyl) diphenyl-alpha hydroxyacetamide 7. N-(N',N'-dimethylaminopropyl) diphenyl-alpha-hydroxyacetamide 8~ N-P-methoxybenzyl diphenyl-alpha-hydroxyacetamide 9. N-P-chlorobenzyl diphenyl-alpha-hydroxyacetamid~

10. N-P-methoxyphenethyl diphenyl-alpha-hydroxyacetamide 11. N-3,4-dimethoxyphenethyl diphenyl-alpha hydroxyacetamide 12. N-hydroxyethylthioethyl diphenyl-alpha-. hydroxyacetamide 13. N~isopropyl diphenyl-alpha-hydroxyacetamide 14. N t-butyl diphenyl-alpha-hydroxyacetamide 15. N-allyl diphenyl-alpha-hydroxyacetamide Other heterocyclic ring derivatives of phenyl alpha-acyloxyacetamide have been synthetized and tested for thelr therapeutic efficacy against dermatologic and other disorders and diseases. We have found that other phenyl alpha-acyloxyacetamide derivatives with heterocyclic ring substitution are therapeutically effective but with various ranges of efficacy. These compounds are listed below:
1. N-3'-picolyl phenyl-alpha-hydroxyacetamide 2. N-3'-picolyl d.iphenyl-alpha-hydrOxyacetarnide 3. N-3'-picolyl phenyl-alpha-acetoxyacetamide 4. N-3'-picolyl diphenyl-alpha-acetoxyacetamide ... . .. ,. ~... ........ ~ .. , . .. . . ~ .. .... . . . . .. . .... ... . .. ..
.. .. ... . ... ........ ... . . ... . ". .

5. N-3'-picolyl phenyl-alpha-phenylacetoxy-acetamide 6. N-3'-picolyl diphenyl-alpha-phenylacetoxy-acetamide S Phenyl alpha-acyloxyacetamide derivatives of the instant invention may also be utilized in cornbination l"ith or in small amounts as additives to enhance therapeutic effects of other drugs such as corticosteroids of either synthetic or nonsynthetic origin to alleviate the symptoms of prurigo, atopic dermatitis, psoriasis, acne, eczema, seborrheic dermatitis and other skin conditions characterized by inflammation, disturbed keratinization and pruritus. Commonly used corticosteroids include hydrocortisone, hydrocortisone-21-acetate, hydrocortisone-17-valerate, hydrocortisone-17-butyrate, triamcinolone acetonide, betamethasone and prednisone.
Phenyl-alpha-acyloxyacetamide derivatives may also be utilized in combination with other dermatologic drugs for topical, intravaginal or systemic administration to alleviate the symptoms of dermatitis and/or pruritus caused by fungal, bacterial or viral infection or by parasitic infestations. Commonly used topical, intravaginal or oral agents for the above infections and infestations include antiyeast, anti-fungal, antibacterial, antiviral, anti-inflammatory, keratolytic, antipsoriatic and antieczematic agents such as clotrimazole, miconazole, nystatin, neomycin, gramicidin~
haloprogin, griseofulvin, 5alicylic acid, sodium thiosulfate, selenium sulfide, zinc pyrithione, benzyl , ~, .. .. . ... . ... -~.~75~
, benzoate, crotamiton, lindane, phenol, menthol, amphoterioins, penicillins, corticosteroids, antihistamines, antibiotics, anthralin, tar preparationS
and the like.
It has already been established through tests in animals and humans that phenyl alpha-acyloxyacetamide derivatives are therapeutically effective for topical or-systemic treatment of various dermatologic and other conditions. For example, in topical treatment of pruritus ani N-ethyl phenyl-alpha-acetoxyacetamide and N-phenethyl phenyl-alpha-acetoxyacetamide in a concentration of from 1 to S percent are therapeutically effective when topically applied on a regular basis to cause complete relief from itching and scratching. In systemic treatment of domestic dogs for common scratching N-ethyl phenyl-alpha-acetoxyacetamide or N-phenethyl phenyl-alpha-acetoxyacetamide given orally in a single dose of 5 to lO
mg per kg body weight has been found to be therapeutically effective in relieving scratching for more than 8 hours.
Accordingly, it is an object of this invention to provide medicinal compositions containing at least one phenyl alpha-acyloxyacetamide derivative which when topically or systemically administered will substantially alleviate the symptoms of various dermatologic and other conditions and disorders.
It is another object of this invention to provide methods for treating various dermatologic and other conditions with topical preparations or systemic .. .. , ,, .,, .,, ,,, ", ~

compositions containing phenyl-alpha-acyloxyacetamide derivatives.

PF(EPARATION OF THE THERAPEUTIC COMPOSITIONS
Phenyl alpha-acyloxyacetamide derivatives of the instant invention may be formulated either for topical application or for systemic administration. In the topical preparations phenyl,alpha-acyloxyacetamide aerivatives may be formulated in solution, lotion, gel, shampoo, spray, stick, powder, cream or ointment containing from ~.01 to 50 percent and preferably from about 0.1 to 10 percent by weight of the total composition.
To prepare a typical solution form phenyl alpha-acyloxyacetamide derivatives are initially dissolved in ethanol or acetone. Propylene glycol, water, glycerol, butanediol or the like may be added to the compositions.
For example a typical therapeutic solution containing 5%
N-ethyl phenyl-alpha-acetoxyacetamide is formulated in ethanol, water and propylene glycol in a volume ratio of 50:30:20, respectively.
Phenyl alpha-acyloxyacetamide derivatives in a lotion, cream or ointment composition may be ~ormulated as follows. Phenyl alpha-acyloxyacetamide derivatives are intially dissolved in ethanol, acetone, or propylene glycol. The solution thus prepared may be admixed in a conventional manner with commonly available lotion, cream or ointment bases such as hydrophilic ointment U.S.P.

.. .. . .. , .,,, . .. ~ ., . .. , . .. ~ . .. , .. ~ .. ..
. ..... ~........ . ...........

~5~

A typical gel composition of this invention utilizes at least one of the phenyl alpha-acyloxyacetamide dexivatives, dissolved in a mixtuxe of ethanol, water and propylene glycol in a volume ratio of 40:40:20, S respectively. A gelling agent such as hydroxyethylcellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose is then added ~o the mixture with agitation. The preferred concentration of the gelling agent may range from 0.1 to 3 percent by weight of the total composition.
To prepare a typical shampoo formulation phenyl alpha-acyloxyacetamide derivatives are disolved in a mixture of ethanol, water and propylene glycol. A
surfactant such as triethanolaminelaurylsulfate may then be added to the solution.
For systemic use the phenyl alpha-acyloxyacetamide derivatives may be formulated for oral administration or for parenteral injections. In oral preparations the phenyl alpha-acyloxyacetamide derivatives may be formulated in tablet form or in gelatin capsules with or without mixing with gelatin powder. Each tablet or capsule may contain from 10 to 300 mg of a phenyl alpha-acyloxyacetamide derivative. For parenteral injections the phenyl alpha-acyloxyacetamide derivatives are prepared under sterilized conditions usually in 1 to 10 percent concentration in water or saline as solubilized form or fine suspension.

The compounds of the invention may be prepared according to the following reac~ion sche~es:

aH
HNRlR2 ~ ~ C CONRlR2 R4 ÇOOR~ or~anic amine ~ R4 phenyl -hydroxyacetamide derivative phenyl ~-hydroxyacetlc ester ~-O-acylatlon / (R3Co)20 / or R3COHal ~C CONRLR2 phenyl a-acyloxvacetamide derivative -20a-~.~

wherein R to R are as defined above, R i9 part of the ester group and Hal is Cl or Br.

HNRlR2 ~ CONR,R2 / I organic amine R

phenyl ~-acyloxyacetyl halide phenyl a-acyloxyacetamide derivative wherein R to R and Hal are as defined above.
In the first scheme the phenyl-alpha-hydroxyacetic ester, organic amine and acylation reagents are com-mercially available.
In the second scheme the phenyl-alpha-acyloxy-acetyl halide may be prepared according to the following reaction scheme:

Q l R3COHal acyl halide Q
COOH SOHal2 or the like > ~ -C - COHal phenyl ~-acyloxyace~yl halide phenyl ~-hydroxyacetic acld -20b-~, .

wherein R , P~ and Hal are as defined above.

In general, the syntheses of phenyl-alpha-acyloxyacetamide derivatives involve the formation of two chemical bonds: an amide linkage at the carboxyl end and an ester bond at the alpha-hydroxyl group, when the starting material is a commercially available compound.
Altho~gh various methods are known for the formation of an amide bond in synthetic organic chemistry for simple compounds, the synthesis of phenyl-alpha-hydroxyacetamide derivatives is relatively unknown because these compounds possess an alpha-hydroxy group which may interfere or undergo unexpected reactions. To form an acyloxy bond at the alpha-hydroxy position is also a challenging problem since the hydroxy group is attached to a carbon atom at the alpha side chain position of the phenyl group. Factors such as steric hindrance and chemical reactivity of the hydroxyl group have to be considered. Under certain conditions whether an amide linkage or an ester bond should be first synthesized has to be determined.
We have now discovered that phenyl-alpha-acyloxyacteamide derivatives may be synthesized in good yields by either of the above noted reaction schemes.
In the first synthetic process a unique simple amidation procedure has been developed. A phenyl alpha-hydroxyacetic ester (1 mole) in a beaker is heated with an organic amine (1.5 to 2.0 moles) at 60 - 70C for 3 -20c-to S hours. After standing at room temperature for 1 hours most phenyl-alpha hydroxyacetamide derivatives separate as white crystalline products ~hich may be washed with water and dried at 40C in vacuum. Most crystalline phenyl-alpha-hydroxyacetamide derivatives thus synthesized are practically pure. However, they may be purified by dissolving in two parts of hot ethanol, and the resulting filtrate is cooled externally with an ice water bath. White crystals thus formed are washed with either ether or n-hexane. The yield is usually very good. For example both N-benzyl phenyl-alpha-hydroxyacetamide and N-phenethyl phenyl-alpha-hydroxyacetamide are obtained in yields of higher than 99 percent based on phenyl alpha-hydroxyacetic acid methyl or ethyl ester.
For acylation to the alpha-hydroxy group of a phenyl-alpha-hydroxy acetamide derivative various synthetic approaches have been tried including an acyl chloride and acyl bromide in pyridine or other solvents.
We have discovered that one of the best and simplest methods is to use an acyl anhydride and a small catalytic amount of concentrated sulfuric acid. An ordinary three-necked round bottom flask may be used to carry out the acylation reaction. However, we have found that it is much simpler and convenient to utilize a stainless steel reaction vessel. Generally, the phenyl-alpha-hydroxyacetamide derivative (1 mole) is heated with an acyl anhydride (4 to 6 moles) to 60C and -20d-0.1 to 1 ml of concentrated sulfuric acid is added. Theexothermic acylation takes place lmmediately and the reaction vessel may be cooled externally with an ice water bath to maintain the reaction temperature at 80 -90C. After the initial exothermic reaction has subsided the reaction vessel is heated at 80 - 90C for 3 hours to complete the acylation. If the acylated product does not separate as crystals on cooling, the reaction mixture is usually evaporated at 60 - 70C in vacuum to remove the volatile components. The residue is then mixed with ice water. At this point if the phenyl-alpha-acyloxyacetamide derivative still does not separate as a crystalline product, then chloroform or other organic solvent is added to extract the product.
The organic layer is washed with dilute sodium bicarbonate, dilute HCl and dried with a dehydrating agent. On evaporation of the organic solvent most phenyl-alpha-acyloxyacetamide derivatives will separate as crystalline products. Phenyl-alpha-acyloxyacetamide derivatives thus synthesized may be purified by recrystallization from ethanol, The yield of the pure product ranges from 30 to 60 percent based on the phenyl-alpha-hydroxyacetic ester.
By the above two-step method N-benzyl phenyl-alpha-acetoxyacetamide and N-phenethyl phenyl-alpha-acetoxyacetamide are synthesized in a yield of 48 and 46 percent, respectively, starting from phenyl alpha-- 20e -;` `~ j`

