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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date 8 November 2007 (08.11.2007) PCT (10) International Publication Number W O 2007/127639 A3 YINGLING, Jeffrey, D . [US/US]; 3913 Summer Brook Drive, Apex, N C 27539 (US). (74) Agent: HARTWIG, Gregory, J.; Michael Best & Friedrich LLP, 100 East Wisconsin Avenue, Suite 3300, Milwaukee, W I 53202-4108 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (51) International Patent Classification: C07C 219/10 (2006.01) C07C 69/612 (2006.01) C07C 233/65 (2006.01) C07C 69/618 (2006.01) C07C 251/48 (2006.01) C07D 295/145 (2006.01) C07C 317/44 (2006.01) C07D 295/15 (2006.01) C07C 405/00 (2006.01) C07D 333/00 (2006.01) C07C 409/38 (2006.01) C07D 231/28 (2006.01) C07C 69/738 (2006.01) C07D 207/273 (2006.01) C07C 69/736 (2006.01) (21) International Application Number: PCT/US2007/066782 (22) International Filing Date: (25) Filing Language: (26) Publication Language: (30) Priority Data: 1 1/412,207 17 April 2007 (17.04.2007) English English 2 6 April 2006 (26.04.2006) US (71) Applicant (for all designated States except US): AERIE PHARMACEUTICALS, INC. [US/US]; 7020 Kit Creek Road, P.O. Box 12320, Research Triangle Park, N C 27709 (US). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, MT, NL, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventors; and (75) Inventors/Applicants (for US only): DELONG, Mitchell, A . [US/US]; 8203-204 Autumn Hill T e r race, Raleigh, N C 27617 (US). MCFADDEN, JUl, M . [US/US]; 3930 Crawford Dairy Road, Chapel Hill, N C 27516 (US). ROYALTY, Susan, M . [US/US]; 110 Arrow Head Way, Cary, N C 27513 (US). TOONE, Eric, J. [CA/US]; 2601 Evans Street, Durham, N C 27705 (US). Published: — with international search report — before the expiration of the time limit for amending the claims and to be republished in the event o receipt of f amendments (88) Date of publication of the international search report: 12 June 2008 (54) Title: PRODRUG DERIVATIVES OF ACIDS USING ALCOHOLS WITH HOMOTOPIC HYDROXY GROUPS AND METHODS FOR THEIR PREPARATION AND USE (57) Abstract: This invention relates to novel homotopic prodrugs and medicaments and methods for their preparation, testing and use. I n one embodiment, the homotopic prodrug has the general formula (I) wherein (II) i s a biologically-active moiety comprising a carboxylic acid functional group, and R b i s a homotopically-symmetrical alcohol bonded to the biologically-active moiety through the carboxylic acid functional group t o form a n ester linkage, a s well a s optical isomers, enantiomers, pharmaceutically acceptable salts, biohydrolyzable amides, esters, and imides thereof and combinations thereof. INTERNATIONAL SEARCH REPORT International application N o PCT/US2007/066782 A CLASSIFICATION OFSUBJECT MATTER , INV. C07C219/10 C07C409/38 C07D295/145 C07C233/65 C07C69/738 C07D295/15 C07C251/48 C07C69/736 C07D333/00 C07C317/44 C07C69/612 C07D231/28 C07C405/00 C07C69/618 C07D207/273 According to International Patent Classification (IPC) o r t o both national classificalion and IPC B . FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) C07C C07D Documentation searched other than minimum documentation t o the extent lhat such documents are included m the fields searched Electronic data base consulted during the international search (name of data base and where practical, search terms used) EPO-Internal , PAJ, CHEM ABS Data, BEILSTEIN Data, WPI Data C. DOCUMENTS CONSIDERED T O BE RELEVANT Category * Citation of document, with indication, where appropriate, of the relevant passages Relevant t o claim No U S 3 746 728 A (WEISBACH J ET AL) 17 July 1973 (1973-07-17) 10,11, 14,15, 19-24, 26-43 the whole document W O 02/12549 A (UNIV VANDERBILT 14 February 2002 (2002-02-14) figures [US]) 10 U S 4 198 429 A (BARTMANN WILHELM [DE] ET AL) 15 April 1980 (1980-04-15) 10,11, 14,15, 19-24, 26-43 the whole document -/-- Further documents are listed i n the continuation o f Box C * Special categories of cited documents "A" document defining the general state of the art which is not considered t o b e o f particular relevance 1E " 1T " See patent family annex later document published after the international filing date o r p