WO2007115001A1 - Prostaglandin ep4 agonists - Google Patents

Prostaglandin ep4 agonists Download PDF

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Publication number
WO2007115001A1
WO2007115001A1 PCT/US2007/064360 US2007064360W WO2007115001A1 WO 2007115001 A1 WO2007115001 A1 WO 2007115001A1 US 2007064360 W US2007064360 W US 2007064360W WO 2007115001 A1 WO2007115001 A1 WO 2007115001A1
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WIPO (PCT)
Prior art keywords
prostaglandin
compound
prodrug
amino acid
substituted
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PCT/US2007/064360
Other languages
French (fr)
Inventor
Wha Bin Im
Robert M. Burk
Mark Holoboski
Original Assignee
Allergan, Inc.
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Publication date
Application filed by Allergan, Inc. filed Critical Allergan, Inc.
Priority to AU2007233285A priority Critical patent/AU2007233285B2/en
Priority to JP2009504375A priority patent/JP2009532491A/en
Priority to EP07758870A priority patent/EP2027085A1/en
Priority to BRPI0710579-7A priority patent/BRPI0710579A2/en
Priority to MX2008012553A priority patent/MX2008012553A/en
Priority to CA002648159A priority patent/CA2648159A1/en
Publication of WO2007115001A1 publication Critical patent/WO2007115001A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to therapeutically active compounds and their delivery and use. Particularly, this invention relates to the delivery and use of prostaglandin EP 4 agonists.
  • Prostaglandins can be described as derivatives of prostanoic acid which have the following structural formula:
  • prostaglandins are known, depending on the structure and substituents carried on the alicyclic ring of the prostanoic acid skeleton. Further classification is based on the number of unsaturated bonds in the side chain indicated by numerical subscripts after the generic type of prostaglandin [e.g. prostaglandin Ei (PGEi), prostaglandin E2 (PGE2)], and on the configuration of the substituents on the alicyclic ring indicated by ⁇ or ⁇ [e.g. prostaglandin F2 ⁇ (PGF2 ⁇ )].
  • PGEi prostaglandin Ei
  • PGE2 prostaglandin E2
  • PPF2 ⁇ prostaglandin F2 ⁇
  • R is ⁇ -thienyl, phenyl, phenoxy, monosubstituted phenyl or monosubstituted phenoxy, said substituents being selected from the group consisting of chloro, fluoro, phenyl, methoxy, trifluoromethyl and (Ci -
  • R.sup.3 is hydrogen, (Ci -C 5 )alkyl, phenyl or/>-biphenyl;
  • R 4 is COR 5 or SO 2 R 5 ;
  • R 5 is phenyl or (Ci -C 5 )alkyl.
  • 10-Hydroxyprostaglandin analogues that is natural prostaglandin E compounds where the hydroxide is present on carbon 10 rather than carbon 11, are known in several patent documents including U.S. Patent No. 4,171,375; U.S. Patent No. 3,931,297; FR 2408567; DE 2752523, JP 53065854, DE 2701455, SE 7700257, DK 7700272, NL 7700272, JP 52087144, BE 850348, FR 2338244, FR 2162213, GB 1405301, and ES 409167; all of which are expressly incorporated by reference herein.
  • B is CO 2 H, or CO 2 R, CONR 2 , CONHCH 2 CH 2 OH, CON(CH 2 CH 2 OH) 2 , CH 2 OR, P(O)(OR) 2 , CONRSO 2 R, SONR 2 , or
  • R is H, Ci. 6 alkyl
  • D is -(CH 2 ) n -, -X(CH 2 ) n , or -(CH 2 ) n X-, wherein n is from 0 to 3 and X is S or O;
  • E is an aromatic or heteroaromatic moiety having from 0 to 4 substituents, said substituents each comprising from 1 to 6 non-hydrogen atoms is disclosed herein.
  • Prostaglandin EP 4 selective agonists are believed to have several medical uses.
  • U.S. Patent No. 6,552,067 B2 expressly incorporated by reference herein, teaches the use of prostaglandin EP 4 selective agonists for the treatment of "methods of treating conditions which present with low bone mass, particularly osteoporosis, frailty, an osteoporotic fracture, a bone defect, childhood idiopathic bone loss, alveolar bone loss, mandibular bone loss, bone fracture, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth in a mammal.”
  • U.S. Patent No. 6,586,468 Bl expressly incorporated by reference herein, teaches that prostaglandin EP 4 selective agonists "are useful for the prophylaxis and/or treatment of immune diseases (autoimmune diseases (amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjoegren's syndrome, arthritis, rheumatoid arthritis, systemic lupus erythematosus, etc.), post-transplantation graft rejection, etc.), asthma, abnormal bone formation, neurocyte death, pulmopathy, hepatopathy, acute hepatitis, nephritis, renal insufficiency, hypertension, myocardial ischemia, systemic inflammatory syndrome, pain induced by ambustion, sepsis, hemophagocytosis syndrome, macrophage activation syndrome, Still's diseases, Kawasaki diseases, burn, systemic granuloma, ulcerative colititis, Crohn's diseases, hypercytokinemia at di
  • IBD Inflammatory bowel disease
  • NSAIDs Nonsteroidal anti-inflammatory drugs
  • EP 4 works to keep mucosal integrity, to suppress the innate immunity, and to downregulate the proliferation and activation of CD4+ T cells.
  • a compound comprising a prodrug of a prostaglandin EP 4 agonist, wherein said prodrug is an ester, ether, or amide of a carbohydrate; or said prodrug is an ester, ether, or amide of an amino acid is disclosed herein.
  • a prostaglandin EP 4 agonist is broadly defined as a compound which an ordinary person in the art reasonably believes agonizes a prostaglandin EP 4 receptor according to any one or more of numerous assays for determination of the EP 4 activity that are well known to those of ordinary skill in the art. While not intending to be limiting, one such assay is given in the example below.
  • the prostaglandin EP 4 agonist is selective for a prostaglandin EP 4 receptor relative to other prostaglandin receptor subtypes. In another embodiment, the prostaglandin EP 4 agonist is at least 10 times more active at the EP 4 receptor than at any other prostaglandin receptor subtype. In another embodiment, the prostaglandin EP 4 agonist is at least 100 times more active at the EP 4 receptor than at any other prostaglandin receptor subtype. In another embodiment, the prostaglandin EP 4 agonist is at least 1000 times more active at the EP 4 receptor than at any other prostaglandin receptor subtype. While not intending to be limiting, typical assays for the other receptor subtypes are also given in examples below. While not intending to limit the scope of the invention in any way, compounds according to the structures below are examples prostaglandin EP 4 agonists:
  • X is S or O
  • E is Ci.i 2 alkyl, R 2 , or -Y-R 2 wherein Y is CH 2 , S, or O, and R 2 is aryl or heteroaryl.
  • A may be a group which is related to one of these three moieties in that any carbon is substituted with S and/or O.
  • A may be an S substituted moiety such as one of the following or the like.
  • A may be an 0 substituted moiety such as one of the following or the like.
  • A may have both an O and an S substituted into the chain, such as one of the following or the like.
  • A is -(CH 2 ) n -Ar-(CH 2 ) o - wherein Ar is interarylene or heterointerarylene, the sum of m and o is from 1 to 4, and wherein one CH 2 may be substituted with S or O.
  • A comprises from 1 to 4 CH 2 moieties and Ar, e.g.
  • A comprises O, from 0 to 3 CH 2 moieties, and Ar, e.g., -0-Ar-, Ar-CH 2 -O-, -O-Ar-(CH 2 ) 2 -, -0-CH 2 -Ar-, -0-CH 2 - Ar-(CH 2 ) 2 , and the like; or
  • A comprises S, from 0 to 3 CH 2 moieties, and Ar, e.g., -S-Ar-, Ar-CH 2 -S-, -S-Ar-(CH 2 ) 2 -, -S-CH 2 -Ar-, -S-CH 2 -Ar- (CH 2 ) 2 , and the like.
  • Interarylene or heterointerarylene refers to an aryl ring or ring system or a heteroaryl ring or ring system which connects two other parts of a molecule, i.e. the two parts are bonded to the ring in two distinct ring positions.
  • Interarylene or heterointerarylene may be substituted or unsubstituted.
  • an unsubstituted interarylene has 4 potential positions where a substituent could be attached.
