# Patent

## Title
Therapeutic substituted cyclopentanones

## Abstract

Compounds are disclosed herein comprising




    or a pharmaceutically acceptable salt, or a metabolite or a prodrug thereof;
    wherein a dashed line indicates the presence or absence of a bond;
    Y, A, and B are described herein


Therapeutic methods, manufacturing methods, compositions, and medicaments related thereto are also disclosed.

## Background
CROSS REFERENCE TO RELATED APPLICATIONS
This is a national stage application under 35 U.S.C. § 371 of PCT application PCT/US 2006/014319, filed on Apr. 17, 2006, which claims the benefit of Provisional Application No. 60/672,837, filed on Apr. 18, 2005.


BACKGROUND OF THE INVENTION
Description of the Related Art
Ocular hypotensive agents are useful in the treatment of a number of various ocular hypertensive conditions, such as post-surgical and post-laser trabeculectomy ocular hypertensive episodes, glaucoma, and as presurgical adjuncts.
Glaucoma is a disease of the eye characterized by increased intraocular pressure. On the basis of its etiology, glaucoma has been classified as primary or secondary. For example, primary glaucoma in adults (congenital glaucoma) may be either open-angle or acute or chronic angle-closure. Secondary glaucoma results from pre-existing ocular diseases such as uveitis, intraocular tumor or an enlarged cataract.
Considering all types together, glaucoma occurs in about 2% of all persons over the age of 40 and may be asymptotic for years before progressing to rapid loss of vision. Certain eicosanoids and their derivatives are currently commercially available for use in glaucoma management. Eicosanoids and derivatives include numerous biologically important compounds such as prostaglandins and their derivatives. Prostaglandins can be described as derivatives of prostanoic acid which have the following structural formula:




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 E1 (PGE1), 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 15,15-dimethyl prostaglandins are known. These are described in documents such as the following: US Patent Application Publication No. 2004/0157901, and related documents;

    Pernet et al in U.S. Pat. No. 4,117,014 (filed 23 Dec. 1976);
    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 E1 methyl ester and its 15-epimer pp 304-308, Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-organic Chemistry (1972-1999), (3), 1978;
    Plantema, O. G. et al., Synthesis of 10,10-dimethylprostaglandin E1, Tetrahedron Letters, (51), 1975, 4595-4598;
    Hamon, A., et al., Synthesis of (±)- and 15-EP1(±)-10,10-Dimthylprostaglandin E1; 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), Jun. 10, 1988 & JP 63 002972 A (Nippon Iyakuhin Kogyo K K), 7 Jan. 1988;

the disclosure of these documents are hereby expressly incorporated by reference.



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)


DESCRIPTION OF THE INVENTION
Compounds are disclosed herein comprising




or a pharmaceutically acceptable salt, or a metabolite or a prodrug thereof;

wherein a dashed line indicates the presence or absence of a bond;

Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl functional group;

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)m—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; and

B is naphthyl.

Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl functional group;
An organic acid functional group is an acidic functional group on an organic molecule. While not intending to be limiting, organic acid functional groups may comprise an oxide of carbon, sulfur, or phosphorous. Thus, while not intending to limit the scope of the invention in any way, in certain compounds Y is a carboxylic acid, sulfonic acid, or phosphonic acid functional group, i.e. one of the structures shown below.




Salts of any of these acids of any pharmaceutically acceptable form are also contemplated.
Additionally, an amide or ester of one of the organic acids shown above comprising up to 12 carbon atoms is also contemplated. In an ester, a hydrocarbyl moiety replaces a hydrogen atom of an acid such as in a carboxylic acid ester, e.g. CO2Me, CO2Et, etc.
In an amide, an amine group replaces an OH of the acid. Examples of amides include CON(R2)2, CON(OR2)R2, CON(CH2CH2OH)2, and CONH(CH2CH2OH) where R2 is independently H, C1-C6 alkyl, phenyl, or biphenyl. Moieties such as CONHSO2R2 are also amides of the carboxylic acid notwithstanding the fact that they may also be considered to be amides of the sulfonic acid R2—SO3H.
While not intending to limit the scope of the invention in any way, Y may also be hydroxymethyl or an ether thereof comprising up to 12 carbon atoms. Thus, compounds having a structure shown below are possible.