hydroxyacetic acid methyl ester.
In the second synthetic process there are three steps involved for the synthesis of a phenyl~
alpha-acyloxyacetamide derivative. The first and second steps, however, may be combined and thus there is no need to isolate the product after the first step operation. In general, a phenyl-alpha-hydroxyacetic acid is reacted with an acyl halide and the resulting phenyl-alpha-acyloxyacetic acid is then halogenated with thionyl chloride or the like to form phenyl-alpha-acyloxyacetyl halide. This halide can be isolated by distillation at elevated temperature in vacuum. For example, phenyl-alpha-acetoxyacetyl chloride can be prepared in a yield of 80 percent from phenyl-alpha-hydroxyacetic acid.
Various conditions have been utili~ed and examined for the synthesis of phenyl-alpha-acyloxyacetamide derivatives from phenyl-alpha-acyloxyacetyl halides and organic amines. We have found that a higher yield is obtained when a phenyl-alpha-acyloxyacetyl halide is reacted with an organic amine in a non-a~ueous system. Under such conditions N-p-chlorobenzyl phenyl-alpha-acetoxyacetamide is obtained in a yield of 80 percent, N-p-fluorobenzyl phenyl-a]pha-acetoxyacetamide of 56 percent, N-p-methoxybenzyl phenyl-alpha-acetoxyacetamide of 72 percent, N-(3,4-dimethoxy benzyl) phenyl-alpha-acetoxyacetamide of 64 percent, N-p-methylbenzyl phenyl-alpha~acetoxyacetamide of 68 -20f-~J~7t~

percentr N-~-butyl phenyl alpha-acetoxyacetamide o~ 50 percent, N-p-methoxyphenethyl phenyl alpha-acetoxyacetamide of 56 percent, N-(3,~-dimethoxyphenethyl) phenyl alpha-acetoxyacetamide of 80 percent and N-hydroxyethylthioethyl phenyl-alpha-acetamide of 63 percent.

-20g-- .
, . ~ . .

The following are illustrative examples of syntheses, formulations and compositions according to this invention. Although the examples utilize only selected formulations useful accordingly to this invention, it should be understood that ~he following examples are illustrative and not limited. Therefore, any of the aforementioned phenyl alpha-acyloxyacetamide derivatives may be substituted according to the teachings of this invention in the following examples:

_ample l Synthesis of N-ethyl phenyl alpha-acetoxyacetamide The following method may be applied to synthesis of all N-alkyl phenyl alpha-acetoxyacetamides.
Mandelic acid ethyl ester 400 ml and ethylamine 70 in water, 400 ml are heated to 60 degrees C. for 5 hours.
The mixture is then evaporated at 50 degrees C. in vacuum to remove water, excess ethylamine and other volatile components. The residue on standing at room temperature forms crystalline N-ethyl mandelic amide 350 g.
N-ethyl mandelic amide 50 g synthesized as above is dissolved in acetic anhydride 200 ml, and concentrated sulfuric acid 1 ml is added. The mixture is heated at 80-90 degrees C. for 5 hours to complete the acetylation~
After evaporating at 60 degrees C. in vacuum a syrupy residue thus obtained is mixed with 400 ml of ice water The oily product is extracted with chloroform 300 ml, and is washed with 5% aqueous sodium bicarbonate 200 ml and .. , , , ,,, ",, , .. , .. , " , , ~ .7.. ' ............. ... . ~ .. . . . . . .

0.5 N HCL 200 ml, and is dried with anhydrous sodium sulfa~e. On evaporation of the chloroform s01ution at 40 degrees C. in ~acuum white crystalline product is formed from the syrupy residue, and ~he crystals are washed with ether. N-ethyl phenyl alpha-acetoxyacetamide 32 g thus synthesized is identified by infrared spectroscopy, high performance liquid chromotography and thin-layer chromatography with a mobility of 0.79 on a solvent system of benzene:methanol 1:1.

Example 2 N-ethyl phenyl alpha-acetoxyacetamide 5~ solution may be formulated as follows.
N-ethyl phenyl alpha-acetoxyacetamide 5 g is dissolved in 95 ml solution prepared from ethanol, water 1~ and propylene glycol in a volume ratio of 50:30:20, respectively. The therapeutic solution thus prepared is suitable for topical administration, for example on hairy skin of domestic dogs and on scalp of humans.

Example _ N-ethyl phenyl alpha-acetoxyacetamide 5% cream may be formulated as follows.
N-ethyl phenyl alpha-acetoxyacetamide 5 g is dissolved in ethanol 15 ml, and the solution is mixed with 80 g of hydrophilic ointment USP. Continue mixing until a uniform consistency is obtained.

~r~q~

Example 4 N-ethyl phenyl alpha-acetoxyacetamide 7% gel may be formulated as follows.
N-ethyl phenyl alpha-acetoxyacetamide 7 g is dissolved in 50 ml of ethanol, 20 ml of propylene glycol and 21 ml of water. Hydroxypropylcellulose 2 g is added to the mixture with agitation. Continue agitation until uniform gel is formed.

Example 5 N-ethyl phenyl alpha-acetoxyacetamide 3% composition in water-nonwashable cream may be formulated as follows:
Part A: Sorbitan sesquioleate 10 g Petrolatum 15 g Mineral oil 15 g Beeswax 15 g Isopropyl myristate 10 g Part B: Water 20 ml Propylene glycol5 ml - Glycerol 3 ml Sorbitol 3 g Magnesium oxide 0.1 g Heat Part A and Part B to 80 degrees C. Add Part B
slowly to Part A with agitation- Continue agitation until the mixture is congealed- Add 10% aqueous phosphoric acid ... , . , ... . .. .. . .. .. , . ... , . ..... .. ., . ~, .... . ~ . .. ... .. ... . .... . ... .

~ 24 -0.5 ml and aluminum chlorohydroxide 0.5 g followed by 3 g of powdered N-ethyl phenyl alpha-acetoxyacetamide.

Example 6 Synthesis of N-phenethyl phenyl alpha-acetoxyacetamide The following method may be applied to synthesis of all N-aralkyl phenyl alpha-acetoxyacetamides.
Mandelic acid ethyl ester 190 ml and phenethylamine 190 ml are heated to 70-~0 degrees C. for 2 hours. The mixture is then mixed with 2 liters of cold water, and white crystals thus formed are washed with 1 liter of 5% sodium carbonate solution. N-phenethyl mandelic amide 272 g thus prepared is suitable for the following synthesis of N-phenethyl phenyl alpha-acetoxyacetamide.
N-phenethyl mandelic amide 100 g synthesized as above is dissolved in acetic anhydride 230 ml, and concentrated sulfuric acid 0.5 ml is added. The mixture is heated at 70-80 degrees C. for 3 hours to complete the acetylation. After evaporation at 70-80 degrees C. in vacuum a syrupy residue thus obtained is mixed with 1.5 liters of cold water. Sodium bicarbonate powder 100 g is added to the mixture and the product is extracted with 300 ml of chloroform, and is dried with anhydrous sodium sulfate. On evaporation of chloroform white crystals are formed from a syrupy residue. The crystals are thoroughly washed with n-hexane, yield is 72 g.
N-phenethyl phenyl alpha-acetoxyacetamide thus synthesized is identified by infrared spectroscopy, high performance liquid chromatography and thin-layer chromatography with a mobility of 0.66 on a solvent sy~tem o~ benzene:methanol 1:1.

Example 7 N-phenethyl phenyl alpha-acetoxyacetamide 3~ solution may be formulated as follows.
N-phenethyl phenyl alpha-acetoxyacetamide 3 g is dissolved in 97 ml solution prepared from ethanol, water and 1,3-butanediol in a volume ratio of 60:20:20, respectively.
The therapeutic solution thus prepared may be stored in amber glass dropper bottles.

Example 8 --N-phenethyl phenyl alpha-acetoxyacetamide 4% cream may be formulated as follows.
N-phenethyl phenyl alpha-acetoxyacetamide 4 g is dissolved in 12 ml of ethanol, and the solution is mixed with 84 g of hydrophilic ointment USP. Continue mixing until a uniform consistency is obtained.

Example 9 Synthesis of N-methyl phenyl alpha-acetoxyaCetamide Mandelic acid ethyl ester 250 ml and methylamine 40% in water, 400 ml are heated to 60-70 degrees C. for 3 hours~
The mixture is evaporated at 50 degrees C. in vacuum to remove water, excess methylamine and other volatile materials. The residue on standing at room temperature forms crystalline N-methyl mandelic amide 207 g.

