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Title:
USE OF 17-KETOSTEROIDS FOR THE TREATMENT OF TOXOPLASMOSIS AND CRYPTOSPORIDOSIS
Document Type and Number:
WIPO Patent Application WO/2000/032176
Kind Code:
A2
Abstract:
The invention provides the use of 17-ketosteroid compounds, e.g., 16$g(a)-bromoepiandrosterone, 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', to treat or prevent Toxoplasmosis or Cryptosporidiosis in patients in need of such treatment or prophylaxis. The formula (1) compounds can also be used to ameliorate or reduce one or more symptoms associated with such infections.

Inventors:
AHLEM CLARENCE NATHANIEL
FRINCKE JAMES MARTIN
PRENDERGAST PATRICK T
THADIKONDA KRUPAKAR PAUL
Application Number:
PCT/US1999/028080
Publication Date:
June 08, 2000
Filing Date:
November 24, 1999
Export Citation:
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Assignee:
HOLLIS EDEN PHARMACEUTICALS (US)
International Classes:
A61K31/565; C07J1/00; C07J3/00; (IPC1-7): A61K31/00
Domestic Patent References:
WO1997038695A11997-10-23
WO1998047516A11998-10-29
Foreign References:
US4956355A1990-09-11
Other References:
K.R. RASMUSSEN: "Effects of dehydroepiandrosterone in immunosuppressed adult mice infected with Cryptosporidium parvum" J. PARASITOL., vol. 81, no. 3, 1995, pages 429-433, XP000922937
Attorney, Agent or Firm:
Hunt, Dale C. (Martens Olson & Bea, LLP 16th floor 620 Newport Center Drive Newport Beach CA, US)
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Claims:
CLAIMS What is claimed is:
1. A method to treat or prevent a Toxoplasma or Cryptosporidium infection in a subject, or to ameliorate or reduce one or more symptoms of a Toxoplasma or Cryptosporidium infection, comprising administering to a subject an effective amount of a compound having formula 1, wherein Q1 is C(R1)2 or C(O); Q2 isC (Ri) 2,C (' (Y),C (Y)orCH2CH2 ; Q3 isH orC (R1) 3; Q4 isC (R1) 2,C (O), hydroxyvinylidine or methyl methylene; Qs isC (R1) 2orC (O); X and Y independently areOH,H, lower alkyl,0C (O)R5, C (0)OR5, halogen or =0; each R I independently isH, halogen,OH, C16 alkoxy, or C16 alkyl; R2 isH,OH, halogen, C1 6 alkyl, C1 6 alkoxy,OR3, an ester, a thioester, a thioacetal, a sulfate ester, a sulfonate ester or a carbamate or R2, together with the R1 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 118 alkyl, C2 18 alkenyl, C218 alkynyl, a Ci. ig ester or a C 118 thioester, where any of the foregoing Ci. ig 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. is fatty acid, C210 alkynyl, (J) nphenylCi. 5aIkyl, (J) nphenylC25alkenyl; each Rs independently is straight or branched C1 l4 alkyl; each R6 independently is C 1. 14 straight or branched alkyl; and each R7 independently is C I _ 14 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 14 alkyl, C 14 alkenyl, C 14 alkoxy, carboxy, nitro, sulfate, sulfonyl, a C 16 carboxyl ester or a C 16 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 R1 group is bonded to carbon atoms at the 1, 2, 4, 5, 6or 17 positions 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 Toxoplasma or Cryptosporidium infection is a Toxoplasma 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 Toxoplasma or Cryptosporidium infection is an infection caused by one or more of Cryptosporidium parvum, and Toxoplasma gondii.
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 5 wherein the subject is a human or a primate.
7. The method of claim 6 wherein the formula 1 compound is one or more compounds selected from compound groups 121.
8. The method of claim 7 wherein the formula 1 compound is 16abromo3> hydroxySaandrostan17one or 16abromodehydroepiandrosterone.
9. The method of claim 1 wherein the subject is coinfected with a retrovirus.
10. The method of claim 10 wherein the subject is a human, a primate or a feline and the retrovirus is HIV1, HIV2, SIV, SHIV or FIV.
11. The method of claim 1 wherein the formula 1 compound has the formula 1B or 1C wherein, each R1 independently isH,OH, a halogen,CHCH2,CHCHCH3,CCH,CCCH3, or, RI, together with the hydrogen atom that is bonded to the same carbon atom comprises =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 C1l8 alkyl, optionally substituted Ci.
12. 18 alkenyl, optionally substituted C 1 _ 1 g alkynyl, optionally substituted aryl, optionally substituted arylC 16 alkyl, optionally substituted arylC2 6 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 11 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 comprisesC (O) orCH2CH2 ; and RI at the 7position isH,OH or, when taken with the hydrogen atom that is bonded to the same carbon atom, RI is =O.