Additionally, ethers of these compounds are also possible. An ether is a functional group wherein a hydrogen of an hydroxyl is replaced by carbon, e.g., Y is CH2OCH3, CH2OCH2CH3, etc.
Finally, while not intending to limit the scope of the invention in any way, Y may be a tetrazolyl functional group, such as compounds having a structure according to the formula below.




An unsubstituted tetrazolyl functional group has two tautomeric forms, which can rapidly interconvert in aqueous or biological media, and are thus equivalent to one another. These tautomers are shown below.





Additionally, if R2 is C1-C6 alkyl, phenyl, or biphenyl, other isomeric forms of the tetrazolyl functional group such as the one shown below are also possible, unsubstituted and hydrocarbyl substituted tetrazolyl up to C12 are considered to be within the scope of the term “tetrazolyl.”





While not intending to limit the scope of the invention in any way, in one embodiment, Y is selected from the group consisting of CO2(R2), CON(R2)2, CON(OR2)R2, CON(CH2CH2OH)2, CONH(CH2CH2OH), CH2OH, P(O)(OH)2, CONHSO2R2, SO2N(R2)2, SO2NHR2, and tetrazol-R2; wherein R2 is independently H, C1-C6 alkyl, phenyl, or biphenyl.
In relation to the identity of A disclosed in the chemical structures presented herein, 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)m—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.
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.




Alternatively, while not intending to limit the scope of the invention in any way, A may be an O substituted moiety such as one of the following or the like.





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.




Alternatively, while not intending to limit the scope of the invention in any way, in certain embodiments A is —(CH2)n—Ar—(CH2)n— 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—Ar—CH2—, —CH2Ar—(CH2)2—, —(CH2)2—Ar—(CH2)2—, and the like;
in another embodiment A comprises O, from 0 to 3 CH2 moieties, and Ar, e.g., —O—Ar—, Ar—CH2—O—, —O—Ar—(CH2)2—, —O—CH2—Ar—, —O—CH2—Ar—(CH2)2, and the like; or
in another embodiment A comprises S, from O 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, —(CH2)2—S—Ar, and the like.
In another embodiment, the sum of m and o is from 2 to 4 wherein one CH2 may be substituted with S or O.
In another embodiment, the sum of m and o is 3 wherein one CH2 may be substituted with S or O.
In another embodiment, the sum of m and o is 2 wherein one CH2 may be substituted with S or O.
In another embodiment, the sum of m and o is 4 wherein one CH2 may be substituted with S or O.
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. Unsubstituted interarylene or heterointerarylene has no substituents other than the two parts of the molecule it connects. Substituted interarylene or heterointerarylene has substituents in addition to the two parts of the molecule it connects.
In one embodiment, Ar is substituted or unsubstituted interphenylene, interthienylene, interfurylene, interpyridinylene, interoxazolylene, and interthiazolylene. 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)m—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, otherwise known as m-interphenylene, such as when A has the structure shown below.




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—.
In other embodiments, A has one of the following structures, where Y is attached to the aromatic or heteroaromatic ring.




In another embodiment A is —CH2OCH2Ar.
In another embodiment A is —CH2SCH2Ar.
In another embodiment A is —(CH2)3Ar.
In another embodiment A is —CH2—O—(CH2)4.
In another embodiment A is —CH2S(CH2)4.
In another embodiment A is —(CH2)6—.
In another embodiment A is cis —CH2CH═CH—(CH2)3—.
In another embodiment A is —CH2C≡C—(CH2)3—.
In another embodiment A is —S(CH2)3S(CH2)2—.
In another embodiment A is —(CH2)4OCH2—.
In another embodiment A is cis —CH2CH═CH—CH2OCH2—.
In another embodiment A is —CH2CH≡CH—CH2OCH2—.
In another embodiment A is —(CH2)2S(CH2)3—.
In another embodiment A is —CH2—Ph—OCH2—, wherein Ph is interphenylene.
In another embodiment A is —CH2-mPh—OCH2—, wherein mPh is m-interphenylene.
In another embodiment A is —CH2—O—(CH2)4—.
In another embodiment A is —CH2—O—CH2—Ar—, wherein Ar is 2,5-interthienylene.
In another embodiment A is —CH2—O—CH2—Ar—, wherein Ar is 2,5-interfurylene.
B is naphthyl, meaning unsubstituted and substituted naphthyl attached at the 1 or 2 position. An embodiment having unsubstituted 1-naphtyl is shown below.




