WO2006042195A1 - Alkyl benzamides - Google Patents

Alkyl benzamides Download PDF

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Publication number
WO2006042195A1
WO2006042195A1 PCT/US2005/036356 US2005036356W WO2006042195A1 WO 2006042195 A1 WO2006042195 A1 WO 2006042195A1 US 2005036356 W US2005036356 W US 2005036356W WO 2006042195 A1 WO2006042195 A1 WO 2006042195A1
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Prior art keywords
compound according
alkyl
compound
ococh
compounds
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PCT/US2005/036356
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French (fr)
Inventor
Jean-François ROSSIGNOL
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Romark Laboratories, L.C.
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Publication of WO2006042195A1 publication Critical patent/WO2006042195A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof

Definitions

  • the present invention relates to alkyl derivatives of nitazoxanide and tizoxanide and isomers thereof. More specifically, the present invention is directed to compounds possessing anti-parasitic, antibacterial, antiviral and antifungal activities, and to methods of treatment and/or prevention of parasitic, bacterial, viral and/or fungal diseases in humans and animals using said compounds and pharmaceutical compositions thereof.
  • Tizoxanide (Compound A) and nitazoxanide (Compound B) are compounds according to formula (I) in which:
  • benzamide compounds that possess improved potency and/or improved target specificity compared to the compounds of the prior art.
  • benzamide derivatives lacking antibacterial activity would be beneficial in order to avoid disruption of the gut flora when administered orally.
  • the present inventors have surprisingly discovered that certain alkyl derivatives of tizoxanide and nitazoxanide, and isomers of such derivatives, possess improved anti-parasitic, antibacterial, antiviral and antifungal activities.
  • the present invention is directed to compounds according to formula (I) :
  • the Ri substituent is -OH or -OCOCH 3
  • one of the R2-R5 stibstituents is alkyl and the remaining positions are -H, and salts, solvates or hydrates thereof.
  • the invention is directed to a method of treating or preventing a parasitic, bacterial, viral or fungal disease in a human or animal subject by administering an effective amount of the compound of formula
  • the invention is directed to pharmaceutical compositions comprising at least one compound according to formula (I) and a pharmaceutically acceptable carrier.
  • the invention is directed to compounds according to formula (I) comprising an -OH or - OCOCH 3 substituent at any one position among R x -R 5 , and in which one of the remaining Ri-R 5 substituents is alkyl and the remainder are -H, including salts, solvates and hydrates thereof.
  • the invention is directed to a method of treating or preventing a parasitic, bacterial, viral or fungal disease in a human or animal subject by- administering to the subject an effective amount of the compound of according to the fourth embodiment .
  • the invention is directed to pharmaceutical compositions comprising a compound according to the fourth embodiment and a pharmaceutically acceptable carrier.
  • the present invention is directed to compounds according to formula (I) , their methods of use, and pharmaceutical compositions thereof:
  • one of Ri-R 5 is -OH or -OCOCH 3 , and is preferably -
  • R 1 -R 5 is alkyl , preferably Ci-C 4 alkyl , most preferably -
  • the compounds of the present invention include organic and inorganic salts, solvates and hydrates of the compounds according to formula (I) .
  • alkyl includes both branched alkyl and linear alkyl.
  • the compounds of the present invention possess improved activity against certain parasitic, bacterial, viral and fungal diseases, including but not limited to pathogens against which tizoxanide and/or zitaxoanide exhibit activity, as described, for example, in U.S. Patent Nos. 4,315,018; 5,578,621; and 5,856,348.
  • Compound D is effective against at least H. Pylori, C. jejuni, Influenza A and B, Herpes VZV, G. intestinalis, P. falciparum and T. vaginalis.
  • Compound C can be synthesized by de-acetylating Compound D, for example in the presence of a strong acid such as concentrated hydrochloric acid.
  • Compound H can be synthesized from 5-methyl salicylic acid and 2-amino-5-nitro thiazole as shown in the following scheme:
  • Compound H is effective against at least G. intestinalis and T. vaginalis.
  • Compound G can be synthesized by de-acetylating Compound H for example in the presence of a strong acid such as concentrated hydrochloric acid.
  • Compound G is effective against at least G. intestinalis and T. vaginalis.
  • Compound F can be synthesized from 4-methyl salicylic acid and 2-amino-5-nitro thiazole as shown in the following scheme:
  • Compound F is effective against at least G. intestinalis and T. vaginalis.
  • Compound E can be synthesized by de-acetylating Compound F for example in the presence of a strong acid such as concentrated hydrochloric acid.
  • Compound E is effective against at least G. intestinalis and T. vaginalis.
  • Compounds C, D, E and G are significantly more potent than nitazoxanide against Giardia intestinalis.
  • Compounds E and G exhibit improved activity, compared to tizoxanide, against Trichomonas vaginalis, with Compound E (methyl group at R 4 ) being the most effective.
  • the methyl group at R 2 , R 3 or R 4 therefore improves the activity of nitazoxanide and tizoxanide.

