Field of the Invention
Provided herein are the acid addition salts of compounds of Formula I.
(Formula Removed)
The acid addition salts of Formula I disclosed herein can be used to treat benign prostatic hyperplasia (BPH) and the related symptoms thereof. Further, these compounds can be used to treat lower urinary tract symptoms (LUTS) that may or may not be associated with BPH. Process for preparing the compounds disclosed herein, pharmaceutical compositions thereof, and the methods of treating BPH or related symptoms thereof and LUTs that may or may not be associated with BPH are also provided.
Background of the Invention
Benign prostatic hyperplasia (BPH) is a condition, which develops in elderly males and refers to the benign overgrowth of the stromal and epithelial elements of the prostate with aging. The symptoms of BPH vary, but the most common ones involve changes or problems with urination, such as hesitant, interrupted, weak stream or urgency and leaking or dribbling or more frequent urination, especially at night. Consequences of BPH can involve hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection.
There are two components of BPH, static and a dynamic component. The static component is due to enlargement of the prostate gland, which may result in compression of the urethra and obstruction to the flow of the urine from the bladder. The dynamic component is due to increased smooth muscle tone of the bladder neck and prostate itself and is regulated by α-1 adrenergic receptors. There are several reports that an antagonist with high affinity for α1a or α1a/α1d can cause some degree of vasodilatation but that it is much smaller than with non-subtype-selective α1a adrenoceptor antagonist. Further, there is increased vascular α1b adrenoceptor expression in elderly patients and thus α1a/α1d selective agents with selectivity over α1b adrenoceptor subtype would be of particular importance in benign prostatic hyperplasia. Antagonism of both α1a adrenoceptor and α1d
adrenoceptor is important to relieve lower urinary tract symptoms especially associated (suggestive of) with BPH. Targeting α1a adrenoceptor with antagonists is important in relaxing prostate smooth muscle and relieving bladder outlet obstruction whereas aid adrenoceptor antagonism is important to target irritative symptoms.
Compounds of Formula I disclosed in our Co-pending patent application No. 992/DEL/2004, filed on May 31, 2004, are adrenergic receptor antagonists. Compound disclosed in the said patent application exhibit low nanomolar affinity towards α1a and α1d adrenoceptor subtypes and good selectivity for α1a vs. α1b adrenoceptor subtypes. The relatively lower affinity at α1b adrenoceptors limits the cardiovascular side effect such as orthostatic hypotension.
Summary of the Invention
Generally provided herein are the acid addition salts of compounds of Formula I,
(Formula Removed)
which can be used to treat benign prostatic hyperplasia or related symptoms thereof, lower urinary tract symptoms associated with or without BPH, and process for preparing these compounds (salts). Pharmaceutically acceptable solvates, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs and metabolites of compounds disclosed herein are also within the scope of this invention. The pharmaceutical compositions comprising the compounds disclosed herein, their prodrugs, metabolites, enantiomers, diastereomers, N-oxides, polymorphs, solvates alone or in combination with pharmaceutical ly acceptable carriers, optionally included excipients and diluents that are useful for the treatment of benign prostatic hyperplasia or related symptoms thereof, lower urinary tract symptoms associated with or without BPH are included in this invention.
The acid addition salts disclosed herein exhibit better solubility, stability, excellent storage and handling stabilities, and are less susceptible to degradation at lower temperatures.
Other aspects of the invention will be set forth in the description which follows, and in part will be apparent from the description or may be learnt by the practice of the invention.
In one aspect, provided herein are the compounds having the structure of Formula II:
(Formula Removed)
pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs and metabolites thereof, wherein,
A can be organic acid (e.g. acetic, succinic, maleic, trifluoroacetic, oxalic, citric, malonic, tartaric, adipic, ascorbic, camphor sulfonic, nicotinic, butyric, lactic or glucuronic acid), inorganic acid (e.g. hydrobromic, phosphoric, sulfuric, nitric, boric or perchloric acid); R1 and R2 can be independently hydrogen, hydroxy or halogen; X can be CO, CHOH or CH2; R3 and R4 can be independently hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy or C5-C6 cycloalkoxy.
In an embodiment, provided herein are the acid addition salts of compounds having the structure of Formula II, pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs and metabolites thereof, wherein, A can be tartaric, succinic, maleic or phosphoric acid.