πority date and not i n conflict with the application but cited to understand the principle o r theory underlying the Invention 1X - document of particular relevance the claimed invention cannot b e considered novel o r cannot be considered t o involve a n inventive step when the document Is taken alone 1Y - earlier document but published o n o r after the international filing date "L" document which may throw doubts o n priority cla ιm(s) o r which is cited to establish the publication date of another citation o r other special reason (as specified) 1O " document referring t o a n oral disclosure, use, exhibition o r other means 1P 1 document published prior t o the international filing date but later than the priority date claimed Date of the actual completion of the international search document of particular relevance the claimed invention cannot b e considered t o involve an inventive step when the document Is combined with one o r more other such docu¬ ments, such combination being obvious t o a person skilled i n the art ■& ' document member of the same patent family Date of mailing of the international search report 19 December 2007 24/04/2008 Authorized officer Name and mailing address of the ISA/ European Patent Office P B 5818 Patentlaan 2 N L - 2280 H V RlJSWI|k TeI (+31-70) 340-2040 T x 3 1 651 epo nl, Fax (+31-70) 340-3016 Form PCT/ISA/210 (second sheet) (April 2005) Bedel , Chri sti a n INTERNATIONAL SEARCH REPORT International application No PCT/US2007/066782 C(Contlnuatlon). Category* DOCUMENTS CONSIDERED TO BE RELEVANT Relevant t o claim No. Citation of document, with indication, where appropriate, o f the relevant passages X 0 001 255 A (HOECHST A G [DE]) 4 Apri l 1979 (1979-04-04) page 10, l ines 1 , 2 page 10, l ine 12 - l i ne 2 7 page 27, l ine 2 0 - l ine 29; example 9 c c l aims 1 , 4 EP 10 X J P 1 1 180949 A (ASAHI GLASS C O LTD) 6 July 1999 (1999-07-06) 10, 1 1 , 14, 15, 19-24, 26-43 the X WO whole document 10, 1 1 , 14,15, 19-24, 26-43 93/14743 A (ALLERGAN INC [US]) 5 August 1993 (1993-08-05) the X WO whole document 10, 1 1 , 14,15, 19-24, 26-43 00/04898 A (MERCK C O INC [US] ; PONTICELLO GERALD S [US] ; SUGRUE MICHAEL F [US]) 3 February 2000 (2000-02-03) page 8 , l ines 19,20 page 10, l ines 1 , 2 examples page 26, l ine 29; claims X KOZAK KEVIN R ET AL: 1-6 10, 1 1 , 14, 15, 19-24, 26-43 "Metabol ism of . prostagl andi n glycerol esters and prostagl andi n ethanol amides i n vitro and i n vivo" JOURNAL OF BIOLOGICAL CHEMISTRY, AMERICAN SOCIETY O F BIOLOCHEMICAL BIOLOGISTS, BIRMINGHAM, , US, vol . 276, no: 4 0 , 5 October 2001 (2001-10-05) , pages 36993-36998, XP008085529 ISSN: 0021-9258 the whole document 235 357 C (FARBENFABRIKEN BAYER & CO) 19 May 1910 (1910-05-19) the whole document DE X 1 X P . GOMIS: "Preparation et proprietes de quelques esters d e I a phenoxymethyl peni c i 1 1i ne" BULL. SOC .CHIM.FR. , no. 1 1968, pages 420-424, XP009092578 page 422, left-hand column, paragraph 2 page 422, right-hand column ; example 5c -/-- 1 Form PCT/ISA/21 0 (continuation of second sheet) (April 2005) INTERNATIONAL SEARCH REPORT International application No PCT/US2007/066782 C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Relevant to claim No. Category* Citation of document, with indication, where appropriate, of the relevant passages ALEXANDER ZLATKOV: "Synthesis, Toxicological , Pharmacological Assessment, and i n Vitro Bronchodilating Activity of some 7-Theophyl 1inyl acetyl oxyglycol s " ARCH. PHARM. PHARM. MED. CHEM., vol. 331, no. 10, 1998, pages 313-318, XP002461611 the whole document Form PCT/ISA/21 0 (continuation of second sheet) (April 2005) International Application No. PCT/US2007 /066782 FURTHER INFORMATION CONTINUED FROM PCTΛSA/ 210 Continuation o f Box II. 1 Although claims 32-43 are directed t o a .method of treatment o f the human/animal body, the search has been carried out and based o n the alleged effects of the compound/composition. Continuation Claims Nos.: o f Box II. 1 1-9, 25,27-43 Rule 39.1(iv) therapy PCT - Method for treatment of the human or animal body by Continuation Claims Nos.: o f Box I I .2 1-9,25,27-31, (partly) Present claims 1-7 and 25,27-31 encompass compounds/compositions defined only by their desired function ("biologically active moiety"), contrary t o the requirements o f clarity o f Article. 