  • Ar is substituted or unsubstituted interphenylene, interthienylene, interfurylene, or interpyridinylene.
  • Ar is interphenylene (Ph).
  • A is -(CH 2 ) 2 -Ph-. While not intending to limit scope of the invention in any way, substituents may have 4 or less heavy atoms, or in other words, non hydrogen atoms. Any number of hydrogen atoms required for a particular substituent will also be included.
  • the substituent may be hydrocarbyl having up to 4 carbon atoms, including alkyl up to C 4 , alkenyl, alkynyl, and the like; hydrocarbyloxy up to C 3 ; CF 3 ; halo, such as F, Cl, or Br; hydroxyl; NH 2 and alkylamine functional groups up to C 3 ; other N or S containing substituents; and the like.
  • A is -(CH 2 ) D i-Ar-(CH 2 ) O - wherein Ar is interphenylene, the sum of m and o is from 1 to 3, and wherein one CH 2 may be substituted with S or O.
  • A is -CH 2 -Ar-OCH 2 -.
  • A is -CH 2 -Ar-OCH 2 - and Ar is interphenylene.
  • Ar is attached at the 1 and 3 positions, such as when A has the structure shown below.
  • Ci. 12 alkyl is alkyl having from 1 to 12 carbon atoms, including: linear alkyl, such as methyl, ethyl, n-propyl, n-butyl, etc.; branched alkyl, such as iso-propyl, iso-butyl, t-butyl, isopentyl, etc.; cyclic alkyl. such as cyclopropyl, cyclobutyl, cyclohexyl, etc.; including substituted cvcloalkyl.
  • E may be any of these groups.
  • linear alkyl of Ci_ 6 is contemplated herein, especially butyl.
  • cyclohexyl cyclopentyl
  • substituted cyclohexyl and cyclobutyl having less than 9 carbon atoms are particularly useful groups.
  • E may also be R or Y-R wherein Y is CH 2 , S or O and R is aryl or heteroaryl.
  • E may be aryl, heteroaryl, -CH 2 -aryl, -S-aryl, -O-aryl,-CH 2 -heteroaryl, -S-heteroaryl, or -O-heteroaryl.
  • Aryl is defined as an aromatic ring or ring system as well as a substituted derivative thereof, wherein one or more substituents are substituted for hydrogen. While not intending to limit the scope of the invention in any way, phenyl, naphthyl, biphenyl, terphenyl, and the like are examples of aryl.
  • Heteroaryl is defined as aryl having at least one non-carbon atom in an aromatic ring or ring system. While not intending to limit the scope of the invention in any way, in many cases one or more oxygen, sulfur, and/or nitrogen atoms are present. While not intending to limit the scope of the invention in any way, examples of heteroaryl are furyl, thienyl, pyridinyl, benzofuryl, benzothienyl, indolyl, and the like. The substituents of aryl or heteroaryl may have up to 12 non-hydrogen atoms each and as many hydrogens as necessary.
  • the substituents may be: hvdrocarbyl, such as alkyl, alkenyl, alkynyl, and the like, and combinations thereof; hydrocarbyloxy, meaning O-hydrocarbyl such as OCH 3 , OCH 2 CH 3 , O-cyclohexyl, etc, up to 11 carbon atoms; hydro xyhydrocarbyl, meaning hydrocarbyl-OH such as CH 2 OH, C(CH 3 ) 2 OH, etc, up to 11 carbon atoms; nitrogen substituents such as NO 2 , CN, and the like, including amino, such as NH 2 , NH(CH 2 CH 3 OH), NHCH 3 , and the like up to 11 carbon atoms; carbonyl substituents, such as CO 2 H, ester, amide, and the like; halogen, such as chloro, fluoro, bromo, and the like fluorocarbonyl, such as
  • the number of non -hydrogen atoms is 6 or less in a substituent. In other embodiments, the number of non-hydrogen atoms is 3 or less in a substituent. In other embodiments, the number of non-hydrogen atoms on a substituent is 1. In certain embodiments, the substituents contain only hydrogen, carbon, oxygen, halo, nitrogen, and sulfur.
  • the substituents contain only hydrogen, carbon, oxygen, and halo.
  • R 1 is H, chloro, or fluoro.
  • R 1 is H.
  • R 1 is chloro.
  • R is phenyl, naphthyl, biphenyl, thienyl, or benzothienyl having from O to 2 substituents selected from the group consisting of F, Cl, Br, methyl, methoxy, and CF 3 .
  • R 2 is CH 2 -naphthyl, CH 2 -biphenyl, CH 2 -(2-thienyl), CH 2 -(3-thienyl), naphthyl, biphenyl, 2-thienyl, 3-thienyl, CH 2 -(2-(3-chlorobenzothienyl)), CH 2 -(3-benzothienyl), 2-(3-chlorobenzothienyl), or 3-benzothienyl.
  • R 2 is CH 2 -(2-thienyl), CH 2 -(3-thienyl), 2-thienyl, 3-thienyl, CH 2 -(2-(3- chlorobenzothienyl)), CH 2 -(3-benzothienyl), 2-(3-chlorobenzothienyl), or 3-benzothienyl.
  • Prodrugs of prostaglandin EP 4 agonists comprising
  • R 4 is H, halo or Ci_ 6 alkyl.
  • Halo is a group 7 atom such as fluoro, chloro, bromo, iodo, and the like.
  • Ci- 6 alkyl is linear, branched, or cyclic alkyl having from 1 to 6 carbons including, but not limited to, methyl, ethyl, propyl isomers, butyl isomers, pentyl isomers, hexyl isomers, cyclopropyl, cylobutyl, cyclohexyl, and the like.
  • Prodrugs of prostaglandin EP4 agonists according to the structures below are also contemplated.
  • esters, ethers, or amide prodrugs herein may incorporate either a direct bond to the amino acid, or may alternatively incorporate a spacer group including, but not limited to, polvols such as ethylene glycol, glycerine, and the like, or oligomers or polymers thereof; dicarboxylic acids such as succinic acid, maleic acid, malonic acid, azelaic acid, and the like; hydro xycarboxylic acids such as lactic acid, hydroxyacetic acid, citric acid, and the like; polyamines such as ethylene diamine and the like; and esters, amides, or ethers to form combinations of any of the above.
  • polvols such as ethylene glycol, glycerine, and the like, or oligomers or polymers thereof
  • dicarboxylic acids such as succinic acid, maleic acid, malonic acid, azelaic acid, and the like
  • hydro xycarboxylic acids such as lactic acid, hydroxy
  • the amino acid used may be a natural or an unnatural amino acid.
  • the structures shown below exemplify amino acid prodrugs for natural amino acids, where R represents the side chain characteristic of a natural amino acid, and where R and the amide nitrogen may be connected as per proline.
  • Pharmaceutically acceptable salts of compounds of these structures, whether anionic, cationic, or zwitterionic, are also useful.
  • R is selected from the group consisting of H, methyl, iso-propyl, sec-butyl, benzyl, indol-3- ylmethyl, hydroxymethyl, CHOHCH 3 , CH 2 CONH 2 , /7-hydroxybenzyl, CH 2 SH, (CH 2 ) 4 NH 2 , (CH 2 ) 3 NHC(NH 2 ) 2 + , methyhmidizol-5-yl, CH 2 CO 2 H, or (CH 2 ) 2 CO 2 H
  • unnatural ammo acids are also ⁇ -ammo acids
  • the structure would be the same except that R would represent a side chain from a natural ammo acid
  • any stereoisomer may be used
  • the enantiomers of the natural ammo acids are specifically contemplated herein as unnatural ammo acids
  • useful types of unnatural amino acids include, but are not limited to: phenylalanine derivatives, particularly those where the ring is substituted, such as L-Dopa; or those where the phenyl is replaced with another aromatic group such as naphthyl or a heterocylic ring; ⁇ -amino acids and homo amino acids; cyclic amino acids; alanine derivatives; glycine derivatives; tyrosine derivatives, particularly those where the ring is substituted with an additional ring substituent; those where the phenyl is replaced with another aromatic group such as naph
  • L-dopa D-penicillamine, D-2- naphthylanaline, D-4-hydroxyphenylglycine, L-homophenylalanine, (2R, 3S)-phenylisoserine, thienylalanine, allylglycine, 3 -methy phenylalanine, 3-pyridylalanine, 4-thiazolylalanine, 4,4'biphenylalanine, A- aminomethylphenylalanine, 4-flurophenylalanine, 3,4-dichlorophenylalanine, pipecolic acid, ⁇ -homolysine, ⁇ - homophenylalanine, ⁇ -homoserine, ⁇ -homotryptophan, 3-amino-3-benzo[l,3]dioxol-5-yl propionic acid, 3-amino-3-
  • Ester prodrugs Of EP 4 agonists may also be based upon amino acids, as demonstrated by the examples shown below.