Pharmaceutically acceptable salts, metabolites, or prodrugs thereof are also contemplated.
An embodiment having unsubstituted 2-napthyl is shown below.




Pharmaceutically acceptable salts, metabolites, or prodrugs thereof are also contemplated.
The substituents of naphthyl may have up to 6 non-hydrogen atoms each and as many hydrogen atoms as necessary. Thus, while not intending to limit the scope of the invention in any way, the substituents may be:
hydrocarbyl, i.e. a moiety consisting of only carbon and hydrogen such as alkyl, alkenyl, alkynyl, and the like, including linear, branched or cyclic hydrocarbyl, and combinations thereof;
hydrocarbylox, meaning O-hydrocarbyl such as OCH3, OCH2CH3, O-cyclohexyl, etc, up to 5 carbon atoms; other ether substituents such as CH2OCH3, (CH2)2OCH(CH3)2, and the like; thioether substituents including S-hydrocarbyl and other thioether substituents;
hydroxyhydrocarbyl, meaning hydrocarbyl-OH such as CH2OH, C(CH3)2OH, etc, up to 5 carbon atoms;
nitrogen substituents such as NO2, CN, and the like, including
amino, such as NH2, NH(CH2CH3OH), NHCH3, and the like up to 5 carbon atoms;
carbonyl substituents, such as CO2H, ester, amide, and the like;
halogen, such as chloro, fluoro, bromo, and the like
fluorocarbyl, such as CF3, CF2CF3, etc.;
phosphorous substituents, such as PO32−, and the like;
sulfur substituents, including S-hydrocarbyl, SH, SO3H, SO2-hydrocarbyl, SO3-hydrocarbyl, and the like.
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, halogen, nitrogen, and sulfur. In other embodiments, the substituents contain only hydrogen, carbon, oxygen, and halogen.
Another embodiment comprises




or a pharmaceutically acceptable salt, metabolite, or a prodrug thereof.

One embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease in mammals, said compound comprising




or a pharmaceutically acceptable salt, or a metabolite or a prodrug thereof;

wherein a dashed line indicates the presence or absence of a bond;

Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl functional group;

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)m—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; and

B is naphthyl.

Another embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease in mammals, said compound comprising the compound above wherein Y and B are as described above and wherein A is —(CH2)6—, cis —CH2CH═CH—(CH2)3—, or CH2C≡C—(CH2)3—.
Another embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease in mammals, said compound comprising the compound above wherein Y and B are as described above and wherein A is cis —CH2CH═CH—(CH2)3—.
Another embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease in mammals, said compound comprising the compound above wherein Y and A are as described above and wherein B is 2-naphthyl.
Another embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease in mammals, said compound comprising the compound above wherein Y and A are as described above and wherein B is unsubstituted naphthyl.
Another embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease in mammals, said compound comprising the compound above wherein Y and A are as described above and wherein B is unsubstituted 2-naphthyl.
Another embodiment is use of a compound in the manufacture of a medicament for the treatment of inflammatory bowel disease in mammals, said compound comprising




or a pharmaceutical salt, prod rug, or metabolite thereof,

wherein R is H, methyl, ethyl, propyl, or isopropyl.

One embodiment is a compound comprising




or a pharmaceutically acceptable salt, or a metabolite or a prodrug thereof;

wherein a dashed line indicates the presence or absence of a bond;

Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl functional group;

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)m—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; and

B is naphthyl.

Another embodiment is the compound above wherein Y and B are as described above and wherein A is (CH2)6—, cis —CH2CH═CH—(CH2)3—, or CH2C≡C—(CH2)3—.
Another embodiment is the compound above wherein Y and B are as described above and wherein A is cis CH2CH═CH—(CH2)3—.
Another embodiment is the compound above wherein Y and A are as described above and wherein B is 2-naphthyl.
Another embodiment is the compound above wherein Y and A are as described above and wherein B is unsubstituted naphthyl.
Another embodiment is the compound above wherein Y and A are as described above and wherein B is unsubstituted 2-naphthyl.
Another embodiment is a compound comprising




or a pharmaceutical salt, prod rug, or metabolite thereof,

wherein R is H, methyl, ethyl, propyl, or isopropyl.

