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(12) Patent Application Publication (10) Pub. No.: US 2009/0156618 A1 Tollefson (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2009/0156618 A1 Tollefson (43) Pub US 20090156618A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0156618 A1 Tollefson (43) Pub. Date: Jun. 18, 2009 (54) 1-(1-(2-ETHOXYETHYL)-3-ETHYL-7- Related U.S. Application Data (4-METHYLPYRIDIN-2-YLAMINO) - 1H-PYRAZOLO 4.3-D PYRIMIDIN-5-YL) (60) Provisional application No. 60/735,320, filed on Nov. PPERDINE-4-CARBOXYLIC ACID AND 10, 2005. SALTS THEREOF Publication Classification (51) Int. Cl. (75) Inventor: Michael B. Tollefson, Dardenne A 6LX 3/59 (2006.01) Prairie, MO (US) C07D 487/04 (2006.01) A6IP 9/12 (2006.01) A6IP 25/00 (2006.01) Correspondence Address: A6IP 9/00 (2006.01) PFZER INC. PATENT DEPARTMENT, Bld 114 M/S 114, (52) U.S. Cl. ...................................... 514/262.1; 54.4/262 EASTERN PONT ROAD (57) ABSTRACT GROTON, CT 06340 (US) The present invention comprises 1-(1-(2-ethoxyethyl)-3- ethyl-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo 4.3-d (73) Assignee: Pfizer Inc pyrimidin-5-yl)piperidine-4-carboxylic acid and its salts. The invention further comprises pharmaceutical composi tions, methods of treatment, and synthetic methods relating to (21) Appl. No.: 111558,306 1-(1-(2-ethoxyethyl)-3-ethyl-7-(4-methylpyridin-2- ylamino)-1H-pyrazolo 4.3-dipyrimidin-5-yl)piperidine-4- (22) Filed: Nov. 9, 2006 carboxylic acid and its salts. Patent Application Publication Jun. 18, 2009 Sheet 2 of 2 US 2009/0156618 A1 "SOIHZ US 2009/0156618 A1 Jun. 18, 2009 1-(1-(2-ETHOXYETHYL)-3-ETHYL-7- 1H-pyrazolo 4,3-dipyrimidin-5-yl)piperidine-4-carboxylic (4-METHYLPYRIDIN-2-YLAMINO) - acid and its pharmaceutically acceptable salts. 1H-PYRAZOLO 4.3-D PYRIMIDIN-5-YL) 0007. In another embodiment, the invention comprises a PPERDINE-4-CARBOXYLIC ACID AND pharmaceutical composition comprising 1-(1-(2-ethoxy SALTS THEREOF ethyl)-3-ethyl-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo 4.3-dpyrimidin-5-yl)piperidine-4-carboxylic acid, or a FIELD OF THE INVENTION pharmaceutically acceptable salt thereof, and a pharmaceuti cally-acceptable carrier. 0001. The present invention relates generally to 1-(1-(2- 0008. In another embodiment, the invention comprises a ethoxyethyl)-3-ethyl-7-(4-methylpyridin-2-ylamino)-1H pharmaceutical composition comprising 1-(1-(2-ethoxy pyrazolo 4.3-dpyrimidin-5-yl)piperidine-4-carboxylic acid ethyl)-3-ethyl-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo and its salts. The present invention further relates to pharma 4.3-dpyrimidin-5-yl)piperidine-4-carboxylic acid, or a ceutical compositions comprising this compound or its salts, pharmaceutically acceptable salt thereof, one or more addi methods of treatment employing this compound or its salts, tional therapeutic agents, and a pharmaceutically acceptable and methods of preparing this compound or its salts. In gen carrier. eral, the compound and its salts inhibit the cyclic guanylate 0009. In another embodiment, the invention comprises monophosphate-specific phosphodiesterase type 5 (“PDE5') methods for treating a condition in a Subject by administering enzyme. to a subject a therapeutically effective amount of 1-(1-(2- ethoxyethyl)-3-ethyl-7-(4-methylpyridin-2-ylamino)-1H BACKGROUND OF THE INVENTION pyrazolo 4.3-dipyrimidin-5-yl)piperidine-4-carboxylic acid, 0002 Hypertension is a condition associated with, among or a pharmaceutically acceptable salt thereof. Conditions that other physiological problems, an increased risk of stroke, can be treated in accordance with the present invention myocardial infarction, atrial fibrillation, heart failure, periph include cardiovascular conditions, metabolic conditions, cen eral vascular disease and renal impairment. Despite the tral nervous system conditions, pulmonary conditions, sexual numerous drugs available in various pharmacological catego dysfunction, pain, and renal dysfunction. ries to treat hypertension and related physiological problems, 0010. In another embodiment, the invention comprises not all patients respond to Such drugs as effectively or as methods for treating a condition in a Subject by administering safely as desired. Additional therapeutic agents for the treat to a subject a therapeutically effective amount of 1-(1-(2- ment of hypertension and/or related conditions are still ethoxyethyl)-3-ethyl-7-(4-methylpyridin-2-ylamino)-1H needed. pyrazolo 4.3-dipyrimidin-5-yl)piperidine-4-carboxylic acid, 0003. One class of therapeutic agents reported in the lit or a pharmaceutically acceptable salt thereof, one or more erature as useful for the treatment of hypertension are inhibi additional therapeutic agents, and a pharmaceutically accept tors of the PDE5 enzyme (“PDE5 inhibitors'). In general, able carrier. Conditions that can be treated inaccordance with vascular endothelial cells secrete nitric oxide which acts on the present invention include cardiovascular conditions, vascular Smooth muscle cells and leads to the activation of metabolic conditions, central nervous system conditions, pull guanylate cyclase and the accumulation of cyclic guanosine monary conditions, sexual dysfunction, pain, and renal