WO2004012737A1 - Use or arylsulfonamido-substituted hydroxamid acid matrix metalloproteinase inhibitors for the treatment or prevention of toxemia - Google Patents

Use or arylsulfonamido-substituted hydroxamid acid matrix metalloproteinase inhibitors for the treatment or prevention of toxemia Download PDF

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Publication number
WO2004012737A1
WO2004012737A1 PCT/EP2003/008316 EP0308316W WO2004012737A1 WO 2004012737 A1 WO2004012737 A1 WO 2004012737A1 EP 0308316 W EP0308316 W EP 0308316W WO 2004012737 A1 WO2004012737 A1 WO 2004012737A1
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WIPO (PCT)
Prior art keywords
arylsulfonamido
matrix metalloproteinase
acid matrix
toxin
hydroxamic acid
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Ceased
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PCT/EP2003/008316
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French (fr)
Inventor
Kenneth Wayne Culver
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Novartis Pharma GmbH Austria
Novartis AG
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Novartis Pharma GmbH Austria
Novartis AG
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Priority to AU2003253346A priority Critical patent/AU2003253346A1/en
Publication of WO2004012737A1 publication Critical patent/WO2004012737A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to a method of preventing or treating toxemia by administering an effective amount of an arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor to a patient in need thereof.
  • a number of bacterial toxins are activated by metalloproteinases or include metalloproteinase activity. It is an object of the present invention to prevent or reduce the effect of a bacterial toxin by inhibiting the metalloproteinase activity of the toxin or by inhibiting activation of the toxin by inhibiting a metalloprotease activating factor.
  • Arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor compounds have been described in the art as useful for the treatment of gelatinase, stromelysin and collagenase dependent pathological conditions in mammals, including pathological conditions involving abnormal connective tissue and basement membrane matrix metabolism, such as arthritis (e.g. osteoarthritis and rheumatoid arthritis), tissue ulceration (e.g. corneal, epidermal and gastric ulceration), abnormal wound healing, periodontal disease, bone disease (e.g. Paget's disease and osteoporosis), tumor metastasis or invasion, as well as HIV-infection and associated disorders.
  • arthritis e.g. osteoarthritis and rheumatoid arthritis
  • tissue ulceration e.g. corneal, epidermal and gastric ulceration
  • abnormal wound healing e.g. corneal, epidermal and gastric ulceration
  • periodontal disease e.g. Paget's disease and osteo
  • the present invention relates a method of for the prevention or treatment of toxemia in a . mammal exposed to a bacterial toxin activated by or possessing metalloproteinase activity, which comprises administering a therapeutically effective amount of a arylsulfonamido- substituted hydroxamic acid matrix metalloproteinase inhibitor to the mammal.
  • the bacterial toxin activated by or possessing metalloproteinase activity may have an intrinsic metalloproteinase component.
  • it is also intended to include toxins which do not have an intrinsic metalloproteinase component, but wherein the bacteria itself, the toxin or some other bacterial product acts through a pathway which interacts with a metalloproteinases or an associated pathways.
  • Arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitors suitable for use according to the present method are described in U.S. Patent Nos. 5,455,258 and 5,770,624, which are here incorporated by reference in their entirety.
  • the compounds described in these patents the compounds N-hydroxy-(2R)-[[4-methoxybenzenesulfonyl](3- picolyl)amino]-3-methylbutanamide, as described in Example 1 of U.S. Patent No.
  • hydrochloride salts of N-hydroxy-(2R)-[[4- ethoxybenzenesulfonyl](3-picolyl)amino]-2-trans-methoxycyclohexyl]acetamide and N- hydroxy-(2R)-[[4-ethoxybenzenesulfonyl](3-picolyl)amino]-2-trans- methoxycyclohexyl]acetamide are particularly useful pharmaceutically acceptable salt forms.
  • the toxemia is most commonly caused by infection with a toxin-producing bacteria.
  • the infection may be systemic or local.
  • Administration of the arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor should occur as soon as possible after exposure to the toxin producing bacteria or the toxin as the case may be.
  • the mammal is in particular a human.
  • the bacterial toxin activated by or possessing metalloproteinase activity is especially a toxin from a bacteria of a genus selected from Bacillus, Bacteroides, Clostridium, Corynebacterium and Vibrio.
  • the bacterial toxin activated by or possessing metalloproteinase activity is especially a toxin produced by a bacteria selected from Bacillus anthracis, Bacteroides fragilis, Clostridium botulinum, Clostridium difficile, Clostridium tetani, Corynebacterium diphtheriae and Vibrio cholera.
  • the compounds, including their salts, can also be used in the form of their hydrates, or include other solvents used for their crystallization.
  • the arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor is generally administered enterally, such as orally or rectally, transdermally and parenterally, such as intravenously, as a pharmaceutically formulation comprising an effective amount of the arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor and one or more pharmaceutically acceptable carriers.
  • Pharmaceutically acceptable carriers are known to those of skill in the art.
  • the pharmaceutical formulations contain an effective metalloproteinase inhibiting amount of a arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor either alone, or in combination with another therapeutic agent, particularly an antibiotic or an anti- inflammatory agent, particularly an anti-inflammatory agent with cyclooxygenase inhibiting activity or a steroid.
  • a compound of the invention may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation.
  • the present invention further comprises a method of for the prevention or treatment of toxemia in a mammal exposed to a bacterial toxin activated by or possessing metalloproteinase activity, which comprises administering a therapeutically effective amount of a arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor in combination with an antibiotic or an antiinflammatory agent, or both, to the mammal.
  • the dosage of the arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor administered is dependent on the species of mammal, the body weight, age and individual condition, and on the form of administration, and can be determined by one of skill in the art.
  • a typical dosage to a mammal of about 50 to 70kg is in the range from 50 to 1800 mg/day, particularly 600 mg/day of the arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Thoxemia caused by a bacterial toxin is prevented or treated by administration of a arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor.

