Title:
USE OF 17-KETOSTEROIDS FOR THE TREATMENT OF MALARIA AND TRYPANOSOMIASIS
Document Type and Number:
WIPO Patent Application WO/2000/032201
Kind Code:
A2
Abstract:
The invention provides the use of 17-ketosteroid compounds, as well as derivatives, metabolites and precursors of such compounds, and pharmaceutically acceptable salts of any of these compounds, collectively defined herein as the 'compounds of the present invention', in the treatment of malaria, African Trypanosomiasis and American Trypanosomiasis, or to ameliorate or reduce one or more symptoms associated with a $i(Plasmodium) or $i(Trypanosoma) infection. The present invention is further directed to the use of such compounds in the treatment or prevention of one or more kind of parasites and/or one or more diseases caused by such parasites, against one or more kind of Mycoplasma and/or one or more diseases caused by such Mycoplasmas and/or against one or more of the following indications or infections: (a) hairy Leukoplakia, (b) oral candidosis, (c) mouth ulcerations-aphthous/herpetic/bacterial, (d) fungal candida, (e) human papilloma virus, (f) molluscum contagiosum, (g) squamous oral carcinoma, (h) Kaposi's sarcoma oral lesions, (i) periodontitis, (j) necrotizing gingivitis, (k) orafacial herpes zoster, and (1) rotaviruses, as well as all other indications and infections. The compounds of the present invention may also be used to ameliorate or reduce one or more symptoms associated with any infection or condition disclosed herein.
Inventors:
AHLEM CLARENCE NATHANIEL
FRINCKE JAMES MARTIN
PRENDERGAST PATRICK T
FRINCKE JAMES MARTIN
PRENDERGAST PATRICK T
Application Number:
PCT/US1999/028079
Publication Date:
June 08, 2000
Filing Date:
November 24, 1999
Export Citation:
Assignee:
HOLLIS EDEN PHARMACEUTICALS (US)
COLTHURST LTD (IE)
COLTHURST LTD (IE)
International Classes:
A61K31/353; A61K31/357; A61K31/56; A61K31/565; A61K31/566; A61P31/00; A61P33/00; A61P33/02; A61P33/06; C07J1/00; C07J3/00; (IPC1-7): A61K31/56; A61P33/02; A61P33/06
Domestic Patent References:
| WO1997038695A1 | 1997-10-23 | |||
| WO1998047516A1 | 1998-10-29 |
Foreign References:
| US4956355A | 1990-09-11 |
Attorney, Agent or Firm:
Hunt, Dale C. (Martens Olson & Bea, LLP 16th floor 620 Newport Center Drive
Newport Beach CA, US)
Download PDF:
Claims:
CLAIMS What is claimed is:
| 1. | A method to treat or prevent a Trypanosoma or Plasmodium infection, or to ameliorate one or more symptoms associated with a Trypanosoma or Plasmodium infection, in a subject suffering from or subject to a Trypanosoma or Plasmodium infection, comprising administering to the subject an effective amount of a compound having formula 1, wherein Q1 is C(R1)2 or C(O); Q2 isC (Rl) 2,C (Ri) (Y),C (Y) orCH2CH2 ; Q3 isH orC (Rl) 3; Q4 isC (RI) 2,C (O), hydroxyvinylidine or methyl methylene; Qs isC (RI) 2orC (O); X and Y independently areOH,H, lower alkyl,OC (O)R5, C (0)OR5, halogen or =0; each RI independently isH, halogen,OH, Cl6 alkoxy, or Cl 6 alkyl; R2 isH,OH, halogen, C 16 alkyl, C 16 alkoxy,OR3, an ester, a thioester, a thioacetal, a sulfate ester, a sulfate ester or a carbamate or R2, together with the RI that is bonded to the same carbon atom is =O; R3 isS (O) (O)OM,S (O) (O)OCH2CH (OC (O)R6)CH2OC (O)R6, P (O) (O)OCH2CH (OC (O)R7)CH2OC (O)R7, a glucuronide group of structure (A) or R3 is C 1 _ 1 g alkyl, C2_ i g alkenyl, C2 18 alkynyl, a Cl l8 ester or a C 118 thioester, where any of the foregoing Cri18 or C218 moieties are optionally substituted at one or more hydrogen atoms with one or more independently selectedORPR,NHRPR, orSRPR, groups, or R3 is a Ci. ig fatty acid, C210 