  • Pharmaceutically acceptable salts of compounds of these structures, whether anionic, cationic, or zwitterionic, are also useful.
  • spacers illustrated herein may be applied to amino acids to further increase the number kinds of amino acid prodrugs available.
  • Cl amino acid ester prodrug is a prodrug which is an ester at what is traditionally thought of as "Cl" in a prostaglandin.
  • a "Cl” ester is an ester at the carboxylic acid attached to A herein.
  • a carbon which has a chiral center can be construed to include the S isomer, the R isomer, or any mixture of isomers including a 50:50 R/S mixture.
  • the pure isomers of each of the structures above, and any possible isomeric mixtures, including the 50:50 R/S mixtures are contemplated. Methods of preparing these compounds are in United States Patent No. 6,747,037 and United States Patent No. 6,875,787.
  • Amino acid prodrugs are readily obtained by many methods. For example, while not intending to be limiting, one of several procedures used for the coupling of salicylic acid to a methyl ester of alanine, glycine, methionine, or tyrosine (Nakamura et. al. J. Pharm. Pharmacol. 1992, 44, 295-299, and Nakamura et. al. Int. J. Pharm. 1992, 87, 59-66) can be adapted for use with prostaglandin EP 4 agonists.
  • an equimolar amount of dicyclohexylcarbodiimide is added at or below O 0 C to a prostaglandin EP 4 agonist carboxylic acid and stirred about 30 minutes.
  • An equimolar amount of the methyl ester of the amino acid is then added and stirred overnight at room temperature to form the amide.
  • Deprotection of any hydroxyl group can then be carried out by using dilute aqueous acid or another method, depending on the protecting group.
  • the colonic mucosal barrier is central to protecting the inner layers of the colon from irritants such as foods, oxidizing agents, bacterial metabolites, and intestinal flora. While not intending to be bound in any way by theory, it is believed that impaired and/or leaky epithelial layers lead to various inflammations of the colon including immunogenic inflammatory bowel diseases and subsequent secondary inflammations. While not intending to be bound by theory, it is believed that prostaglandin EP 4 receptors mediate two cellular signaling pathways using either the 2 nd messenger cAMP or the phosphorylation of ERK or activation of phosphoinositide 3-kinases and early growth response factor- 1. It is believed that the latter pathways are particularly prominent in epithelial cells.
  • EP 4 agonists applied to the colon should recognize the prostaglandin EP 4 receptor and thus activate one or more of these signaling pathways. This should thus promote epithelial cell growth, proliferation, inhibition of apoptosis, and increases in mucus secretion, reducing permeability to intestinal antigens and irritants.
  • this enhancement and maintenance of the colonic mucosal barrier by prostaglandin EP 4 agonists should be prophylactic and therapeutic for colitis, amebic colitis, collagenous colitis, colitis cystica profunda, colitis cystica superficialis, granulomatous colitis, hemorrhagic colitis, mucous colitis, Crohn's disease, and ulcerative colitis.
  • a number of methods of delivering a drug to the colon via oral dosage forms are known in the art, and are reviewed by Chourasia and Jain in J Pharm Pharmaceut Sci 6 (1): 33-66, 2003. These include 1) administration of a prodrug, including an azo or a carbohydrate based prodrug; 2) coating the drug with, or encapsulating or impregnating the drug into a polymer designed for delivery to the colon, 3) time released delivery of the drug, 4) use of a bioadhesive system; and the like. Intestinal microflora are capable of reductive cleavage of an azo bond leaving the two nitrogen atoms as amine functional groups.
  • Bacteria of the lower GI also have enzymes which can digest glycosides, glucuronides, cyclodextrins, dextrans, and other carbohydrates, and ester prodrugs formed from these carbohydrates have been shown to deliver the parent active drugs selectively to the colon.
  • This prodrug approach has been used to deliver 5-aminosalicylic acid to humans.
  • glucouronide, cyclodextrin, and dextran prodrugs of steroids or non-steroidal anti-inflammatory drugs are useful for delivery of these drugs to the lower GI tract.
  • carbohydrate polymers such as amylase, arabinogalactan, chitosan, chondroiton sulfate, dextran, guar gum, pectin, xylin, and the like, can be used to coat a drug compound, or a drug may be impregnated or encapsulated in the polymer.
  • An amide of salicylic acid and glutamic acid has been shown to be useful for the delivery of salicylic acid to the colon of rabbit and dog.
  • the polymers After oral administration, the polymers remain stable in the upper GI tract, but are digested by the microflora of the lower GI thus releasing the drug for treatment.
  • Polymers which are sensitive to pH may also be used since the colon has a higher pH than the upper GI tract.
  • Such polymers are commercially available.
  • Rohm Pharmaceuticals, Darmstadt, Germany markets pH dependent methacrylate based polymers and copolymers which have varying solubilities over different pH ranges based upon the number of free carboxylate groups in the polymer under the tradename Eudragit®.
  • Eudragit® dosage forms are currently used to deliver salsalazine for the treatment of ulcerative colitis and Crohn's disease. Time release systems, bioadhesive systems, and other delivery systems have also been studied.
  • drugs which may be included in combination therapies with EP4 agonists and their prodrugs include, but are not limited to: 1. Anti-inflammatory drugs such as aminosalicylates and their prodrugs, Sulfasalazine, and the like;
  • Steroids including corticosteroids, and the like;
  • Immunomodulators such as azathioprine, 6-mercaptopurine, cyclosporine, and the like.
  • cytokines such as infliximab, etanercept, onercept, adalimumab, CDP571, CDP870, natalizumab, MLN-02, ISIS 2302, cM-T412, BF-5, vasilizumab, daclizumab, basiliximab, Anti-CD40L, and the like.
  • Plasmids encoding the human EP 1 , EP 2 , EP 3 , EP 4 , FP, TP, IP and DP receptors are prepared by cloning the respective coding sequences into the eukaryotic expression vector pCEP 4 (Invitrogen).
  • the pCEP 4 vector contains an Epstein Barr virus (EBV) origin of replication, which permits episomal replication in primate cell lines expressing EBV nuclear antigen (EBNA-I). It also contains a hygromycin resistance gene that is used for eukaryotic selection.
  • the cells employed for stable transfection are human embryonic kidney cells (HEK-293) that are transfected with and express the EBNA-I protein.
  • HEK-293 -EBNA cells are grown in medium containing Geneticin (G418) to maintain expression of the EBNA-I protein.
  • HEK-293 cells are grown in DMEM with 10% fetal bovine serum (FBS), 250 ⁇ g ml "1 G418 (Life Technologies) and 200 ⁇ g ml "1 gentamicin or penicillin/streptomycin. Selection of stable transfectants is achieved with 200 ⁇ g ml "1 hygromycin, the optimal concentration being determined by previous hygromycin kill curve studies.
  • the plasmid pCEP 4 incorporating cDNA inserts for the respective human prostanoid receptor (20 ⁇ g) is added to 500 ⁇ l of 250 mM CaCl 2 .
  • HEPES buffered saline x 2 (2 x HBS, 280 mM NaCl, 20 mM HEPES acid, 1.5 mM Na 2 HPO 4 , pH 7.05 - 7.12) is then added dropwise to a total of 500 ⁇ l, with continuous vortexing at room temperature. After 30 min, 9 ml DMEM are added to the mixture.
  • the DNA/DMEM/calcium phosphate mixture is then added to the cells, which is previously rinsed with 10 ml PBS.
  • the cells are then incubated for 5 hr at 37° C in humidified 95% air/5% CO 2 .
  • the calcium phosphate solution is then removed and the cells are treated with 10% glycerol in DMEM for 2 min.
  • the glycerol solution is then replaced by DMEM with 10% FBS.
  • the cells are incubated overnight and the medium is replaced by DMEM/10% FBS containing 250 ⁇ g ml "1 G418 and penicillin/streptomycin.