14. The method of claim 1 wherein the formula 1 compound has the formula 1A wherein, R2 isOH, halogen, C1 6 alkoxy,OR3, a C I18 fatty acid, C1 lu alkynyl, (J) nphenyl C 1 salkyl, (J) nphenylC 1 salkenyl, an ester optionally selected from OC(O)(CH2)mR4 and C (O)O (CH2) mR4, or R2 isSC (0)(CH2)mR4.C(0)S(CH2)mR4'0S(0)(0)(CH2) m R4,OS (O) (O)O(CH2) mR4,OC (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 group that is bonded to the same carbon atom is =O; R4 isH, a protecting group, optionally substituted C 118 alkyl, optionally substituted C2 18 alkenyl, optionally substituted C2 18 alkynyl, optionally substituted aryl, optionally substituted arylC 16 alkyl, optionally substituted arylC2 6 alkenyl, optionally substituted arylC26 alkynyl, optionally substituted heterocycleC1 6 alkyl, optionally substituted C26 alkenylheterocycle, optionally substituted C2 6 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 selected O, 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, 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 isBr,Cl,F,I orOH; R52 isOH or, R52, together with theH bonded to the same position, is =O; R49 isH,OH, orOR53; R53 is C1l8 alkyl, C2 18 alkenyl, C2 18 alkynyl, a C 1 _ 1 g ester, a Ci. ig thioester, wherein any of the foregoing Ci. jg or C2 18 groups is substituted at one or more hydrogen atoms with one or more independently selectedO,S,OH,NH2,SH or =O groups or R53 is a thioacetal, a sulfate ester, a sulfonate ester, a carbamate or a thioester; and the dotted line is an optional double bond.
16. The method of claim 14 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 1 _ 18 alkyl, C218 alkenyl, C218 alkynyl, a CI18 ester or a C 118 thioester, wherein any of the foregoing C 1 18 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 16 wherein the formula 44 compound is dehydroepiandrosterone, epiandrosterone, 16abromoepiandrosterone, 16a bromodehydroepiandrosterone, dehydroepiandrosterone3sulfate or 5pandrostan3pol17one.
19. The method of claim 17 wherein the formula 44 compound is 16a bromoepiandrosterone.
20. A method comprising (1) contacting a formula 1 compound and polyethylene glycol to obtain a mixture, (2) vortexing the mixture to form a smooth liquid, (3) contacting additional propylene glycol to the smooth liquid and vortexing to form a uniform suspension, (3) contacting benzyl benzoate with the uniform suspension and vortexing to form a liquid, (4) contacting ethanol with the liquid and vortexing to form a solution; and (5) optionally contacting the solution more propylene glycol to form a formulation.
21. The method of claim 19 wherein the formula 1 compound is dehydroepiandrosterone, epiandrosterone, 16abromoepiandrosterone, 16a bromodehydroepiandrosterone, dehydroepiandrosterone3sulfate or 5 Sandrostan3 Sol17one.
22. The method of claim 20 wherein the formula 1 compound is 16a bromoepiandrosterone.
23. The method of claim 21 wherein the formulation comprises about 4060 mg/mL 16abromoepiandrosterone.
24. The method of claim 22 wherein the formulation comprises about 50 mg/mL 16a bromoepiandrosterone, about 25% polyethylene glycol 300 v/v, about 12.5% dehydrated ethyl alcohol v/v, 5% benzyl benzoate v/v, and 57.5% propylene glycol v/v.
25. A composition comprising about 90110 mg/mL of 16abromoepiandrosterone, about 2733% benzyl benzoate w/w, about 2834% polyethylene glycol 300, about 2531% w/w, propylene glycol, and about 13% w/w benzyl alcohol.
26. The composition of claim 24 comprising about 100 mg/mL of 16a bromoepiandrosterone, about 30.4% benzyl benzoate w/w, about 30.7% polyethylene glycol 300, about 28% w/w, propylene glycol, and about 1.9% w/w benzyl alcohol.
27. A method to treat or prevent a Toxoplasma or Cryptosporidium infection, or to ameliorate one or more symptoms associated with a Toxoplasma or Cryptosporidium infection, in a subject suffering from or subject to a Toxoplasma or Cryptosporidium infection, comprising administering to the subject an effective amount of a composition comprising 16a bromoepiandrosterone, 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.
28. The method of claim 26 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.
29. The method of claim 27 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.
30. The method of claim 26 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.
31. The composition of claim 29 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.
32. The method of claim 1 wherein 2,3,4,5 or 6 RI are not hydrogen.
33. The method of claim 31 wherein the 2,3,4,5 or 6 R1 that are not hydrogen are independently selected fromOH, =O, halogen and C2 4 alkoxy.
Description:
INTERNATIONAL SEARCH REPORT _ Inta onal Applicatlon No PCT/US 99/28080 C. (Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category = Citat on of document, with indication, where appropriate, of the relevant passages Relevant to daim No. X, Y WO 98 47516 A (PRENDERGAST PATRICK T) 8,16-30 29 October 1998 (1998-10-29) abstract page 6, line 18-page 7, line 2; claims FURTHER INFORMATION CONTINUED FROM PCT/ISA/210 Continuation of Box 1.2 Claims Nos.: 1-7,9-15,31,32 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 none 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 and concise, namely claims 8,16-30 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. INTERNATIONAL SEARCH REPORT r----------------- inte jnat Appttcatton No mtormatlon on patenttamily membws PCT/US 99/28080 Patent document Publication Patent family Publication cited in search report date member (s) date US 4956355 A 11-09-1990 AT 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 2204237 A, B 09-11-1988 GR 88100248 A, 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 87259 A, B 01-05-1988 SE 503482 C 24-06-1996 SE 8801406 A 17-10-1988 ZA 8802667 A 28-12-1988 WO 9738695 A 23-10-1997 AU 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 WO 9847516 A 29-10-1998 AU 2574197 A 07-11-1997 EP 0901375 A 17-03-1999 NO 984851 A 17-12-1998