.. . .. . . .. .... . . .... ..

N-methyl mandelic amide 100 g, synthe5ized as above is dissolved in acetic anhydride 200 ml at 60 degrees C. and concentrated sulfuric acid U.5 ml is added. The mixture is heated at 90 95 degrees C. for 5 hours to complete the acetylation. The reaction mixture i5 then evaporated at 70 degrees C.in vacuum and the syrupy residue thus obtained i5 mixed with 1 liter of ice water. Chloroform 200 ml is added to extract the oily prod~ct and the chloroform layer is washed with 5% aqueous sodium bicarbonate, 200 ml and 0.2N
HCL 200 ml, and dried with ~nhydrous sodium sulfate. On evaporation of the chloroform solution at 40 degrees C. in vacuum white crystalline product is formed from the syrupy residue. The crystals are washed with n-hexane. N~methyl phenyl alpha-acetoxyacetamide 66 g thus synthesized is identified by infrared spectroscopy, high performance liquid chromatography and thin-layer chromatography with a mobility of 0.65 on a solvent system of benzene:methanol 1:1.

Example 10 Synthesis of N-ethyl phenyl-alpha-lauroyloxyacetamide The following method may be applied to synthesis of all N-alkyl phenyl-alpha-lauroyloxyacetamides.
N~ethylmandelic amide 17.9 g is dissolved in 50 ml of pyridine, and lauroyl chloride 22 ml is added with stirring.
ExothermiC acylation takes place immediately, and the reaction mixture becomes a semi-solid. After 16 hours at room temperature the mixture is mixed with 800 ml of cold 0.5N HCL solutio~- White crystals thus formed are isolated .. . ... .. . . . . . .

- ~7 -by filtration, washed with 1% sodium bicarbona~e solution, water and dried at 50 degrees C. in a vacuum.
N-ethyl phenyl-alpha-lauroyloxyacetamide 27 g thus synthesized is identified by inPrared spectroscopy, high performance liquid chromatography and thin-layer chromatography with a mobility of 0.83 on a solvent system of benzene:methanol 1:1.

xample 11 Synthesis of N-ethyl phenyl-alpha-lQ -phenylacetoxyacetamide The following method may be applied to synthesis of all N-ethyl phenyl-alpha-acyloxyacetamides.
N-ethyl mandelic amide 90 g is dissolved in 200 ml of pyridine, and phenylacetyl chloride 100 ml is added with stirring. The reaction mixture is cooled externally with ice water bath. The acylation takes place immediately with a formation of precipitates. The stirring is continued for 3 hours and the reaction mixture is mixed with 800 ml of cold ~ water. The product is extracted with 300 ml of chloroform, and the chloroform layer is washed with 300 ml of sodium bicarbonate solution, followed by 300 ml of 0.5N ~CL and is dried over anhydro-ls sodium sulfate. On evaporation of chloroform a syrupy product 145 g is obtained.
N-ethyl phenyl-alpha-phenylacetoxyacetamide thus synthesized is identified by infrared spectroscopy, high performance liquid chromatography and thin-layer chromatography with a mobility of 0.87 on a solvent system of benzene:methanol 1:1.

Example 12 Synthesis of N-benzyl phenyl-alpha-acetoxyacetamide Mandelic acid methyl ester 25~ g and benzylamine 250 ml are heated at 60-70 degress C. for 3 hours. After standing at room temperature for 16 hours the reaction mixture forms white crystalline products. The crystals are washed with water and are dried at 40 degrees C. in vacuum. N-benzyl mandelic amide 375 g thus prepared is suitable for the following synthesis of N-benzyl phenyl-alpha-acetoxyacetamide.
N-benzyl mandelic amide 100 g is suspended in 250 ml of acetic anhydride and the mixture is heated to 60 degrees C.
After all the solid materials have been dissolved in acetic anhydride concentrated sulfuric acid 0.5 ml is added to the solution. Acetylation takes place instantly with exothermic reaction and the reaction mixture turns reddish in color.
After the initial exothermic reaction has subsided the _ mixture is heated to 90-100 degrees C. for 5 hours to complete the acetylation. The reaction mixture is then evaporated at 70-80 degrees C. in vacuum to remove acetic acid, water and the like. The residue is mixed with 300 ml of chloroform. The chloroform layer is washed with 300 ml of 5% aqueous sodium bicarbonate solution, water and dried over anhydrous sodium sulfate. On evaporation of chloroform solution crystalline product 113 g is obtained.
N-benzyl phenyl-alpha-acetoxyacetamide thus synthesized is identified by infrared spectroscopy, high performance 5~

liquid chromatography and thin~layer chromatography with a mobility of 0.56 on a solvent systeM of benzene:methanol 1:1.

Example 13 _nthesis of N-phenethyl phenyl-alpha-benzoxyacetamide N-phenethyl mandelic amide 51 g is dissolved in 200 ml of pyridine, and benzoyl chloride 42 ml is added with stirxing. Exothermic benzoylation takes place immediately and the reaction mixture is cooled externally with a cold water bath. The stirring is continued for 5 hours, and the reaction mixture is mixed with 1 liter of ice water. The product is extracted with 250 ml of chloroform, washed with 300 ml of 5~ sodium bicarbonate, followed by 300 ml of 0.5N
HCL and is dried over anhydrous sodium sulfate. On evaporation of chloroform a crystalline product is obtained.
The crystals are washed with n-hexane and dried. The yield is 85 g.
N-phenethyl phenyl-alpha-benzoxyacetamide thus synthesized is identified by infrared spectroscopy, high performance liquid chromatography and thin-layer chromatography with a mobility of 0.81 on a solvent system of benzene:methanol 1:1.

:~7.,~

Example 14 Synthesis of N-(N~N~-diethylaminoethyl)phen acet-oxyacetamide Mandelic acid methyl ester 166 g and ~,N-diethylaminoethylamine 200 ml are heated at 60-70 degrees C.
Por 3 hours. After standing at room temperature Por 16 houxs the reaction mixture forms white crystalline products. The crystals are washed with n-hexane and dried at 40 degrees C.
in vacuum. N-(N',N5-diethylaminoethyl) mandelic amide 196 g thus prepared is suitable for the following synthesis.
N-(N',N'-diethylaminoethyl) mandelic amide ao g is dissolved in 200 ml of acetic anhydride and the mixture is heated to 60 degrees C. Concentrated sulfuric acid 0.5 ml i5 added to the solution and the acetylation takes place immediately with slight exothermic reaction. The reaction mix~ure is heated to 100-105 degrees C. for 8 hours to complete the acetylation. The mixture is then evaporated at 70-80 degrees C. in vacuum to remove acetic acid, water and the like. The residue is mixed with 500 ml of 5% sodium bicarbonate and the product is extracted with 200 ml of chloroform. The chloroform layer is washed with 300 ml of 5 sodium bicarbonate solution and is dried over anhydrous sodium sulfate. On evaporation of chloroform solution a syrupy product 62 g is obtained.
N-(N' ,N'-diethylaminoethyl) phenyl-alpha-acetoxyacetamide thus synthesized is identified by inPrared spectroscopy, high performance liquid chromatography and . .

thin-layer chromatography with a mobility of 0.46 on a solvent system of benzene:methanol 1:1.

Example 15 Synthesis of N-phenethyl phenyl-alpha-(o-acetylmandeloyloxy)acetamide N-phenethyl mandelic amide 51 g is dissolved in 150-ml of pyridine, and o-acetylmandelic acid chloride 60 ml is added with stixring. Exothermic acylation takes place immediately and the stirring is continued for 5 hours. The reaction mixture is mixed with 1 liter of cold 0.2N HCL. The sticky solid thus formed is extracted with 300 ml of chloroform, washed ~-ith 400 ml of 5% sodium bicar~onate and îs dried over anhydrous sodium sulfate. On evaporation of chloroform a syrupy product 98 g is obtained.
N-phenethyl phenyl-alpha-(o-acetylmandeloyloxy) acetamide thus synthesized is identified by infrared spectroscopy, high performance liquid chromatography and thin-layer chromatography with a mobility of 0.62 on a solvent system of benzene:methanol 1:1.
.
Example 16 Synthesis of N-phenethyl phenyl-alpha--linoleoyloxyacetamlde The following method may be applied to synthesis of all N-aralkyi phenyl-alpha-linoleoyloxyacetamides.
N-phenethyl mandelic amide 25-5 g is dissolved in 50 ml of pyridine, and linoleoyl chloride 30 ml is added with stirring ExothermiC acylation takes place immediately and ~.~?,~S~3~

the stirring is continued for S hours. The reaction mixture is mixed with 800 ml o~ 0.5N HCL and the product is extracted with 200 ml of chloroform. The chloroform solution is washed with 200 ml of 0.sN HCL, 200 ml of 5~ sodium bicarbonate, 200 S ml of water then is dried over anhydrous sodium sulfate. On evaporatiOn of chloroform a syrupy product 42 g is obtained.
N-phenethyl phenyl-alpha-linoleoyloxyacetamide thus synthesized is identified by infrared spectroscopy, high performance liquid chromatography and thin-layer 10 chromatography with a mobility of 0.B0 on a solvent system of benzene:methanol 1:1.

Example 17 5ynthesis of N,N-diethyl phenyl-alpha-acetoxyacetamide The following method may be applied to synthesis of all 15 N,N-dialkyl phenyl-alpha-acetoxyacetamides.
Mandelic acid ethyl ester 150 ml and diethylamine 200 ml are heated to 60-70 degrees C. for 5 hours. The reaction mixture is evaporated at 50~60 degrees C. in vacuum to remove volatile materials. The residue thus obtained is mixed with 20 1 liter of cold water and the oily product is dried over anhydrous sodium sulfate. N,N-diethyl mandelic amide 125 g thus prepared is suitable for the following synthesis.
N,N-diethyl mandelic amide 75 g is dissolved in 200 ml of acetic anhydride and concentrated sulfuric acid 0.5 ml is 25 addedO The reaction mixture is heated to 90 100 for 3 hours to complete the acetylation- The mixture is then evaporated at 60-70 in vacuum to remove acetic acid and the like. The .. , . ., . , .. ~ . . .. ... . .. ..... . . .. . . . . . . . . .. . .
.. .. . . . .. . .. . ... . ... .... . . . . .. . . . . .

residue thus obtained is mixed with 1 liter of 5~ sodium bicarbonate, and the oily product is extracted with 300 ml of chloroform. The chloroform layer is washed with 300 rnl of 5%
sodium bicarbonate and is dried over anhydrous sodium sulfate. On evaporation of chloroform solution a syrupy product 67 g is obtained.
N,N-diethyl phenyl-alpha-acetoxyacetamide thus synthesized is identified by infrared spectroscopy, high performance liquid chromatography and thin-layer chromatography with a mobility of 0.78 on a solvent system of benzene:methanol 1:1.