  • hygromycin B is added to a final concentration of 200 ⁇ g ml "1 .
  • hygromycin B resistant clones are individually selected and transferred to a separate well on a 24 well plate. At confluence each clone is transferred to one well of a 6 well plate, and then expanded in a 10 cm dish. Cells are maintained under continuous hygromycin selection until use.
  • Radioligand binding studies on plasma membrane fractions prepared from cells are performed as follows. Cells washed with TME buffer are scraped from the bottom of the flasks and homogenized for 30 sec using a Brinkman PT 10/35 polytron. TME buffer is added as necessary to achieve a 40 ml volume in the centrifuge tubes. TME is comprised of 50 mM TRIS base, 10 mM MgCl 2 , 1 mM EDTA; pH 7.4 is achieved by adding 1 N HCl. The cell homogenate is centrifuged at 19,000 rpm for 20-25 min at 4 0 C using a Beckman Ti-60 or Tv-70 rotor.
  • the pellet is then resuspended in TME buffer to provide a final protein concentration of 1 mg/ml, as determined by Bio-Rad assay.
  • Radioligand binding assays are performed in a 100 ⁇ l or 200 ⁇ l volume.
  • the binding of [ 3 H] PGE 2 (specific activity 165 Ci/mmol) is determined in duplicate and in at least 3 separate experiments. Incubations are for 60 min at 25° C and are terminated by the addition of 4 ml of ice-cold 50 mM TRIS-HCl followed by rapid filtration through Whatman GF/B filters and three additional 4 ml washes in a cell harvester (Brandel).

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Abstract

A compound comprising a prodrug of a prostaglandin EP4 agonist, wherein said prodrug is an ester, ether, or amide of an amino acid is disclosed herein. Maintenance of the colonic mucosal barrier by method comprising administering a therapeutically effective amount of a prostaglandin EP4 agonist to a colon of a mammal is also disclosed herein. Dosage forms, medicaments, and compositions, related thereto are also disclosed.

Description

PROSTAGLANDIN EP4 AGONISTS
By Inventors Wha-Bin Im, Robert M. Burk, and Mark Holoboski
CROSS-REFERENCE TO RELATED APPLICATION
This application is based on, and claims priority under 35 U.S. C. § 120 to U.S. Provisional Patent Application No. 60/744,234, filed on April 4, 2006, and which is incorporated herein by reference.
FIELD OF THE INVENTION
This invention relates to therapeutically active compounds and their delivery and use. Particularly, this invention relates to the delivery and use of prostaglandin EP4 agonists.
BACKGROUND OF THE INVENTION
Description of Related Art
Prostaglandins can be described as derivatives of prostanoic acid which have the following structural formula:
Figure imgf000002_0001
Various types of prostaglandins are known, depending on the structure and substituents carried on the alicyclic ring of the prostanoic acid skeleton. Further classification is based on the number of unsaturated bonds in the side chain indicated by numerical subscripts after the generic type of prostaglandin [e.g. prostaglandin Ei (PGEi), prostaglandin E2 (PGE2)], and on the configuration of the substituents on the alicyclic ring indicated by α or β [e.g. prostaglandin F2α (PGF2β)].
Certain 10, 10 -dimethyl prostaglandins are known. These are described in documents such as the following: Donde, in United States Patent No. Patent Application Publication No. 20040157901; Pernet ef α/ in US Patent 4,117,014;
Pernet, Andre G. et al., Prostaglandin analogs modified at the 10 and 11 positions, Tetrahedron Letters, (41), 1979, pp. 3933-3936; Plantema, Otto G. et al., Synthesis of (.+-.)-10.10-dimethylprostaglandin El methyl ester and its 15-epimer, Journal of the Chemical Society, Perkin Transactions 1 : Organic and Bio-organic Chemistry (1972-1999), (3), 1978, pp. 304-
308;
Plantema, O. G. et al., Synthesis of 10,10-dimethylprostaglandin El, Tetrahedron Letters, (51), 1975, 4039;
Hamon, A., et al., Synthesis of (+-)- and 15-EPI(+-)-10,10-Dimethylprostaglandin El, Tetrahedron Letters, Elsevier
Science Publishers, Amsterdam, NL, no. 3, January 1976, pp. 211-214; and
Patent Abstracts of Japan, Vol. 0082, no. 18 (C-503), June 10, 1988 & JP 63 002972 A (Nippon Iyakuhin Kogyo KX),
7 January 1988; the disclosures of these documents are hereby expressly incorporated by reference.
United States Patent Application Publication 2004/0142969 Al, expressly incorporated by reference herein, discloses compounds according to the formula below
Figure imgf000003_0001
the application discloses the identity of the groups as follows. m is from 1 to 4; n is from 0 to 4; A is alkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, cycloalkylalkyl, or aryloxyalkyl; E is -CHOH- or -C(O)-; X is -(CH2)2- or -CH=CH-; Y is -CH2-, arylene, heteroarylene, - CH=CH-, -O-, -S(O)P- where p is from 0 to 2, or -NRa- where Ra is hydrogen or alkyl; Z is -CH2OH, -CHO, tetrazol-5-yl, or -COORb where Rb is hydrogen or alkyl; and R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 each independently are hydrogen or alkyl.
United States Patent No. 6,747,037, expressly incorporated by reference herein, discloses prostaglandin EP4 agonists such as
Figure imgf000003_0002
United States Patent No. 6,610,719, expressly incorporated by reference herein, discloses EP4 selected agonists having the structure
Figure imgf000004_0001
the patent describes the identity of the groups as follows: Q is COOR3, CONHR4 or tetrazol-5-yl; A is a single or cis double bond; B is a single or trans double bond; U is
Figure imgf000004_0003
R is α-thienyl, phenyl, phenoxy, monosubstituted phenyl or monosubstituted phenoxy, said substituents being selected from the group consisting of chloro, fluoro, phenyl, methoxy, trifluoromethyl and (Ci -
C3)alkyl;
R.sup.3 is hydrogen, (Ci -C5)alkyl, phenyl or/>-biphenyl;
R4 is COR5 or SO2R5 ; and
R5 is phenyl or (Ci -C5)alkyl.
10-Hydroxyprostaglandin analogues, that is natural prostaglandin E compounds where the hydroxide is present on carbon 10 rather than carbon 11, are known in several patent documents including U.S. Patent No. 4,171,375; U.S. Patent No. 3,931,297; FR 2408567; DE 2752523, JP 53065854, DE 2701455, SE 7700257, DK 7700272, NL 7700272, JP 52087144, BE 850348, FR 2338244, FR 2162213, GB 1405301, and ES 409167; all of which are expressly incorporated by reference herein.
United States Patent Application Serial No. 821,705, filed April 9, 2004, expressly incorporated by reference herein, discloses compounds having the following structure
Figure imgf000004_0002
the groups are identified as follows J is C=O or CHOH;
A is -(CH2)(T, or cis -CH2CH=CH-(CH2)3-, wherein 1 or 2 carbons may be substituted with S or O; B is CO2H, or CO2R, CONR2, CONHCH2CH2OH, CON(CH2CH2OH)2, CH2OR, P(O)(OR)2, CONRSO2R, SONR2, or
Figure imgf000005_0001
R is H, Ci.6 alkyl;
D is -(CH2)n-, -X(CH2)n, or -(CH2)nX-, wherein n is from 0 to 3 and X is S or O; and
E is an aromatic or heteroaromatic moiety having from 0 to 4 substituents, said substituents each comprising from 1 to 6 non-hydrogen atoms is disclosed herein.
Other compounds of interest are disclosed in United States Patent No. 6,670,485; United States Patent No. 6,410,591 ; United States Patent No. 6,538,018; WO 2004/065365; WO 03/074483; WO 03/009872; WO 2004/019938; WO 03/103664; WO 2004/037786; WO 2004/037813; WO 03/103604; WO 03/077910; WO 02/42268; WO 03/008377 WO 03/053923; WO 2004/078103; and WO 2003/035064, all of which are expressly incorporated by reference herein.
Prostaglandin EP4 selective agonists are believed to have several medical uses. For example, U.S. Patent No. 6,552,067 B2, expressly incorporated by reference herein, teaches the use of prostaglandin EP4 selective agonists for the treatment of "methods of treating conditions which present with low bone mass, particularly osteoporosis, frailty, an osteoporotic fracture, a bone defect, childhood idiopathic bone loss, alveolar bone loss, mandibular bone loss, bone fracture, osteotomy, bone loss associated with periodontitis, or prosthetic ingrowth in a mammal."
