Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
  • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
  • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/08—Drugs for disorders of the urinary system of the prostate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• This invention relates to certain novel carboximide derivatives which selectively inhibit binding to the ⁇ i A adrenergic receptor, a receptor which has been shown to be important in the treatment of benign prostatic hyperplasia.
• the compounds of the present invention are potentially useful in the treatment of benign prostatic hyperplasia.
• This invention also relates to methods for synthesizing the novel compounds, pharmaceutical compositions containing the compounds, and method of treating benign prostatic hyperplasia using the compounds.
• Benign prostatic hyperplasia (BPH), a nonmalignant enlargement of the prostate, is the most common benign tumor in men. Approximately 50% of all men older than 65 years have some degree of BPH and a third of these men have clinical symptoms consistent with bladder outlet obstruction (Hieble and Caine, Fed. Proc, 1986; 45:2601). Worldwide benign and malignant diseases of the prostate are responsible for more surgery than diseases of any other organ in men over the age of fifty.
• 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 urine from the bladder.
• the dynamic component is due to increased smooth muscle tone of the bladder neck and the prostate itself (which interferes with emptying of the bladder) and is regulated by alpha 1 adrenergic receptors ( ⁇ ARs).
• ⁇ ARs alpha 1 adrenergic receptors
• Surgical treatment options address the static component of BPH and include transurethral resection of the prostate (TURP), open prostatectomy, balloon dilatation, hyperthermia, stents and laser ablation.
• TURP transurethral resection of the prostate
• open prostatectomy a transurethral resection of the prostate
• balloon dilatation a satisfactory long - term outcome
• hyperthermia a parameter that causes a satisfactory long - term outcome
• stents stents
• laser ablation Surgical treatment options address the static component of BPH and include transurethral resection of the prostate (TURP), open prostatectomy, balloon dilatation, hyperthermia, stents and laser ablation.
• Postoperative urinary tract infection (5-10%), some degree of urinary incontinence (2-4%), as also reoperation (15-20 %) (Wennberg et a/.,JAMA, 1987; 257:933) are some of the other risk factors involved.
• Finasteride Proscar, Merck
• This drug is a competitive inhibitor of the enzyme 5 -reductase which is responsible for the conversion of testosterone to dihydrotestosterone in the prostate gland (Gormley et al., N. Engl. J. Med., 1992; 327:1185).
• Dihydrotestosterone appears to be the major mitogen for prostate growth, and agents which inhibit 5- ⁇ -reductase reduce the size of the prostate and improve urine flow through the prostatic urethra.
• finasteride is a potent 5 ⁇ -reductase inhibitor and causes a marked decrease in serum and tissue concentration of dihydrotestosterone, it is only moderately effective in treating symptomatic BPH (Oesterling, N. Engl. J. Med., 1995; 332:99). The effects of finasteride take 6-12 months to become evident and for many men the clinical improvement is minimal.
• oi -adrenergic receptor blocking agents which act by decreasing the smooth muscle tone within the prostate gland itself
• oi -adrenergic receptor antagonists appear to be much more effective and provide immediate subjective symptomatic improvements and are, therefore, the preferred modalities of treatment in the control of benign prostate hypertrophy.
• Adrenoceptors are also present in blood vessels and play an important role in the regulation of blood pressure.
• ⁇ i-adrenoceptor antagonists are of particular importance as they were originally developed as antihypertensive agents and are likely also to have a beneficial affect on lipid dysfunction and insulin resistance, which are commonly associated with essential hypertension.
• ⁇ AR antagonists in the treatment of BPH is related to their ability to decrease the tone of prostatic smooth muscle, leading to relief of the obstructive symptoms.
• Adrenergic receptors found throughout the body play a dominant role in the control of blood pressure, nasal congestion, prostate function and other processes (Harrison et al., Trends Pharmacol. Sci., 1991 ; 12:62).
• ocrAR blockers terazosin, prazosin, and doxazosin
• terazosin Hytrin, Abbott
• doxazosin doxazosin
• the ⁇ AR blocking agents have a more rapid onset of action. However, their therapeutic effect, as measured by improvement in the symptom score and the peak urinary flow rate, is moderate. (Oesterling, N.Engl. J.Med., 1995; 332:99).
• the vascular side effects e.g., postural hypertension, dizziness, headaches, etc.
• prostatic ⁇ adrenoceptors offer the potential of increased urodynamic benefits. This underscores the importance of the discovery of prostate-selective oc adrenoceptor antagonists which will confer urodynamic improvement without the side effects associated with existing drugs.