,.
Example 18 Synthesis of N-(3'-picolyl)phenyl-alpha-acetoxyacetamide The following method may be applied to synthesis of all N-picolyl phenyl-alpha-acetoxyacetamides.
Mandelic acid ethyl ester 150 ml and 3-aminomethylpyridine 150 ml are mixed with stirring at room temperature for 5 hours~ White crystalline product thus formed is washed with water and is dried at 50 C in vacuum.
N-(3'-picolyl~phenyl-alpha-hydroxyacetamide 165 g thus ~repared is suitable for the following synthesis.
N-(3'-picolyl) phenyl-alpha-hydroxyacetamide 100 g is suspended in 200 ml of acetic anhydride and concentrated sulfuric acid 0.5 ml is added- The reaction mixture is heated to 80 90 degrees C. for 5 hours. During the initial stage of acetylation N-(3~-picolyl)phenyl-alpha-.. . ... .. . . . . ..... .... ... .... .. . . ... ... .... . . .. .. . ... . .

- 34 -hydroxyacetamide dissolves at about 80 degrees C and the acetylation takes place immediately with a change in color of the reac~ion mixture to a reddish solution. The reaction mixture is evaporated at 70-80 degrees C. in vacuum to remove acetic acid and the like. The residue is mixed with 1 liter of cold water and the syrupy product is extracted with 250 ml of chloroform. The chloroform layer is washed with 5% sodium bicarbonate 300 ml and is dried over anhydrous sodium sulfate. On evaporation of chloroform solution a syrupy product 98 g is obtained.
N-(3'-picolyl) phenyl-alpha-acetoxyacetamide thus synthesized is identified by infrared spectroscopy, high performance liquid -hromatography and thin-layer --chromatography with a mobility of 0.62 on a solvent system of benzene:methanol 1:1.

Example 19 Synthesis of N-ethyl diphenyl-alpha-acetoxyacetamide .
The following method may be applied to synthesis of all N-alkyl diphenyl-alpha-acetoxyacetamides.
- 20 Benzilic acid methyl ester 100 g is dissolved in 450 ml of methanol. Ethylamine 70~ in water, 200 ml is added to the solution with stirring. After 2 days at room temperature the reaction mixture is evaporated at 40 degree5 C. in vacuum to remove the volatile materials- The residue is mixed with 400 ml of cold water- White crystals thus formed are washed with water and dried. N-ethyl benzilic amid~ 95 g thus prepared is suitable for the following synthesis.

``, ~ ~ VI~J

- 35 -N-ethyl benzilic amide 83 g is dissolved in 150 ml of acetic anhydride and concentrated sulfuric acid 0.5 ml is added. The mixture is heated to g0-100 degrees C. for 3 hours to complete the acetylation. Cold water 2 liters is added to the reaction mixture, and the sticky solid is extracted with 250 ml of chloroform. The chloroform layer is washed with 300 ml of 5% sodium bicarbonate and is dried over anhydrous sodium sulfate. On evaporation of chloroform solution a syrupy product 79 g is obtained.
N-ethyl diphenyl-alpha-acetoxyacetamide thus synthesized is identified by infrared spectroscopy, high performance liquid chromatography and thin-layer chromatography with a mobility of 0.83 on a solvent system of benzene:methanol l:l.
Alternatively, N-ethyl diphenyl-alpha-acetoxyacetamide may be synthesized by the following different method.
N-ethyl benzilic amide 51 g is dissolved in 200 ml of pyridine and acetyl chloride 24 ml is slowly added to the mixture with stirring and external cooling in an ice water bath. After 5 hours cold 0.2N ~CL, one liter is added to the reaction mixture and the sticky solid is extracted with 200 ml of chloroform. The chloroform layer is washed with 300 ml of 5% sodium bicarbonate and is dried over anhydrous sodium sulfate. On evaporation of chloroform solution a syrupy product 43 g is obtained- N-ethyl diphenyl-alpha-acetoxyacetamide thus synthesized is identical to that prepared by the foregoing method.

- .. . .. ...... .. .. ...... .. .. . . . . . .. .. .. .... .. . ..

36 -Example ?
Synthesis of N-phen ~ d_phe~yl-alpha acetoxyacetamide The following method may be applied to synthesis of all N-aralkyl diphenyl-alpha-acetoxyacetamides.
Benzilic acid methyl ester 200 g and phenethylamine 200 ml are heated to 50-60 degrees C. for 5 hours. White crystals formed after cooling are washed with water and are dried at 40 degrees C. in vacuum. N-phenethyl benzilic amide 225 g thus prepared is suitable for the following synthesis.
N-phenethyl benzilic amide 100 g is suspended in 200 ml of acetic anhydride and concentrated sulfuric acid 0.5 ml is added. The reaction mixture is heated to 90-100 degrees C.
for 5 hours. Yellowish crystals 117 g formed during the cooling process are washed with water and are dried at 40 degrees C. in vacuum.
N-phenethyl diphenyl-alpha-acetoxyacetamide thus synthesized is identified by infrared spectroscopy, high performanCe liquid chromatograophy and thin-layer chromato~raphy with a mobility of 0.82 on a solvent system of benzene:methanol 1:1.

Example 21 For oral administration gelatin capsules containing phenyl-alpha-acyloxyacetamide derivatives in different doses may be prepared as follows.
N-~thyl phenyl-alpha-acetoxyacetamide powder 20 g is thoroughly mixed with 90 g of gelatin powder USP. Each gelatin ~apsule size No. 0 filled with this mixture contains s~

- 37 -75 mg of N-ethyl phenyl-alpha-acetoxyacetamide as an active ingredient.
Gelatin capsules containing 150 mg of N-ethyl phenyl-alpha-acetoxyacetamide in each capsule may also be prepared in the same way but from 20 g of the active ingredient and ~5 g of gelating powder.

Example 22 Phenyl-alpha-acyloxyacetamide derivatives for parenteral injections may be prepared as follows.
N-phenethyl phenyl-alpha-acetoxyacetamide fine powder 0.2 g is suspended in 10 ml saline and the mixture in a sealed injection bottle is sterlized at 100 degrees C. for 20 -minutes. The parenteral composition thus prepared contains 2% of active ingredient, i.e. 20 mg per ml of N-phenethyl phenyl-alpha-acetoxyacetamide.

Example 23 A combination composition containing both a phenyl-alpha-acyloxyacetamide derivative and a corticosteroid may be formulated as ~ollows. N-ethyl phenyl-alpha-acetoxyacetamide 3 g and hydrocortisone-17-valerate 0.2 g are dissolved in 10 ml of acetone, and the solution thus obtained i5 mixed with 88.9 g of hydrophilic ointment USP. Mixing is continued until a uniform consistency is obtained.
The therapeutic composition thus formulated contains 3%

N-ethyl phenyl-alpha-~cetoxyacetamide and 0.2%
hydrocortisone-17-Valerate as active ingredients.

- 38 -Example 24 Synthesis of N-isopropyl phenyl-alpha-acetoxyacetamide Isopropylamine 20 ml is dissolved in 100 ml of ice water and O-acetylmandelic acid chloride 21 ml is added slowly to the solution with stirring. An oily substance is formed instantly in the bottom of the reaction flask during the addition of O-acetylmandelic acid chloride. After 10-minutes the oily substance is separated, dissolved in 100 ml of chloroform, washed with dilute HCl and dried over anhydrous sodium sulfate. On evaporation of the chloroform solution a syrupy product is obtained~ N-isopropyl phenyl-alpha-acetoxyacetamide 18 g thus synthesized is identified by infrared spectrosco~y, high performance liquid chromatography -and thin-layer chromatography with a mobility of 0.81 on a solvent system of benzene:methanol 1:1.

Example 25 Synthesis of N-t~butyl phenyl-alpha-acetoxyacetamide t-Butylamine 19 ml is dissolved in 120 ml of benzene and O-acetylmandelic acid chloride 20 ml is slowly added to the solution with stirring while the reaction flask is cooled externally with an ice water bath. White precipitates are formed instantly during the addition of O-acetylmandelic acid chloride. After two hours at room temperature the reaction mixture is mixed with 200 ml of cold water, and the benzene layer is separated, washed with dilute HCl and dried over anhydrous sodium sulfate- On evaporation of the benzene solution white crystals are formed, and the crystals are ,, . ~, ~ . . ... . . ... . . .. ... . .. . . .. . .
... ....

- 39 -washed with n-hexane. N-t-Butyl phenyl-alpha-acetoxyacetamide 13 g thus synthesized is identified by infrared spectroscopy, high performance liquid chromatography and thin-layer chromatography with a mobility of 0. 71 on a solvent system of benzene:methanol 1:1.

Example 26 Synthesis of N-hydroxyethylthioethyl phenyl-alpha-acetoxyacetamide 2-(~2-Aminoethyl)-~hio) ethanol 25 ml is dissolved in 70 ml of chloroform and O-acetylmandelic acid chloride 20 ml is slowly added to the solution with stirring while the reaction flask is cooled externally with an ice water bath~
After 3 hours at room temperature the reaction mixture is mixed with 200 ml of cold water, and the chloroform layer is separated, washed with dilute sodium bicarbonate, dilute HCl and dried over anhydrous sodium sulfate. On evaporation of the chloroform solution a syrupy product is obtained. N-Hydroxyethylthioethyl phenyl-alpha-acetoxyacetamide 21 g thus ~ synthesized is identified by infrared spectroscopy, high performance liquid chromatography and thin-layer chromatography with a mobility of 0.64 on a solvent system of benzene:methanol 1:1.