Abstract

The present invention relates to alkyl derivatives of nitazoxanide and tizoxanide and isomers thereof. More specifically, the present invention is directed to compounds possessing anti-parasitic, antibacterial, antiviral and antifungal activities, and to methods of treatment and/or prevention of parasitic, bacterial, viral and/or fungal diseases in humans and animals using said compounds and pharmaceutical compositions thereof.

Description

ALKYL BENZAMIDES
Reference to Related Application
This application is based on US provisional application No. 60/617,412 filed October 8, 2004.
BACKGROUND OF THE INVENTION Field of the Invention
The present invention relates to alkyl derivatives of nitazoxanide and tizoxanide and isomers thereof. More specifically, the present invention is directed to compounds possessing anti-parasitic, antibacterial, antiviral and antifungal activities, and to methods of treatment and/or prevention of parasitic, bacterial, viral and/or fungal diseases in humans and animals using said compounds and pharmaceutical compositions thereof.
Discussion of the Related Art
It is known that tizoxanide (2-hydroxy-N- (5-nitro-2- thiazolyl) benzamide, Compound A, U.S. Patent No. 5,578,621) and nitazoxanide (2-acetyloxy-N -(5-nitro-2- thiazolyl)benzamide, Compound B, U.S. Patent No. 3,950,351) possess potent activity against parasites, bacteria, viruses and fungi, as described, for example, in U.S. Patent Nos . 4,315,018; 5,578,621; and 5, 856, 348.
Tizoxanide (Compound A) and nitazoxanide (Compound B) are compounds according to formula (I) in which:
Figure imgf000002_0001
Compound A (tizoxanide) : wherein Ri = -OH and R2-R5 = -H; and Compound B (nitazoxanide) : wherein R1 = -OCOCH3 and R2-R5 = -H.
There is a need in the art for benzamide compounds that possess improved potency and/or improved target specificity compared to the compounds of the prior art. For example, for the treatment of parasitic or viral diseases, benzamide derivatives lacking antibacterial activity would be beneficial in order to avoid disruption of the gut flora when administered orally.
There is therefore a need in the art for benzamide compounds that possess superior activity against parasitic, bacterial, viral and fungal diseases suitable for treatment of humans and animals, and which do not suffer from the above- mentioned drawbacks of the compounds of the prior art. All this and more will be apparent to one of ordinary skill upon reading the following description, non-limiting examples, and claims. %
SUMMARY OF THE INVENTION
The present inventors have surprisingly discovered that certain alkyl derivatives of tizoxanide and nitazoxanide, and isomers of such derivatives, possess improved anti-parasitic, antibacterial, antiviral and antifungal activities.
Thus, in a first embodiment, the present invention is directed to compounds according to formula (I) :
Figure imgf000004_0001
in which the Ri substituent is -OH or -OCOCH3, one of the R2-R5 stibstituents is alkyl and the remaining positions are -H, and salts, solvates or hydrates thereof.
In a second embodiment, the invention is directed to a method of treating or preventing a parasitic, bacterial, viral or fungal disease in a human or animal subject by administering an effective amount of the compound of formula
(I) according to the first embodiment.
In a third embodiment, the invention is directed to pharmaceutical compositions comprising at least one compound according to formula (I) and a pharmaceutically acceptable carrier.
While the compounds of the first embodiment possess Ri substituents that are -OH or -OCOCH3, (as in Compound A (tizoxanide) and Compound B (nitazoxanide) , respectively) , the present invention is not so limited.
Thus, in a fourth embodiment, the invention is directed to compounds according to formula (I) comprising an -OH or - OCOCH3 substituent at any one position among Rx-R5, and in which one of the remaining Ri-R5 substituents is alkyl and the remainder are -H, including salts, solvates and hydrates thereof. In a fifth embodiment, the invention is directed to a method of treating or preventing a parasitic, bacterial, viral or fungal disease in a human or animal subject by- administering to the subject an effective amount of the compound of according to the fourth embodiment .
In a sixth embodiment, the invention is directed to pharmaceutical compositions comprising a compound according to the fourth embodiment and a pharmaceutically acceptable carrier.
Detailed Description of the Invention
The present invention is directed to compounds according to formula (I) , their methods of use, and pharmaceutical compositions thereof:
Figure imgf000005_0001
in which: one of Ri-R5 is -OH or -OCOCH3, and is preferably -
OH; one of R1-R5 is alkyl , preferably Ci-C4 alkyl , most preferably -
CH3 ; and substituents Rx-R5 that are not alkyl, -OH or -OCOCH3 are -H.