U.S. Patent No. 6,586,468 Bl, expressly incorporated by reference herein, teaches that prostaglandin EP4 selective agonists "are useful for the prophylaxis and/or treatment of immune diseases (autoimmune diseases (amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjoegren's syndrome, arthritis, rheumatoid arthritis, systemic lupus erythematosus, etc.), post-transplantation graft rejection, etc.), asthma, abnormal bone formation, neurocyte death, pulmopathy, hepatopathy, acute hepatitis, nephritis, renal insufficiency, hypertension, myocardial ischemia, systemic inflammatory syndrome, pain induced by ambustion, sepsis, hemophagocytosis syndrome, macrophage activation syndrome, Still's diseases, Kawasaki diseases, burn, systemic granuloma, ulcerative colititis, Crohn's diseases, hypercytokinemia at dialysis, multiple organ failure, shock, etc. They are also connected with sleeping disorders and platelet coagulations, and therefore they are thought to be useful for these diseases."
Inflammatory bowel disease (IBD) is a group of disease characterized by inflammation in the large or small intestines and is manifest in symptoms such as diarrhea, pain, and weight loss. Nonsteroidal anti-inflammatory drugs have been shown to be associated with the risk of developing IBD, and recently Kabashima and colleagues have disclosed that "EP4 works to keep mucosal integrity, to suppress the innate immunity, and to downregulate the proliferation and activation of CD4+ T cells. These findings have not only elucidated the mechanisms of IBD by NSAIDs, but also indicated the therapeutic potential of EP4-selective agonists in prevention and treatment of IBD." (Kabashima, et. al, The Journal of Clinical Investigation, April 2002, Vol. 9, 883-893)
BRIEF DESCRIPTION OF THE INVENTION A compound comprising a prodrug of a prostaglandin EP4 agonist, wherein said prodrug is an ester, ether, or amide of a carbohydrate; or said prodrug is an ester, ether, or amide of an amino acid is disclosed herein.
Maintenance of the colonic mucosal barrier by method comprising administering a therapeutically effective amount of a prostaglandin EP4 agonist to a colon of a mammal is also disclosed herein. Dosage forms, medicaments, and compositions, related thereto are also disclosed.
DETAILED DESCRIPTION OF THE INVENTION
A prostaglandin EP4 agonist is broadly defined as a compound which an ordinary person in the art reasonably believes agonizes a prostaglandin EP4 receptor according to any one or more of numerous assays for determination of the EP4 activity that are well known to those of ordinary skill in the art. While not intending to be limiting, one such assay is given in the example below.
In one embodiment, the prostaglandin EP4 agonist is selective for a prostaglandin EP4 receptor relative to other prostaglandin receptor subtypes. In another embodiment, the prostaglandin EP4 agonist is at least 10 times more active at the EP4 receptor than at any other prostaglandin receptor subtype. In another embodiment, the prostaglandin EP4 agonist is at least 100 times more active at the EP4 receptor than at any other prostaglandin receptor subtype. In another embodiment, the prostaglandin EP4 agonist is at least 1000 times more active at the EP4 receptor than at any other prostaglandin receptor subtype. While not intending to be limiting, typical assays for the other receptor subtypes are also given in examples below. While not intending to limit the scope of the invention in any way, compounds according to the structures below are examples prostaglandin EP4 agonists:
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
or a pharmaceutically acceptable salt or a prodrug thereof, wherein a dashed line represents the presence of absence of a bond;
A is -(CH2)(S-, cis -CH2CH=CH-(CH2)3-, or -CH2C≡C-(CH2)3-, wherein 1 or 2 carbon atoms may be substituted with S or O; or A is -(CH2)m-Ar-(CH2)0- wherein Ar is interarylene or heterointerarylene, the sum of m and o is from 1 to 4, and wherein one CH2 may be substituted with S or O;
X is S or O;
J is C=O, CHOH, or CH2CHOH; and
E is Ci.i2 alkyl, R2, or -Y-R2 wherein Y is CH2, S, or O, and R2 is aryl or heteroaryl.
In these structures, a dashed line represents the presence or absence of a bond. Thus, a structure such as the one below,
Figure imgf000009_0001
represents three different structures, depicted as follows.
Figure imgf000009_0002
In relation to the identity of A disclosed in the chemical structures presented herein, in the broadest sense, A is -(CH2)S-, cis -CH2CH=CH-(CH2)3-, or -CH2C≡C-(CH2)3-, wherein 1 or 2 carbon atoms may be substituted with S or O; or A is -(CH2)n-Ar-(CH2)0- wherein Ar is interarylene or heterointerarylene, the sum of m and o is from 1 to 3, and wherein one CH2 may be substituted with S or O.
While not intending to be limiting, A may be -(CH2)6-, cis -CH2CH=CH-(CH2)3-, or -CH2C≡C-(CH2)3-. Alternatively, A may be a group which is related to one of these three moieties in that any carbon is substituted with S and/or O. For example, while not intending to limit the scope of the invention in any way, A may be an S substituted moiety such as one of the following or the like.
Figure imgf000010_0001
Altematively, while not intending to limit the scope of the invention in any way, A may be an 0 substituted moiety such as one of the following or the like.
Figure imgf000011_0001
Alternatively, while not intending to limit the scope of the invention in any way, A may have both an O and an S substituted into the chain, such as one of the following or the like.
Figure imgf000011_0002
Alternatively, while not intending to limit the scope of the invention in any way, in certain embodiments A is -(CH2)n-Ar-(CH2)o- wherein Ar is interarylene or heterointerarylene, the sum of m and o is from 1 to 4, and wherein one CH2 may be substituted with S or O. In other words, while not intending to limit the scope of the invention in any way, in one embodiment A comprises from 1 to 4 CH2 moieties and Ar, e.g. -CH2-Ar-, -(CH2)2-Ar-, -CH2-ArCH2-, - CH2Ar(CH2)2-, -(CH2)2-Ar(CH2)2-, and the like; or
A comprises O, from 0 to 3 CH2 moieties, and Ar, e.g., -0-Ar-, Ar-CH2-O-, -O-Ar-(CH2)2-, -0-CH2-Ar-, -0-CH2- Ar-(CH2)2, and the like; or
A comprises S, from 0 to 3 CH2 moieties, and Ar, e.g., -S-Ar-, Ar-CH2-S-, -S-Ar-(CH2)2-, -S-CH2-Ar-, -S-CH2-Ar- (CH2)2, and the like. Interarylene or heterointerarylene refers to an aryl ring or ring system or a heteroaryl ring or ring system which connects two other parts of a molecule, i.e. the two parts are bonded to the ring in two distinct ring positions. Interarylene or heterointerarylene may be substituted or unsubstituted. Thus, an unsubstituted interarylene has 4 potential positions where a substituent could be attached. In one embodiment, Ar is substituted or unsubstituted interphenylene, interthienylene, interfurylene, or interpyridinylene. In another embodiment Ar is interphenylene (Ph). In another embodiment A is -(CH2)2-Ph-. While not intending to limit scope of the invention in any way, substituents may have 4 or less heavy atoms, or in other words, non hydrogen atoms. Any number of hydrogen atoms required for a particular substituent will also be included. Thus, the substituent may be hydrocarbyl having up to 4 carbon atoms, including alkyl up to C4, alkenyl, alkynyl, and the like; hydrocarbyloxy up to C3; CF3; halo, such as F, Cl, or Br; hydroxyl; NH2 and alkylamine functional groups up to C3; other N or S containing substituents; and the like. In one embodiment A is -(CH2)Di-Ar-(CH2)O- wherein Ar is interphenylene, the sum of m and o is from 1 to 3, and wherein one CH2 may be substituted with S or O.
In another embodiment A is -CH2-Ar-OCH2-. In another embodiment A is -CH2-Ar-OCH2- and Ar is interphenylene. In another embodiment, Ar is attached at the 1 and 3 positions, such as when A has the structure shown below.
Figure imgf000012_0001
In another embodiment A is -(CH2)6-, cis -CH2CH=CH-(CH2)3-, or -CH2C≡C-(CH2)3-, wherein 1 or 2 carbon atoms may be substituted with S or O; or A is -(CH2)2-Ph- wherein one CH2 may be substituted with S or O.
