Title:
POLY(DIALLYLAMINE)-BASED BILE ACID SEQUESTRANTS
Document Type and Number:
WIPO Patent Application WO/1998/029107
Kind Code:
A2
Abstract:
The present invention relates to a method for removing bile acids from a patient and certain polymers of use in the method. The method comprises the step of administering to the patient a therapeutically effective amount of a polymer composition which includes a poly(diallylamine) polymer which is substituted with hydrophobic groups. The hydrophobic groups can be a substituted or unsubstituted, straight chain or branched C�3?-C�24?-alkyl group, an aralkyl group or an aryl group.
Inventors:
HOLMES-FARLEY STEPHEN RANDALL (US)
DHAL PRADEEP K (US)
PETERSEN JOHN S (US)
DHAL PRADEEP K (US)
PETERSEN JOHN S (US)
Application Number:
PCT/US1997/023899
Publication Date:
July 09, 1998
Filing Date:
December 29, 1997
Export Citation:
Assignee:
GELTEX PHARMA INC (US)
HOLMES FARLEY STEPHEN RANDALL (US)
DHAL PRADEEP K (US)
PETERSEN JOHN S (US)
HOLMES FARLEY STEPHEN RANDALL (US)
DHAL PRADEEP K (US)
PETERSEN JOHN S (US)
International Classes:
A61K31/785; A61K31/787; A61K31/795; A61K47/48; A61P3/06; A61P9/10; A61P43/00; C08F26/04; C08G61/12; (IPC1-7): A61K31/00
Foreign References:
| US4759923A | 1988-07-26 | |||
| EP0401705A2 | 1990-12-12 | |||
| DE4002825A1 | 1990-08-02 | |||
| EP0280445A1 | 1988-08-31 | |||
| JPS5610531A | 1981-02-03 | |||
| JPH021358A | 1990-01-05 | |||
| JPS62257481A | 1987-11-10 | |||
| JPS62170591A | 1987-07-27 | |||
| JPS5747302A | 1982-03-18 | |||
| JPS57125233A | 1982-08-04 | |||
| US4360434A | 1982-11-23 | |||
| US3585118A | 1971-06-15 | |||
| US4027009A | 1977-05-31 |
Other References:
MCLEAN ET AL.: "Cyclopolymerization. VI. Preparation and properties of Crosslinked Polyamines by Cyclopolymerization" J. MACROMOL. SCI.-CHEM., vol. A10, no. 5, 1976, pages 857-873, XP002068701
BOLTO ET AL.: "Synthesis of Cross-Linked Polyallylamines Which Are Resistant to Sulfite Attack" J. MACROMOL. SCI.-CHEM., vol. A17, no. 1, 1982, pages 153-166, XP002068702
BOLTO ET AL.: "Synthesis of Cross-Linked Polyallylamines Which Are Resistant to Sulfite Attack" J. MACROMOL. SCI.-CHEM., vol. A17, no. 1, 1982, pages 153-166, XP002068702
Attorney, Agent or Firm:
Elmore, Carolyn S. (Brook Smith & Reynolds, P.C., Two Militia Driv, Lexington MA, US)
Download PDF:
Claims:
CLAIMSWhat is claimed is:
| 1. | A method for removing bile acids from a patient comprising the step of. administering to the patient a therapeutically effective amount of a poly(diallylamine) polymer wherein more than 10% of the amino nitrogen atoms are substituted by a hydrophobic substituent. |
| 2. | The method of Claim 1 wherein the polymer is a homopolymer. |
| 3. | The method of Claim 1 wherein the polymer is a copolymer. |
| 4. | The method of Claim 1 wherein the hydrophobic substituent is a normal or branched C2C24alkyl group. |
| 5. | The method of Claim 1 wherein the polymer comprises a repeat unit of the general formula wherein R2 is hydrogen, a substituted or unsubstituted C1C24alkyl group, a substituted or unsubstituted arylalkyl group or a substituted or unsubstituted aryl group; R1 is a substituted or unsubstituted C3 C24alkyl group, a substituted or unsubstituted arylalkyl group or a substituted or unsubstiuted aryl group; and X is a pharmaceutically acceptable anion. |
| 6. | The method of Claim 5 wherein X is a conjugate base of an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid, sulfuric acid, Lglutamic acid, Laspartic acid, pyruvic acid, mucic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine. |
| 7. | The method of Claim 5 wherein R1 is a normal or branched C3C24alkyl group which is substituted by an amino group, an ammonium group, an amido group, a hydroxyl group, a sulfone group, a sulfoxide group or an alkoxy group. |
| 8. | The method of Claim 5 wherein R1 is an alkyl group selected from the group consisting of hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl and tetradecyl. |