In another aspect, provided herein are the compounds selected from:
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate,
5,6-Dihydroxy-2-{3-[4-(2-methoxy-5-methylphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate,
5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione succinate,
5-Fluoro-6-hydroxy-2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione succinate,
5-Hydroxy-2-{3-[4-(2-methoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-l,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3-dione succinate,
2-{3-[4-(2-CyclopentyIoxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione succinate,
5-Fluoro-2-{3-[4-(5-fluoro-2-methoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione succinate,
5-Fluoro-2-{3-[4-(5-fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(5-Fluoro-2-propoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-1,3-dione succinate,
2-{3-[4-(2-CyclopentyIoxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione succinate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate,
5,6-Dihydroxy-2-{3-[4-(2-methoxy-5-methylphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate,
5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione maleate,
5-Fluoro-6-hydroxy-2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-1,3-dione maleate,
5-Hydroxy-2-{3-[4-(2-methoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-l,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-1,3-dione maleate,
5-Fluoro-2-{3-[4-(5-fluoro-2-methoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione maleate,
5-Fluoro-2-{3-[4-(5-fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(5-Fluoro-2-propoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-1,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione maleate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy- hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate,
5,6-Dihydroxy-2-{3-[4-(2-methoxy-5-methylphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate,
5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione tartarate,
5-Fluoro-6-hydroxy-2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione tartarate,
5-Hydroxy-2-{3-[4-(2-methoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-l,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione tartarate,
5-Fluoro-2-{3-[4-(5-fluoro-2-methoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindoIe-1,3-dione tartarate,
5-Fluoro-2-{3-[4-(5-fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxy-5-fIuorophenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(5-Fluoro-2-propoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-1,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-1,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3 -dione tartarate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l ,3-dione tartarate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy- hexahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate,
5,6-Dihydroxy-2-{3-[4-(2-methoxy-5-methylphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate,
5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione phosphate,
5-Fluoro-6-hydroxy-2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione phosphate,
5-Hydroxy-2-{3-[4-(2-methoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-l,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-oxo-propyI}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxy-5-fIuorophenyl)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione phosphate,
5-Fluoro-2-{3-[4-(5-fluoro-2-methoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione phosphate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione phosphate,
5-Fluoro-2-{3-[4-(5-fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione phosphate,
2-{3-[4-(5-Fluoro-2-propoxyphenyl)-piperazin-1-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione phosphate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione phosphate,
2-{3-[4-(5-F!uoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy- hexahydro-isoindole-l,3-dione phosphate,
pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs and metabolites thereof.
In another aspect, provided herein is a method for the treatment of a patient suffering from a disease or disorder mediated through α1a and/or α1d adreriergic receptor, comprising administering to a patient, a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein.
In an embodiment, provided herein is a method for the treatment of a patient suffering from benign prostatic hyperplasia (BPH) and related symptoms, comprising administering to a patient, a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein.
In another aspect, provided herein is a method for the treatment of a patient suffering from lower urinary tract symptoms (LUTS) with or without BPH, comprising administering to a patient, a therapeutical ly effective amount of a compound or pharmaceutical composition disclosed herein. LUTS may include, for example, irritative symptoms (e. g. frequent urination, urgent urination, nocturia or unstable bladder contractions), obstructive symptoms (e. g. hesitancy, poor stream, prolong urination or feelings of incomplete emptying).
In another aspect, provided herein is a method for the treatment of a patient suffering from BPH or LUTS with or without BPH, comprising administering to a patient, a therapeutical ly effective amount of one or more compounds (or compositions) described herein in combination with one or more bladder selective muscarinic receptor antagonists and/or testosterone 5a-reductase inhibitors.
In yet another aspect, provided herein is a process for preparing the acid addition salts as described above.
Detailed Description of the Invention
The compounds of the present invention may be prepared by techniques well known in the art and familiar to the average synthetic organic chemist. In addition, the compounds of the present
invention may be prepared by the following reaction sequence:
Scheme I
(Scheme Removed)
The compounds of Formula II can be prepared by following Scheme I. Thus, compounds of Formula I can be reacted with an organic or inorganic acid to give compounds of Formula II (wherein A, R1-R4 and X are the same as defined earlier). Using the methods well known to one of ordinary skilled in art then can isolate the compounds of Formula II.
The reaction of compounds of Formula I with an organic or inorganic acid can be carried out in one or more solvents. "Solvents" as used herein include, but are not limited to, aliphatic hydrocarbons (e.g. hexane, cyclohexane or heptane), aromatic hydrocarbons (e.g. benzene, toluene or xylene), halogenated hydrocarbons (e.g. dichloromethane, dichloroethane, chloroform or carbon tetrachloride), ethers (e.g. diethyl ether, tetrahydrofuran or dioxane), ketones (e. g. acetone or diethyl ketone), esters (e. g. ethyl acetate or propyl acetate), nitriles (e. g. acetonitrile or propionitrile), or alcoholic solvents (e. g. methanol, ethanol or isopropanol). The solvents disclosed herein are used provided they have no adverse effect on the reaction and they can dissolve the starting material and the acid to some extent.