In another embodiment A is -(CH2)6-, cis -CH2CH=CH-(CH2)3-, or -CH2C≡C-(CH2)3-, wherein 1 or 2 carbon atoms may be substituted with S or O; or A is -(CH2)2-Ph-.
J is C=O, CHOH, or CH2CHOH. Thus, while not intending to limit the scope of the invention in any way. Compounds such as the ones below are useful as the prostaglandin EP4 agonists.
Figure imgf000012_0002
Figure imgf000013_0001
Ci.12 alkyl is alkyl having from 1 to 12 carbon atoms, including: linear alkyl, such as methyl, ethyl, n-propyl, n-butyl, etc.; branched alkyl, such as iso-propyl, iso-butyl, t-butyl, isopentyl, etc.; cyclic alkyl. such as cyclopropyl, cyclobutyl, cyclohexyl, etc.; including substituted cvcloalkyl. such as methylcyclohexyl, ethylcyclopropyl, dimethylcycloheptyl, etc, and including moieties such as CH2-cyclohexyl, where the cyclic group is not the point of attachment to the rest of the molecule; and any combination of the other types of alkyl groups listed above.
Thus, E may be any of these groups. In particular, linear alkyl of Ci_6 is contemplated herein, especially butyl.
Other particularly useful groups are cyclohexyl, cyclopentyl, and substituted cyclohexyl and cyclobutyl having less than 9 carbon atoms.
E may also be R or Y-R wherein Y is CH2, S or O and R is aryl or heteroaryl. Thus, E may be aryl, heteroaryl, -CH2-aryl, -S-aryl, -O-aryl,-CH2-heteroaryl, -S-heteroaryl, or -O-heteroaryl.
Aryl is defined as an aromatic ring or ring system as well as a substituted derivative thereof, wherein one or more substituents are substituted for hydrogen. While not intending to limit the scope of the invention in any way, phenyl, naphthyl, biphenyl, terphenyl, and the like are examples of aryl.
Heteroaryl is defined as aryl having at least one non-carbon atom in an aromatic ring or ring system. While not intending to limit the scope of the invention in any way, in many cases one or more oxygen, sulfur, and/or nitrogen atoms are present. While not intending to limit the scope of the invention in any way, examples of heteroaryl are furyl, thienyl, pyridinyl, benzofuryl, benzothienyl, indolyl, and the like. The substituents of aryl or heteroaryl may have up to 12 non-hydrogen atoms each and as many hydrogens as necessary. Thus, while not intending to limit the scope of the invention in any way, the substituents may be: hvdrocarbyl, such as alkyl, alkenyl, alkynyl, and the like, and combinations thereof; hydrocarbyloxy, meaning O-hydrocarbyl such as OCH3, OCH2CH3, O-cyclohexyl, etc, up to 11 carbon atoms; hydro xyhydrocarbyl, meaning hydrocarbyl-OH such as CH2OH, C(CH3)2OH, etc, up to 11 carbon atoms; nitrogen substituents such as NO2, CN, and the like, including amino, such as NH2, NH(CH2CH3OH), NHCH3, and the like up to 11 carbon atoms; carbonyl substituents, such as CO2H, ester, amide, and the like; halogen, such as chloro, fluoro, bromo, and the like fluorocarbonyl, such as CF3, CF2CF3, etc.; phosphorous substituents. such as PO3 2", and the like; sulfur substituents, including S-hydrocarbyl, SH, SO3H, SO2-hydrocarbyl, SO3-hydrocarbyl, and the like. In certain embodiments, the number of non -hydrogen atoms is 6 or less in a substituent. In other embodiments, the number of non-hydrogen atoms is 3 or less in a substituent. In other embodiments, the number of non-hydrogen atoms on a substituent is 1. In certain embodiments, the substituents contain only hydrogen, carbon, oxygen, halo, nitrogen, and sulfur.
In other embodiments, the substituents contain only hydrogen, carbon, oxygen, and halo.
In certain embodiments A is -(CH2)6-, cis -CH2CH=CH-(CH2)3-, or -CH2C≡C-(CH2)3-, wherein 1 or 2 carbon atoms may be substituted with S or O; and E is Ci-β alkyl, R , or -Y-R wherein Y is CH2, S, or O, and R is aryl or heteroaryl. In one embodiment R1 is H, chloro, or fluoro. In another embodiment R1 is H. In another embodiment, R1 is chloro.
In other embodiments R is phenyl, naphthyl, biphenyl, thienyl, or benzothienyl having from O to 2 substituents selected from the group consisting of F, Cl, Br, methyl, methoxy, and CF3. In other embodiments R2 is CH2-naphthyl, CH2-biphenyl, CH2-(2-thienyl), CH2-(3-thienyl), naphthyl, biphenyl, 2-thienyl, 3-thienyl, CH2-(2-(3-chlorobenzothienyl)), CH2-(3-benzothienyl), 2-(3-chlorobenzothienyl), or 3-benzothienyl.
In other embodiments R2 is CH2-(2-thienyl), CH2-(3-thienyl), 2-thienyl, 3-thienyl, CH2-(2-(3- chlorobenzothienyl)), CH2-(3-benzothienyl), 2-(3-chlorobenzothienyl), or 3-benzothienyl.
While not intending to limit the scope of the invention in any way, compounds according to the structures below, wherein x is 0 or 1 and R1 is H, chloro, fluoro, bromo, methyl, methoxy, or CF3, are also examples of prostaglandin EP4 agonists.
Figure imgf000015_0001
While not intending to limit the scope of the invention in any way, compounds according to the structures below are also examples of prostaglandin EP4 agonists.
Figure imgf000015_0002
While not intending to limit the scope of the invention in any way, compounds according to the structures below are also examples of prostaglandin EP4 agonists.
Figure imgf000016_0001
While not intending to limit the scope of the invention in any way, compounds according to the structures below are also examples of prostaglandin EP4 agonists.
Figure imgf000016_0002
While not intending to limit the scope of the invention in any way, compounds according to the structures below, wherein x is 0 or 1 and R1 is H, chloro, fluoro, bromo, methyl, methoxy, or CF3, are also examples of prostaglandin EP4 agonists.
Figure imgf000017_0001
While not intending to limit the scope of the invention in any way, compounds according to the structures below are also examples of prostaglandin EP4 agonists
Figure imgf000017_0002
Furthermore, the following United States Patent Applications or Patents, all of which are expressly incorporated by reference herein, disclose compounds which are prostaglandin EP4 agonists United States Patent No 6,552,067, United States Patent No 6,747,054, United States Patent Application Publication No 20030120079, and United States Patent Application Publication No 20030207925, United States Patent Application Publication No. 20040157901; United States Patent No. 4,117,014; United States Patent Application Publication No. 2004/0142969; United States Patent No. 6,747,037; United States Patent No. 6,610,719; U.S. Patent No. 4,171,375; U.S. Patent No. 3,931,297; United States Patent Application Serial No. 821,705, filed April 9, 2004; United States Patent No. 6,670,485; United States Patent No. 6,410,591; and United States Patent No. 6,538,018.
Methods and prodrugs related to all of these prostaglandin EP4 agonists are specifically contemplated herein.
Prodrugs of prostaglandin EP4 agonists comprising
Figure imgf000018_0001
are also contemplated herein; wherein R4 is H, halo or Ci_6 alkyl.
Halo is a group 7 atom such as fluoro, chloro, bromo, iodo, and the like.
Ci-6 alkyl is linear, branched, or cyclic alkyl having from 1 to 6 carbons including, but not limited to, methyl, ethyl, propyl isomers, butyl isomers, pentyl isomers, hexyl isomers, cyclopropyl, cylobutyl, cyclohexyl, and the like. Prodrugs of prostaglandin EP4 agonists according to the structures below are also contemplated.
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
The esters, ethers, or amide prodrugs herein may incorporate either a direct bond to the amino acid, or may alternatively incorporate a spacer group including, but not limited to, polvols such as ethylene glycol, glycerine, and the like, or oligomers or polymers thereof; dicarboxylic acids such as succinic acid, maleic acid, malonic acid, azelaic acid, and the like; hydro xycarboxylic acids such as lactic acid, hydroxyacetic acid, citric acid, and the like; polyamines such as ethylene diamine and the like; and esters, amides, or ethers to form combinations of any of the above.