Another embodiment is a method comprising administering a compound to a mammal for the treatment of inflammatory bowel disease, said compound comprising




or a pharmaceutically acceptable salt, or a metabolite or a prodrug thereof;

wherein a dashed line indicates the presence or absence of a bond;

Y is an organic acid functional group, or an amide or ester thereof comprising up to 12 carbon atoms; or Y is hydroxymethyl or an ether thereof comprising up to 12 carbon atoms; or Y is a tetrazolyl functional group;

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)m—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; and

B is naphthyl.

Another embodiment is a method comprising administering a compound to a mammal for the treatment of inflammatory bowel disease, said compound comprising the compound above wherein Y and B are as described above and wherein A is —(CH2)6—, cis —CH2CH═CH—(CH2)3—, or CH2C≡C—(CH2)3—.
Another embodiment is a method comprising administering a compound to a mammal for the treatment of inflammatory bowel disease, said compound comprising the compound above wherein Y and B are as described above and wherein A is cis —CH2CH═CH—(CH2)3—.
Another embodiment is a method comprising administering a compound to a mammal for the treatment of inflammatory bowel disease, said compound comprising the compound above wherein Y and A are as described above and wherein B is 2-naphthyl.
Another embodiment is a method comprising administering a compound to a mammal for the treatment of inflammatory bowel disease, said compound comprising the compound above wherein Y and A are as described above and wherein B is unsubstituted naphthyl.
Another embodiment is a method comprising administering a compound to a mammal for the treatment of inflammatory bowel disease, said compound comprising the compound above wherein Y and A are as described above and wherein B is unsubstituted 2-naphthyl.
Another embodiment is a method comprising administering a compound to a mammal for the treatment of inflammatory bowel disease, said compound comprising




or a pharmaceutical salt, prod rug, or metabolite thereof,

wherein R is H, methyl, ethyl, propyl, or isopropyl.

Another embodiment is a composition comprising a compound, wherein said compound is a liquid which is ophthalmically acceptable, wherein the compound is any compound or class of compounds disclosed herein.
The compounds disclosed herein are useful for the prevention or treatment of glaucoma or ocular hypertension in mammals, or for the manufacture of a medicament for the treatment of glaucoma or ocular hypertension. They are also useful for the treatment of those diseases disclosed in the art as being amenable to treatment by prostaglandin EP4 agonist, such as the ones listed previously.
A “pharmaceutically acceptable salt” is any salt that retains the activity of the parent compound and does not impart any additional deleterious or untoward effects on the subject to which it is administered and in the context in which it is administered compared to the parent compound. A pharmaceutically acceptable salt also refers to any salt which may form in vivo as a result of administration of an acid, another salt, or a prodrug which is converted into an acid or salt.
Pharmaceutically acceptable salts of acidic functional groups may be derived from organic or inorganic bases. The salt may comprise a mono or polyvalent ion. Of particular interest are the inorganic ions, lithium, sodium, potassium, calcium, and magnesium. Organic salts may be made with amines, particularly ammonium salts such as mono-, di- and trialkyl amines or ethanol amines. Salts may also be formed with caffeine, tromethamine and similar molecules. Hydrochloric acid or some other pharmaceutically acceptable acid may form a salt with a compound that includes a basic group, such as an amine or a pyridine ring.
A “prodrug” is a compound which is converted to a therapeutically active compound after administration, and the term should be interpreted as broadly herein as is generally understood in the art. While not intending to limit the scope of the invention, conversion may occur by hydrolysis of an ester group or some other biologically labile group. Generally, but not necessarily, a prodrug is inactive or less active than the therapeutically active compound to which it is converted. Ester prodrugs of the compounds disclosed herein are specifically contemplated. An ester may be derived from a carboxylic acid of Cl (i.e. the terminal carboxylic acid of a natural prostaglandin), or an ester may be derived from a carboxylic acid functional group on another part of the molecule, such as on a phenyl ring. While not intending to be limiting, an ester may be an alkyl ester, an aryl ester, or a heteroaryl ester. The term alkyl has the meaning generally understood by those skilled in the art and refers to linear, branched, or cyclic alkyl moieties. C1-6 alkyl esters are particularly useful, where alkyl part of the ester has from 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and combinations thereof having from 1-6 carbon atoms, etc.
Those skilled in the art will readily understand that for administration or the manufacture of medicaments the compounds disclosed herein can be admixed with pharmaceutically acceptable excipients which per se are well known in the art. Specifically, a drug to be administered systemically, it may be confected as a powder, pill, tablet or the like, or as a solution, emulsion, suspension, aerosol, syrup or elixir suitable for oral or parenteral administration or inhalation.
For solid dosage forms or medicaments, non-toxic solid carriers include, but are not limited to, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, the polyalkylene glycols, talcum, cellulose, glucose, sucrose and magnesium carbonate. The solid dosage forms may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release. Liquid pharmaceutically administrable dosage forms can, for example, comprise a solution or suspension of one or more of the presently useful compounds and optional pharmaceutical adjutants in a carrier, such as for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like. Typical examples of such auxiliary agents are sodium acetate, sorbitan monolaurate, triethanolamine, sodium acetate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 16th Edition, 1980. The composition of the formulation to be administered, in any event, contains a quantity of one or more of the presently useful compounds in an amount effective to provide the desired therapeutic effect.
Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol and the like. In addition, if desired, the injectable pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like.
The amount of the presently useful compound or compounds administered is, of course, dependent on the therapeutic effect or effects desired, on the specific mammal being treated, on the severity and nature of the mammal's condition, on the manner of administration, on the potency and pharmacodynamics of the particular compound or compounds employed, and on the judgment of the prescribing physician.
A liquid which is ophthalmically acceptable is formulated such that it can be administered topically to the eye. The comfort should be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort. In the case that comfort cannot be maximized, the liquid should be formulated such that the liquid is tolerable to the patient for topical ophthalmic use. Additionally, an ophthalmically acceptable liquid should either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.
For ophthalmic application, solutions or medicaments are often prepared using a physiological saline solution as a major vehicle. Ophthalmic solutions are often maintained at a comfortable pH with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.
Preservatives that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. A useful surfactant is, for example, Tween 80. Likewise, various useful vehicles may be used in the ophthalmic preparations of the present invention. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.
Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.
Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.
In a similar vein, an ophthalmically acceptable antioxidant for use in the present invention includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene.
Other excipient components which may be included in the ophthalmic preparations are chelating agents. A useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.
The ingredients are usually used in the following amounts:














Ingredient
Amount (% w/v)









active ingredient
about 0.001-5



preservative
0-0.10



vehicle
0-40



tonicity adjustor
1-10



buffer
0.01-10



pH adjustor
q.s. pH 4.5-7.5



antioxidant
as needed



surfactant
as needed



purified water
as needed to make 100%










For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound disclosed herein are employed. Topical formulations may be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.
The compounds disclosed herein are also useful in combination with other drugs useful for the treatment of glaucoma or other conditions.
For the treatment of glaucoma, combination treatment with the following classes of drugs are contemplated:
β-Blockers (or β-adrenergic antagonists) including carteolol, levobunolol, metiparanolol, timolol hemihydrate, timolol maleate, β1-selective antagonists such as betaxolol, and the like, or pharmaceutically acceptable salts or prodrugs thereof;
Adrenergic Agonists including
non-selective adrenergic agonists such as epinephrine borate, epinephrine hydrochloride, and dipivefrin, and the like, or pharmaceutically acceptable salts or prodrugs thereof; and
α2-selective adrenergic agonists such as apraclonidine, brimonidine, and the like, or pharmaceutically acceptable salts or prod rugs thereof,
Carbonic Anhydrase Inhibitors including acetazolamide, dichlorphenamide, methazolamide, brinzolamide, dorzolamide, and the like, or pharmaceutically acceptable salts or prodrugs thereof;
Cholinergic Agonists including
direct acting cholinergic agonists such as carbachol, pilocarpine hydrochloride, pilocarbine nitrate, pilocarpine, and the like, or pharmaceutically acceptable salts or prodrugs thereof;
chlolinesterase inhibitors such as demecarium, echothiophate, physostigmine, and the like, or pharmaceutically acceptable salts or prodrugs thereof;
Glutamate Antagonists and other neuroprotective agents such as Ca2+ channel blockers such as memantine, amantadine, rimantadine, nitroglycerin, dextrophan, detromethorphan, CGS-19755, dihydropyridines, verapamil, emopamil, benzothiazepines, bepridil, diphenylbutylpiperidines, diphenylpiperazines, HOE 166 and related drugs, fluspirilene, eliprodil, ifenprodil, CP-101,606, tibalosine, 2309BT, and 840S, flunarizine, nicardipine, nifedimpine, nimodipine, barnidipine, verapamil, lidoflazine, prenylamine lactate, amiloride, and the like, or pharmaceutically acceptable salts or prod rugs thereof;