The solvent used to dissolve compounds of Formula I can be the same as or different from the solvent employed to acid provided that the choice of the solvent to dissolve the acid does not adversely affect the solubility of compounds of Formula I when the two solutions are added together during the treatment step.
Acid can be added to the compound in any proportion with respect to compounds of Formula I which results in the formation of at least some of the desired acid addition salt.
The solution of compounds of Formula I ( free base) can be treated with an organic or inorganic acid directly, for example, by bubbling gaseous acid into the solution or acid can first be dissolved in a solvent and then added as a solution of acid. The acid solution can be added all at once or can be added in two or more portions, or can be added incrementally.
The reaction of compounds of Formula I can be conducted at any temperature at which compound of Formula I is soluble in the chosen solvent.
Following the addition of acid, the solution can be aged for a period of time to permit intimate mixing of acid and compounds of Formula I.
The reaction temperature and duration of reaction will depend on the selection of reagents, solvents and the like.
An illustrative list of compound useful for treatment of BPH or related synptoms and LUTs associated with or without BPH is shown below:
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 1),
5,6-Dihydroxy-2-{3-[4-(2-methoxy-5-methylphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione succinate (Compound No. 2),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 3),
5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione succinate (Compound No. 4),
5-Fluoro-6-hydroxy-2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione succinate (Compound No. 5),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione succinate (Compound No. 6),
5-Hydroxy-2-{3-[4-(2-methoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-l,3-dione succinate (Compound No. 7),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 8),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 9),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione succinate (Compound No. 10),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3-dione succinate (Compound No. 11),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione succinate (Compound No. 12),
5-Fluoro-2-{3-[4-(5-fluoro-2-methoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 13),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione succinate (Compound No. 14),
5-Fluoro-2-{3-[4-(5-fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 15),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 16),
2-{3-[4-(5-Fluoro-2-propoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione succinate (Compound No. 17),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 18),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 19),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 20),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 21),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 22),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 23),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 24),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione maleate (Compound No. 25),
5,6-Dihydroxy-2-{3-[4-(2-methoxy-5-methylphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione maleate (Compound No. 26),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate (Compound No. 27),
5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione maleate (Compound No. 28),
5-FIuoro-6-hydroxy-2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione maleate (Compound No. 29),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione maleate (Compound No. 30),
5-Hydroxy-2-{3-[4-(2-methoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-l,3-dione maleate (Compound No. 31),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione maleate (Compound No. 32),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione maleate (Compound No. 33),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate (Compound No. 34),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3-dione maleate (Compound No. 35),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione maleate (Compound No. 36),
5-Fluoro-2-{3-[4-(5-fluoro-2-methoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione maleate (Compound No. 37),
2-{3-[4-(5-FIuoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione maleate (Compound No. 38),
5-Fluoro-2-{3-[4-(5-fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione maleate (Compound No. 39),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate (Compound No. 40),
2-{3-[4-(5-Fluoro-2-propoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione maleate (Compound No. 41),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione maleate(Compound No. 42)
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isomdole-l,3-dione maleate(Compound No. 43)
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyi}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate(Compound No. 44)
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate(Compound No. 45)
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate(Compound No. 46)
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate(Compound No. 47)
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy- hexahydro-isoindole-l,3-dione maleate(CompoundNo. 48)
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 49)
5,6-Dihydroxy-2-{3-[4-(2-methoxy-5-methylphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione tartarate(Compound No. 50)
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate (Compound No. 51),
5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione tartarate(CompoundNo. 52),
5-Fluoro-6-hydroxy-2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione tartarate(Compound No. 53),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-1-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione tartarate(Compound No. 54),
5-Hydroxy-2-{3-[4-(2-methoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-l,3-dione tartarate(Compound No. 55),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yI]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 56),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 57),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 58),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyI)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3-dione tartarate(Compound No. 59),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione tartarate(Compound No. 60),
5-Fluoro-2-{3-[4-(5-fluoro-2-methoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-1,3-dione tartarate(Compound No. 61),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione tartarate(Compound No. 62),