Description

USE OF ARYLSULFONAMIDO-SUBSTITUTED HYDROXAMID ACID MATRIX METALLOPROTEINASE INHI ITORS FOR THE TREATMENT OR PREVENTION OF TOXEMIA
Method of Preventing or Treating Toxemia using arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitors
This invention relates to a method of preventing or treating toxemia by administering an effective amount of an arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor to a patient in need thereof.
Background
Many of the deleterious effects of bacterial infection are caused by toxins which the bacteria produce. Although many bacterial infections can be successfully treated with antibiotics, toxemia resulting from the bacterial production of toxin can lead to seriously adverse effects, including death, when antibiotics are not administered promptly or are ineffective. Thus, in addition to antibacterial treatments, there is also a great need for agents that neutralize or reduce the toxicity of the such bacterial toxins.
A number of bacterial toxins are activated by metalloproteinases or include metalloproteinase activity. It is an object of the present invention to prevent or reduce the effect of a bacterial toxin by inhibiting the metalloproteinase activity of the toxin or by inhibiting activation of the toxin by inhibiting a metalloprotease activating factor.
Arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor compounds have been described in the art as useful for the treatment of gelatinase, stromelysin and collagenase dependent pathological conditions in mammals, including pathological conditions involving abnormal connective tissue and basement membrane matrix metabolism, such as arthritis (e.g. osteoarthritis and rheumatoid arthritis), tissue ulceration (e.g. corneal, epidermal and gastric ulceration), abnormal wound healing, periodontal disease, bone disease (e.g. Paget's disease and osteoporosis), tumor metastasis or invasion, as well as HIV-infection and associated disorders.
Detailed Description The present invention relates a method of for the prevention or treatment of toxemia in a . mammal exposed to a bacterial toxin activated by or possessing metalloproteinase activity, which comprises administering a therapeutically effective amount of a arylsulfonamido- substituted hydroxamic acid matrix metalloproteinase inhibitor to the mammal.
The bacterial toxin activated by or possessing metalloproteinase activity may have an intrinsic metalloproteinase component. However, in this application, it is also intended to include toxins which do not have an intrinsic metalloproteinase component, but wherein the bacteria itself, the toxin or some other bacterial product acts through a pathway which interacts with a metalloproteinases or an associated pathways.
Arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitors suitable for use according to the present method are described in U.S. Patent Nos. 5,455,258 and 5,770,624, which are here incorporated by reference in their entirety. Among the compounds described in these patents, the compounds N-hydroxy-(2R)-[[4-methoxybenzenesulfonyl](3- picolyl)amino]-3-methylbutanamide, as described in Example 1 of U.S. Patent No. 5,455,258, and N-hydroxy-(2R)-[[4-ethoxybenzenesulfonyl](3-picolyl)amino]-2-trans- methoxycyclohexyl]acetamide, as described in Example 2(p) of U.S. Patent No. 5,770,624, and pharmaceutically acceptable salts thereof, are particularly useful, especially N-butyloxy- (2R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamide and pharmaceucically acceptable salts therof. The hydrochloride salts of N-hydroxy-(2R)-[[4- ethoxybenzenesulfonyl](3-picolyl)amino]-2-trans-methoxycyclohexyl]acetamide and N- hydroxy-(2R)-[[4-ethoxybenzenesulfonyl](3-picolyl)amino]-2-trans- methoxycyclohexyl]acetamide are particularly useful pharmaceutically acceptable salt forms.
The toxemia is most commonly caused by infection with a toxin-producing bacteria. The infection may be systemic or local. Administration of the arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor should occur as soon as possible after exposure to the toxin producing bacteria or the toxin as the case may be.
The mammal is in particular a human. The bacterial toxin activated by or possessing metalloproteinase activity is especially a toxin from a bacteria of a genus selected from Bacillus, Bacteroides, Clostridium, Corynebacterium and Vibrio. The bacterial toxin activated by or possessing metalloproteinase activity is especially a toxin produced by a bacteria selected from Bacillus anthracis, Bacteroides fragilis, Clostridium botulinum, Clostridium difficile, Clostridium tetani, Corynebacterium diphtheriae and Vibrio cholera.
In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.
The compounds, including their salts, can also be used in the form of their hydrates, or include other solvents used for their crystallization.
The arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor is generally administered enterally, such as orally or rectally, transdermally and parenterally, such as intravenously, as a pharmaceutically formulation comprising an effective amount of the arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor and one or more pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers are known to those of skill in the art.
The pharmaceutical formulations contain an effective metalloproteinase inhibiting amount of a arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor either alone, or in combination with another therapeutic agent, particularly an antibiotic or an anti- inflammatory agent, particularly an anti-inflammatory agent with cyclooxygenase inhibiting activity or a steroid.
In conjunction with another active ingredient, a compound of the invention may be administered either simultaneously, before or after the other active ingredient, either separately by the same or different route of administration or together in the same pharmaceutical formulation. Thus, the present invention further comprises a method of for the prevention or treatment of toxemia in a mammal exposed to a bacterial toxin activated by or possessing metalloproteinase activity, which comprises administering a therapeutically effective amount of a arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor in combination with an antibiotic or an antiinflammatory agent, or both, to the mammal.
The dosage of the arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor administered is dependent on the species of mammal, the body weight, age and individual condition, and on the form of administration, and can be determined by one of skill in the art. A typical dosage to a mammal of about 50 to 70kg is in the range from 50 to 1800 mg/day, particularly 600 mg/day of the arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor.