Prostamides such as bimatoprost, or pharmaceutically acceptable salts or prodrugs thereof; and

Prostaglandins including travoprost, UFO-21, chloprostenol, fluprostenol, 13,14-dihydro-chloprostenol, isopropyl unoprostone, latanoprost and the like.

Cannabinoids including CB1 agonists such as WIN-55212-2 and CP-55940 and the like, or pharmaceutically acceptable salts or prodrugs thereof.

For treatment of diseases affecting the eye including glaucoma, these compounds can be administered topically, periocularly, intraocularly, or by any other effective means known in the art.

Treatment of inflammatory bowel disease may be accomplished by the administration of the compounds described herein to the suffering mammal. Inflammatory bowel disease describes a variety of diseases characterized by inflammation of the bowels including, but not limited to, ulcerative colitis and Crohn's disease. Treatment may be accomplished by oral administration, by suppository, or parenteral administration, or some other suitable method.
For the treatment of inflammatory bowel disease and similar disorders, the compounds disclosed herein may be used in combination with other therapeutically active agents.
For the treatment of inflammatory bowel disease, combination treatment with the following classes of drugs are contemplated:
aminosalicylates including sulfasalazaline, mesalazine, sulfasalazine, mesalamine, Olsalazine, balsalazide, and the like;
corticosteroids including methotrexate, cortisone, hydrocortisone, prednisone, prednisolone, methylprednisone, triamcinolone, fluoromethalone, dexamethasone, medrysone, betamethasone, loteprednol, fluocinolone, flumethasone, mometasone, and the like;
immunomodulators including azathioprine, 6-mercaptopurine, cyclosporine, and the like; and
inhibitors of inflammatory cytokines (TNF) such as infliximab, CDP571, CDP870, etanercept, onercept, adalimumab, and the like.
While not intending to limit the scope of the invention in any way, delivery of the compounds disclosed herein to the colon via oral dosage forms may be accomplished by any of a number of methods known in the art. For example, reviews by Chourasia and Jain in J Pharm Pharmaceut Sci 6 (1): 33-66, 2003 and Shareef et. al (AAPS PharmSci 2003; 5 (2) Article 17) describe a number of useful methods. While not intending to limit the scope of the invention in any way these methods 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.
While not intending to be bound in any way by theory, it is believed that intestinal microflora are capable of reductive cleavage of an azo bond leaving the two nitrogen atoms as amine functional groups. While not intending to limit the scope of the invention in any way, the azo prodrug approach has been used to deliver to 5-aminosalicylic acid to the colons of humans in clinical trials for the treatment of inflammatory bowel disease. It is also believed that 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. For example, 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. 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.
While not intending to limit the scope of the invention in any way, carbohydrate polymers such as amylase, arabinogalactan, chitosan, chondroiton sulfate, dextran, guar gum, pectin, xylin, and the like, or azo-group containing polymers can be used to coat a drug compound, or a drug may be impregnated or encapsulated in the polymer. It is believed that 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.
Synthetic Procedures
Compounds were prepared according to procedures disclosed in U.S. Patent Application Publication No. 2004/0157901, incorporated by reference herein, where compound 13 of Scheme 4 was substituted with naphthaldehyde, which is commercially available. Variations to the α-chain not disclosed in this publication may be made according to the numerous methods known in the art.
Biological Activity
The activity of compounds disclosed herein is tested according to the following procedures.