6 PCT, because the result-to-be-achieved type o f definition does not allow the scope o f the claim t o b e ascertained. The fact that any compound/composition could b e screened does not overcome this objection, a s the skilled person would not have knowledge beforehand a s t o whether it would fall within the scope claimed, except for the compounds/compositions disclosed i n the description. Undue experimentation would b e required t o screen compounds randomly. This non-compliance with the substantive provisions i s t o such an extent, that the search was performed taking into consideration the non-compliance i n determining the extent o f the search for claims 1-7 and 25,27-31. The present claims 1-7 and 25,27-31 relate t o a n extremely large number of possible compounds/compositions . Support and disclosure i n the sense of Article 6 and 5 PCT i s t o b e found however for only a very small proportion o f the compounds/compositions claimed, (see p .48-63). The non-compliance with the substantive provisions i s t o such a n extent, that the search was performed taking into consideration the non-compliance i n determining the extent o f the search o f claims 1-7 and 25,27-31(PCT Guidelines 9.19 and 9.23). The search o f claims 1-7 was restricted t o those claimed compounds which appear t o b e supported and a generalisation o f their structural formulae, namely claims the subject-matter o f 10,11,14,15,19-24,26. However, a NON-EXAUSTI V E search in X f ire Beil stein database has provided many novelty destroying documents disclosing biologically active moieties esterified with a polyalkohol (as a sample o f these documents International Application No. PCT/US2007 /066782 FURTHER INFORMATION CONTINUED FROM PCT SA/ 210 see documents D9-D11 in search report), t o illustrate the fact that this concept i s well known i n the prior art (see also unity objection). Claim 8 The present claim 8 encompasses compounds defined only by their desired function, namely "prostaglandin", defined i n the description o n page 10, paragraph 5 1 a s " a fatty acid derivative which has a variety of potent biological activities of a hormonal or regulatory nature", contrary t o the requirements o f clarity o f Article 6 PCT, because the result-to-be-achieved type o f definition does not allow the scope o f the claim t o b e ascertained. The fact that any compound could b e screened does not overcome this objection, a s the skilled person would not have knowledge beforehand a s t o whether it would fall within the scope claimed, except for the compounds disclosed in the description, see p .48-74. Undue experimentation would be required t o screen compounds randomly. claim 9 Claim 9 defines what the so-called biological moities should be, namely at least one o f travaprost, latanoprost and bimatoprost. However each o f these known drugs i s already biologically active a s ester or amide derivatives o f prostaglandins. The examining division does not understand how these already esterified drugs can b e further esterified by a polyol moiety. The search authority has considered that the scope o f claim 9 i s included in the scope o f claim 10. Claims 32-43 The subject-matter of these claims have been searched i n s o far a s they refer t o the compounds/compositions defined i n claims 10,11,14,15,19,26-31 The applicant's attention i s drawn t o the fact that claims relating t o inventions i n respect of which n o international search report has been established need not b e the subject o f a n international preliminary examination (Rule 66.1(e) PCT). The applicant i s advised that the EPO policy when acting a s a n International Preliminary Examining Authority. i s normally not t o carry out a preliminary examination o n matter which has not been searched. This i s " the case irrespective o f whether or not the claims are amended following receipt o f the search report or during any Chapter I I procedure. If the application proceeds into the regional phase before the EPO, the applicant i s reminded that a search may b e carried out during examination before the EPO (see EPO Guideline C-VI, 8.5), should the problems