The amino acid used may be a natural or an unnatural amino acid. The structures shown below exemplify amino acid prodrugs for natural amino acids, where R represents the side chain characteristic of a natural amino acid, and where R and the amide nitrogen may be connected as per proline. Pharmaceutically acceptable salts of compounds of these structures, whether anionic, cationic, or zwitterionic, are also useful.
Figure imgf000022_0001
In certain embodiments, R is selected from the group consisting of H, methyl, iso-propyl, sec-butyl, benzyl, indol-3- ylmethyl, hydroxymethyl, CHOHCH3, CH2CONH2, /7-hydroxybenzyl, CH2SH, (CH2)4NH2, (CH2)3NHC(NH2)2 +, methyhmidizol-5-yl, CH2CO2H, or (CH2)2CO2H
Of course analogous prodrugs of unnatural ammo acids may also be made If the unnatural ammo acids are also α-ammo acids, the structure would be the same except that R would represent a side chain from a natural ammo acid For a natural ammo acid, any stereoisomer may be used In fact, the enantiomers of the natural ammo acids are specifically contemplated herein as unnatural ammo acids Examples of useful types of unnatural amino acids include, but are not limited to: phenylalanine derivatives, particularly those where the ring is substituted, such as L-Dopa; or those where the phenyl is replaced with another aromatic group such as naphthyl or a heterocylic ring; β-amino acids and homo amino acids; cyclic amino acids; alanine derivatives; glycine derivatives; tyrosine derivatives, particularly those where the ring is substituted with an additional ring substituent; those where the phenyl is replaced with another aromatic group such as naphthyl or a heterocylic ring; or ethers at the phenolic oxygen; linear core amino acids diamino acids.
Specifically, the following unnatural amino acids are contemplated herein: L-dopa, D-penicillamine, D-2- naphthylanaline, D-4-hydroxyphenylglycine, L-homophenylalanine, (2R, 3S)-phenylisoserine, thienylalanine, allylglycine, 3 -methy phenylalanine, 3-pyridylalanine, 4-thiazolylalanine, 4,4'biphenylalanine, A- aminomethylphenylalanine, 4-flurophenylalanine, 3,4-dichlorophenylalanine, pipecolic acid, β-homolysine, β- homophenylalanine, β-homoserine, β-homotryptophan, 3-amino-3-benzo[l,3]dioxol-5-yl propionic acid, 3-amino-3-
(6-methoxy-pyridin-3-yl)propionic acid, 3-amino-4-(3,4-difluorophenyl)butyric acid, 3-amino-4-(4- fluorophenyl)butyric acid, 3-amino-5-hexenoic acid, 2-tetrahydroisoquinolineacetic acid, 3-amino-5- phenylpentanoic acid, and azetidine-3-carboxylic acid.
Ester prodrugs Of EP4 agonists may also be based upon amino acids, as demonstrated by the examples shown below. Pharmaceutically acceptable salts of compounds of these structures, whether anionic, cationic, or zwitterionic, are also useful.
Figure imgf000023_0001
Since amino acids such as serine, threonine, and tyrosine, and many unnatural amino acids have hydroxyl functional groups in their side chains, ether prodrugs Of EP4 agonists based upon amino acids are also possible, as demonstrated in the examples below. Pharmaceutically acceptable salts of compounds of these structures, whether anionic, cationic, or zwitterionic, are also useful.
Figure imgf000024_0001
In addition, the spacers illustrated herein may be applied to amino acids to further increase the number kinds of amino acid prodrugs available.
These amino acids with hydro xyl functional groups may also be used to formed Cl amino acid ester prodrugs. For the purposes herein, Cl amino acid ester prodrug is a prodrug which is an ester at what is traditionally thought of as "Cl" in a prostaglandin. For prostaglandins not having the same carbon skeleton as a natural prostaglandin, a "Cl" ester is an ester at the carboxylic acid attached to A herein.
Prodrugs of the compounds shown below, and use of the compounds, or salts or prodrugs thereof, for any method, composition, or treatment disclosed herein, are specifically contemplated herein.
Figure imgf000024_0002
Unless indicated by a wedge or a dash, a carbon which has a chiral center can be construed to include the S isomer, the R isomer, or any mixture of isomers including a 50:50 R/S mixture. In particular, the pure isomers of each of the structures above, and any possible isomeric mixtures, including the 50:50 R/S mixtures, are contemplated. Methods of preparing these compounds are in United States Patent No. 6,747,037 and United States Patent No. 6,875,787.
Amino acid prodrugs are readily obtained by many methods. For example, while not intending to be limiting, one of several procedures used for the coupling of salicylic acid to a methyl ester of alanine, glycine, methionine, or tyrosine (Nakamura et. al. J. Pharm. Pharmacol. 1992, 44, 295-299, and Nakamura et. al. Int. J. Pharm. 1992, 87, 59-66) can be adapted for use with prostaglandin EP4 agonists. In this procedure, an equimolar amount of dicyclohexylcarbodiimide is added at or below O0C to a prostaglandin EP4 agonist carboxylic acid and stirred about 30 minutes. An equimolar amount of the methyl ester of the amino acid is then added and stirred overnight at room temperature to form the amide. Deprotection of any hydroxyl group can then be carried out by using dilute aqueous acid or another method, depending on the protecting group.
While not intending to be bound by theory, it is commonly believed by those skilled in the art that the colonic mucosal barrier is central to protecting the inner layers of the colon from irritants such as foods, oxidizing agents, bacterial metabolites, and intestinal flora. While not intending to be bound in any way by theory, it is believed that impaired and/or leaky epithelial layers lead to various inflammations of the colon including immunogenic inflammatory bowel diseases and subsequent secondary inflammations. While not intending to be bound by theory, it is believed that prostaglandin EP4 receptors mediate two cellular signaling pathways using either the 2nd messenger cAMP or the phosphorylation of ERK or activation of phosphoinositide 3-kinases and early growth response factor- 1. It is believed that the latter pathways are particularly prominent in epithelial cells.
While not intending to be bound by theory, it is believed that activation of the signaling pathways promotes cell proliferation, cell growth, cell metabolism and the inhibition of apoptosis. Thus, while not intending to be bound in any way by theory, EP4 agonists applied to the colon should recognize the prostaglandin EP4 receptor and thus activate one or more of these signaling pathways. This should thus promote epithelial cell growth, proliferation, inhibition of apoptosis, and increases in mucus secretion, reducing permeability to intestinal antigens and irritants. Thus, while not intending to be bound by theory, this enhancement and maintenance of the colonic mucosal barrier by prostaglandin EP4 agonists should be prophylactic and therapeutic for colitis, amebic colitis, collagenous colitis, colitis cystica profunda, colitis cystica superficialis, granulomatous colitis, hemorrhagic colitis, mucous colitis, Crohn's disease, and ulcerative colitis.
A number of methods of delivering a drug to the colon via oral dosage forms are known in the art, and are reviewed by Chourasia and Jain in J Pharm Pharmaceut Sci 6 (1): 33-66, 2003. These include 1) administration of a prodrug, including an azo or a carbohydrate based prodrug; 2) coating the drug with, or encapsulating or impregnating the drug into a polymer designed for delivery to the colon, 3) time released delivery of the drug, 4) use of a bioadhesive system; and the like. Intestinal microflora are capable of reductive cleavage of an azo bond leaving the two nitrogen atoms as amine functional groups. Bacteria of the lower GI also have enzymes which can digest glycosides, glucuronides, cyclodextrins, dextrans, and other carbohydrates, and ester prodrugs formed from these carbohydrates have been shown to deliver the parent active drugs selectively to the colon. This prodrug approach has been used to deliver 5-aminosalicylic acid to humans. In vivo and in vitro studies on rats and guinea pigs with prodrugs of dexamethasone, prednisolone, hydrocortisone, and fludrocortisone, suggest that glycoside conjugates may be useful for the delivery of steroids to the human colon. Other in vivo studies have suggested that glucouronide, cyclodextrin, and dextran prodrugs of steroids or non-steroidal anti-inflammatory drugs are useful for delivery of these drugs to the lower GI tract. Similarly, carbohydrate polymers such as amylase, arabinogalactan, chitosan, chondroiton sulfate, dextran, guar gum, pectin, xylin, and the like, can be used to coat a drug compound, or a drug may be impregnated or encapsulated in the polymer. An amide of salicylic acid and glutamic acid has been shown to be useful for the delivery of salicylic acid to the colon of rabbit and dog. After oral administration, the polymers remain stable in the upper GI tract, but are digested by the microflora of the lower GI thus releasing the drug for treatment. Polymers which are sensitive to pH may also be used since the colon has a higher pH than the upper GI tract. Such polymers are commercially available. For example, Rohm Pharmaceuticals, Darmstadt, Germany, markets pH dependent methacrylate based polymers and copolymers which have varying solubilities over different pH ranges based upon the number of free carboxylate groups in the polymer under the tradename Eudragit®. Several Eudragit® dosage forms are currently used to deliver salsalazine for the treatment of ulcerative colitis and Crohn's disease. Time release systems, bioadhesive systems, and other delivery systems have also been studied.