The compounds of the present invention include organic and inorganic salts, solvates and hydrates of the compounds according to formula (I) . The term "alkyl" includes both branched alkyl and linear alkyl.
The compounds of the present invention possess improved activity against certain parasitic, bacterial, viral and fungal diseases, including but not limited to pathogens against which tizoxanide and/or zitaxoanide exhibit activity, as described, for example, in U.S. Patent Nos. 4,315,018; 5,578,621; and 5,856,348.
Suitable formulations and dosages will be readily understood by one of ordinary skill from the formulations and dosages of prior art benzamide compounds as set forth in U.S. Patent Nos. 6,117,894 (acid-stabilized compounds) and 5,968,961 (particle size) .
Certain U.S. patents have been referred to herein, which are hereby incorporated for their cited teachings, and in their respective entireties, by reference.
The invention is now illustrated by the following, non- limiting, examples:
EXAMPLE 1: Compound D (2-acetyloxy-3-methyl-N- (5-nitro-2- thiazolyl) benzamide)
Compound D is a compound according to formula (I) in which Ri = -OCOCH3, R2= -CH3 and R3, R4 and R5 = -H.
Compound D is synthesized from 3-methyl salicylic acid and 2-amino-5-nitro thiazole as shown in the following scheme:
Figure imgf000007_0001
Figure imgf000007_0002
in which: Ac2O is acetic anhydride, SOCl2 is thionyl chloride, Et3N is triethylamine, and THF is tetrahydrofuran. Other synthesis methods, reagents and adaptations will readily occur to those of skill in the art, and the compounds of the present invention are not limited by their method of synthesis, which is provided for illustrative purposes only. Throughout this disclosure -OAc and -OCOCH3 are equivalent.
Compound D is effective against at least H. Pylori, C. jejuni, Influenza A and B, Herpes VZV, G. intestinalis, P. falciparum and T. vaginalis.
EXAMPLE 2: Compound C (2-hydroxy-3-methyl-N- (5-nitro-2- thiazolyl) benzamide)
Compound C is a compound according to formula (I) in which Ri = -OH, R2= -CH3 and R3, R4, R5 = -H. Compound C can be synthesized by de-acetylating Compound D, for example in the presence of a strong acid such as concentrated hydrochloric acid.
Compound C possesses comparable or improved activity compared to nitazoxanide against Helicobacter pylori (IC50 = 2 μg/mL) , Campylobacter jejuni (IC50=4 μg/mL) , Influenza A (IC50 =0.18 μg/mL) , Influenza B (IC50 =0.18 μg/mL) , and Herpes Varicella A (IC50 =0.9 μg/mL) .
EXAMPLE 3: Compound H (2-acetyloxy-5-methyl-N- (5-nitro-2- thiazolyl) benzamide)
Compound H is a compound according to formula (I) in which Rx = -OCOCH3, R4= -CH3 and R2, R3, R5 = -H.
Compound H can be synthesized from 5-methyl salicylic acid and 2-amino-5-nitro thiazole as shown in the following scheme:
Figure imgf000008_0001
Compound H is effective against at least G. intestinalis and T. vaginalis.
EXAMPLE 4: Compound G (2-hydroxy-5-methyl-N- (5-nitro-2- thiazolyl) benzamide)
Compound G is a compound according to formula (I) in which Ri = -OH, R4= -CH3 and R2, R3, R5 = -H.
Compound G can be synthesized by de-acetylating Compound H for example in the presence of a strong acid such as concentrated hydrochloric acid.
Compound G is effective against at least G. intestinalis and T. vaginalis.
EXAMPLE 5: Compound F (2-acetyloxy-4-methyl-N- (5-nitro-2- thiazolyl) benzamide)
Compound F is a compound according to formula (I) in which Ri = -OCOCH3, R3= -CH3 and R2, R4, R5 = -H.
Compound F can be synthesized from 4-methyl salicylic acid and 2-amino-5-nitro thiazole as shown in the following scheme:
Figure imgf000010_0001
Figure imgf000010_0002
Compound F is effective against at least G. intestinalis and T. vaginalis.
EXAMPLE 6: Compound E (2-hydroxy-4-methyl-N- (5-nitro-2- thiazolyl) benzamide)
Compound E is a compound according to formula (I) in which Ri = -OH, R3= -CH3 and R2, R4, R5 = -H.
Compound E can be synthesized by de-acetylating Compound F for example in the presence of a strong acid such as concentrated hydrochloric acid.
Compound E is effective against at least G. intestinalis and T. vaginalis.
EXAMPLE 7: Comparative Testing
Compounds C, D, E and G were tested in vitro against the protozoa, Giardia intestinalis and Trichomonas vaginalis with the results shown in TABLE I. TABLE I
Figure imgf000011_0001
* Micromolar concentrations of drugs required to inhibit 50% of the growth of the organisms .
Compounds C, D, E and G are significantly more potent than nitazoxanide against Giardia intestinalis.
Compounds E and G exhibit improved activity, compared to tizoxanide, against Trichomonas vaginalis, with Compound E (methyl group at R4) being the most effective. The methyl group at R2, R3 or R4 therefore improves the activity of nitazoxanide and tizoxanide. A comparison of the results for Compounds C and D shows that these compounds are most potent when Ri = OH instead of -OCOCH3.