5-Fluoro-2-{3-[4-(5-fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione tartarate(CompoundNo. 63),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yI]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 64),
2-{3-[4-(5-Fluoro-2-propoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione tartarate(Compound No. 65),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 66),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 67),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyI)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 68),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dionetartarate(Compound'No. 69),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 70),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 71),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyI}-5,6-dihydroxy- hexahydro-isoindole-l,3-dione tartarate(Compound No. 72),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 73),
5,6-Dihydroxy-2-{3-[4-(2-methoxy-5-methylphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindoIe-1,3-dione phosphate(Compound No. 74),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 75),
5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione phosphate(Compound No. 76),
5-Fluoro-6-hydroxy-2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione phosphate(Compound No. 77),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione phosphate(Compound No. 78),
5-Hydroxy-2-{3-[4-(2-methoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-l,3-dione phosphate(Compound No. 79),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-clione phosphate(Compound No. 80),
2-{3-[4-(2-CyclopentyloxyphenyI)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 81),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 82),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3-dione phosphate(Compound No. 83),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione phosphate(Compound No. 84),
5-FIuoro-2-{3-[4-(5-fluoro-2-methoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 85),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione phosphate(Compound No. 86),
5-Fluoro-2-{3-[4-(5-fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 87),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 88),
2-{3-[4-(5-Fluoro-2-propoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione phosphate(Compound No. 89),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 90),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 91),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 92),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 93),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 94),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 95),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy- hexahydro-isoindole-l,3-dione phosphate(Compound No. 96),
pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs and metabolites thereof.
As used, herein, the term 'aging' means allowing the reactants to allow remaining in contact for a time under the conditions effective for the completion of the reaction. The present invention also includes within its scope prodrugs of these agents. In general, such prodrugs will be functional derivatives of these compounds, which are readily convertible in vivo into the required compound. Conventional procedure for the selection and preparation of suitable prodrugs are described, for example, in "design of prodrugs", Ed. H Bundgaard, Elsevier, 1985. The present invention also includes metabolites, which become active upon introduction into the biological system. The compounds of the invention possess two chiral centers, they may, therefore, exist as enantiomers and diastereomers. It is to be understood that all such isomers and racemic mixtures therefore are encompassed within the scope of the present invention.
The crystalline or amorphous forms of compounds disclosed herein may exist as polymorphs and as such are intended to be included in the present invention.
Compounds described herein can be administered to a patient (e.g., human or animal) orally, parenterally, topically, rectally, internasally, subcutaneously or transdermally. Pharmaceutical compositions of the present invention can comprise pharmaceutically effective amounts of one or more compounds of the present invention formulated together with one or more pharmaceutically acceptable carriers.
The term "pharmaceutically acceptable carriers" is intended to include non-toxic, inert solid, semi-solid or liquid filter, diluent, encapsulating material or formulation auxiliary of any type.
Solid form preparations for oral administration includes capsules, tablets, pills, powder, granules, cachets or suppositories. For solid form preparations, one or more active compounds can be mixed with one or more inert, pharmaceutically acceptable excipients or carriers, for example, sodium citrate, dicalcium phosphate and/or one or more fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol, silicic acid or mixtures thereof; one or more binders, for example, carboxymethylcellulose, alginates, gelatins, polyvinylpyrolidinone, sucrose, acacia or mixtures thereof; disintegrating agents, for example, agar-agar, calcium carbonate, potato starch, alginic acid, certain silicates, sodium carbonate or mixtures thereof; absorption accelators, for example, quaternary ammonium compounds; wetting agents, for example, cetyl alcohol, glycerol, monostearate or mixtures thereof; adsorbents, for example, kaolin; lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium lauryl sulfate or mixtures thereof.
For capsules, tablets or pills, dosage forms can also comprise one or more buffering agents.
Solid preparations of tablets, capsules, pills or granules can also be prepared with one or more coatings and/or shells, for example, enteric coating and other coatings well known in the pharmaceutical formulating art.
Liquid form preparations for oral administration include pharmaceutical ly acceptable emulsions, solutions, suspensions, syrups or elixirs. For liquid form preparations, one or more active compounds can be mixed with water and/or other solvent(s), one or more solubilizing agents or emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor or sesame oil), glycerol, fatty acid esters of sorbitan or mixtures thereof. In addition to inert diluents, oral compositions can also include one or more adjuvants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents or mixtures thereof.
Injectable preparations (e.g., sterile injections, aqueous or oleaginous suspensions) may be formulated according to methods known to one of ordinary skill in the art, for example, using one or more suitable dispersing agents, wetting agents, suspending agents or mixtures thereof. Acceptable carriers or solvents that may be employed include, for example, water, Ringer's solution, U.S.P., isotonic sodium chloride or mixtures thereof.