which led t o the Article 17(2) declaration b e overcome. International application No. INTERNATIONAL Box No. I l Observations SEARCH REPORT PCT/US2007/066782 where certain claims were found unsearchable (Continuation of item 2 of first sheet) This international search report has not been established in respect o f certain claims under Article 17(2)(a) for the. following reasons: 1. [yj Claims Nos.: 1-Q 25,27-43 PCT/ISA/210 because they relate t o subject matter not required t o b e searched b y this Authority, namely: see FURTHER INFORMATION sheet 2. ] claims No s. : 1-9, 25,27-31 , (partly) because they relate t o parts of the international application that d o not comply with the prescribed requirements to such a n extent that n o meaningful international search can b e carried out, specifically: see FURTHER INFORMATION sheet PCT/ISA/210 3. j Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences o f Rule 6.4(a). Box No. Ill Observations where unity of invention i s lacking (Continuation of item 3 of first sheet) Searching Authority found multiple inventions in this international application, a s follows: This International see additional sheet 1. A s all required additional search fees were timely paid b y the applicant, this international search report covers allsearchable - claims. 2. A s all searchable claims could b e searched without effort justifying a n additional fees, this Authority did not invite payment o f additional fees. 3. A s only some o f the required additional search fees were timely paid by the applicant, this international search reportcovers only those claims for which fees were paid, specifically claims Nos.: 4. J Y N O required additional search fees were timely paid b y the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it Is covered by claims Nos.: see annex Remark o n Protest The additional search fees were accompanied b y the applicant's protest and, where applicable, the payment o f a protest fee. The additional search fees were accompanied b y the applicant's protest but the applicable protest fee was not paid within the time limit specified in the invitation. N o protest accompanied the payment o f additional search fees. Form PCT/ISA/210 (continuation o f first sheet (2)) (April 2005) International Application No. PCT/US2007 /066782 FURTHER INFORMATION CONTINUED FROM POT/ISA/ 2 1 0 This International Searching Authority found multiple (groups of) inventions in this international application, a s follows: 1. claims: 10,11,14,15,19-24,26 and 27-43( all partly) pentacyclic prostaglandin derivatives with clearly defined chemical structure 2 . claim: 12 hexacyclic prostaglandin derivative with a clearly defined chemical structure 3 . claim: 13 Pentaheterocyclic prostaglandin derivative with a clear chemical structure 4 . claims: 16,17,18 esterified ethacrinic acid , benzoxyacetate and esterified cinnamic acid 5 . claims: 44-51 Method of ranking susceptibility o f a n ester derivative t o hydrolysis INTERNATIONAL SEARCH REPORT Information on patent family members International application No PCT/US2007/066782 Patent family member(s) Publication date Patent document cited in search report Publication date U S 3746728 WO A A 17-07-1973 14-02-2002 NONE 0212549 AU AU CA CA EP EP WO 8474701 8475301 2422306 2422803 1307585 1307538 0212445 2639777 856170 2628564 282677 459930 2355821 1586600 53002454 7706771 7707266 7703805 678178 526475 4002478 2742407 473381 55601 1100114 54055554 7805289 A A Al Al Al Al Al A Al Al A Al Al A A A A A A B2 A Al Al A B A A 18-02-2002 18-02-2002 14-02-2002 14-02-2002 07-05-2003 07-05-2003 14-02-2002 04-01-1979 27-12-1977 05-01-1978 26-12-1977 01-12-1978 20-01-1978 25-03-1981 11-01-1978 28-12-1977 26-12-1977 30-05-1978 15-02-1983 13-01-1983 27-03-1980 29-03-1979 16-04-1979 31-03-1983 28-09-1985 02-05-1979 29-08-1979 US 4198429 A 15-04-1980 AU BE DE DK ES FR GB JP NL SE ZA E P 0001255 A 04-04-1979 AT AU AU DE ES IL IT JP ZA J P 11180949 WO A A 06-07-1999 05-08-1993 NONE 9314743 AU US 3603193 5288754 5001199 2337399 1109546 2002521332 A A A Al Al T 01-09-1993 22-02-1994 14-02-2000 03-02-2000 27-06-2001 16-07-2002 WO 0004898 A 03-02-2000 AU CA EP JP D E 235357 C NONE Form PCT/ISA/210 (patent family annex) (April 200B)