• EP 078800 discusses oci-adrenergic receptor antagonistic activity of pyrimidinedione, pyrimidinetrione and triazinedione derivatives. These compounds, however, had low ⁇ i-adrenergic blocking activity as compared to known oc ⁇ -antagonists.
• the prostate tissue of higher species like man and dog has a predominant concentration of ⁇ - ⁇ A -adrenoceptor subtype. This makes it possible to develop agents with selective action against these pathological urodynamic states.
• the present invention is directed to the development of novel oi -adrenoceptors and which would thus offer a viable selective relief for prostate hypertrophy as well as essential hypertension, without the side effects associated with known CXIA ⁇ AR antagonists.
• the objective of the present invention is to provide novel carboximide derivatives that exhibit significantly greater ⁇ 1A -adrenergic blocking potency than available with known compounds in order to provide specific treatment for benign prostatic hyperplasia. It is also an object of the invention to provide a process for synthesis of the novel compounds.
• compositions containing the novel compounds which are useful in the treatment of benign prostatic hyperplasia are provided.
• X is selected from the group consisting of
• points of attachment are depicted by hashed bonds, and where one point of attachment is bonded to the carbonyl adjacent to the nitrogen and the second point of attachment is bonded to the other carbonyl;
• W is O, S, SO or S0 2 o A is -(CH 2 )m- , — CH 2 CH— CH 2 — , — CH 2 CH 2 — C —
• R11 where m is one of the integers 2,3 or 4 ;
• Rn is independently selected from H, F, Cl, Br, I, OH, straight or branched lower (C ⁇ -6 ) alkyl, lower (C-
• Y is selected from the group consisting of
• R ⁇ and R 2 are independently selected from H, OH, CN, N0 2 , Cl, F, Br, I, OR 3 ,
• compositions for the treatment of benign prostatic hyperplasia comprise an effective amount of at least one of the above compounds of Formula I and/or an effective amount of at least one physiologically acceptable acid addition salt thereof, with a pharmaceutically acceptable carrier and optionally included excipients.
• Pharmaceutically acceptable, non-toxic acid addition salts of the compounds of the present invention having the utility of the free bases of Formula I may be formed with inorganic or organic acids, by methods well known in the art and may be used in place of the free bases.
• suitable acids for formation of such acid addition salts are malic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylene salicylic, methanesulfonic, ethane disulfonic , acetic, propionic , tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfamic, phosphoric, hydrobromic, sulfuric, cyclohexylsulfamic , hydrochloric, and nitric acids.
• the present invention also includes within its scope prodrugs of the compounds of Formula I.
• prodrugs will be functional derivatives of these compounds which readily get converted in vivo into the defined compounds.
• Conventional procedures for the selection and preparation of suitable prodrugs are known.
• the invention also includes the enantiomers, diastereomers, N-oxides, polymorphs , pharmaceutically acceptable salts and pharmaceutically acceptable solvates of these compounds , as well as metabolites having the same type of activity.
• the invention further includes pharmaceutical compositions comprising the molecules of Formula I , or prodrugs , metabolites , enantiomers , diastereomers , N-oxides , polymorphs , solvates or pharmaceutically acceptable salts thereof , in combination with a pharmaceutically acceptable carrier and optionally included excipients.
• the invention is directed to methods for selectively blocking ⁇ 1A receptors by delivering in the environment of said receptors, e.g., to the extracellular medium (or by administering to a mammal possessing said receptors), an effective amount of the compounds of the invention.
• points of attachment are depicted by hashed bonds, and where one point of attachment is bonded to the carbonyl adjacent to the nitrogen and the second point of attachment is bonded to the other carbonyl;
• W is O, S, SO or SO 2
• O A is -(CH 2 )m- , — CH 2 CH — CH 2 — , — CH 2 CH 2 — C-
• R11 where m is one of the integers 2,3 or 4 ;
• R 11 is independently selected from H, F, Cl, Br, I, OH, straight or branched lower (C ⁇ -6 ) alkyl, lower (C-i- ⁇ ) alkoxy, lower (C- ⁇ -6 ) perhaloalkyl and lower (d- ⁇ ) perhaloalkoxy;
• Y is selected from the group consisting of
• Ri and R 2 are independently selected from H, OH, CN, N0 2 , Cl, F, Br, I, OR 3 , COR 3 , OCOR 3 , COOR3, NH 2 , N(R 4 , R 5 ), lower (C ⁇ -4 )alkyl, lower (C 1-4 )alkoxy, lower (C 1-4 )alkylthio, lower (C ⁇ -4 ) perhaloalkyl, lower (C ⁇ -4 ) perhaloalkoxy, lower (C ⁇ -4 ) alkoxy substituted with one or more of F, Cl, Br, I, OH, or OR 3 , optionally substituted group selected from aryl, aryloxyaralkyl, heterocyclyl or heteroaryl and said substituents being H, F, Cl, Br, I, OH, OR 3 , lower (C ⁇ -4 )alkyl, lower (C ⁇ - )alkyl substitued with one or more of F, Cl, Br, I, OH or
• Scheme I shows the synthesis of the compounds of Formula I wherein X, Y, A, Re, R 7 , Rs, R9 and R 1 0 are as defined above.