Claims

What is Claimed is:
1. A compound according to Formula (I)
Figure imgf000012_0001
wherein
Ri is -OH or -OCOCH3; and
R2-R5 are -H except that one of R2-R5 is alkyl, or a salt, solvate or hydrate thereof .
2. The compound according to claim 1, wherein said alkyl is Ci-C4 alkyl.
3. The compound according to claim 2, wherein R5 is -H.
4. The compound according to claim 3, wherein said alkyl is - CH3.
5. The compound according to claim 4, wherein Ri is -OH.
6. The compound according to claim 5, wherein R2 is -CH3.
7. The compound according to claim 5, wherein R3 is -CH3.
8. The compound according to claim 5, wherein R4 is -CH3.
9. The compound according to claim 4, wherein Ri is -OCOCH3.
10. The compound according to claim 9, wherein R2 is -CH3.
11. The compound according to claim 9, wherein R3 is -CH3.
12. The compound according to claim 9, wherein R4 is -CH3.
13. A method of treating or preventing a parasitic, bacterial, viral or fungal disease in a human or animal subject comprising administering to said subject an effective amount of a compound according to Formula (I) :
Figure imgf000013_0001
wherein
Ri is -OH or -OCOCH3; and
R2-R5 are -H except that one of R2-R5 is alkyl, or a salt, solvate or hydrate thereof.
14. The method of claim 13, wherein said disease is a disease that is susceptible to treatment by tizoxanide or nitazoxanide.
15. The method of claim 14, wherein said disease is associated with a pathogen selected from the group consisting of Giardia intestinalis, Trichomonas vaginalis, Helicobacter pylori, Campylobacter jejuni, Influenza B A, and Herpes Varicella A.
16. A pharmaceutical composition comprising at least one compound according to claim 1 and a pharmaceutically acceptable carrier.
17. A compound according to Formula (I) :
Figure imgf000014_0001
wherein
Ri-R5 are -H, except that one of R1-R5 is -OH or -OCOCH3 and one of Ri-R5 is alkyl, or a salt, solvate or hydrate thereof.
18. The compound according to claim 17, wherein said alkyl is C1-C4 alkyl.
19. The compound according to claim 18, wherein said alkyl is -CH3.
20. A method of treating a parasitic, bacterial, viral or fungal disease in human or animal subject comprising administering to said subject an effective amount of the compound according to claim 17.
21. A pharmaceutical composition comprising at least one compound according to claim 17 and a pharmaceutically acceptable carrier.
PCT/US2005/036356 2004-10-08 2005-10-07 Alkyl benzamides WO2006042195A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US61741204P 2004-10-08 2004-10-08
US60/617,412 2004-10-08
US11/244,787 2005-10-06
US11/244,787 US20060194853A1 (en) 2004-10-08 2005-10-06 Alkyl benzamides

