Disclosed herein are compositions comprising an amide related to a prostaglandin and a biogenic amine. Other aspects relate to certain chemical compounds, pharmaceutical compositions, and methods of treating glaucoma.

The invention relates to processes for preparing carbaprostacyclin analogues and intermediates prepared from the processes. The invention also relates to cyclopentenone intermediates in racemic or optically active form.

Disclosed herein are compounds having formula (I) wherein a dashed line represents the presence or absence of a bond; Y is an organic acid functional group, or an amide or ester thereof; or Y is hydroxymethyl or an ester thereof; or Y is a tetrazolyl functional group; A is (CH.sub.2).sub.6, cis-CH.sub.2CHCH(CH.sub.2).sub.3, or CH.sub.2CC(CH.sub.2).sub.3, wherein 1 or 2 carbon atoms may be replaced by S or O; or A is (CH.sub.2).sub.mAr(CH.sub.2).sub.o, wherein Ar is interarylene or heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein 1 CH.sub.2 may be replaced by S or O, and 1 CH.sub.2CH.sub.2 may be replaced by CHCH or CC; U.sup.1 and U.sup.2 are independently selected from H, O, OH, F, Cl, and CN; and B is aryl or heteroaryl, for use as acular hypotensive agent.

This present invention relates to an improved process to prepare prostacyclin derivatives. One embodiment provides for an improved process to convert benzindene triol to treprostinil via salts of treprostinil and to purify treprostinil.

Novel processes for the preparation of a compound of Formula I-2 substantially free of the 5,6-trans isomer:

##STR00001##

wherein

##STR00002##

R.sub.2, R.sub.3 and R.sub.4 are as defined in the specification are provided. Novel intermediates for the preparations of isomer free Prostaglandins and derivatives thereof are also provided.

This present invention relates to an improved process to prepare prostacyclin derivatives. One embodiment provides for an improved process to convert benzindene triol to treprostinil via salts of treprostinil and to purify treprostinil.

Disclosed herein are compounds having the formula (I) wherein a dashed line represents the presence or absence of a bond; Y is an organic acid functional group, or an amide or ester thereof; or Y is hydroxymethyl or an ether thereof; or Y is a tetrazolyl functional group; A is (CH.sub.2).sub.6, cis CH.sub.2CHCH(CH.sub.2).sub.3, or CH.sub.2CC(CH.sub.2).sub.3, wherein 1 or 2 carbon atoms may be replaced by S or O; or A is (CH.sub.2).sub.mAr(CH.sub.2).sub.o wherein Ar is interarylene or heterointerarylene, the sum of m and o is 1, 2, 3, or 4, and wherein 1 CH.sub.2 may be replaced by S or O, and 1 CH.sub.2CH.sub.2 may be replaced by CHCH or CC; U.sup.1 and U.sup.2 are independently selected from H, O, OH, F, Cl, and CN; and B is aryl or heteroaryl, for use as acular hypotensive agent. ##STR00001##

The subject of the invention is process for the preparation of the prostaglandin amides of the general formula I, ##STR00001## where in the formula, the bonds marked with dotted lines may be single or double bonds, in the case of double bounds at positions 5,6 and 13,14 they may be in cis or in trans orientation, Q stands for a hydroxyl-group and Z stands for a hydroxyl- or oxo-group, R.sup.1 and R.sup.2 independently represent hydrogen atom or a straight or branched C.sub.1-10 alkyl- or aralkyl-group, optionally substituted with ONO.sub.2 group, or an aralkyl- or aryl-group, which contains heteroatom, R.sup.3 represents a straight or branched, saturated or unsaturated C.sub.4-6 hydrocarbon group, or a C.sub.4-10 alkylcycloalkyl- or cycloalkyl-group, or an optionally with alkyl group or halogen atom substituted phenyl-, C.sub.7-10 alkylaryl- or hetaryl-group, Y represents (CH.sub.2).sub.n group or O atom or S atom, and where n=0-3.

The subject of the invention is process for the preparation of the prostaglandin amides of the general formula I, ##STR00001## where in the formula, the bonds marked with dotted lines may be single or double bonds, in the case of double bounds at positions 5,6 and 13,14 they may be in cis or in trans orientation, Q stands for a hydroxyl-group and Z stands for a hydroxyl- or oxo-group, R.sup.1 and R.sup.2 independently represent hydrogen atom or a straight or branched C.sub.1-10 alkyl- or aralkyl-group, optionally substituted with ONO.sub.2 group, or an aralkyl- or aryl-group, which contains heteroatom, R.sup.3 represents a straight or branched, saturated or unsaturated C.sub.4-6 hydrocarbon group, or a C.sub.4-10 alkylcycloalkyl- or cycloalkyl-group, or an optionally with alkyl group or halogen atom substituted phenyl-, C.sub.7-10 alkylaryl- or hetaryl-group, Y represents (CH.sub.2).sub.n group or O atom or S atom, and where n=0-3.

The subject of the invention is a process for the preparation of high purity prostaglandin acid of the general formula II wherein the bonds marked with dotted lines represent single or double bonds wherein the double bonds may be cis- or trans oriented, Y represents 0 or CH.sup.2, and R.sup.3 stands for a phenyl group which is optionally substituted with CF.sub.3, wherein the crude prostaglandin acid of the general formula II is purified by normal phase silicagel chromatography.

##STR00001##