| 9. | The method of Claim 8 wherein R2 is methyl and R1 is selected from the group consisting of octyl, decyl and dodecyl. |
| 10. | The method of Claim 1 wherein the polymer is characterized by a repeat unit of the general formula wherein R is a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group. |
| 11. | The method of Claim 10 wherein R is a C3C24alkyl group. |
| 12. | The method of Claim 11 wherein the alkyl group is selected from the group consisting of hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl and tetradecyl. |
| 13. | The method of Claim 11 wherein the alkyl group is substituted by an amino group, an ammonium group, an amido group, a hydroxyl group, a sulfoxide group, a sulfone group or an alkoxy group. |
| 14. | The method of Claim 1 wherein the polymer comprises a first monomer of the general formula wherein R1 is hydrogen, a substituted or unsubstituted C1C24alkyl group or a substituted or unsubstituted aryl group; R2 is a substituted or unsubstituted C3 C24alkyl group or a substituted or unsubstiuted aryl group; and X is a pharmaceutically acceptable anion; and a second monomer of the general formula wherein R is hydrogen, a substituted or unsubstituted alkyl group or a substituted or unsubstituted aryl group. |
| 15. | The method of Claim 1 wherein the polymer is a crosslinked polymer. |
| 16. | The method of Claim 15 wherein the polymer is crosslinked by a multifunctional comonomer. |
| 17. | The method of Claim 16 wherein the multifunctional comonomer is selected from the group consisting of diacrylates, triacrylates, tetraacrylates, dimethacrylates, diacrylamides, dimethacrylamides, diallylacrylamides and polyvinylarenes. |
| 18. | The method of Claim 17 wherein the multifunctional comonomer is selected from the group consisting of ethylene glycol diacrylate, propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate, butylene glycol dimethacrylate, methylene bis (methacrylamide), ethylene bis(acrylamide), ethylene bis(methacrylamide), ethylidene bis(acrylamide), ethylidene bis(methacrylamide), bisphenol A dimethacrylate, bisphenol A diacrylate, pentaerythritol tetraacrylate, trimethylolpropane triacrylate and divinylbenzene. |
| 19. | The method of Claim 16 wherein the multifunctional comonomer is a multifunctional diallylamine. |
| 20. | The method of Claim 19 wherein the multifunctional diallylamine is a bis(diallylamino)alkane or a bis(diallylalkylammonio)alkane. |
| 21. | The method of Claim 20 wherein the multifunctional diallylamine is llObis(diallylmethylammonio)decane dibromide. |
| 22. | The method of Claim 15 wherein the polymer is crosslinked by a bridging unit selected from the group consisting of straight chain or branched, substituted or unsubstituted alkylene groups, diacylalkylene groups, diacylarene groups and alkylene bis(carbamoyl) groups. |
| 23. | The method of Claim 22 wherein the bridging units are selected from the group consisting of (CH2) n, wherein n is an integer from about 2 to about 20; CH2CH(OH)CH2; C(O)CH2CH2C(O); CH2CH(OH)O(CH2)m OCH(OH)CH2, wherein m is 2 to about 4; C(O) (C6H2(COOH)2)C(O); and C(O)NH(CH2)pNHC(O), wherein p is an integer from about 2 to about 20. |
| 24. | A method for removing bile acids from a patient comprising the step of administering to the patient a therapeutically effective amount of a polymer characterized by a diallylamine monomer wherein the amino nitrogen atom is substituted with an ammonioalkyl group. |
| 25. | The method of Claim 24 wherein the polymer comprises a repeat unit of the general formula wherein R1 is hydrogen, a substituted or unsubstituted C1C24alkyl group, a substituted or unsubstituted arylalkyl group or a substituted or unsubstituted aryl group; R2 is an ammonioalkyl group; and X is a pharmaceutically acceptable anion. |