alkynyl, (J) nphenylCI salkyl, (J) nphenylC25alkenyl; each Rs independently is straight or branched Cl 14 alkyl; each R6 independently is C I 14 straight or branched alkyl; and each R7 independently is Cl l4 straight or branched alkyl or a glucuronide group of structure (A); each RPR independently isH or an independently selected protecting group; nisO, 1, 2 or 3; each J independently is halogen, C I 4 alkyl, C2 4 alkenyl, C 14 alkoxy, carboxy, nitro, sulfate, sulfonyl, a C 16 carboxyl ester or a Cl 6 sulfate ester; M is hydrogen, sodium,S (O) (O)OCH2CH (OC (O)R6)CH2OC (O)R6,P (O) (O)O CH2CH (OC (O)R7)CH2OC (O)R7 or a glucuronide group of structure (A); and the dotted lines represent an optional double bond, provided that there are not double bonds at both the 45 and 56 positions and provided that when a double bond is present, zero or I RI group is bonded to carbon atoms at the 1, 2, 4, 5, 6or 17positions so that these carbon atoms are tetravalent; and the salts, stereoisomers, positional isomers, metabolites, analogs, precursors, hydrates, tautomers, ionized forms and solvates thereof. |
| 2. | The method of claim 1 wherein the Trypanosoma or Plasmodium infection is a Trypanosoma cruzi, Trypanosoma brucei, Trypanosoma gambiense, Trypanosoma rhodesiense, Trypanosoma brucei rhodesiense, Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale or a Plasmodium berghei infection. |
| 3. | The method of claim 2 wherein the formula 1 compound is one or more compounds selected from compound groups 121. |
| 4. | The method of claim 2 wherein the Trypanosoma or Plasmodium infection is a Trypanosoma cruzi infection. |
| 5. | The method of claim 4 wherein the formula 1 compound is one or more compounds selected from compound groups 121. |
| 6. | The method of claim 2 wherein the Trypanosoma or Plasmodium infection is a Plasmodium berghei or a Plasmodium falciparum infection. |
| 7. | The method of claim 5 wherein the subject is a human or a primate. |
| 8. | The method of claim 7 wherein the formula 1 compound is one or more compounds selected from compound groups 121. |
| 9. | The method of claim 8 wherein the formula 1 compound is 16abromo3 (3 hydroxy5aandrostan17one or 16abromodehydroepiandrosterone. |
| 10. | The method of claim I wherein the subject is coinfected with a retrovirus. |
| 11. | The method of claim 10 wherein the subject is a human and the retrovirus is HIV1 or HIV2. |
| 12. | The method of claim 1 wherein the formula 1 compound has the formula 1B or 1C IB 1C wherein, each RI independently isH,OH, a halogen,CHCH2,CHCHCH3,CCH,CCCH3, or, the other moiety that is bonded to the same carbon atom is absent and RI is =O; R2 isOC (O)R4,SC (O)R4,OS (O) (O)R4,OS (O) (O)OR4,OC (O)NHR4, orO C(S)R4; R4 isH, a protecting group, optionally substituted Cl 18 alkyl, optionally substituted Cl 18 alkenyl, optionally substituted C 1 _ 1 g alkynyl, optionally substituted aryl, optionally substituted aryiC 16 alkyl, optionally substituted arylC26 alkenyl, optionally substituted arylC2 6 alkynyl, optionally substituted heterocycleCI 6 alkyl, optionally substituted C26 alkenylheterocycle, optionally substituted C26 alkynylheterocycle or an optionally substituted heterocycle, where any of the foregoing moieties are optionally substituted at one, two, three, four, five or more carbon or hydrogen atoms with one or more independently selectedO,S,NRPR,ORPR,NHRPR, SRPR, =O, =S,CN,N02,F,Cl,Br orI groups or atoms; and each RPR independently isH or an independently selected protecting group; Q2 isC (RI) 2 ; and Q3 and Q6 independently areH,CH3 orCH20H. |