Dosage forms for topical or transdermal administration includes ointments, pastes, creams, lotions, gel, powders, solutions, spray, inhalants or patches. Active compound can be admixed under sterile conditions with one or more pharmaceutically acceptable carriers, as well as any preservatives or buffers as may be required. Ophthalmic formulations, eardrops, eye ointments, powders and solutions are also encompassed within the scope of this invention.
Pharmaceutical preparations may be in unit dosage form. In particular, preparations may be subdivided into unit dosage forms containing appropriate and therapeutically effective quantities of one or more active ingredients. Unit dosage forms can be packaged preparations containing discrete capsules, powders, in vials or ampoules, ointments, capsules, cachets, tablets, gels, creams, or any combination thereof and in appropriate numbers of unit dosages.
Formulations of the present invention may be formulated by methods known to one of ordinary skill in the art to provide immediate release, as well as sustained- or delayed-release of active ingredients after administration to a patient.
Compounds described herein, bladder selective muscarinic receptor antagonists and/or 5a reductase inhibitors can be formulated in combination to achieve desired therapeutic effects, i.e., combination therapies. As such, the dosage amounts of such active ingredients can be adjusted accordingly, without undue experimentation and well within the abilities of one of ordinary skill in the art. As one of ordinary skill in the art can appreciate, dosage amounts of compounds described herein, bladder selective muscarinic receptor antagonists and/or 5α reductase inhibitors may be independently optimized and combined to achieve a synergistic therapeutic result. In accordance with methods encompassed herein, individual components of any combination can be administered separately in any sequence at the same or different times during the course of therapy, or concurrently in divided or single combination forms.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate the particular aspect of the disclosure and do not limit the present invention as defined by the claims.
Examples Example 1: Preparation of compound of Formula II (Anorganic acid)
To a solution of compound of Formula I in alcoholic solvent corresponding acid (1 equiv.) is added and the solution is stirred for about 1 hour. The solvent is concentrated to l/5th of the total volume. The salt is precipitated by addition of a non-polar solvent. The salt is filtered off, washed with ether and dried under vacuum.
For example, a compound of Formula I (lOg, 0.02157 moles) is dissolved in absolute ethanol (200 mL) at about 40°C. To this maleic acid (2.5g, 0.02157 moles) dissolved in absolute ethanol (lOmL) is added at about 25-35°C and stir for about 2 hours at same temperature. Cool the reaction mass to about 0-5°C and maintain for about 2 hours and add diethyl ether (500 mL) and stir for about 4 hours at same temperature. The solid thus formed is filtered and wash with diethyl ether (10 mL) and dry in vacuum at about 40°C for about 6 hours to give maleate salt.
The following compounds are prepared following the procedure described above:
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 1),
5,6-Dihydroxy-2-{3-[4-(2-methoxy-5-methylphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione succinate (Compound No. 2),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 3),
5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione succinate (Compound No. 4),
5-Fluoro-6-hydroxy-2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione succinate (Compound No. 5),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione succinate (Compound No. 6),
5-Hydroxy-2-{3-[4-(2-methoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-1,3-dione succinate (Compound No. 7),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 8),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 9),
2-{3-[4-(2-CyclopentyloxyphenyI)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 10),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3-dione succinate (Compound No. 11),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione succinate (Compound No. 12),
5-Fluoro-2-{3-[4-(5-fluoro-2-methoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 13),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione succinate (Compound No. 14),
5-Fluoro-2-{3-[4-(5-fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 15),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 16),
2-{3-[4-(5-Fluoro-2-propoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione succinate (Compound No. 17),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 18),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 19),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 20),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 21),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 22),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione succinate (Compound No. 23),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate (Compound No. 24),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate (Compound No. 25),
5,6-Dihydroxy-2-{3-[4-(2-methoxy-5-methylphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione maleate (Compound No. 26),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate (Compound No. 27),
5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione maleate (Compound No. 28),
5-Fluoro-6-hydroxy-2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione maleate (Compound No. 29),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-]-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione maleate (Compound No. 30),
5-Hydroxy-2-{3-[4-(2-methoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-1,3-dione maleate (Compound No. 31),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione maleate (Compound No. 32),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione maleate (Compound No. 33),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione maleate (Compound No. 34),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-1,3-dione maleate (Compound No. 35),
2-{3-[4-(2-CyclopentyIoxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione maleate (Compound No. 36),
5-Fluoro-2-{3-[4-(5-fluoro-2-methoxyphenyl)-piperazin-l-yI]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione maleate (Compound No. 37),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione maleate (Compound No. 38),
