Use of colchinol derivatives as vascular damaging agents

• US 6,423,753 B1
• Filed: 01/05/2000
• Issued: 07/23/2002
• Est. Priority Date: 07/08/1997
• Status: Expired due to Fees

• Current Assignee: Angiogene Pharmaceuticals Ltd.
• Original Assignee: Angiogene Pharmaceuticals Ltd.
• Inventors: Dougherty, Graeme
• Primary Examiner(s): Lambkin, Deborah C.
• Application Number:
  US09/477,805
• Time in Patent Office: 930 Days
• Field of Search: 568/733, 568/660, 514/719, 514/721, 514/729
• US Class Current: 514/719
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• 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 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/27 of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• CPC Class Codes: A61K 31/661 Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 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 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07C 217/74 with rings other than six-membered aromatic rings being part of the carbon skeleton
• CPC Class Codes: C07C 233/23 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2603/32 Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes
• CPC Class Codes: C07C 271/24 with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 275/28 : having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
• CPC Class Codes: C07C 307/08 : having nitrogen atoms of the sulfamide groups bound to carbon atoms of rings other than six-membered aromatic rings
• CPC Class Codes: C07C 311/07 : having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07F 9/12 : with hydroxyaryl compounds

Abstract

Colchinol derivatives of formula

wherein

R₁, R₂, R₃ and R₆ are each independently H, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, alkanoyl, PO₃H₂; X is carbonyl (CO), thiocarbonyl (CS), methylene (CH₂) or a group CHR₄; R₄ is OH, O-alkyl or NR₈R₉; R₅ and R₇ are each independently H, alkyl, halogen, hydroxy, alkoxy, nitro or amino; R₈ is H, optionally substituted alkyl, cycloalkyl, alkanoyl, thioalkanoyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylsulphonyl, arylsulphonyl, aminosulphonyl, alkylaminosulphonyl, dialkylaminosulphonyl or arylaminosulphonyl; and R₉ is H, alkyl or cycloalkyl; and the pharmaceutically acceptable salts, solvates, and hydrates thereof have been found to be useful for treatment of diseases involving angiogenesis. Some of these compounds are novel. Particularly preferred are those compounds in which R₆ is PO₃H₂.

Claims

1. A method for the treatment of a disease where inappropriate angiogenesis occurs in a warm-blooded animal comprising administering to said animal a compound of the formula

wherein

R₁, R₂, R₃ and R₆ are each independently H, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, alkanoyl, PO₃H₂;

X is carbonyl (CO), thiocarbonyl (CS), methylene (CH₂) or a group CHR₄;

R₄ is OH, O-alkyl or NR₈R₉;

R₅ and R₇ are each independently H, alkyl, halogen, hydroxy, alkoxy, nitro or amino;

R₈ is H, optionally substituted alkyl, cycloalkyl, alkanoyl, thioalkanoyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylsulphonyl, arylsulphonyl, aminosulphonyl, alkylaminosulphonyl, dialkylaminosulphonyl or arylaminosulphonyl; and

R₉ is H, alkyl or cycloalkyl;

and the pharmaceutically acceptable salts, solvates and hydrates thereof.

2. The method according to claim 1 wherein at least one of R₁, R₂, R₃ and R₆ is PO₃H₂.

3. The method according to claim 2 wherein R₆ is PO₃H₂.

4. The method according to any one of claims 1 to 3 in which R₁, R₂ and R₃ are alkyl.

5. The method according to any one of claims 1 to 3 in which R₄ is acylamino.

6. The method according to claim 1 in which R₆ is PO₃H₂, R₁, R₂ and R₃ are alkyl and R₄ is acylamino.

7. A compound of the formula

wherein

R₁, R₂, R₃ and R₆ are each independently H, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, alkanoyl or PO₃H₂, provided that at least one of R₁, R₂, R₃ and R₆ is PO₃H₂;

X is carbonyl (CO), thiocarbonyl (CS), methylene (CH₂) or a group CHR₄;

R₄ is OH, O-alkyl or NR₈R₉;

R₅ and R₇ are each independently H, alkyl, halogen, hydroxy, alkoxy, nitro or amino;

R₈ is H, optionally substituted alkyl, cycloalkyl, alkanoyl, thioalkanoyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylsulphonyl, arylsulphonyl, aminosulphonyl, alkylaminosulphonyl, dialkylaminosulphonyl or arylaminosulphonyl; and

R₉ is H, alkyl or cycloalkyl;

and pharmaceutically acceptable salts, solvates, and hydrates thereof.

8. The compound according to claim 7 in which R₆ is PO₃H₂.

9. The compound according to claim 8 in which R₁, R₂ and R₃ are alkyl and R₄ is acylamino.

10. A compound of the formula

wherein

R₁, R₂ and R₃ are each independently H, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, alkanoyl, or PO₃H₂;

R₆ is PO₃H₂;

R₄ is H or NR₈R₉;

R₅ and R₇ are each independently H, alkyl, halogen, alkoxy, nitro or amino;

R₈ is H, optionally substituted alkyl, cycloalkyl, alkanoyl, thioalkanoyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylsulphonyl, arylsulphonyl, aminosulphonyl, alkyaminosulphonyl, dialkylaminosulphonyl or arylaminosulphonyl; and

R₉ is H, alkyl or cycloalkyl;

and pharmaceutically acceptable salts, solvates and hydrates thereof.

13. A pharmaceutical composition comprising a compound according to any one of claims 7 to 12 and a pharmaceutically acceptable excipient.

14. A pharmaceutical composition according to claim 13 wherein the compound is N-acetylcolchinol-O-phosphate.

16. A process for the preparation of a compound of formula II or IIA as claimed in claim 10 or 11, said process comprising treatment of a compound of formula (2) with alkaline hydrogen peroxide

wherein R₁, R₂, R₃, R₄, R₅, R₆ and R₇ are as defined in claim 10 or 11.

11. A compound of the formula

wherein

R₁, R₂ and R₃ are each independently H, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, alkanoyl or PO₃H₂;

R₆ is H, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl or PO₃H₂;

R₄ is H or NR₈R₉;

R₅ and R₇ are each independently H, alkyl, halogen, nitro or amino;

R₈ is H, optionally substituted alkyl, cycloalkyl, alkanoyl, thioalkanoyl, aryl, heteroaryl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, alkylsulphonyl, arylsulphonyl, aminosulphonyl, alkylaminosulphonyl, dialkylaminosulphonyl or arylaminosulphonyl; and

R₉ is H, alkyl or cycloalkyl;

with the proviso that, when R₁, R₂ and R₃ are all methyl groups and R₄ is hydrogen, acetylamino, acetylmethylamino, amino, methylamino or dimethylamino then R₆ is not hydrogen, methyl, hydroxyethyl, or acetoxyethyl;

and pharmaceutically acceptable salts, solvates and hydrates thereof.

12. A compound according to claim 11 in which R₁, R₂ and R₃ are alkyl and R₄ is acylamino.

15. The compound N-acetylcolchinol-O-phosphate, or a salt, solvate or hydrate thereof.