| 13. | The method of claim 12 wherein Q3 and Q6 are bothCH3 in the (3configuration; and Q2 isCH2,C (O),CH (Br),CH (I), orCH (OH) with the Br, I or OH moieties in the aconfiguration, or Q2, together with the hydrogen atom that is bonded to the same carbon atom comprisesC (O) orCH2CH2 ; and R at the 7position isH,OH or, when taken with the hydrogen atom that is bonded to the same carbon atom, Rl is =O. |
| 14. | The method of claim 1 wherein the formula I compound has the formula 1A wherein, R2 isOH, halogen, Ci. alkoxy,OR3, a C l 18 fatty acid, C I 10 alkynyl, (J) nphenyl C15alkyl, (J) nphenytCj. 5atkeny), an ester optionally selected from OC (O) (CH2) mR4 and C (O)O (CH2) mR4, or R2 isSC (O)(CH2)mR4, C(O)S(CH2)mR4, OS(O)(O)(CH2)m R4,0S (O) (O)O (CH2) mR4,0C (O)NH (CH2) mR4,NHC (O)O (CH2) mR4,OC (S) (CH2) mR4,C (S)O(CH2) mR4,OC (O)(CH2) mR4 orC(O)O(CH2)mR4, or R2, together with the RI that is bonded to the same carbon atom is =O; R4 isH, a protecting group, optionally substituted Cl l8 alkyl, optionally substituted C2 18 alkenyl, optionally substituted C2 18 alkynyl, optionally substituted aryl, optionally substituted arylCI 6 alkyl, optionally substituted arylC2 6 alkenyl, optionally substituted arylC26 alkynyl, optionally substituted heterocycleCI 6 alkyl, optionally substituted C26 alkenylheterocycle, optionally substituted C26 alkynylheterocycle or an optionally substituted heterocycle, where any of the foregoing moieties are optionally substituted at one, two, three, four, five or more carbon or hydrogen atoms with one or more independently selectedO,S,NRPR,ORPR,NHRPR, SRPR, =O, =S,CN,N02,F,Cl,Br orI groups or atoms; each RPR independently isH or an independently selected protecting group; m is 0, 1, 2 or 3; and the dotted line is an optional double bond. |
| 15. | The method of claim 1 wherein the formula 1 compound has the formula 45 wherein, R50 isH,OH or =0; R51 is Br, Cl, F, I orOH; R52 isOH or, R52, together with theH bonded to the same position, is =O; R49 isH,OH, orOR53; R53 is C 1. 1 g alkyt, C218 alkenyl, C218 alkynyl, a CI18 ester, a CI18 thioester, wherein any of the foregoing Ci. ig or C218 groups is substituted at one or more hydrogen or carbon atoms with one or more independently selectedO,S,OH,NH2,SH or =O groups or R53 is a thioacetal, a sulfate ester, a sulfate ester, a carbamate or a thioester; and the dotted line is an optional double bond. |
| 16. | The method of claim 15 wherein R49 isOC (O)CH2CH2CH (R54)CH (R55) CH2R56 wherein R54 isNH2,OH,SH,OP03,S03 orOS03; R55 isH,NH2,OH,SH, OP03,S03 orOS03; and R56 is C I 18 alkyl, C2 18 alkenyl, C218 alkynyl, a C I 18 ester or a Ci. ig thioester, wherein any of the foregoing Ci. ig or C218 groups is substituted at one or more hydrogen atoms with one or more independently selectedOH,NH2,SH or =O groups. |
| 17. | The method of claim 1 wherein the formula 1 compound has the formula 44 wherein, Y is hydrogen or a halogen; R44 isH,S (O) (O)OH,S (O) (O)ONa,S (O) (O)OCH2CH (OC (O)R6)CH2OC (O) R6,P (O) (O)OCH2CH (OC (O)R7)CH2OC (O)R7 or a glucuronide group of structure (A); and the dotted line is an optional double bond. |
| 18. | The method of claim 17 wherein the formula 44 compound is dehydroepiandrosterone, epiandrosterone, 16abromoepiandrosterone, 16a bromodehydroepiandrosterone, dehydroepiandrosterone3sulfate or 5$androstan3 Fol17one. |