Radioligand Binding
Cells Stably Expressing EP1, EP2, EP4, and FP Receptors
HEK-293 cells stably expressing the human or feline FP receptor, or EP1, EP2, or EP4 receptors are washed with TME buffer, scraped from the bottom of the flasks, and homogenized for 30 sec using a Brinkman PT 10/35 polytron. TME buffer is added to achieve a final 40 ml volume in the centrifuge tubes (the composition of TME is 100 mM TRIS base, 20 mM MgCl2, 2M EDTA; 10N HCl is added to achieve a pH of 7.4).
The cell homogenate is centrifuged at 19000 r.p.m. for 20 min at 4° C. using a Beckman Ti-60 rotor. The resultant pellet is resuspended in TME buffer to give a final 1 mg/ml protein concentration, as determined by Biorad assay. Radioligand binding competition assays vs. [3H—]17 phenyl PGF2α (5 nM) are performed in a 100 μl volume for 60 min. Binding reactions are started by adding plasma membrane fraction. The reaction is terminated by the addition of 4 ml ice-cold TRIS-HCl buffer and rapid filtration through glass fiber GF/B filters using a Brandel cell harvester. The filters are washed 3 times with ice-cold buffer and oven dried for one hour. Non-specific binding is determined with 10 uM unlabeled 17 phenyl PGF2α.
[3H—] PGE2 (5 nM; specific activity 180 Ci mmol) is used as the radioligand for EP receptors. Binding studies employing EP1, EP2, EP3, EP4 are performed in duplicate in at least three separate experiments. A 200 μl assay volume is used. 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). Non-specific binding is determined with 10−5M of unlabeled PGE2.
Methods for FLIPRTM Studies
(a) Cell Culture
HEK-293(EBNA) cells, stably expressing one type or subtype of recombinant human prostaglandin receptors (prostaglandin receptors expressed: hDP/Gqs5; hEP1; hEP2/Gqs5; hEP3A/Gqi5; hEP4/Gqs5; hFP; hIP; hTP), are cultured in 100 mm culture dishes in high-glucose DMEM medium containing 10% fetal bovine serum, 2 mM 1-glutamine, 250 μg/ml geneticin (G418) and 200 μg/ml hygromycin B as selection markers, and 100 units/ml penicillin G, 100 μg/ml streptomycin and 0.25 μg/ml amphotericin B.
(b) Calcium Signal Studies on the FLIPRTM
Cells are seeded at a density of 5×104 cells per well in Biocoat® Poly-D-lysine-coated black-wall, clear-bottom 96-well plates (Becton-Dickinson) and allowed to attach overnight in an incubator at 37° C. Cells are then washed two times with HBSS-HEPES buffer (Hanks Balanced Salt Solution without bicarbonate and phenol red, 20 mM HEPES, pH 7.4) using a Denley Cellwash plate washer (Labsystems). After 45 minutes of dye-loading in the dark, using the calcium-sensitive dye Fluo-4 AM at a final concentration of 2 μM, plates are washed four times with HBSS-HEPES buffer to remove excess dye leaving 100 μl in each well. Plates are re-equilibrated to 37° C. for a few minutes.
Cells are excited with an Argon laser at 488 nm, and emission is measured through a 510-570 nm bandwidth emission filter (FLIPRTM, Molecular Devices, Sunnyvale, Calif.). Drug solution is added in a 50 μl volume to each well to give the desired final concentration. The peak increase in fluorescence intensity is recorded for each well. On each plate, four wells each serve as negative (HBSS-HEPES buffer) and positive controls (standard agonists: BW245C (hDP); PGE2 (hEP1; hEP2/Gqs5; hEP3A/Gqi5; hEP4/Gqs5); PGF2α (hFP); carbacyclin (hTP); U-46619 (hTP), depending on receptor). The peak fluorescence change in each drug-containing well is then expressed relative to the controls.
Compounds are tested in a high-throughput (HTS) or concentration-response (CoRe) format. In the HTS format, forty-four compounds per plate are examined in duplicates at a concentration of 10−5 M. To generate concentration-response curves, four compounds per plate are tested in duplicates in a concentration range between 10−5 and 10−11 M. The duplicate values are averaged. In either, HTS or CoRe format each compound is tested on at least 3 separate plates using cells from different passages to give an n≧3.