| 26. | The method of Claim 24 wherein the polymer is characterized by a repeat unit of the general formula wherein R is an ammonioalkyl group. |
| 27. | The method of Claim 24 wherein the ammonioalkyl group is of the general formula wherein n is an integer from 2 to about 20, X is an anion, and R4, R5 and K6 are each, independently, hydrogen or a C1C24alkyl group. |
| 28. | The method of Claim 27 wherein at least one of R4, R5 and K is a C6C22alkyl group. |
| 29. | The method of Claim 25 wherein the polymer comprises from about 1 mole percent to 100 mole percent of the diallylamine repeat unit having an ammonioalkyl substituted amino nitrogen atom. |
| 30. | The method of Claim 24 wherein the polymer is crosslinked. |
| 31. | The method of Claim 30 wherein the polymer comprises a multifunctional comonomer. |
| 32. | The method of Claim 31 wherein the multifunctional monomer is selected from the group consisting of diacrylates, dimethacrylates, diacrylamides, dimethacrylamides and polyvinylarenes. |
| 33. | The method of Claim 32 wherein the multifunctional comonomer is selected from the group consisting of ethylene glycol diacrylate, propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate, butylene glycol dimethacrylate, methylene bis (methacrylamide), ethylene bis(acrylamide), ethylene bis (methacrylamide), ethylidene bis(acrylamide), ethylidene bis(methacrylamide), bisphenol A dimethacrylate, bisphenol A diacrylate, diallylacrylamide and divinylbenzene. |
| 34. | 32 The method of Claim 30 wherein the multifunctional comonomer is a multifunctional diallylamine. |
| 35. | The method of Claim 34 wherein the multifunctional diallylamine is a bis(diallylamino)alkane or a bis(diallylalkylammonio)alkane. |
| 36. | The method of Claim 35 wherein the multifunctional diallylamine is 1,10bis (diallylmethylammonio)decane dibromide. |
| 37. | The method of Claim 30 wherein the polymer is crosslinked by bridging units selected from the group consisting of straight chain or branched, substituted or unsubstituted alkylene groups, diacylalkylene groups, diacylarene groups and alkylene bis (carbamoyl) groups. |
| 38. | The method of Claim 37 wherein the bridging units are selected from the group consisting of (CH2)0, wherein n is an integer from about 2 to about 20; CH2CH (OH) CH2; C(O)CH2CH2C(O); CH2CH(OH)O(CH2)nOCH(OH)CH2, wherein n is 2 to about 4; C(O)(C6H2(COOH)2)C(O); and C(O)NH(CH2)pNHC(O), wherein p is an integer from about 2 to about 20. |
| 39. | A polymer characterized by a diallylamine monomer wherein the amino nitrogen atom is substituted by an ammonioalkyl substituent. |
| 40. | The polymer of Claim 39, said polymer comprising a repeat unit of the general formula wherein R1 is hydrogen, a substituted or unsubstituted C1C24alkyl group, a substituted or unsubstituted arylalkyl group or a substituted or unsubstituted aryl group; R2 is an ammonioalkyl group; and X is a pharmaceutically acceptable anion. |
| 41. | The polymer of Claim 39, said polymer being characterized by a repeat unit of the general formula wherein R is an ammonioalkyl group. |
| 42. | The polymer of Claim 39 wherein the ammonioalkyl group is of the general formula wherein n is an integer from 2 to about 20, X is an anion, and R4, K5 and R6 are each, independently, hydrogen or a C1C24alkyl group. |
| 43. | The polymer of Claim 42 wherein at least one of R4, R5 and K is a C6C22alkyl group. |
| 44. | The polymer of Claim 40, said polymer comprising from about 1 mole percent to 100 mole percent of the diallylamine repeat unit having an ammonioalkyl substituted amino nitrogen atom. |
| 45. | The polymer of Claim 40, said polymer being crosslinked. |
| 46. | The polymer of Claim 45, said polymer comprising a multifunctional comonomer. |
| 47. | The polymer of Claim 46 wherein the multifunctional monomer is selected from the group consisting of diacrylates, dimethacrylates, diacrylamides, dimethacrylamides and polyvinylarenes. |