| 19. | The method of claim 1 wherein the method further comprises simultaneously or sequentially administering an effective amount a plasma concentrationenhancing compound selected from bavachinin A, didymin, flavanomarein, flavanone azine, flavanone diacetylhydrazone, flavanone hydrazone, silandrin, silybin, silychristin, isosilybin, a compound having the structure (E) and a compound of formula 2A or 2B wherein a double or a single bond is present at the dotted line and when a double bond is present (i) the optionally substituted phenyl ring at the 2or 3position is present and the R8 that is bonded to the carbon is absent, and (ii) one R8 at the adjacent 2or 3position is absent; Xi isOorC (R8) 2 ; X2 isC (O)orC (Rl 1) 2; each R8 independently isH,OH, halogen, C 16 alkyl, C 16 alkoxy, glucuronide, a C 125 fatty acid, the residue of a formula 2A or 2B compound where a hydrogen atom is removed to form the formula 2A or 2B compound radical,CH2CH=C (CH3) 2, glucoside, a group having structure (B) or (C), RI 0 is C 16 alkyl, C 16 alkoxy, neohesperidoside, apioglucoside, rutinoside, glucoside, galactoside, rhamnoside, arabinoside, or a stereoisomer, hydrate, analog, derivative or metabolite of any of these moieties, any of which are optionally independently substituted at one or more hydrogen atoms withOH, halogen, C 16 alkyl, C 16 alkoxy, glucuronide or a C 1. 25 fatty acid or RIO isH,OH or halogen; each RI l independently isH,OH, halogen, C 16 alkyl, C 16 alkoxy, a glucuronide group of structure (A), a C 125 fatty acid, or both Rl l together are =O; and the salts, stereoisomers, positional isomers, metabolites, analogs, precursors, hydrates, tautomers, ionized forms and solvates thereof. |
| 20. | The method of claim 19 wherein the plasma concentrationenhancing compound is naringin or naringenin. |
| 21. | The method of claim 20 wherein the subject is a human or a primate. |
| 22. | The method of claim 21 wherein the formula 1 and the plasma concentration enhancing compound are administered simultaneously. |
| 23. | The method of claim 19 further comprising administering to the subject, or treating the subject with, one or more of ribavirin, alpha interferon, a macrophage stimulating factor, an oxidation agent and oxygen ventialtion. |
| 24. | The method of claim 23 wherein the plasma concentrationenhancing compound is naringin or naringenin. |
| 25. | The method of claim 24 wherein the subject is a human or a primate. |
| 26. | The method of claim 25 wherein the formula 1 compound and the plasma concentrationenhancing compound are administered simultaneously. |
| 27. | The method of claim 1 wherein 2,3,4,5 or 6 Ri are not hydrogen. |
| 28. | The method of claim 27 wherein the 2,3,4,5 or 6 Ri that are not hydrogen are independently selected fromOH, halogen and C2 4 alkoxy. |
| 29. | A method to treat or prevent a Trypanosoma, Plasmodium or Mycoplasma infection, or to ameliorate one or more symptoms associated with a Trypanosoma, Plasmodium or Mycoplasma infection, in a subject suffering from or subject to a Trypanosoma, Plasmodium or Mycoplasma infection, comprising administering to the subject an effective amount of a composition comprising 16abromoepiandrosterone, and 2,3,4 or 5 excipients selected from polyethylene glycol, dehydrated ethanol, benzyl benzoate, benzyl alcohol and propylene glycol, wherein the composition optionally comprises less than about 3% v/v, or less than about 1% v/v, or less than about 0.5% v/v of water, or less than about 0.1% v/v of water. |
| 30. | The method of claim 29 wherein the composition comprises 16a bromoepiandrosterone at a concentration of about 4555 mg/mL, 2030% v/v polyethylene glycol 300, polyethylene glycol 400 or a mixture of polyethylene glycol 300 and 400,1015% v/v dehydrated ethyl alcohol, 2.57.5% v/v benzyl benzoate, and 5560% v/v propylene glycol. |
