Guanylhydrazones and their use to treat inflammatory conditions

• US 5,854,289 A
• Filed: 04/15/1996
• Issued: 12/29/1998
• Est. Priority Date: 01/21/1994
• Status: Expired due to Term

• Current Assignee: Ferring BV (Ferring Holding SA)
• Original Assignee: The Picower Institute For Medical Research
• Inventors: Tracey, Kevin J., Cerami, Anthony, Ulrich, Peter, Bianchi, Marina
• Primary Examiner(s): Kumar, Shailendra
• Application Number:
  US08/632,305
• Time in Patent Office: 988 Days
• Field of Search: 514/596, 514/597, 514/632, 514/634, 514/636, 514/357, 514/825, 514/903, 514/614, 514/615, 514/616
• US Class Current: 514/615
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 31/175 having the group , >N—C(O)—N=N— or , e.g. carbonohydrazides, carbazones, semicarbazides, semicarbazones; Thioanalogues thereof
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/60 Salicylic acid; Derivatives thereof
• CPC Class Codes: A61K 31/621 having the hydroxy group in position 2 esterified, e.g. benorylate
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07C 275/38 being further substituted by doubly-bound oxygen atoms
• CPC Class Codes: C07C 275/40 being further substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 281/18 : the other nitrogen atom being further doubly-bound to a carbon atom, e.g. guanylhydrazones

Abstract

This invention concerns new methods and compositions that are useful in preventing and ameliorating cachexia, the clinical syndrome of poor nutritional status and bodily wasting associated with cancer and other chronic diseases. More particularly, the invention relates to aromatic guanylhydrazone (more properly termed amidinohydrazone) compositions and their use to inhibit the uptake of arginine by macrophages and/or its conversion to urea. These compositions and methods are also useful in preventing the generation of nitric oxide (NO) by cells, and so to prevent NO-mediated inflammation and other responses in persons in need of same. In another embodiment, the compounds can be used to inhibit arginine uptake in arginine-dependent tumors and infections, and autoimmune or other diseases in which activated macrophages are involved, such as septic shock, heumatoid arthritis and multiple sclerosis.

Claims

1. A method for treating multiple sclerosis (autoimmune encephalomyelitis) comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof having a formula:

##STR5## wherein;

X₂ =GhyCH--, GhyCCH₃ -- or H--;

X₁, X'"'"'₁ and X'"'"'₂, independently=GhyCH--, GhyCCH₃ --;

Z=--NH(CO)NH--, or --A--(CH₂),--A--, n=2-10; and

A=independently --NH(CO)--, --(CO)NH--, NH(CO)NH--, --NH-- or --O--.

2. The method of claim 1 wherein when X₂ is GhyCH-- or GhyCCH₃ --, X₂ is meta or para to X₁ and X'"'"'₂ is meta or para to X'"'"'₁.

3. The method of claim 2 wherein the compound is N,N'"'"'-bis(3,5-diacetylphenyl)decanediamide tetrakis(amidinohydrazone).

4. The method of claim 3 wherein the salt is a hydrochloride.

5. A method for treating arthritis comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof having a formula:

##STR6## wherein;

X₂ =GhyCH--, GhyCCH₃ -- or H--;

X₁, X'"'"'₁ and X'"'"'₂, independently=GhyCH--, GhyCCH₃ --;

Z=--NH(CO)NH--, or --A--(CH₂)_n --A--, n=2-10; and

A=independently --NH(CO)--, --(CO)NH--, NH(CO)NH--, --NH-- or --O--.

6. The method of claim 5 wherein when X₂ is GhyCH-- or GhyCCH₃ --, X₂ is meta or para to X₁ and X'"'"'₂ is meta or para to X'"'"'₁.

7. The method of claim 5 wherein the compound is N,N'"'"'-bis(3,5-diacetylphenyl)decanediamide tetrakis(amidinohydrazone).

8. The method of claim 5 wherein the salt is a hydrochloride.