| 48. | The polymer of Claim 47 wherein the multifunctional comonomer is selected from the group consisting of ethylene glycol diacrylate, propylene glycol diacrylate, butylene glycol diacrylate, ethylene glycol dimethacrylate, butylene glycol dimethacrylate, methylene bis (methacrylamide), ethylene bis(acrylamide), ethylene bis(methacrylamide), ethylidene bis(acrylamide), ethylidene bis(methacrylamide), bisphenol A dimethacrylate, bisphenol A diacrylate, diallylacrylamide and divinylbenzene. |
| 49. | The polymer of Claim 45 wherein the multifunctional comonomer is a multifunctional diallylamine. |
| 50. | The polymer of Claim 49 wherein the multifunctional diallylamine is a bis(diallylamino)alkane or a bis(diallylalkylammonio)alkane. |
| 51. | The polymer of Claim 50 wherein the multifunctional diallylamine is lBlObis(diallylmethylammonio)decane dibromide. |
| 52. | The polymer of Claim 45 wherein the polymer is cross linked by bridging units selected from the group consisting of straight chain or branched, substituted or unsubstituted alkylene groups, diacylalkylene groups, diacylarene groups and alkylene bis (carbamoyl) groups. |
| 53. | The polymer of Claim 52 wherein the bridging units are selected from the group consisting of (CH2) n s wherein n is an integer from about 2 to about 20; CH2CH (OH) CH2; C(O)CH2CH2C(O); CH2CH(OH)O(CH2)nOCH(OH)CH2, wherein n is 2 to about 4; C(O)(C6H2(COOH)2)C(O) and and C(O)NH(CH2)pNHC(O), wherein p is an integer from about 2 to about 20. |
| 54. | A method for removing bile acids from a patient comprising the step of administering to the patient a therapeutically effective amount of a crosslinked poly(diallylamine) polymer wherein more than 10% of the amino nitrogen atoms bear a C3C24alkyl group. |
| 55. | The method of Claim 54 wherein more than 20% of the amino nitrogen atoms bear a C3C24alkyl group. |
Description:
INTERNATIONAL SEARCH REPORT lhtemanoaal 4ppllcatlon No PCT/US97/23899 C. (Gontinuaaa DOGUMENTS CONSIPEHED to BE RELEVaNT s Cstegory-irilon o1 documen, with indealon, whe apprvpriae, of ihe relevant passages Felevant to claim No. . i i 31 August 1988 (1988-08-31) 42,44 claims 3-8 X JP 56 010531 A (TEIJIN LTD) 39,40,45 3 February 1981 (1981-02-03) the whole document X JP 02 001358 A (SANYO CHEM IND LTD) 39,40,45 5 January 1990 (1990-01-05) the whole document X JP 62 257481 A (SANYO CHEM IND LTD) 39-45 10 November 1987 (1987-11-10) the whole document X JP 62 170591 A (TORAY IND INC) 39-45 27 July 1987 (1987-07-27) the whole document X JP 57 047302 A (MITSUBISHI PETROCHEM CO 39-45 LTD) 18 March 1982 (1982-03-18) page X; example 4 X JP 57 125233 A (KARUPU KOGYO KK) 37-42 4 August 1982 (1982-08-04) the whole document X US 4 360 434 A (KAWAGUCHI TAKEYUKI ET AL) 39 23 November 1982 (1982-11-23) example 17 ; table 5 XMCLEAN ET AL. :"Cyclopolymerization_ VI. 39-47, Preparation and properties of Crosslinked 49-53 Polyamines by Cyclopolymerization" J. MACROMOL. SCI.-CHEM vol. A10, no. 5,1976, pages 857-873, XP002068701 page 858, paragraph 2-page 872, paragraph 5; figures 1,2; tables 1-5 X BOLTO ET AL. :"Synthesis of Cross-Linked 39-47, Polyallylamines Which Are Resistant to 49-53 Sulfite Attack" J. MACROMOL. SCI.-CHEM., vol. A17. no. 1,1982, pages 153-166, XP002068702 page 154, paragraph 2-page 162, paragraph 4 ; tables 1-4 A US 3 585 118 A (HARADA SUSUMU ET AL) 39 15 June 1971 (1971-06-15) example1 _ z 1 INTERNATIONAL SEARCH REPORT Ilnamaponal Applicelion No W camory ° = = « PCT/US 97/23899 C.