- ~o -Example 27 Synthesis of N~(3,4-dimethoxyphenethyl) phenyl-alpha-acetoxyacetamide Beta-(3,4-Dimethoxyphenyl)ethylamine 38 ml i9 dissolved in 120 ml of benzene and O-acetylmandelic acid chloride 20 ml is slowly added to the solution with stirring while the reaction flask is cooled externally with an ice water bath.
White precipitates are formed instantly during the addition of O-acetylmandelic acid chloride. After one hour at room temperature the reaction mixture is mixed with 200 ml of cold water, and the benzene layer is separated, washed with dilute ~odium bicarbonate, dilute HCl and dried over anhydrous sodium sulfate. The benzene solution is cooled externally with an ice water b~th, and white crystals are formed. The crystals are washed with water and ether. N-t3,4-dimethoxyphenethyl) phenyl-alpha-acetoxyacetamide 33 g thus synthesized is identified by infrared spectroscopy, high performance liquid chromatography and TLC with a mobility of 0.82 on a solvent system of benzene:methanol 1:1.

Example 28 Synthesis of N-P-chlorobenzyl phenyl-alpha-acetoxyacetamide - 4-Chlorobenzylamine 30 ml is dissolved in 100 ml of chloroform and O-acetylmandelic acid chloride 20 ml is slowly added to the solution with stirring while the reaction flask is cooled externally with an ice water bath. White precipitateS are f~rmed instantly during the addition of O-acetylmandelic acid chloride- After one hour at room . , .. " ., .. , .. , .. ~ .. ... .. ....... ... ... . . . .. ... ..... ..

r ~ 41 ~
temperature the reaction mixture is mixed with 300 ml of cold water, and the chloroform layer is separated, washed with dilute sodium bicarbonate, dilute ~ICl and dried over anhydrous sodium sulfate. On evaporation o~ the chloroform solution white crystals are obtained. The crystals are washed with ether. N-P-Chlorobenzyl phenyl-alpha-acetoxyacetamide 28 g thus synthesized is identified by infrared spectroscopy, high performance liquid chromatography and thin-layer chromatography with a mobility of 0.77 on a solvent system of benzene:methanol l:l.

Example 23 Synthesis of N-P~methoxybenzyl phenyl-alpha- -acetoxyacetamide P-Methoxybenzylamine 29 ml is dissolved in 130 ml of chloroform and O-acetylmandelic acid chloride 20 ml is slowly added to the solution with stirring while the reaction flask is cooled externally with an ice water bath. White precipitates are formed instantly during the addition of O-~ acetylmandelic acid chloride. After one hour at room temperature the reaction mixture is mixed with 200 ml of coldwater, and the chloroform layer is separated, washed with dilute HCl and dried over anhydrous sodium sulfate. On evaporation of the chloroform solution a syrupy residue is obtained. After trituration in dilute HCl the syrupy product becomes white crystals which are washed with ether. N-P-MethoxybenZyl phenyl-alpha-acetoxy acetamide 26 g thus synthesized is identified by infrared spectroscopy, high performance liquid chromatography and thin-layer . .. . . . . .. . . .

3~

~hromatog~aphy with a mobility of 0 76 on a solvent systern of benzene:methanol 1:1.

Example 30 Synthesis of N-P-methoxyphenethyl phenyl-alpha-acetoxyacetamide P-Methoxyphenethylamine 30 ml is dissolved in 150 ml of chloroform and O-acetylmandelic acid chloride 20 ml is slowly added to the solution with stirring while the reaction flas~
is cooled externally with an ice water bath. White precipitates are formed instantly during the addition of O-acetylmandelic acid chloride. After 3 hours at room temperatur~ the reaction mixture is mixed with 300 ml of cold water, and the chloroform layer is separated, washed with dilute ~Cl and dried over anhydrous sodium sulfate. On evaporation o~ the chloroform solution a syrupy residue is obtained. After cooled in an ice water bath the syrupy residue becomes a crystalline product. The crystals are ~ washed with ether. N-P-methoxyphenethyl phenyl-alpha-acetoxyacetamide 21 g thus synthesized is identified by infrared spectroscopy, high performance liquid chromatography and thin-layer chromatography with a mobility of 0.66 on a solvent system of benzene:methanol 1:1.

_ample 31 A combination composition containing both a phenyl-alpha-acyloXyacetamide derivative and an anti-inflammatory corticosterOid may be formulated as follows. N-Benzyl phenyl-alpha-acetoxyacetamide 5 g and triamcinolone acetonide 0.1 g are dissolved in 7 ml of acetone, and the solution thus obtained is mixed with 88 g of hydrophilic ointment VSP.
Mixing is continued until a uniform consistency i5 obtained.
The therapeutic composition thus formulated contains 5~
N-benzyl phenyl-alpha-acetoxyacetamide and 0.1~ triamcinolone acetonide as active ingredients.

Example 32 A combination composition containing both a phenyl-alpha-acyloxyacetamide derivative and an antiparasitic lindane, gamma benæene hexachloride may be formulated as follows. N-Phenethyldiphenyl-alpha-acetoxyacetamide 3 g and lindane 1 g are discolved in 10 ml of acetone, and the solution thus obtained is mixed with 86 g of hydrophilic ointment USP. Mixing is continued until a uniform consistency is obtained.
The therapeutic composition thus formulated contains 3 N-phenethyl diphenyl-alpha-acetoxy-acetamide and 1~ lindane as active ingredients.

Example 33 A combination composition containing both a phenyl-alpha-acyloxyacetamide derivative and an anti-fungal agent, clotrimazole, may be formulated as follows- N-p-chloroben phenyl-alpha-acetoxyacetamide 4 g and clotrimazole 1 g are dissolved in 10 ml of acetone, and the solution thus obtained is mixed with 85 g of hydrophilic ointment USP. Mixing is continued until a uniform consistency is obtained.

- - ~, .. . . ........ ~ .,. .. .. . ". . .... . .....

The therapeutic composition thus formulated contains 4 N-P-chlorobenzyl phenyl-alpha-acetoxyacetamide and 1%
clotrimazole as active ingredients.

Example 34 A combination composition containing antipruritic, anti-inflammatory and antibiotic agents may be formulated as follows. Finely powdered N-(3,4-dimethoxyphenethyl) phenyl-alpha-acetoxyacetamide 3 g, triamcinolone acetonide 0.1 g, neomycin sulfate 0.5 g and polymyxin B sulfate 0.05 g are directly mixed with 97 g of hydrophilic ointment USP. Mixing is continued until a uniform consistency is obtained.
The therapeutic composition ~hus formulated contains four active ingredients: N-(3,4-dimethoxyphenethyl)phenyl-alpha-acetoxyacetamide 3~, triamcinolone acetonide 0.1~, Neomycin sulfate 0.5%, and polymyxin B sulfate 0.05%.

ANIMAL STUDIES
(1) ACUTE AND SUBAC~TE TOXICITY
Twenty mice were given each phenyl-alpha-acyloxyacetamide derivative as single subcutaneous injections at various doses. It was found that all the phenyl-alpha-acyloxyacetamide derivatives tested at doses up to 400 mg/kg were nontoxic, i.e. all mice were alive and healthy at the end of 5 weeks after the administration of the substance~
The LD50 of each phenyl-alpha-acy]oxyacetamide derivative was found to be higher than 1 g/kg.

.. ~ . , . . ... ... . . ... ... .... ", .. ........ .. , ... , . , ., .. , . .. , , . . . . . . . .... . . ~ , ..

(2) CHRONIC TOXICITY
Twenty mice were given each phenyl-alpha-acyloxyacetamide derivative subcutaneously twice weekly in doses of 80 mg/kg for 3 months. It was found that phenyl-alpha-acyloxyacetamide derivative in a total dose of 1,920 mg/kg given over such 3 month periods were nontoxic for mice.

(3) SCREENING COMPO~NDS FOR ANTI-PRURITIC EFFECT
tA) Topical Application Either the mouse or the rat may be used as a screening model for anti-pruritic compounds. sefore testing hair is plucked from the test site of skin in haired animals.
Therefore hairless strains of mouse or the strain of rat known as fuzzy rat is preferred as a screening model for the ~
present purpose.
A test composition containing 5% phenyl-alpha-acyloxyacetamide derivative in solution was topically applied to the left dorsal skin of a hairless mouse and a control vehicle solution was topically applied to the right dorsal skin of the same mouse. The same topical applications were repeated three times at 30 minute intervals. A challenging composition containing a pruritic agent, i.e. itch provoking substance, was then topically applied in a volume of O.OS ml on both left and right dorsal skin of the same mouse. For the next 30 minutes the mouse was carefully observed for signs and symptom5 of scratching or lic~ing at the skin sites where the challenging pruritic composition had been topically applied.

- 46 ~

If the mouse scratched or lick~ed indiscriminately at both left and right sides, the test composition was determined to have no anti-pruritic property. On the other hand if the mouse scratched or licked only the right side of S the skin and did not scratch or lick, or did so minimally the left side of the skin, the test composition was determined to have an anti-pruritic effect. To confirm the anti-pruritic effect of the test composition, the test solution was later topically applied to the right instead of the left dorsal skin of the same mouse. The same topical applica~ions were repeated three times at 30 minute intervals. A challenging composition containing the same pruritic agent was then topically applied on the right dorsal skin site of the same mouse. If the mouse did no~ scratch or lick, or did so minimally, the right test site o~ the skin, the test composition was confirmed to have anti-pruritic effect.
Occasionally, a mouse might not scratch or lick either side of the dorsal skin following topical application of a pruritic composition on both sides of the dorsal skin althou~h only the left side of the dorsal skin had been topically treated with an anti-pruritic composition. This situation might conceivably arise when an anti-pruritic compound in the composition topically applied on the left side of mouse skin had been substantially absorbed through the skin and had thus exerted its systemic anti-pruritic effect. To eliminate such pos5ibilities a different mouse instead of the same mouse is used as a control study. At s~

- 47 ~
least two mice were used to screen anti-pruritic effect of each phenyl-alpha-acyloY.yacetamide derivative-We have found that the pheny1-alpha-acy1oxyacetamide derivatives which include N-ethyl phenyl-alpha-acetoxyacetamide and N-phenethyl phenyl-alpha-acetoxyacetamide tested by the above screening method showed a substantial anti-pruritic effect, tB) Systemic Administration Either the mouse or the rat may be used as a screening model for anti-pruritic compounds. Again, the hairless mouse or the fuzzy rat is a preferred strain in each species.
A test composition in a volume of 0.1 ml containing 5% phenyl-alpha-acyloxyacetamide derivative in solution was injected subcutaneously to the hairless mouse.
The same procedure was repeated once more 3 hours later. Two hours after the second injection the mouse was challenged with a pruritic composition either applied topically or administered subcutaneously, When the challenging composition containing a pruritic agent was given topically the solution in a volume of 0.05 ml was applied to the left dorsal skin. A control vehicle solution containing no pruritic agent in the same volume of 0.05 ml was topically applied on the right dorsal skin. For the next 30 minutes the mouse was carefully observed for signs and symptoms of scratching or licking at the skin sites where the pruritic ,, , " , , , , . ~ , .. . ,.. .... .. , . . ~, .. , . . , - .. . .. . .