• the preparation comprises reacting , ⁇ -dicarboximides of Formula II with a suitable strong base, at a temperature ranging from 20-100°C for a period varying between one to several hours to produce the corresponding compounds of Formula I.
• the suitable base is selected from the group consisting of sodium hydroxide and potassium hydroxide. More specifically, the hydrolysis of compound of Formula II is carried out in a solution of the base made in a polar solvent selected from the group consisting of water, methanol and ethanol.
• the preferable temperature conditions for the reaction are 90-100°C.
• the starting compound of Formula II can be prepared by the process as disclosed in our internal application number RLL-236WO filed concurrently herewith.
• the invention is explained in detail in the example given below which is provided by way of illustration only and therefore should not be construed to limit the scope of the present invention.
• Receptor binding assays were performed using native ⁇ -adrenoceptors.
• the affinity of different compounds for OC-IA and OC-IB adrenoceptor subtypes was evaluated by studying their ability to displace specific [ 3 H] prazosin binding from the membranes of rat submaxillary and liver respectively (Michel et al, Br J Pharmacol.; 1989; 98:883).
• the binding assays were performed according to U'Prichard et al. (Eur J Pharmacol., 1978; 50:87) with minor modifications. Submaxillary glands were isolated immediately after sacrifice. The liver was perfused with buffer (Tris HC1 50 mM, NaCI 100mM, 10 mM EDTA pH 7.4).
• the tissues were homogenised in 10 volumes of buffer (Tris HCI 50 mM, NaCI 100mM, 10 mM EDTA pH 7.4).
• the homogenate was filtered through two layers of wet gauge and filtrate was centrifuged at 500 g for 10 min. The supernatant was subsequently centrifuged at 40,000 g for 45 min.
• the pellet thus obtained was resuspended in the same volume of assay buffer (Tris HCI 50 mM, 5 mM EDTA pH 7.4) and were stored at -70°C until the time of assay.
• the membrane homogenates (150-250 ⁇ g protein) were incubated in 250 ⁇ l of assay buffer(Tris HCI 50 mM, EDTA 5 mM, pH 7.4) at 24-25°C for 1 hour. Non specific binding was determined in the presence of 300 nM prazosin. The incubation was terminated by vacuum filtration over GF/B fibre filters. The filters were then washed with ice cold 50mM Tris HCI buffer (pH 7.4). The filtermats were dried and bound radioacivity retained on filters was counted. The IC 5 o and Kd were estimated by using the non linear curve fitting program using G Pad Prism software.
• Ki le (1 +lJKd) where L is the concentration of [ 3 H] prazosin used in the particular experiment (Table I).
• Aorta, prostrate and spleen tissues were isolated from urethane anaesthetized (1.5 g/kg) male wister rats. Isolated tissues were mounted in organ bath containing Krebs Henseleit buffer of the following composition (mM): NaC1 118; KCI 4.7; CaCI 2 2.5; MgS0 4 7H 2 O 1.2; NaHCO 3 25; KH 2 P0 4 1.2; glucose 11.5.
• Buffer was maintained at 37°C and aereated with a mixture of 95% O 2 and 5% C0 2 .
• a resting tension of 2g (aorta) or 1g (spleen and prostate) was applied to tissues. Contractile response was monitored using a force displacement transducer and recorded on chart recorders. Tissues were allowed to equilibrate for 2 hours. At the end of equilibration period, concentration response curves to norepinephrine (aorta) and phenylepinephrine (spleen and prostate) were obtained in the absence and presence of tested compound (at concentration of 0.1 ,1 and 10 ⁇ M). Antagonist affinity was calculated and expressed as pK B values in Table II.
• MAP mean arterial pressure
• IUP intraurethral pressure

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• 2002
  • 2002-04-08 AU AU2002251409A patent/AU2002251409A1/en not_active Abandoned
  • 2002-04-08 CN CNA028290976A patent/CN1627946A/zh active Pending
  • 2002-04-08 MX MXPA04009821A patent/MXPA04009821A/es not_active Application Discontinuation
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