(Concinuatlpn D4CUMENTS CaNSIDERED TQ B RELEVPHT CatBoory° ition of document, with indlcadon, where appropriate, af fie relrW ant passagEs Aelevant to claim No. A US 4 027 009 A (GRIER NATHANIEL ET AL) 1-55 31 May 1977 (1977-05-31) the whole document 1 International application No. INTERNATIONAL SEARCH REPORT PCT/US 97/23899 Box Observations where certain claims were found unsearchable (Continu ation of item 1 of first sheet) This Intematoral Search Repart has not been established in respect of certain claims under rticle 17 (2) (a) for the following reasons : a Claim Nos ; beqa se they relate to subject matter not required to be searched by this Authority, amely : 2. L CiairrisNos. : j -because they relate to parts of the International Application that do not comply With tjhe prescribed raquiremBnts to such an extent that no meaningful International Search can be carried out, specifically : 3. ; Cliis Nos. : because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6. 4 (a). l Box 11 Ob rvations where unity of invention is lacking (Continuation of He) n 2 of first sheet) This Intemqtic nal Searching Authority found multiple inventions in this intemational aoplicati In as follows : 1. li requirrn addiiSonal ssarcii fees were timely paid by the applicant, this lmernoional Search Report covers ait sqasq hable claims. 2. g A$ II searchable claims could be searched without effort justifying an additional felb this Authority did not invite payment of a y additional fee. 3. Ap nly some of the required additional search fees were timely paid by the applicnt this International Search Report cov rs only those daims for which fees were paid, specifically claims Nos.- 1 (partially) 2, 4-14,15|-16 (p) 19-23,24 (p) 25-29, 3q-31 (p) 34-36. 37-55 (p) 4. ji Notaquired additional search fees were timely paid by the applicant. Consequenti, this tnternational Search Report is res iaed to the invention first mentioned in the daims ; it is covered by claims Nos, Remark on protest The additional search fees wWre accompanied by the applicanfs protest. No protest accompanied the payment of additional search fees. INTERNATIONAL SEARCH REPORT I cemaponal ApPilion No Iniormaion on patcnt tamllY members pCT/US 97/23899 Publicaton Patentfamily Publication citeif search report date member (s) date US 4759923 A 26-07-1988 EP 02966 2 A Z8-12-1988 JP 10229 : 4 A 25-01-1989 EP 4401735 A 12-12-1990 AU 54950 ! 0 A 06-12-1990 CA 20164 7 A 05-12-1990 HU 540 9 A 28-01-1991 JP 30202 6 A 29-01-1991 US H12 6 H 01-02-1994 ZA 90043 0 A 27-03-1991 DE 4002825 A 02-08-1990 CA 20076 41 A D1-08-1990 FR 26423 0 A 03-08-1990 GB 22276 3 A, B 08-08-1990 IT 12380 9 B 05-07-1993 JP 22358 0 A 18-09-1990 ER 280445 A 31-08-1988 GB 220282 A 05-10-1988 AU 5980 9 B 14-06-1990 AU 11673 8 A 18-08-1988 BR 88006 1 A 27-09-1988 FI 880641 A 14-08-1988 JP 1721329 C 24-12-1992 JP 4008556 B 17-02-1992 JP 63264993 A O1-11-1988 NZ 223507 A 28-06-1989 ZA 8801E 25 A 11-08-1988 JP 56010531 A ^ 03-02-. 981 ^ JP r 1396 40 C ^ 24-08-1. 987 JP 62001111 B 13-01-1987 ------------------------------------------------------------
---------- Jp 02sD1358 A 05-G1-199G NONE JQ 02001358 A 05-01-1990 NONE _______-___ JP 62257481__^A______1_11=1987__r___NONE_____ ________.. _______^____ Jp 62170591 A 27-07-1987 JP 1979 36 C 17-10-1995 JP 7003 35 B 18-01-1995 JP 57047302 A 18-03-1982 NONE --.----------.---------. -... .-. . .. JP 57125233 A 04-08-1982 NONE _ ___., __________________ _____.. _____,. ____.. ___. _________.. ___________ US 4360434 A 23-11-1982 NONE US3585118 A 15-@6-1971 CA 925 T69 A s 5-1973 CH 533 47 A 28-02-1973 DE 1957 56 A 21-05-1970 FR 2023 40 A 21-08-1970 GB 1275L57 A 24-B5-1972 -t-------r---.--------.---.--. .----.--.--, --.-.-. . . . . e _ _ _ R 4027009 A 31-05-1977 AU 6976374 A 04-12-1975 CA 1028953 A 04-04-1978 DE 2427924 A 02-01-1975 FR 2241 321 A 21-03-1975 GB 1460515 A 06-01-1977 IE 3 406 B 27-09-1978 IL 4 967 A 31-10-1977 NL 7407 307 A 13-12-1974 PH 14665 A 20-10-1981 INTERNATIONAL SEARCH REPORT 1 tematlonal Appiioauon No Intormatian on patent tamilv tembers PCT/US 97/23899 PCT/US 97/z3899 Pte document Publication Patentfamily Publication cite i saaroh report date mamber (s) dace US BE 8161 1 A 10-12-1974 ZA 740369 A 28-01-1976 -I