Claims

I claim:
1. A method for the prevention or treatment of toxemia in a mammal exposed to a bacterial toxin activated by or possessing metalloproteinase activity, which comprises administering a therapeutically effective amount of a arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor to the mammal.
2. A method of claim 1 wherein the arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor is selected from N-hydroxy-(2R)-[[4-methoxybenzenesulfonyl](3- picolyl)amino]-3-methylbutanamide and N-hydroxy-(2R)-[[4-ethoxybenzenesulfonyl](3- picolyl)amino]-2-trans-methoxycyclohexyl]acetamide, or a pharmaceutically acceptable salt thereof.
3. A method of claim 1 wherein the arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor is selected from N-hydroxy-(2R)-[[4-methoxybenzenesulfonyl](3- picolyl)amino]-3-methylbutanamide.
4. A method of claim 1 wherein the bacterial toxin is a toxin produced by bacteria of a genus selected from Bacillus, Bacteroides, Clostridium, Corynebacterium and Vibrio.
5. A method of claim 1 wherein the bacterial toxin is a toxin produced by a bacteria selected from Bacillus anthracis, Bacteroides fragilis, Clostridium botulinum, Clostridium difficile, Clostridium tetani, Corynebacterium diphtheriae and Vibrio cholera.
6. A method of claim 1 wherein the bacterial toxin is a toxin produced by Bacillus anthracis.
7. A method of claim 1 wherein the bacterial toxin is a toxin produced by Bacteroides fragilis.
8. A method of claim 1 wherein the bacterial toxin is a toxin produced by Clostridium botulinum.
9. A method of claim 1 wherein the bacterial toxin is a toxin produced by Clostridium difficile.
10. A method of claim 1 wherein the bacterial toxin is a toxin produced by Clostridium tetani.
11. A method of claim 1 wherein the bacterial toxin is a toxin produced by Corynebacterium diphtheriae.
12. A method of claim 1 wherein the bacterial toxin is a toxin produced by Vibrio cholera.
13. A method of claim 6 wherein the arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor is selected from N-hydroxy-(2R)-[[4-methoxybenzenesulfonyl](3- picolyl)amino]-3-methylbutanamide.
14. A method of claim 7 wherein the arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor is selected from N-hydroxy-(2R)-[[4-methoxybenzenesulfonyl](3- picolyl)amino]-3-methylbutanamide.
15. A method of claim 8 wherein the arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor is selected from N-hydroxy-(2R)-[[4-methoxybenzenesulfonyl](3- picolyl)amino]-3-methylbutanarnide.
16. A method of claim 9 wherein the arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor is selected from N-hydroxy-(2R)-[[4-methoxybenzenesulfonyl](3- picolyl)amino]-3-methylbutanamide.
17. A method of claim 10 wherein the arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor is selected from N-hydroxy-(2R)-[[4-methoxybenzenesulfonyl](3- picolyl)amino]-3-methylbutanamide.
18. A method of claim 11 wherein the arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor is selected from N-hydroxy-(2R)-[[4-methoxybenzenesulfonyl](3- picolyl)amino]-3-methylbutanamide.
19. A method of claim 12 wherein the arylsulfonamido-substituted hydroxamic acid matrix metalloproteinase inhibitor is selected from N-hydroxy-(2R)-[[4-methoxybenzenesulfonyl](3- picolyl)amino]-3-methylbutanamide.
PCT/EP2003/008316 2002-07-29 2003-07-28 Use or arylsulfonamido-substituted hydroxamid acid matrix metalloproteinase inhibitors for the treatment or prevention of toxemia Ceased WO2004012737A1 (en)

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US60/399,291 2002-07-29

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2023542498A (en) * 2020-09-11 2023-10-10 アーティザン バイオサイエンシーズ， インコーポレイテッド Small molecule inhibitors of bacterial toxins

Citations (3)

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Publication number Priority date Publication date Assignee Title
US5455258A (en) * 1993-01-06 1995-10-03 Ciba-Geigy Corporation Arylsulfonamido-substituted hydroxamic acids
US5770624A (en) * 1995-12-15 1998-06-23 Novartis Corp. Certain alpha-substituted arylsulfonamido acetohydroxamic acids
WO2002038796A2 (en) * 2000-11-08 2002-05-16 Beth Israel Deaconess Medical Center, Inc. Methods for determining protease cleavage site motifs

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US5455258A (en) * 1993-01-06 1995-10-03 Ciba-Geigy Corporation Arylsulfonamido-substituted hydroxamic acids
US5770624A (en) * 1995-12-15 1998-06-23 Novartis Corp. Certain alpha-substituted arylsulfonamido acetohydroxamic acids
WO2002038796A2 (en) * 2000-11-08 2002-05-16 Beth Israel Deaconess Medical Center, Inc. Methods for determining protease cleavage site motifs

Non-Patent Citations (2)

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Title
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SCOZZAFAVA A ET AL: "Protease inhibitors - Part 5. Alkyl/arylsulfonyl- and arylsulfonylureido-/arylureido- glycine hydroxamate inhibitors of Clostridium histolyticum collagenase", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 35, no. 3, March 2000 (2000-03-01), pages 299 - 307, XP004341234, ISSN: 0223-5234 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2023542498A (en) * 2020-09-11 2023-10-10 アーティザン バイオサイエンシーズ， インコーポレイテッド Small molecule inhibitors of bacterial toxins
EP4210738A4 (en) * 2020-09-11 2024-11-06 Artizan Biosciences, Inc. SMALL MOLECULE INHIBITORS OF BACTERIAL TOXINS

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