5-Fluoro-2-{3-[4-(5-fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione maleate (Compound No. 39),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole- 1,3-dione maleate (Compound No. 40),
2-{3-[4-(5-Fluoro-2-propoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione maleate (Compound No. 41),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione maleate(Compound No. 42)
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione maleate(Compound No. 43)
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate(Compound No. 44)
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate(Compound No. 45)
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate(Compound No. 46)
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate(Compound No. 47)
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy- hexahydro-isoindole-l,3-dione maleate(Compound No. 48)
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 49)
5,6-Dihydroxy-2-{3-[4-(2-methoxy-5-methylphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione tartarate(Compound No. 50)
2-{3-[4-(2-CyclopentyloxyphenyI)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindoie-l,3-dione tartarate (Compound No. 51),
5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione tartarate(Compound No. 52),
5-Fluoro-6-hydroxy-2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione tartarate(Compound No. 53),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione tartarate(Compound No. 54),
5-Hydroxy-2-{3-[4-(2-methoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-l,3-dione tartarate(Compound No. 55),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 56),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 57),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 58),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3-dione tartarate(Compound No. 59),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione tartarate(Compound No. 60),
5-Fluoro-2-{3-[4-(5-fluoro-2-methoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 61),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione tartarate(Compound No. 62),
5-Fluoro-2-{3-[4-(5-fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 63),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 64),
2-{3-[4-(5-Fluoro-2-propoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione tartarate(Compound No. 65),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 66),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-1,3-dione tartarate(Compound No. 67),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 68),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione tartarate(Compound No. 69),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 70),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate(Compound No. 71),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy- hexahydro-isoindole-l,3-dione tartarate(Compound No. 72).
Example 2: Preparation of compounds of Formula II (A-inorganic acid)
An equimolar quantity of compound of Formula I can be added in dichloromethane. The solid, which precipitates, is then filtered, washed with non-polar solvent to obtain the inorganic salt of the respective compound.
For example, a compound of Formula I (1 Ig, 0.0237 moles) is dissolved in dichloromethane (250 mL) at about 25-35°C. Cool the reaction to about 5-10°C and then add 88% ortho phosphoric acid (2.32gm) dissolved in dichloromethane (15 mL) dropwise. Allow the reaction to stir at about 25-35°C for about 2-3 hours. Add hexane (420 mL) and stir at about 25-35°C for about 48 hours. The solid thus formed is filtered, washed with hexane (25 mL) and dried at about 40°C under vacuum for about 15 hours to give phosphate salt.
The following compounds are prepared following the procedure given above:
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 73),
5,6-Dihydroxy-2-{3-[4-(2-methoxy-5-methylphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione phosphate(Compound No. 74),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 75),
5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione phosphate(Compound No. 76),
5-Fluoro-6-hydroxy-2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione phosphate(Compound No. 77),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-1,3-dione phosphate(Compound No. 78),
5-Hydroxy-2-{3-[4-(2-methoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-1,3-dione phosphate(Compound No. 79),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione phosphate(Compound No. 80),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione phosphate(Compound No. 81),
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-oxo-propyI}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 82),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3-dione phosphate(Compound No. 83),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione phosphate(Compound No. 84),
5-Fluoro-2-{3-[4-(5-fluoro-2-methoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 85),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione phosphate(Compound No. 86),
5-Fluoro-2-{3-[4-(5-fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 87),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 88),
2-{3-[4-(5-Fluoro-2-propoxy-phenyl)piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione phosphate(Compound No. 89),
2-{3-[4-(2-Cyclopentyloxy-phenyl)piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 90),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-1,3-dione phosphate(Compound No. 91),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 92),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 93),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione phosphate(Compound No. 94),
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yI]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate(Compound No. 95),
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy- hexahydro-isoindole-l,3-dione phosphate(Compound No. 96).
Pharmacological Activity
Radioligand Binding Assays: Receptor binding assays are performed using native α-1 adrenoceptors. The affinity of different compounds for α1a and α1b adrenoceptor subtypes is evaluated by studing their ability to displace specific [3H]prazpsin binding from the membranes of rat submaxillary and liver respectively (Michel et al, Br JPharmacol, 98, 883-889 (1989)). The binding assays are performed according to U'Prichard et al. (Eur J Pharmacol, 50:87-89 (1978) with minor modifications.