Coadministration of prostaglandin EP4 agonists, either in a single composition or in separate dosage forms, is also contemplated. While not intending to limit the scope of the invention in any way, drugs which may be included in combination therapies with EP4 agonists and their prodrugs include, but are not limited to: 1. Anti-inflammatory drugs such as aminosalicylates and their prodrugs, Sulfasalazine, and the like;
2. Steroids, including corticosteroids, and the like;
3. Immunomodulators such as azathioprine, 6-mercaptopurine, cyclosporine, and the like; and
4. Humanized monoclonal antibodies against pro-inflammatory cytokines such as infliximab, etanercept, onercept, adalimumab, CDP571, CDP870, natalizumab, MLN-02, ISIS 2302, cM-T412, BF-5, vasilizumab, daclizumab, basiliximab, Anti-CD40L, and the like.
One useful assay for determining prostaglandin EP4 activity and selectivity of compounds is described below.
HUMAN RECOMBINANT EP1, EP2, EP3, EP4, FP, TP, IP and DP RECEPTORS: STABLE TRANSFECTANTS.
Plasmids encoding the human EP1, EP2, EP3, EP4, FP, TP, IP and DP receptors are prepared by cloning the respective coding sequences into the eukaryotic expression vector pCEP4 (Invitrogen). The pCEP4 vector contains an Epstein Barr virus (EBV) origin of replication, which permits episomal replication in primate cell lines expressing EBV nuclear antigen (EBNA-I). It also contains a hygromycin resistance gene that is used for eukaryotic selection. The cells employed for stable transfection are human embryonic kidney cells (HEK-293) that are transfected with and express the EBNA-I protein. These HEK-293 -EBNA cells (Invitrogen) are grown in medium containing Geneticin (G418) to maintain expression of the EBNA-I protein. HEK-293 cells are grown in DMEM with 10% fetal bovine serum (FBS), 250 μg ml"1 G418 (Life Technologies) and 200 μg ml"1 gentamicin or penicillin/streptomycin. Selection of stable transfectants is achieved with 200 μg ml"1 hygromycin, the optimal concentration being determined by previous hygromycin kill curve studies.
For transfection, the cells are grown to 50-60% confluency on 10 cm plates. The plasmid pCEP4 incorporating cDNA inserts for the respective human prostanoid receptor (20 μg) is added to 500 μl of 250 mM CaCl2. HEPES buffered saline x 2 (2 x HBS, 280 mM NaCl, 20 mM HEPES acid, 1.5 mM Na2 HPO4, pH 7.05 - 7.12) is then added dropwise to a total of 500 μl, with continuous vortexing at room temperature. After 30 min, 9 ml DMEM are added to the mixture. The DNA/DMEM/calcium phosphate mixture is then added to the cells, which is previously rinsed with 10 ml PBS. The cells are then incubated for 5 hr at 37° C in humidified 95% air/5% CO2. The calcium phosphate solution is then removed and the cells are treated with 10% glycerol in DMEM for 2 min. The glycerol solution is then replaced by DMEM with 10% FBS. The cells are incubated overnight and the medium is replaced by DMEM/10% FBS containing 250 μg ml"1 G418 and penicillin/streptomycin. The following day hygromycin B is added to a final concentration of 200 μg ml"1.
Ten days after transfection, hygromycin B resistant clones are individually selected and transferred to a separate well on a 24 well plate. At confluence each clone is transferred to one well of a 6 well plate, and then expanded in a 10 cm dish. Cells are maintained under continuous hygromycin selection until use.
RADIOLIGAND BINDING
Radioligand binding studies on plasma membrane fractions prepared from cells are performed as follows. Cells washed with TME buffer are scraped from the bottom of the flasks and homogenized for 30 sec using a Brinkman PT 10/35 polytron. TME buffer is added as necessary to achieve a 40 ml volume in the centrifuge tubes. TME is comprised of 50 mM TRIS base, 10 mM MgCl2, 1 mM EDTA; pH 7.4 is achieved by adding 1 N HCl. The cell homogenate is centrifuged at 19,000 rpm for 20-25 min at 40C using a Beckman Ti-60 or Tv-70 rotor. The pellet is then resuspended in TME buffer to provide a final protein concentration of 1 mg/ml, as determined by Bio-Rad assay. Radioligand binding assays are performed in a 100 μl or 200 μl volume. The binding of [3H] PGE2 (specific activity 165 Ci/mmol) is determined in duplicate and in at least 3 separate experiments. Incubations are for 60 min at 25° C and are terminated by the addition of 4 ml of ice-cold 50 mM TRIS-HCl followed by rapid filtration through Whatman GF/B filters and three additional 4 ml washes in a cell harvester (Brandel). Competition studies are performed using a final concentration of 2.5 or 5 nM [3H] PGE2 and non-specific binding is determined with 10"5 M unlabelled PGE2. For all radioligand binding studies, the criteria for inclusion are >50% specific binding and between 500 and
1000 displaceable counts or better.

Claims

CLAIMSWhat is claimed is:
1. A compound comprising a prodrug of a prostaglandin EP4 agonist, wherein said prodrug is an ester, ether, or amide of an amino acid.
2. The compound of claim 2 wherein said prostaglandin EP4 agonist is a compound selected from the group consisting of
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
or a pharmaceutically acceptable salt or a prodrug thereof, wherein a dashed line indicates the presence or absence of a bond;
A is -(CH2)(S-, cis -CH2CH=CH-(CH2)3-, or -CH2C≡C-(CH2)3-, wherein 1 or 2 carbon atoms may be substituted with S or O; or A is -(CH2)m-Ar-(CH2)0- wherein Ar is interarylene or heterointerarylene, the sum of m and o is from
1 to 4, and wherein one CH2 may be substituted with S or O;
X is S or O;
J is C=O, CHOH, or CH2CHOH; and
E is Ci-I2 alkyl, R , or -Y-R wherein Y is CH2, S, or O, and R is aryl or heteroaryl.
3. The compound of claim 3 wherein A is -(CH2)6-, cis -CH2CH=CH-(CH2)3-, or -CH2C≡C-(CH2)3-, wherein 1 or 2 carbon atoms may be substituted with S or O; and E is Ci_6 alkyl, R2, or -Y-R2 wherein Y is CH2, S, or O, and R is aryl or heteroaryl.
4. The compound of claim 4 wherein R is phenyl, naphthyl, biphenyl, thienyl, or benzothienyl having from O to 2 substituents selected from the group consisting of F, Cl, Br, methyl, methoxy, and CF3.
5. The compound of claim 5 wherein R2 is CH2-naphthyl, CH2-biphenyl, CH2-(2-thienyl), CH2-(3-thienyl), naphthyl, biphenyl, 2-thienyl, 3-thienyl, CH2-(2-(3-chlorobenzothienyl)), CH2-(3 -benzothienyl), 2-(3- chlorobenzothienyl), or 3 -benzothienyl.
6. The compound of claim 5 wherein the prostaglandin EP4 agonist comprises
Figure imgf000030_0002
wherein x is O or 1, and R1 is H, chloro, fluoro, bromo, methyl, methoxy, or CF3.
7. The compound of claim 7 wherein the prostaglandin EP4 agonist comprises
Figure imgf000031_0001
The compound of claim 1, which is a prodrug of
Figure imgf000031_0002
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1, which is a prodrug of
Figure imgf000031_0003
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1, wherein the amino acid is a natural amino acid.
11. The compound of claim 1, wherein the amino acid is an unnatural amino acid.
12. The compound of claim 1, wherein the prodrug is a Cl amino acid ester.
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