~f ~,$~

composition and ~he control vehicle solution had been topically applied.
If the mouse scratched or licked only the left side of the skin where the pruritic composition had been topically applied the test composition which was injected subcutaneously at two and five hours earlier was determined to have no anti-pruritic property. I~ the mouse did not scratch nor lick, or did so minimally at both the left and the right side of the skin, the tes~ composition which was injected subcutaneously at two and five hours earlier was determined to have anti-pruritic effect.
When the challenging composition containing a pruritic agent was administered subcutaneously the pruritic solution in a volume of 0.1 ml was injected in the left dorsal skin and the control vehicle solution in the same volume was injected in the right doral skin. For the next 30 minutes the mouse was carefully observed for signs and symptoms of scratching or licking the skin sites where the pruritic composition and the control vehicle solution had been injected subcutaneously. The criteria for aetermination of anti-pruritic or non-antipruritic effect of the test composition were the same as described in the foregoing. At least two mice were used to screen anti-pruritic effect of each phenyl-alpha-acyloxyacetamide derivative.
We have found that the phenyl-alpha-acyloxyacetamide derivatives which include N-ethyl phenyl-alpha-acetoxyacetamide and N-phenethyl phenyl-alpha-,,,, ,~,, ."~ .. ,. ... .., . - -, acetoxyacetamide tested by the above screening rnethod showed a substantial ~nti-pruritic effect.

ANTI-PRURITIC EFFECT ON NORMAL HllMAN SKIN
-Itch provoking pruritic compositions were prepared as follows: papain 0.5% solution was prepared by dissolving papain 50 mg in 10 ml of saline, and histamine 0.2% solution was prepared by dissolving histamine dihydrochloride 20 mg in 10 ml of saline. Itching was provoked or induced as follows:
a pruritic composition in a volume of ~.05 ml containing papain or histamine dihydrochloride as a pruritic agent was topically applied on the flexor forearm of normal human adult volunteers and the ckin site was gently pricked rapidly through the solution with a 26-gauge needle to the level of the papillary dermis as described by Bernstein et al4 (J. E.
Bernstein, R. M. Swift, K. Soltani and A. L. Lorincz:
Antipruritic Effect of an Opiate Antagonist, Naloxone Hydrochloride in Journal of Investigative Dermatology 78, 82-83, 1982). This technique provoked or induced itch sensation at the test skin site within a few minutes following the topical application of the pruritic composition. After itch sensation had been induced a composition containing 2 to 5% N-ethyl phenyl-alpha-acetoxyacetamide, N-phenethyl phenyl-alpha-acetoxyaCetamide or other phenyl-alpha-acyloxyacetamide derivatives of the instant invention was topically applied on the pruritic skin site. The vehicle alone cream containing no active ingredient was used as a control.

.. . . .. . .. . ..

~r~ 5 We have found that the composition containlng N-ethyl phenyl-alpha-acetoxyacetamide~ N-phenethyl phenyl-alpha-acetoxyacetamide, N-phenethyl diphenyl-a1pha-acetoxyacetamide or other phenyl-alpha-acylo~yacetamide derivative tested by the above screening method showed a sub5tantial anti-pruritic effect. The vehicle alone cream did not show any anti-pruritic effect.

PRURITUS
Patients with various kinds of pruritic disorders participated in this s~udy. The cases included atopic eczema, patchy eczema, chronic eczema of the hands, lichen simplex chronicus, contact allergic eczema, pruritus of the aged, pruritus of hepatic origin, pruritus ani, pruritus vulvae, scalp pruritus and pruritus of other disorders such as mycosis fungoides, psoriasis and pityriasis rubra pilaris~
Therapeutic compositions containing phenyl-alpha-- acyloxyacetamides at 2 to 5~ concentrations in cream, ointment, lotion or solution were prepared according to the Examples. The medicinal compositions were topically applied by the patient in an amount sufficient to cover the itching area of skin. Applications were made one to two times daily or as frequently as necessary and without occlusive dressings.
The therapeutic composi~ions containing phenyl-alpha-acyloxyacetamides provided the anti-pruritic effect after a few minutes to a few hours, depending on the active ingredient and some variability in degree of response among .

paticnts following topical application In general, however, the therapeutic compositions of the instant invention exerted their anti-pruritic effect rather promptly following topical adminiStration.
Two parameters have been used to compare degrees of anti-pruritic effect of phenyl-alpha-acyloxyacetamides. The first parameter is whether the relief of itching is complete (2+) or incomplete (l+). The second parameter is the number of hours the patient stays free of pruritus after the initial anti-pruritic effect. Most phenyl-alpha-acyloxyacetamides give 8 to more than 24 hours 12~) of complete relief from itChin~, some compounds provide less than 8 hours ~l+) of relief from pruritu~. Therefore, the overall anti-pruritic effect of a compound may range from 2+ to 4+. For example, the anti-pruritic effect is 2+ when a compound gives an inComplete relief from itching and lasts for less than 8 hours; 3+ for either complete relief but lasting for less than 8 hours or incomplete relief but lasting for more than 8 hourS~ 4+ for complete relief and iasting for more than 8 hours.
The test results are summarized on the following tables.

.. .. ... . . .. .... . . ... .. . . .. ... . . . . . .

~ 52 -Topical Anti-pruritic Effect of the First Category of Phenyl-alpha-acyloxy~ce~amides on Eczemas, and Other Pruritic Disorders Number Anti-of pruritic Compounds Patients Effect 1. N-ethyl phenyl-alpha-acetoxyacetamide 14 4+
2. N-phenethyl phenyl-alpha acetoxyacetamide 16 4 3. N-benzyl phenyl-alpha-acetoxyacetamide 19 4+
4. N-ethyl phenyl alpha phenylacetoxy acetamide 6 4+
5. N,N-diethyl phenyl-alpha-acetoxyacetamide 5 4+
6. N-phenethyl phenyl-alpha-propionyloxyacetamide 2 3+~
7. N methyl phenyl-alpha-acetoxyacetamide 3 3+
8. N-t-butyl phenyl-alpha-acetoxyacetamide 4 4+
9. N-isopropyl phenyl-alpha-acetoxyacetamide . 3 3+
10. N-P-chlorobenzyl phenyl-alpha-acetoxyacetamide 3 4+
11. N-P-methoxybenzyl phenyl-alpha-acetoxyacetamide 4 4+
12. N-P-methoxyphenethyl phenyl-alpha-acetoxyacetamide 4 4+
13. N-(3,4-dimethoxyphenethyl) phenyl-alpha acetoxyacetamide 5 4+
14. N,N-dibenzyl phenyl-alpha-acetoxyacetamide 3 3+
15. N-hydroxyethylthioethyl phenyl-alpha-acetoxyacetamide 4 3+

As shown by the above table, ten phenyl-alpha-acyloxyacetamide derivatives cornpletely abolished itch sensations for more than 8 hours in all the patients tested.
The remaining five phenyl-alpha-acyloxyacetamide derivatives completely abolished itch sensations but the anti-pruritic effect lasted for only 4 to 7 hours.

Topical Anti-pruritic Effect of the Second Cateqory of Phenyl-alpha-acyloxyacetamides on Eczémas and Other Pruritic Disorders Number Anti-of pruritic Compounds Patients Effect 1. N-ethyl diphenyl-alpha acetoxyacetamide 7 4+

2. N-phenethyl diphenyl-alpha-acetoxyacetamide 21 4+

3. N-phenethyl diphenyl-alpha-propionyloxyacetamide 2 3+

4. N-benzyl diphenyl-alpha-acetoxyacetamide 2 4 5. N,N-diethyl diphenyl-alpha-acetoxyacetamide 2 4+

6. N-ethyl diphenyl-alpha-phenylacetoxyacetamide 3 4 7. N-(N',N'-diethylaminoethyl) diphenyl-alpha-acetoxyacetamide 9 4+

As shown by the above table, 5iX phenyl-alpha-acyloxyacetamide derivatives completely abolished itch sensations for more than 8 hours in all the patients tested.
N-phenethyl diphenyl-alpha-propionyloxyacetamide also completely abolished itch sensations but the anti-pruritic effect lasted for less than 8 hours.

~ ,5~
- 5~ -Topical Anti-pruritic ~ffect of the Intermediate and Related Compounds on Eczemas and Other Prurltic Disorders Number Anti-Of pruritir Compounds Patients Effect 1. N-ethyl phenyl-alpha-hydroxyacetamide 4 2+
2. N-phenethyl phenyl-alpha hydroxyacetamide 3 3+
10 3. N-benzyl phenyl-alpha-hydroxyacetamide 3 2 4. N-methyl phenyl-alpha-hydroxyacetamide 2 2 5. N-3'-picolyl phenyl-alpha-hydroxyacetamide 2 2+
6. N-3'-picolyl phenyl-alpha-acetoxyacetamide 2 3+
7. N-(N',N'-diethylaminoethyl)phenyl-alpha-hydroxyacetamide 2 2+
8. N-(N',N'-diethylaminoethyl)phenyl-alpha-acetoxyacetamide 2 3+
9. N-phenethyl phenyl-alpha-(0-acetylmandeloyloxy)-acetamide 2 3+

As noted by the above table, the intermediate and related compounds of phenyl-alpha-acyloxyacetamide ~ derivatives showed various degrees of anti-pruritic effect in all the patients tested.