dys monophosphate (“cGMP). The accumulation of c(GMP function. causes the muscles to relax and the blood vessels to dilate, 0011. In another embodiment, the invention comprises use leading to a reduction in blood pressure. The coMP is inac of 1-(1-(2-ethoxyethyl)-3-ethyl-7-(4-methylpyridin-2- tivated by hydrolysis to guanosine 5'-monophosphate ylamino)-1H-pyrazolo 4.3-dipyrimidin-5-yl)piperidine-4- (“GMP) by c0MP-specific phosphodiesterases. One carboxylic acid, or a pharmaceutically acceptable salt cGMP-phosphodiesterase involved in the inactivation of thereof, for the manufacture of a medicament for the treat cGMP is the PDE5 enzyme. Inhibitors of the PDE5 enzyme ment of a condition in a Subject. Such conditions include decrease the rate of c(GMP hydrolysis. This reduction in cardiovascular conditions, metabolic conditions, central ner cGMP hydrolysis potentiates the actions of nitric oxide lead Vous system conditions, pulmonary conditions, sexual dys ing to a lowering of blood pressure. function, pain, and renal dysfunction. 0004 Compounds that are PDE5 inhibitors have been 0012. In another embodiment, the invention comprises reported in the literature. For example, WO2005049616 methods for making 1-(1-(2-ethoxyethyl)-3-ethyl-7-(4-me reports one class of pyrazolo 4.3-dpyrimidinyl compounds. thylpyridin-2-ylamino)-1H-pyrazolo4.3-dpyrimidin-5-yl) WO2005049.617 reports another class of pyrazolo 4.3-dpy piperidine-4-carboxylic acid, or a pharmaceutically accept rimidinyl compounds. WO2004096810 reports another class able salt thereof. of pyrazolo 4,3-dipyrimidinyl compounds. EP 1348707 reports another class of pyrazolo 4.3-dipyrimidinyl com BRIEF DESCRIPTION OF THE DRAWINGS pounds. 0005. The identification of additional compounds that are 0013 FIG. 1 shows a graph illustrating the effect on blood PDE5 inhibitors is desirable. Such compounds can be used to pressure of repeated oral administration of 1-(1-(2-ethoxy treat Subjects suffering from or Susceptible to hypertension ethyl)-3-ethyl-7-(4-methylpyridin-2-ylamino)-1H-pyrazolo and/or related physiological problems and further expand the 4.3-dpyrimidin-5-yl)piperidine-4-carboxylic acid (1 mg/kg range of treatment options available for Such subjects. daily oral dose), alone and in combination with enalapril, in a conscious spontaneous hypertensive rat model. SUMMARY OF THE INVENTION 0014 FIG. 2 shows a graph illustrating the effect on 24-hour urinary c0MP of repeated oral administration of 0006. In one embodiment, the invention comprises 1-(1- 1-(1-(2-ethoxyethyl)-3-ethyl-7-(4-methylpyridin-2- (2-ethoxyethyl)-3-ethyl-7-(4-methylpyridin-2-ylamino)- ylamino)-1H-pyrazolo 4.3-dipyrimidin-5-yl)piperidine-4- US 2009/0156618 A1 Jun. 18, 2009 carboxylic acid (1 mg/kg daily oral dose), alone and in com 0040. The term “cGMP-mediated condition” refers to any bination with enalapril, in a conscious spontaneous condition mediated by c0MP, whether through direct regu hypertensive rat model. lation by c0MP, or through indirect regulation by c0MP as a component of a signalling pathway. DETAILED DESCRIPTION OF THE INVENTION 0041. The term “PDE5-mediated condition” refers to any condition mediated by the PDE5 enzyme. 0015 This detailed description of embodiments is 0042. The term “hypertensive subject” refers to a subject intended only to acquaint others skilled in the art with appli having hypertension, Suffering from the effects of hyperten cants inventions, its principles, and its practical application sion or susceptible to a hypertensive condition if not treated to so that others skilled in the art may adapt and apply the prevent or control Such hypertension. inventions in their numerous forms, as they may be best Suited 0043. The term “pharmaceutically acceptable carrier' to the requirements of a particular use. These inventions, refers to a carrier that is compatible with the other ingredients therefore, are not limited to the embodiments described in this of the composition and is not deleterious to the subject. Such specification, and may be variously modified. carriers may be a pharmaceutically acceptable material, com position or vehicle. Such as a liquid or solid filler, diluent, A. ABBREVIATIONS AND DEFINITIONS excipient, solvent or encapsulating material, involved in car 0016. As used in reference to H NMR, the symbol “6” rying or transporting a chemical agent. The preferred com refers to a "H NMR chemical shift. position depends on the method of administration. 0017. As used in reference to "H NMR, the abbreviation 0044) The term “therapeutically effective amount” refers “br” refers to a broad H NMR signal. to that amount of drug or pharmaceutical agent that will elicit 0018. As used in reference to "H NMR, the abbreviation the biological or medical response of a tissue, system or “d” refers to a doublet "H NMR peak. animal that is being sought by a researcher or clinician. 0019. As used in reference to "H NMR, the abbreviation 0045. The term “treatment' (and corresponding terms “m” refers to a multiplet "H NMR peak. “treat' and “treating) includes palliative, restorative, and 0020. As used in reference to "H NMR, the abbreviation preventative treatment of a subject.
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