| 31. | The method of claim 30 wherein the composition comprises 16a bromoepiandrosterone at a concentration of about 50 mg/mL, about 25% v/v polyethylene glycol 300, about 12.5% v/v dehydrated ethyl alcohol, about 5% v/v benzyl benzoate, about 57.5% v/v propylene glycol and less than about 0.5% v/v water. |
| 32. | The method of claim 29 wherein the composition comprises 16a bromoepiandrosterone at a concentration of about 85105 mg/mL, about 2733% w/w benzyl benzoate, about 2733% w/w polyethylene glycol 300, about 2530% w/w propylene glycol and about 13% w/w benzyl alcohol. |
| 33. | The composition of claim 32 wherein the composition comprises 16a bromoepiandrosterone at a concentration of about 100 mg/mL, about 30.4% w/w benzyl benzoate, about 30.7% w/w polyethylene glycol 300, about 28% w/w propylene glycol and about 1.9% w/w benzyl alcohol. |
| 34. | A method to enhance phagocytosis of Plasmodium or Trypanosoma infected cells in an infected subject comprising administering to the infected subject an effective amount of a compound of formula I wherein Q isC (RI) 2orC (O); Q2 iSC (RI) 2,C (RI) (Y),C (Y)orCH2CH2; Q3 isH orC (RI) 3 ; Q4 isC (RI) 2,C (O), hydroxyvinylidine or methyl methylene; Qs isC (RI) 2orC (O); X and Y independently areOH,H, lower alkyl,0C (O)R5, C (0)OR5, halogen or =0; each RI independently isH, halogen,OH, C 16 alkoxy, or C 16 alkyl; R2 isH,OH, halogen, C 16 alkyl, C 16 alkoxy,OR3, an ester, a thioester, a thioacetal, a sulfate ester, a sulfonate ester or a carbamate or R2, together with the RI that is bonded to the same carbon atom is =O; R3 isS (O) (O)OM,S (O) (O)OCH2CH (OC (O)R6)CH2OC (O)R6, P (O) (O)OCH2CH (OC (O)R7)CH2OC (O)R7, a glucuronide group of structure (A) or R3 is C I 18 alkyl, C2 18 alkenyl, C2 18 alkynyl, a C I18 ester or a Cl. tu thioester, where any of the foregoing C 118 or C218 moieties are optionally substituted at one or more hydrogen atoms with one or more independently selectedORPR,NHRPR, orSRPR, groups, or R3 is a C118 fatty acid, C210 alkynyl, (J) nphenylCl 5alkyl, (J) nphenylC2salkenyl; each Rs independently is straight or branched Cl l4 alkyl; each R6 independently is Cl l4 straight or branched alkyl; and each R7 independently is C I14 straight or branched alkyl or a glucuronide group of structure (A); each RPR independently isH or an independently selected protecting group; n is 0, 1, 2 or 3; each J independently is halogen, C l 4 alkyl, C2 4 alkenyl, C 14 alkoxy, carboxy, nitro, sulfate, sulfonyl, a C 16 carboxyl ester or a Cl6 sulfate ester; M is hydrogen, sodium,S (O) (O)OCH2CH (OC (O)R6)CH2OC (O)R6,P (O) (O)O CH2CH (OC (O)R7)CH2OC (O)R7 or a glucuronide group of structure (A); and the dotted lines represent an optional double bond, provided that there are not double bonds at both the 45 and 56 positions and provided that when a double bond is present, zero or 1 RI group is bonded to carbon atoms at the 1, 2, 4, 5, 6or 17positions so that these carbon atoms are tetravalent; and the salts, stereoisomers, positional isomers, metabolites, analogs, precursors, hydrates, tautomers, ionized forms and solvates thereof. |
| 35. | The method of claim 34 wherein the formula 1 compound is a 16 haloepiandrosterone or a 16halodehydroepiandrosterone. |
| 36. | The method of claim 35 wherein the 16haloepiandrosterone or 16halo dehydroepiandrosterone is 16abromoepiandrosterone or 16abromodehydroepiandrosterone. |
Description:
FURTHERINFORMAMON CONnNUEDFROM PCTASA/210 Continuation of Box 1.2 Claims Nos.: 34 The present claims do not meet the requirements of Art. 6 PCT, because they relate to an extremely large number of possible compounds. They contain so many options, variables and possible permutations that a meaningful search over the whole of the claimed scope is impossible.