.. .. .. . . .. ....... . . .. ... .. . . . . . . . . . . .... .

S~5l~3~

Topical Antipruritic and Anti-inflammatory Effects of Combination Compositions on Poison Ivy Dermatitis, Insect Bite Reactions, Sea Nettle Sting Reactions and Other Like Conditions .
Anti-Mumber Anti- Inflam-of pruritic matory Compo _tionsSubjects Effect Effect 1. N-benzyl phenyl-alpha-acetoxyacetamide and triamcinolone acetonide 3 4+ 4 2. N-Phenethyl phenyl-alpha-acetoxyacetamide and hydro-cortisone-17-valerate 2 4+ 4+

3. N-Phenethyl diphenyl-alpha-acetoxyacetamide and hydro-cortisone-21-acetate 3 4+ 4+

4. N-(N',N'-diethylaminoethyl) diphenyl-alpha-acetoxy-acetamide and hydrocortisone 2 4+ 4+

As shown by the above table, all the combination compositions completely abolished itch sensations from poison ivy contacts and mosquito bites, the stinging sensation from - sea nettle contacts and other like conditions from environmental contacts and also substantially improved the appearance of the affected area of the skin.

, .. .. . . .. , .. . . , .. , . ,. , ~ . ~ . , ~ D, Topical Antipruritic and Anti-fungal Effects of Combination Compositions on Fungal Infections of the Skin Number Anti- Anti-of pruritic fungal 5 CompositionsSubjects Effect Effect 1. N-phenethyl phenyl-alpha-acetoxyacetamide and clotrimazole 3 4+4+
2. N-Benzyl phenyl-alpha-acetoxyac2tamide and clotrimazole 2 4~4+
3. N-phenethyl diphenyl-alpha acetoxyacetamide-and miconazole 2 4~4+
15 4. N-Ethyl phenyl-alpha-acetoxyacetamide and miconazole 3 4+4+

As shown by the above table, all the combination compositions completely abolished itch sensations from fungal infections, and also eradicated such infections.

Topical Antipruritic and Antiparasitic Effects of Combination Compositions on Pediculosis and Scables InfestatiOns . Anti-Number Anti- Para-of pruritic sitic CompositionsPatients Effect Effect 1. N-P-chlorobenzyl phenyl-alpha-acetoxyacetamide and lindane ~ 4+4+
2. N-phenethyl diphenyl-alpha acetoxyacetamide and lindane 2 4-~ 4+

As shown by the above table, all the combination compositionS completely abolished itch sensations from lice .

- 57 ~
and mites, and also successfully eradicated such infestations.

Topical Antipruritic and Anti-infectious Effects of Combination Composilions on 5 Bacterial, Viral and Yeast Infections Anti-Number Anti- Inec-of pruritic tious Compositions Patients Effect Effect 10 1. N-P-methoxyphenethyl phenyl-alpha-acetoxyacetamide, neomycin and polymyxin B 2 4+ 4+

2. N-p-fluorobenzyl phenyl-alpha-acetoxyacetamide, neomycin, polymyxin B and triamcinolone acetonide 3 4+ 4+

As shown by the above table, all the combination compositions effectively abolished itch sensations from various infections, and also successfully eradicated such infections.

SYSTEMIC ADMINISTRATION
Three dogs with summer eczema-prurigo were treated with oral administration of phenyl-alpha-acyloxyacetamide derivativeS. Gelatin capsules containing N-ethyl phenyl-alpha-acetoxyaCetamide or N-phenethyl phenyl-alpha-acetoxyacetamide at dosages ranging from 50 mg to 150 mg per capsule were prepared according to Example9. Single doses of 5 mg/kg to 10 mg/kg were administered orally to the dogs, All three dogs stopped scratching within one hour following oral administration of N-ethyl phenyl-alpha-~f~

acetoxy~cetamide or N-phenethyl phenyl-alpha-acetOxy~cetamide. This anti-scratch or anti-pruritic e~fect lasted ~or approximately 8 hours. Following the oral adminis4:ratin of N-ethyl phenyl-alpha-acetoxyacetamide or N-phene4:hYl phenyl-alpha-acetoxyacetamide, all three dogs were me~tallY alert as usual and did not have any signs or symptom~ of drowsiness or intoxication.
Oral doses containing N-ethyl phenyl-alpha-acetOx~cetamide or N-phenethyl phenyl-alpha-acetoxyacetamide were ad~inistered repeatedly to the dogs at intervals of two to seve~al days- Each time the phenyl~alpha-acyloxyacetamide derivatiVe provided the same anti-pruritic or anti-scratching effect, No evidence of adverse effects was detected.
T~e foregoing results suggest and imply that members of phenyl_~alpha-acyloxyacetamide derivatives are predictably useful ~5 systemic anti-pruritic agents for treatment of humans ~as well as animals with dermatologic conditions or disease8 aSSOCiated with itching.

TRANQUILIzING EFFECTS

1. Topical Administration.
~irless mice, ten in each group, were used in this study N-phenethyl phenyl-alpha-acetoxyacetamlde, N-ethyl phenyl-~lpha-acetoxyacetamide or other phenyl-alpha-acylOxy~cetamide derivative of the instant invention was prepare~ as a 5% solution in acetone: water, 8:2 or ethanol:water, 8:2. A test solution was topically applied to the lei~ dorsal sXin of hairleSS mice. The same topical applications were repeated ~hree times a~ 30 minu~e intervals. A vehicle alone solution containing acetone and water or ethanol and water was used as a control. For the next 8 hours and also 2~ hours later all mice were carefully S observed and examined for any signs or evidence of calming or quieting effects cal~sed by the test compound.
Normally when a mouse is picked up by the tail with thumb and forefinger the mouse strugyles trying to free itself; and if the mouse is placed on a horizontal metallic grid uniformly spaced at ~ mm, the mouse nervously pulls itself across the grid, again trying to free itself from the restraining grip of the fingers.
If during the above observation period the mouse behaved the same before and after the topical treatment when picked up by the tail and placed on the metallic grid, the test compound was determined to have no significant tranquilizing effect by topical administration. On the other hand, if the mouse was calm and quiet after the topical treatment when picked up by the tail and also did not struggle on the metallic grid, the test compound was determined to have a tranquilizing or sedative effect.
We have found that phenyl-alpha-acyloxyacetamide derivatives of the instant invention on topical administration showed various degrees of tranquilizing action, from minimally detectable to marked effects. For example, whereas N-ethyl phenyl-alpha-acetoxyacetamide exerted no detectable signs of sedation, N-phenethyl phenyl-S~a58 alpha~ac~toxyacetamide showed marked degrees of tranquilizing effect a~ter topical administration.

2. Systemic Administration.
Halrless mice, white hairy mice and dogs were used in these st~dies.
N-phenethyl phenyl-alpha-acetoxyacetamide, N-ethyl phenyl-alpha-acetoxyacetamide or other phenyl-alpha-acyloxyaCetamide derivative of the instant invention was prepared as a 1 to 2% solution or as gelatin capsules containlng 75 to 300 mg per capsule of the active ingredient.
Hairless mice or white hairy mice five in each group were injected subcutaneously with the test solution in a volume of 0.1 ml. The same procedure was repeated once more 3 hours later. For the next 8 hours and also at 24 hours later, all the mice were carefully ohserved and examined for any signs and evid~nceS of calming or quieting effects caused by the test compound.
Parameters and criteria used for sedative or tranquiliZing effect were the same as that described in the fOre~oin~ section. We have found that phenyl-alpha-acylOxya~etamide derivatives of the instant invention on subcutaneous administration to mice showed various degrees from minimallY detectable to marked effect of tranquilizing actiOn. For example, whereas N-ethyl phenyl-alpha-acetoxya~etamide exerted no detectable signs of sedation N-pheneth~l phenyl-alpha-acetoxyacetamide showed marked degrees of calming effect after subcutaneous administration to the mouse.
Three dogs weighing betwe~n 10 to ~0 kg were given orally N-phenethyl phenyl-alpha-acetoxyacetamide or N~ethyl phenyl-alpha-acetoxyacetamide in gelating capsules at doses of 5 to 10 mg per kg. For the next 10 hours the dogs were carefully observea and examined for any signs or evidence of calming or sedative effects caused by the test compound.
We have found that whereas N-ethyl phenyl-alpha-acetoxyacetamide exerted no detectable signs of sedation N-phenethyl phenyl alph~-acetoxyacetamide showed mild tranquilizing effect on oral administration to dogs. No soporific or drowsy effects have been detected in these dogs after oral administration of phenyl-alpha-acyloxyacetamide derivatives of the instant invention. In comparative studies these dogs at different times were given orally known tranquilizers such as Valium*and antihistamine drugs such as Benadryl.* Whereas known tranquilizers and antihistamine drugs exerted substantial sedative effects on the dogs on oral administration, these known drugs also caused soporific and drowsy effects in the dogs.
The foregoing results suggest and imply that members of phenyl-alpha-acyloxyacetamide derivatives are predictably useful as tranquilizers for treatment of anxiety or mental tension in humans, as well as animals.

* trade mark ~s~
-- ~i2 --ANALGE S I C EFFECT S
To test whether in addition to tranquilizing effects in animals, analgesic properties of phenyl-alpha-acyloxyacetamide derivatives o~ the instant invention might exist we administered sys~emically these compounds to dogs.
N-ethyl phenyl-alpha-acetoxyacetamide or N-phenethyl phenyl-alpha-acetoxyacetamide in single oral doses of approximately 8 mg per kg was given to two dogs disabled with hind limb arthritis secondary to hip dysplasia. One dog weighed 23 kg;
the other weighed 28 kg.
The disability in both animals was such that they were unable to jump up upon a test table, 45 cm L x 45 cm W x 45 cm H, on which had been placed a piece of food as an inducement; nor were they able to run about or romp, their movements being limited to walking with evident stiffness of gait.
Two to three hours after oral administration of the N-ethyl phenyl-alpha-acetoxyacetamide or the N-phenethyl phenyl-alpha-acetoxyacetamide the physical incapacities of these dogs were observed to have been diminished.
Walking was improved and the animals would then trot with some ease. Both were able to jump up upon the table to claim the food placed thereupon.
The foregoi~g results suggest and imply that members of phenyl-alpha-acyloxyacetamide derivatives are predictably useful as analgesic agents for treatment of various aches, pains and discomforts of skin, joints and other body parts in humans, as well as animals.