TABLE 1









EP2
EP4
OTHER














Ca2+

Ca2+
RECEPTORS



Ki
EC50
Ki
EC50
Ca2+


STRUCTURE
(nM)
(nM)
(nM)
(nM)
EC50 (nM)


















High Rf Diastereomer
>10K
>10K
14
0.17
EP3 (4018)NA:EP1, DP, FP, IP, TP


 





Low Rf Diastereomer
16888
>10K
111
1.3
EP3 (1019)NA:EP1, DP, FP, IP, TP


 





High Rf Diastereomer
36229
NA
1244
16.3
EP3 (1019)NA:EP1, DP, FP, IP, TP


 





Low Rf Diastereomer
NA
>10K
1857
8
EP3NA:EP1, DP, FP, IP, TP









Table 1 shows the results of these tests carried out on the compounds shown in the table. While not intending to limit the scope of the invention in any way, these results show that the compounds are selective for the EP4 receptor over the other prostaglandin receptors.
Intraocular Pressure (IOP)
Intraocular pressure studies in dogs involved pneumatonometry performed in conscious, Beagle dogs of both sexes (10-15 kg). The animals remained conscious throughout the study and were gently restrained by hand. Drugs were administered topically to one eye as a 25 μL volume drop, the other eye received 25 μL vehicle (0.1% polysorbate 80:10 mM TRIS) as a control. Proparacaine (0.1%) was used for corneal anesthesia during tonometry. Intraocular pressure was determined just before drug administration and at 2, 4 and 6 hr thereafter on each day of the 5 day study. Drug was administered immediately after the first IOP reading.
An analogous procedure was carried out with cynomolgus monkeys with measurements at 2, 4, 6, and 24 hours after a single dose.
Ocular Surface Hyperemia
Ocular surface hyperemia was visually assessed and scored according to a system typically used clinically.














Hyperemia Score
Assigned Value



















<1 trace
0.5



1 mild
1



moderate
2



severe
3










Ocular surface hyperemia was evaluated at the same time points as intraocular pressure measurement. It should be noted that untreated dog eyes frequently have a pink/red tone. Thus, values of trace or even mild are not necessarily out of the normal range. A similar procedure was used to determine rabbit hyperemia.

Results of these procedures for two compounds are shown in Table 2.











TABLE 2









Dog
Monkey
Rabbit














Max ΔIOP
Max
Max ΔIOP
Max


Compound
Conc.
(mm Hg)
Hyperemia
(mm Hg)
Hyperemia









0.005%
2
1.3
8
0.1


 






0.005%
5
1.0
6
0.1









The foregoing description details specific methods and compositions that can be employed to practice the present invention, and represents the best mode contemplated. However, it is apparent for one of ordinary skill in the art that further compounds with the desired pharmacological properties can be prepared in an analogous manner, and that the disclosed compounds can also be obtained from different starting compounds via different chemical reactions. Similarly, different pharmaceutical compositions may be prepared and used with substantially the same result. Thus, however detailed the foregoing may appear in text, it should not be construed as limiting the overall scope hereof; rather, the ambit of the present invention is to be governed only by the lawful construction of the appended claims.

## Claims

1. A compound of the formula



or a pharmaceutically acceptable salt thereof;
wherein a dashed line indicates the presence or absence of a bond;
Y is selected from the group consisting of CO2(R2), CON(R2)2, CON(OR2)R2, CON(CH2CH2OH)2, CONH(CH2CH2OH), CH2OH, P(O)(OH)2, CONHSO2R2, SO2N(R2)2, SO2NHR2, and tetrazolyl-R2; wherein R2 is independently H, C1-C6 alkyl, phenyl, or biphenyl;
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)m—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; and
B is naphthyl.

2. The compound of claim 1 wherein A is —(CH2)6—, cis —CH2CH═CH—(CH2)3—, or —CH2C≡C—(CH2)3—.

3. The compound claim 2 wherein A is cis —CH2CH═CH—(CH2)3—.

4. The compound of claim 3 represented by the formula



or a pharmaceutical salt thereof,
wherein R is H, methyl, ethyl, propyl, or isopropyl.

5. The compound of claim 1 wherein B is 2-naphthyl.

6. The compound of claim 1 wherein B is unsubstituted naphthyl.

7. The compound of claim 5 wherein B is unsubstituted 2-naphthyl.

8. A compound represented by the formula



or a pharmaceutically acceptable salt thereof, wherein a dashed line represents the presence or absence of a bond.

9. The compound of claim 8 represented by the formula



or a pharmaceutically acceptable salt thereof.

10. The compound of claim 8 represented by the formula



or a pharmaceutically acceptable salt thereof.

11. A method comprising topically administering the compound of claim 1 to a mammal for the treatment of glaucoma or ocular hypertension.

12. A method comprising administering the compound of claim 1 to a mammal for the treatment of inflammatory bowel disease.