Derivatives of cis-1,2,3,6-tetrahydrophthalimide for the treatment of benign prostatic hyperplasia

The synthesis of two cis -1,2,3,6-tetrahydrophthalimide derivatives 5j [R = 2-[OCH(CH 3 ) 2 ]C 6 H 4 and L = (CH 2 ) 3 ] and 5l [R = 2-(CH 2 CH 3 )C 6 H 4 and L = (CH 2 ) 3 ] having high affinity and selectivity for the α 1A -adrenergic receptor is reported. Abstract Synthesis and binding profile of tetrahydrophthalimide derivatives are reported. The compounds show excellent affinities for α 1A - and good selectivities over α 1B -adrenergic receptors, and thus can be used in the treatment of benign prostatic hyperplasia. Keywords cis -1,2,3,6-Tetrahydrophthalimide BPH α 1A -Adrenergic receptor Arylpiperazine Benign prostatic hyperplasia (BPH) is progressive non-malignant enlargement of prostate gland. 1 BPH is associated with obstruction of urethra due to increased mass of the prostate (static component) and increased smooth muscle tone in the bladder neck and prostate (dynamic component) as well as symptoms such as increased frequency, hesitancy, reduced urine flow, and large residual volume. The disease can be treated by α 1 -adrenergic receptor antagonists and 5α-reductase inhibitors. 2 The α 1 -adrenergic receptor is a G-protein coupled receptor (GPCR). Competitive α 1 -receptor antagonists such as prazosin, terazosin, and doxazosin block not only prostatic but also central nervous system and vascular receptors leading to a variety of side effects such as postural hypotension. 3 The α 1 -adrenergic receptor is pharmacologically heterogeneous and has been divided into α 1A -, α 1B -, and α 1D -subtypes. 4 The α 1A -adrenergic receptor is most prevalent in prostate and urethra, and is responsible for smooth muscle contraction. 5 Tamsulosin ( 1 ), having modest selectivity for α 1A - over α 1B -receptors, has shown promise in therapy. 6 However, an agent with higher selectivity for α 1A - over α 1B - is desired. 2 Compounds containing arylpiperazine structures often show good affinities for the α 1 -adrenergic receptor. 7 The arylpiperazine moiety is usually connected through a linker to a terminal molecular fragment such as an imide, for example, succinimide, glutarimide, or phthalimide which represents a structural element appropriate for interacting with the α 1 -receptor. 8 In order to study the effect of hydrophobicity on the imide group, we synthesized a series of arylpiperazines ( 2 ) containing cis -1,2,3,6-tetrahydrophthalimide and measured their affinities at α 1A - and α 1B -adrenergic receptors. cis -1,2,3,6-Tetrahydrophthalimide ( 3 ) was alkylated with 1,3-dibromopropane in the presence of K 2 CO 3 and Bu 4 NBr in acetone. Bromo compound 4 was coupled with N -arylpiperazine using K 2 CO 3 and KI in DMF ( Scheme 1 ) 9 to give compounds 5a – l . Arylpiperazines that were not commercially available were prepared by the procedure depicted in Scheme 2 . 2-Nitrophenol ( 6 ) was alkylated in the presence of K 2 CO 3 in DMF. Reduction of nitro compound ( 7 ) afforded the corresponding aniline ( 8 ) which on treatment with bis- N -(2-chloroethyl)amine hydrochloride in n -butanol furnished 9 . For the synthesis of arylpiperazines with a fluoro or alkyl group at the 2-position, the corresponding nitro compound ( 10 ) was reduced to 11 and then coupled with bis- N -(2-chloroethyl)amine hydrochloride. 10 Derivatives with branched alkyl chains were prepared as shown in Scheme 3 . 2-Methoxyphenylpiperazine ( 12 ) on treatment with the corresponding substituted acrylonitrile ( 13 ) provided the Michael adduct ( 14 ), which on reduction followed by treatment with cis -1,2,3,6-tetrahydrophthalic anhydride afforded 16 . 11 Biological data of selected compounds are outlined in Table 1 . The affinities of different compounds for α 1A - and α 1B -adrenoceptor subtypes were evaluated by studying their ability to displace specific [ 3 H]prazosin binding from the membranes of rat submaxillary and liver, respectively. 12 The binding assays were performed according to U’Prichard et al. 13 with minor modifications. Most compounds in Table 1 have high affinity for the α 1A -adrenergic receptor. Arylpiperazines containing a straight 3-carbon linker: • In general, have high affinities for the α 1A -adrenergic receptor. • In general, have high selectivity over the α 1B -adrenergic receptor. • Affinity for the α 1A -adrenergic receptor increases with the size of the substituent at the ortho -position of the phenyl ring ( 5k < l and 5a < f < g ∼ j ∼ h ) but declines with very large substituents ( 5i ). • Selectivity for the α 1A - versus the α 1B -adrenergic receptor correlates with the size of the substituent at the ortho -position of the phenyl ring. • An electron-withdrawing group at the ortho -position of the phenyl ring is detrimental to α 1A -adrenergic receptor affinity ( 5e ). Arylpiperazines with branching in the linker have decreased activity ( 5f vs 16a , b ) Aralkylpiperazines ( 5b , c ) have low α 1A -adrenergic receptor affinity compared to the arylpiperazine analogue 5f . 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