Submaxillary glands are isolated immediately after sacrifice. The liver is perfused with buffer (Tris hydrochloric acid 50 mM, sodium chloride 100 mM, 10 mM ethylene diamine tetra acetic acid pH 7.4). The tissues are homogenized in 10 volumes of buffer (Tris HC1 50 mM, NaCl 100 mM, EDTA 10 mM, pH 7.4). The homogenate is filtered through two layers of wet guaze and filtrate is centrifuged at 500g for 10 min. The supernatant is subsequently centrifuged at 40, OOOg for 45 min. The pellet thus obtained is resuspended in the same volume of assay buffer (Tris HC1 50 mM, EDTA 5 mM, pH 7.4) and are stored at -70 °C until the time of assay.
The membrane homogenates (150-250 µg protein) are incubated in 250 µl of assay buffer (Tris HC1 50 mM, EDTA 5 mM, pH 7.4) at 24-25 °C for I hour. Non-specific binding is determined in the presence of 300 nM prazosin. The incubation is terminated by vaccum filtration over GF/B fibre filters. The filters are then washed with ice-cold 50 mM Tris HC1 buffer (pH 7.4). The filtermats waere dried and bounded radioactivity retained on filters is counted. The IC50 and Kd are estimated by using the non-linear curve-fitting program using G pad prism software. The value of inhibition constant Ki is calculated from competitive binding studies by using Cheng and Prusoff equation (Cheng and Prusoff, Biochem Pharmacol, 1973, 22:3099-3108), Ki = 1C50 /(1+L/Kd) where L is the concentration of [3H] prazosin used in the particular experiment.
In vitro functional studies (In vitro α1a Adrenoceptor selectivity)
In order to study selectivity of action of the present compounds towards different α1a adrenoreceptor subtypes, the ability of these compounds to antagonize α1a adrenoreceptor agonist induced contractile response of aorta (α1d), prostate (α1a ) and spleen ( α1b) is studied. Aorta,
prostate and spleen tissue are isolated from thipentane anaesthetized (≈ 300 mg/Kg) male wistar rats. Isolated tissues are mounted in organ bath containing Krebs Henseleit buffer of the following composition (mM): sodium chloride (NaCl) 118; potassium chloride (KC1) 4.7; calcium chloride (CaCl2) 2.5; magnesium sulphate hepta hydrate (MgSO4. 7H2O) 1.2; sodium bicarbonate (NaHCO3) 25; potassium dihydrogen phosphate (KH2PO4) 1.2; glucose 11.1. Buffer was maintained at 37 °C and aerated with a mixture of 95% oxygen (O2) and 5% carbon dioxide (CO2). A resting tension of 2 g (aorta and spleen) or 1 g (prostate) is applied to tissues. Contractile response is monitored using a force displacement transducer and recorded on chart recorders. Tissues are allowed to equilibrate for 1 and 1/2 hour. At the end of equilibration period, concentration response curves to nor epinephrine (aorta) and phenyl epinephrine (spleen and prostate) are obtained in the absence and presence of the tested compound (at concentration of 0.1, 1 and 10 µM).

WE CLAIM:
1. Acid addition salts of compounds having the structure of Formula II:
(Formula Removed)
pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs and metabolites thereof, wherein:
A is an organic acid selected from acetic, succinic, maleic, trifluoroacetic, oxalic, citric, malonic, adipic, ascorbic, camphor sulfonic, nicotinic, butyric, lactic and glucuronic acid; an inorganic acid selected from hydrochloric, hydrobromic, phosphoric, sulfuric, nitric, boric and perchloric; RI and R2 are independently hydrogen, hydroxy or halogen; X is CO, CHOH or CH2; R3 and R4 are independently hydrogen, halogen, C1-C3 alkyl, C1-C3, alkoxy or C5-C6 cycloalkoxy.
2. Acid addition salts of claim 1, wherein A is selected from tartaric, succinic, maleic and
phosphoric acid.