Furthermore, support within the meaning of Article 6 PCT and disclosure within the meaning of Article 5 PCT is to be found for only a very small proportion of the compounds claimed.
Consequently, the search had to be limited to the general inventive concept (i. e. the use of 17-ketosteroids, in particular derivatives of dehydroepiandrosterone) and to those parts of the claims which appear to be clear, supported and disclosed, namely claims 9,17,18,29-33,35 and 36 It should also be noted in this respect that claim 33 is erroneously directed to a composition and that although claim 29 and dependent claims thereof mention the treatment of mycoplasma infection, which is not a parasitic infection, this subject-matter was also mentioned in the documents retrieved during the limited search. An objection of lack of unity of invention is therefore not raised.
The applicant's attention is drawn to the fact that claims, or parts of claims, relating to inventions in respect of which no international search report has been established need not be the subject of an international preliminary examination (Rule 66.1 (e) PCT). The applicant is advised that the EPO policy when acting as an International Preliminary Examining Authority is normally not to carry out a preliminary examination on matter which has not been searched. This is the case irrespective of whether or not the claims are amended following receipt of the search report or during any Chapter II procedure. INTERNATIONALSEARCHREPORT..------- ! lsOmssnon petwd fimily mornbom PCT/US99/28079 PatentdocumentPublicationPatent family Publication ciSd in seafch repon dste member (s) dFe US4956355A11-09-1990AT 401470 B 25-09-1996 AT 98488 A 15-02-1996 AU 608824 B 18-04-1991 AU 1467888 A 20-10-1988 BE 1004315 A 03-11-1992 CA 1325594 A 28-12-1993 CH 675358 A 28-09-1990 DE 3812595 A 27-10-1988 DK 208188 A 17-10-1988 FI 881773 A 17-10-1988 FR 2615394 A 25-11-1988 GB 2204237A,B 09-11-1988 GR 88100248A,B 31-01-1989 IL 86089 A 15-11-1992 IT 1227073 B 14-03-1991 JP 1025722 A 27-01-1989 JP 2577771 B 05-02-1997 KR 9614988 B 23-10-1996 LU 87202 A 17-11-1988 NL 8800926 A 16-11-1988 NZ 224272 A 25-09-1991 NZ 236303 A 27-07-1997 OA 8729 A 31-03-1989 PH 25907 A 19-12-1991 PT 87259A,B 01-05-1988 SE 503482 C 24-06-1996 SE 8801406 A 17-10-1988 ZA 8802667 A 28-12-1988 WO9738695A23-10-1997AU 2574197 A 07-11-1997 CA 2251733 A 23-10-1997 CN 1216470 A 12-05-1999 EP 0901375 A 17-03-1999 NO 984851 A 17-12-1998 WO9847516A29-10-1998AU 2574197 A 07-11-1997 EP 0901375 A 17-03-1999 NO 984851 A 17-12-1998