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WO2006110814A2 (en) * 2005-04-12 2006-10-19 Romark Laboratories, L.C. Methods for treating diseases through inhibition the function of molecular chaperones such as protein disulfide isomerases, pharmaceutical compositions comprising them, and screening methods for identifying therapeutic agents
US20100330173A1 (en) * 2009-06-26 2010-12-30 Romark Laboratories L.C. Compounds and methods for treating influenza
US8124632B2 (en) 2007-08-03 2012-02-28 Romark Laboratories, L.C. Alkylsulfonyl-substituted thiazolide compounds
US8846727B2 (en) 2009-05-12 2014-09-30 Romark Laboratories, L.C. Haloalkyl heteroaryl benzamide compounds
WO2017173056A1 (en) 2016-03-31 2017-10-05 Romark Laboratories L.C. Thiazolide compounds for treating viral infections
US11173149B2 (en) 2017-04-18 2021-11-16 Romark Laboratories L.C. Inhibition of protein disulfide-isomerase A3
WO2022020243A1 (en) 2020-07-20 2022-01-27 Romark Laboratories L.C. Crystalline salts of tizoxanide and 2-hydroxy-n-(5-chloro-1,3-thiazol-2-yl)benzamide (rm-4848) with ethanolamine, morpholine, propanolamine, piperazine and n-methylpiperazine
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CN115197164A (en) * 2021-04-12 2022-10-18 杜心赟 Novel thiazole compound and preparation method and application thereof
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EP2047850A3 (en) * 2005-04-12 2009-07-29 Romark Laboratories, L.C. Methods for treating diseases through inhibition of the function of molecular chaperones such as protein disulfide isomerases , pharmaceutical compositions comprising them, and screening methods for identifying therapeutic agents
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US8124632B2 (en) 2007-08-03 2012-02-28 Romark Laboratories, L.C. Alkylsulfonyl-substituted thiazolide compounds
US8895752B2 (en) 2007-08-03 2014-11-25 Romark Laboratories L.C. Alkylsulfonyl-substituted thiazolide compounds
US9126992B2 (en) 2009-05-12 2015-09-08 Romark Laboratories, L.C. Haloalkyl heteroaryl benzamide compounds
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US8846727B2 (en) 2009-05-12 2014-09-30 Romark Laboratories, L.C. Haloalkyl heteroaryl benzamide compounds
US9820975B2 (en) 2009-06-26 2017-11-21 Romark Laboratories L.C. Compounds and methods for treating influenza
US20100330173A1 (en) * 2009-06-26 2010-12-30 Romark Laboratories L.C. Compounds and methods for treating influenza
US11850237B2 (en) 2009-06-26 2023-12-26 Romark Laboratories L.C. Compounds and methods for treating influenza
US9023877B2 (en) 2009-06-26 2015-05-05 Romark Laboratories L.C. Compounds and methods for treating influenza
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CN108042535A (en) * 2009-06-26 2018-05-18 罗马克实验室有限公司 For treating the Compounds and methods for of influenza
US10363243B2 (en) 2009-06-26 2019-07-30 Romark Laboratories L.C. Compounds and methods for treating influenza
US9345690B2 (en) 2009-06-26 2016-05-24 Romark Laboratories L.C. Compounds and methods for treating influenza
EP3895706A1 (en) 2009-06-26 2021-10-20 Romark Laboratories, L.C. Thiazolinide compounds for treating non-influenza viral infections
US10912768B2 (en) 2009-06-26 2021-02-09 Romark Laboratories L.C. Compounds and methods for treating influenza
US11135202B2 (en) 2016-03-31 2021-10-05 Romark Laboratories L.C. Thiazolide compounds for treating viral infections
EP3677282A1 (en) 2016-03-31 2020-07-08 Romark Laboratories, L.C. Thiazolide compounds for treating viral infections
WO2017173056A1 (en) 2016-03-31 2017-10-05 Romark Laboratories L.C. Thiazolide compounds for treating viral infections
US11173149B2 (en) 2017-04-18 2021-11-16 Romark Laboratories L.C. Inhibition of protein disulfide-isomerase A3
WO2022020243A1 (en) 2020-07-20 2022-01-27 Romark Laboratories L.C. Crystalline salts of tizoxanide and 2-hydroxy-n-(5-chloro-1,3-thiazol-2-yl)benzamide (rm-4848) with ethanolamine, morpholine, propanolamine, piperazine and n-methylpiperazine
WO2022046622A1 (en) 2020-08-24 2022-03-03 Romark Laboratories L.C. Use of thiazolides against coronaviruses

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