3. A compound, which is:
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyI}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate,
5,6-Dihydroxy-2-{3-[4-(2-methoxy-5-methylphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate,
5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione succinate,
5-Fluoro-6-hydroxy-2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-1,3-dione succinate,
5-Hydroxy-2-{3-[4-(2-methoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-l,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-1,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione succinate,
5-Fluoro-2-{3-[4-(5-fluoro-2-methoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-1,3-dione succinate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione succinate,
5-Fluoro-2-{3-[4-(5-fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-1,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(5-Fluoro-2-propoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione succinate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-• hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione succinate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione succinate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate,
5,6-Dihydroxy-2-{3-[4-(2-methoxy-5-methylphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate,
5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione maleate,
5-Fluoro-6-hydroxy-2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-1,3-dione maleate,
5-Hydroxy-2-{3-[4-(2-methoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-l,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-l,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione maleate,
5-Fluoro-2-{3-[4-(5-fluoro-2-methoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-1,3-dione maleate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione maleate,
5-Fluoro-2-{3-[4-(5-fIuoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione maleate,
2-{3-[4-(5-Fluoro-2-propoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione maleate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione maleate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione tartarate,
5,6-Dihydroxy-2-{3-[4-(2-methoxy-5-methylphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate,
5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione tartarate,
5-Fluoro-6-hydroxy-2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-1,3-dione tartarate,
5-Hydroxy-2-{3-[4-(2-methoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-l,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-1,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-1,3-dione tartarate,
5-Fluoro-2-{3-[4-(5-fluoro-2-methoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione tartarate,
5-Fluoro-2-{3-[4-(5-fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-1,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione tartarate,
2-{3-[4-(5-Fluoro-2-propoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione tartarate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione tartarate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione tartarate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione tartarate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate,
5,6-Dihydroxy-2-{3-[4-(2-methoxy-5-methylphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yI]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate,
5-Fluoro-6-hydroxy-2-{2-hydroxy-3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-1,3-dione phosphate,
5-Fluoro-6-hydroxy-2-{3-[4-(2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isoindole-l,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-1,3-dione phosphate,
5-Hydroxy-2-{3-[4-(2-methoxyphenyl)-piperazin-l-yl]-propyl}-hexahydro-isioindole-l,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-1,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-3a,4,7,7a-tetrahydro-isoindole-1,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-hexahydro-isoindole-l,3-dione phosphate,
5-Fluoro-2-{3-[4-(5-fluoro-2-methoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-1,3-dione phosphate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5-hydroxy-hexahydro-isoindole-l,3-dione phosphate,
5-Fluoro-2-{3-[4-(5-fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-6-hydroxy-hexahydro-isoindole-1,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione phosphate,
2-{3-[4-(5-FIuoro-2-propoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxyphenyl)-piperazin-l-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-l,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-1-yl]-propyl}-5-fluoro-6-hydroxy-hexahydro-isoindole-1,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione phosphate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-oxo-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate,
2-{3-[4-(5-FIuoro-2-isopropoxyphenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-1,3-dione phosphate,
2-{3-[4-(2-Cyclopentyloxy-5-fluorophenyl)-piperazin-l-yl]-2-hydroxy-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate,
2-{3-[4-(5-Fluoro-2-isopropoxyphenyl)-piperazin-l-yl]-propyl}-5,6-dihydroxy-hexahydro-isoindole-l,3-dione phosphate.
4. A pharmaceutical composition comprising a therapeutically effective amount of a compound
of claim 1 together with pharmaceutically acceptable carriers, excipients or diluents.
5. A method for treatment of a patient suffering from disease or disorder mediated through
α1a and/or α1d adrenergic receptors, comprising administering to said patient a therapeutical ly
effective amount of a compound of claim 1 or a pharmaceutical composition of claim 4.
6. A method for treatment of a patient suffering from benign prostatic hyperplasia,
comprising administering to said patient a therapeutical ly effective amount of a
compound of claim 1 or a pharmaceutical composition of claim 4.
7. The method according to claim 5 wherein compound or composition causes minimal fall or
no fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
8. A method for treatment of a patient suffering from lower urinary tract symptoms associated
with or without benign prostatic hyperplasia, comprising administering to said patient a
therapeutically effective amount of a compound of claim 1 or a pharmaceutical composition
of claim 4.
9. A method for preparing compounds having the structure of Formula II,
(Formula Removed)
pharmaceutically acceptable solvates, esters, enantiomers, diastereomers, N-oxides, prodrugs, polymorphs and metabolites thereof, wherein,
A is an organic acid selected from acetic, succinic, maleic, trifluoroacetic, oxalic, citric, malonic, adipic, ascorbic, camphor sulfonic, nicotinic, butyric, lactic and glucuronic; an inorganic acid selected from hydrobromic, phosphoric, sulfuric, nitric, boric and perchloric acid; R1 and R2 are independently hydrogen, hydroxy or halogen; X is CO, CHOH or CH2; R3 and R4 are independently hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy or C5-C6 cycloalkoxy, which method comprises:
reacting a compound of Formula I,
(Formula Removed)
with an organic or inorganic acid to give a compound of Formula II.