.5~

PSORIASIS
The involved skin in psoriasis is hyperplastiC
(thickened); erythematous (red or inflammed), and has thick adherent scales. llhe degree of thickening is such that lesions are elevated up to 1 mm above the sur~ace of adjacent normal skin; erythema is usually an intense red; the thickened adherent scales cause the surface of involved skin to be markedly rough and uneven. These three attributes of thickness, color and texture can be quantified to allow objective measurement of degree of improvement from topically applied therapeutic test materials as follows:

Degree of Improvement Sub-+None Mild Moderate stantial Complete 15(- to 0) (1- to 1~ (2- to 2+)(3- to 3~) (4- to ~) Thickness Highly Detectable Readily Barely Normal elevated reduction apparent elevated thickness Texture Visibly Palpably Uneven Slightly Visibly &
rough rough but notuneven palpably rough smooth Color Intense Red Dark Light Normal red Pink Pink color By means of such parameters degree of change in lesion can be numerically noted and comparisonS made of one treated site to another.
Patients having psoriasis participated in this study.
Therapeutic compositions containing phenyl-alpha-acyloxyacetamide derivatives were prepared according to the Examples. Test areas were kept to minimal size convenient .5 for topical application, i.e. circles approximat~lY 4 cm in diameter. The medicinal creams were topically applied by the patient in an amount (usually about 0.1 milliliter) sufficient to cover the test site. Applications were made two to three times daily and without occlusive dressings.
~est periods did not exceed two weeks.
The following table summarizes the results of those tests:

Effects on Psoriasis of Topical Phenyl-alpha-10 acyloxyacetamide Derivatives and Related Compounds No. of Therapeutic Compounds Patients Effectiveness .
1. N-ethyl phenyl-alpha-, acetoxyacetamide 2 2~

15 2. Phenyl~alpha-hydroxyacetamide 2 2+

3. N,N-diethyl phenyl-alpha hydroxyacetamide 2 2+

4. N-methyl phenyl-alpha-hydroxyacetamide 1 1+

20 5. N-ethyl phenyl-alpha-- hydroxyacetamide 1 1 6. N-phenethylphenyl-alpha-acetoxyacetamide 2 2+

7. N-benzyl phenyl-alpha-acetoxyacetamide 2 3 8. N-ethyl phenyl-alpha phenylacetoxyacetamide 3 3-~

9. N-(3,4~dimethoxyphenethyl) phenyl-alpha-acetoxyacetamide 3 3~

30 The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiment5 are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims and all changes which come within the meaning and equivalency of the claims are therefore intended to be embraced therein.

Claims (37)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of general formula:

(I) wherein:
R1 and R2, independently, represent a group selected from H, and straight, branched and cyclic, saturated and unsaturated alkyl and aralkyl of up to 25 carbon atoms, with the proviso that:
(i) R1 and R2 do not represent an aryl group, (ii) R1 and R2 do not represent a heterocyclic group, (iii) R1 and R2 do not both represent H, when R3, as defined below, represents -CH3 and R4, as defined below, represents H, (iv) R1 and R2 do not represent an identical alkyl group, when R3 represents -CH3 and R4 represents H, (v) when R1 represents -CH2C6H5, R2 does not represent -CH3, claim 1 contd...2 (vi) when R1 and R4 represent H and R3 represents -CH3, R2 does not represent -C(CH3)2C?CH, and (vii) when R1 represents H, R3 represents -CH3 and R4 represents -C6H5, R2 does not represent homo-veratryl; or at least one carbon atom of R1 or R2, as defined above, substituted by a therapeutically non-deviating group selected from N, S and O;
R3 represents a group selected from straight, branched and cyclic, saturated and unsaturated alkyl, aralkyl and aryl of up to 25 carbon atoms; and R4 represents a group selected from H, and straight, branched and cyclic, saturated and unsaturated alkyl, aralkyl and aryl of up to 25 carbon atoms; or at least one H of R1, R2, R3 or R4, as defined above, or the phenyl group substituted by a therapeutically non-deviating group selected from a halogen, and saturated and unsaturated alkyl and alkoxy of up to 9 carbon atoms;
said process comprising:
(a) effecting the reaction scheme:

(II) (III) (IV) claim 1 contd...3 wherein R1 to R4 are as defined above, R5 is part of the ester group and Hal is Cl or Br; or (b) effecting the reaction scheme:

(III) (VII) wherein R1 to R4 and Hal are as defined above; or (c) when required, preparing a pharmaceutically acceptable
1. Claim 1 cont'd...4 salt from the product of step (a) or (b);
   wherein said process is adapted to produce all possible optical isomers of the compound of general formula (I) singly or in combination.
   
   2. A compound of general formula:
   
   (I) wherein:
   
   R1 and R2, independently, represent a group selected from H, and straight, branched and cyclic, saturated and unsaturated alkyl and aralkyl of up to 25 carbon atoms, with the proviso that:
   (i) R1 and R2 do not represent an aryl group, (ii) R1 and R2 do not represent a heterocyclic group, (iii) R1 and R2 do not both represent H, when R3, as defined below, represents -CH3 and R4, as defined below, represents H, (iv) R1 and R2 do not represent an identical alkyl group, when R3 represents -CH3 and R4 represents H, (v) when R1 represents -CH2C6H5, R2 does not represent -CH3,
2. claim 2 contd...2 (vi) when R1 and R4 represent H and R3 represents -CH3, R2 does not represent -C(CH3)2C ? CH, and (Vii) when R1 represents H, R3 represents -CH3 and R4 represents -C6H5, R2 does not represent homo-veratryl; or at least one carbon atom of R1 or R2, as defined above, substituted by a therapeutically non-deviating group selected from N, S and O;
   R3 represents a group selected from straight, branched and cyclic, saturated and unsaturated alkyl, aralkyl and aryl of up to 25 carbon atoms and R4 represents a group selected from H, and straight, branched and cyclic, saturated and unsaturated alkyl, aralkyl and aryl of up to 25 carbon atoms; or at least one H of R1, R2, R3 or R4, as defined above, or the phenyl group substituted by a therapeutically non-deviating group selected from a halogen, and saturated and unsaturated alkyl and alkoxy of up to 9 carbon atoms;
   and a pharmaceutically acceptable salt thereof.
3. 3. M-Ethyl phenyl-alpha-acetoxyacetamide.
4. 4. N-Phenethyl phenyl alpha-acetoxyacetalaide.
5. 5. N-Methyl phenyl-alpha-acetoxyacetamide.
6. 6. N-Ethyl phenyl-alpha-lauroyloxyacetamide.
7. 7. N-Ethyl phenyl-alpha-phenylacetoxyacetamide.
8. 8. N-Benzyl phenyl-alpha-acetoxyacetamide.
9. 9. N-Phenethyl phenyl-alpha-benzoyloxyacetamide.
10. 10. N-(N',N'-Diethylaminoethyl) phenyl-alpha-acetoxy-acetamide, and a pharmaceutically acceptable salt thereof.
11. 11. N-Phenethyl phenyl-alpha-linoleoyloxyacetamide.
12. 12. N-Ethyl diphenyl-alpha acetoxyacetamide.
13. 13. N-Phenethyl diphenyl-alpha-acetoxyacetamide.
14. 14. N-Isopropyl phenyl-alpha-acetoxyacetamide.
15. 15. N-t-Butyl phenyl-alpha-acetoxyacetamide.
16. 16. N-Hydroxyethylthioethyl phenyl-alpha-acetoxy-acetamide.
17. 17. N-(3,4-Dimethoxyphenethyl) phenyl-alpha-acetoxy-acetamide.
18. 18. N-p-Chlorobenzyl phenyl-alpha-acetoxyacetamide.
19. 19. N-p-Methoxybenzyl phenyl-alpha-acetoxyacetamide.
20. 20. N-p-Methoxyphenethyl phenyl-alpha-acetoxyacetamide.
21. 21. N-Phenethyl phenyl-alpha-propionyloxyacetamide.
22. 22. N,N-bibenzyl phenyl-alpha-acetoxyacetamide.
23. 23. N-Phenethyl diphenyl-alpha-acetoxyacetamide.
24. 24. N-Benzyl diphenyl-alpha-acetoxyacetamide.
25. 25. N,N-Diethyl diphenyl-alpha-acetoxyacetamide.
26. 26. N-Ethyl-diphenyl-alpha-phenylacetoxyacetamide.
27. 27. N-(N',N'-Diethylaminoethyl) diphenyl-alpha-acetoxy-acetamide, and a pharmaceutically acceptable salt thereof.
28. 28. N-p-Fluorobenzyl phenyl-alpha-acetoxyacetamide.
29. 29. A therapeutic composition for topical or systemic administration comprising a therapeutically effective amount of the compound of claim 2, 3 or 4 and a pharmaceutically acceptable carrier.
30. 30. A therapeutic composition for topical or systemic administration comprising a therapeutically effective amount of the compound of claim 5, 6 or 7 and a pharmaceutically acceptable carrier.
31. 31. A therapeutic composition for topical or systemic administration comprising a therapeutically effective amount of the compound of claim 8, 9 or 10 and a pharmaceutically acceptable carrier.
32. 32. A therapeutic composition for topical or systemic administration comprising a therapeutically effective amount of the compound of claim 11, 12 or 13 and a pharmaceutically acceptable carrier.
33. 33. A therapeutic composition for topical or systemic administration comprising a therapeutically effective amount of the compound of claim 14, 15 or 16 and a pharmaceutically acceptable carrier.
34. 34. A therapeutic composition for topical or systemic administration comprising a therapeutically effective amount of the compound of claim 17, 18 or 19 and a pharmaceutically acceptable carrier.
35. 35. A therapeutic composition for topical or systemic administration comprising a therapeutically effective amount of the compound of claim 20, 21 or 22 and a pharmaceutically acceptable carrier.
36. 36. A therapeutic composition for topical or systemic administration comprising a therapeutically effective amount of the compound of claim 23, 24 or 25 and a pharmaceutically acceptable carrier.
37. 37. A therapeutic composition for topical or systemic administration comprising a therapeutically effective amount of the compound of claim 26, 27 or 28 and a pharmaceutically acceptable carrier.